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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Sinovac COVID-19 vaccine, CoronaVac,

March 26, 2021 3:02 am / Leave a comment


sinovac
File:SINOVAC COVID-19 vaccine.jpg

Sinovac COVID-19 vaccine, CoronaVac,

  • PiCoVacc

CoronaVac, also known as the Sinovac COVID-19 vaccine,[1] is an inactivated virus COVID-19 vaccine developed by the Chinese company Sinovac Biotech.[2] It has been in Phase III clinical trials in Brazil,[3] Chile,[4] Indonesia,[5] the Philippines,[6] and Turkey.[7]

It relies on traditional technology similar to BBIBP-CorV and BBV152, other inactivated-virus COVID-19 vaccines in Phase III trials.[8] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[9]

Brazil announced results on 13 January 2021 showing 50.4% effective at preventing symptomatic infections, 78% effective in preventing mild cases needing treatment, and 100% effective in preventing severe cases.[10] Final Phase III results from Turkey announced on 3 March 2021 showed an efficacy of 83.5%.[11] Interim results in Indonesia were announced on 11 January 2021 with an efficacy of 65.3%.[12] A detailed report containing confidence intervals, efficacy by age and side effects has not yet been released.

CoronaVac is being used in vaccination campaigns by certain countries in Asia,[13][14][15] South America,[16][17][18] North America,[19][20] and Europe.[21] In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June 2021.[22] As of March 21, 70 million doses of CoronaVac had been administered worldwide.[23

Technology

CoronaVac is an inactivated vaccine. It uses a similar, more traditional technology as in BBIBP-CorV and BBV152, other inactivated-virus vaccines for COVID-19 in Phase III trials.[24][25] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[26] CoronaVac could remain stable for up to three years in storage, which might offer some advantage in vaccine distribution to regions where cold chains are not developed.[27]

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Efficacy

Empty bottle of CoronaVac

On 7 January 2021, results from Phase III trials in Brazil among 13,000 volunteers revealed the vaccine was 78% effective in preventing symptomatic cases of COVID-19 requiring medical assistance (grade 3 on the WHO Clinical Progression Scale[28]) and 100% effective against moderate and severe infections.[29] After mounting pressure from scientists, Butantan said on 12 January that these rates only included volunteers who had mild to severe cases of COVID-19.[30] The overall efficacy, including asymptomatic cases and symptomatic cases not requiring medical assistance (WHO grade 2), was 50.38%.[31] Of the 220 participants infected, 160 cases were in the placebo group and 60 cases in the group that received CoronaVac.[32]

On 3 March 2021, final Phase III results from Turkey showed an efficacy of 83.5%. The final efficacy rate was based on 41 infections, 32 of which had received a placebo, said Murat Akova, head of the Phase III trials in Turkey. He added the vaccine prevented hospitalization and severe illness in 100% of cases, saying six people who were hospitalized were all in the placebo group. The final results were based on a 10,216 participants, 6,648 of whom received the vaccine as part of the Phase III study that began mid-September. Turkey had announced an interim result with 29 infections in December, which placed the efficacy at 91.25%.[33][34]

On 11 January, Indonesia released Phase III results from an interim analysis of 25 cases which showed an efficacy rate of 65.3% based on data of 1,600 participants in the trial.[35] The trial was conducted in the city of Bandung, and it was not clear how Indonesian scientists made their calculations.[30]

Variability in results

Officials said the lowered figure of 50.4% included “very light” cases of COVID-19 among participants omitted in the earlier analysis. Ricardo Palácios, Medical Director of Instituto Butantan said Sinovac’s relatively low efficacy rate of 50% was due to more rigorous standards for what counts as an infection among trial participants. The Institute included six types of cases in its results: asymptomatic, very mild, mild, two levels of moderate, and severe, while western vaccine makers generally included only mild, moderate, and severe categories. Brazil’s trial was also largely made up of frontline health care workers. “They are more exposed to the virus and may explain the relatively low efficacy rate,” said Yanzhong Huang, a senior fellow for global health at the Council on Foreign Relations.[36]

The release of more definitive data on CoronaVac’s efficacy was delayed because Sinovac needed to reconcile results from different trials using varying protocols.[32] According to Instituto Butantan director Dimas Covas, the Brazilian group was considered more vulnerable to infection and exposure to higher viral loads. In Turkish and Indonesian Phase III trials, the composition of volunteers was similar to that of the general population.[37]

COVID-19 variants

On March 10, Instituto Butantan Director Dimas Covas said CoronaVac was efficient against three variants of COVID-19 in the country; British B.1.1.7, South African 501.V2, and Brazil’s P.1, of which are derived variants P.1 from Manaus state, and P.2 from Rio de Janeiro.[38]

CoronaVac and other inactivated virus vaccines have all parts of the virus. Butantan said this may generate a more comprehensive immune response compared to other vaccines using only a part of the spike protein used by COVID-19 to infect cells. Tests run by Butantan used the serum of vaccinated people, which are placed in a cell culture and subsequently infected with the variants. The neutralization consists of determining whether antibodies generated from the vaccine will neutralize the virus in the culture.[38]

Clinical trials

For broader coverage of this topic, see COVID-19 vaccine.

Phase I–II

In a Phase II clinical trial completed in July 2020 and published in The Lancet, CoronaVac showed seroconversion of neutralising antibodies for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group.[39]

In May, CoronaVac began Phase I–II trials in China on adults over the age 60, and in September CoronaVac began Phase I–II trials in China on children ages 3–17.[40] Phase II results for older adults published in The Lancet showed CoronaVac was safe and well tolerated in older adults, with neutralising antibody induced by a 3 μg dose were similar to those of a 6 μg dose.[41]

Phase III

Latin America

In late July 2020, Sinovac began conducting a Phase III vaccine trial to evaluate efficacy and safety on 9,000 volunteer healthcare professionals in Brazil, collaborating with Butantan Institute.[42][43] On 19 October, São Paulo Governor João Doria said the first results of the clinical study conducted in Brazil proved that among the vaccines being tested in the country, CoronaVac is the safest, the one with the best and most promising immunization rates.[44] On 23 October, São Paulo announced the creation of six new centers for trials of CoronaVac, increasing the number of volunteers in the trials to 13,000.[45]

Brazil briefly paused Phase III trials on 10 November after the suicide of a volunteer before resuming on 11 November. Instituto Butantan said the suicide had no relation to the vaccine trial.[46][47]

In August, a Phase III trial was started in Chile, headed by Pontifical Catholic University of Chile, which was expected to include 3,000 volunteers between the ages of 18 and 65.[48]

Europe

In September, Turkey began Phase III trials with 13,000 volunteers on a two-dose 14-day interval.[49] The monitoring process for CoronaVac is underway at 25 centers in 12 cities across the country.[50]

The Governor of West Java Ridwan Kamil participating in phase 3 trial of the Sinovac COVID-19 vaccine in Indonesia.

Asia

In August, Sinovac began Phase III trials in Indonesia with Bio Farma in Bandung involving 1,620 volunteers.[51] In November, Padjadjaran University Medical School provided an update that the trials were running smoothly and that “at most, they found a slight body fever which disappeared within two days”.[52]

In October, Saudi Arabia signed an agreement with Sinovac to distribute CoronaVac to 7,000 healthcare workers, after conducting Phase III trials with the Saudi Arabian National Guard.[53]

Manufacturing

Brazilian version of CoronaVac, manufactured by Butantan

In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June. The figure is double the capacity of 1 billion doses in bulk ingredients the firm said it could reach by February.[22]

After Indonesia’s Phase III trials, Bio Farma plans to ramp up production to 250 million doses a year.[54]

On 9 November, São Paulo began building a facility to produce 100 million doses a year.[55] On 10 December, João Doria said Butantan aimed to fill and finish 1 million doses per day on its production line for a vaccination campaign starting 25 January. Doria said 11 Brazilian states have contacted Butantan seeking doses of CoronaVac.[56]

In Malaysia, Pharmaniaga will manufacture, fill, and finish CoronaVac. Pharmaniaga signed a deal to obtain bulk supply of the vaccine as well as technology transfer from Sinovac.[57]

In Egypt, the government was in “advanced stage” discussions with Sinovac to manufacture CoronaVac for local use and export to African countries.[58]

Market and deployment

As of March 21, 70 million doses of CoronaVac had been administered worldwide.[23]

 
show  Full authorizationshow  Emergency authorization  Eligible COVAX recipient (assessment in progress)[80]

South America

São Paulo State Secretary of Health Jean Gorinchteyn (left) and Instituto Butantan chairman Dimas Covas (right) holding single-dose prefilled syringes of CoronaVac, part of the fourth shipment of Sinovac-manufactured vaccine to arrive in Brazil

In Brazil, São Paulo governor João Doria signed a $90 million contract with Sinovac in September to receive the initial 46 million doses of CoronaVac.[81] The price for CoronaVac was announced to be US$10.3 (about R$59).[82] In January, Brazil announced it would obtain 100 million total doses.[83] On 17 January, ANVISA approved emergency use of CoronaVac, with a 54-year-old nurse in São Paulo being the first to receive a vaccine outside of clinical trials in the country.[16] In early February, Brazil said it intends to buy an additional 30 million doses to be produced locally on top of the existing 100 million doses.[84]

In January, Bolivia authorized use of CoronaVac. Butantan Institute had opened negotiations with South American countries to sell the vaccine, which would be produced in São Paulo.[85]

In October, Chile signed an agreement to purchase 20 million doses of CoronaVac[86] which was approved for emergency use on 20 January.[87] By early March, the country had received 10 million doses of CoronaVac and had vaccinated 4.1 million people.[88]

In February, Colombia had purchased 5 million doses of CoronaVac and was in talks for an additional 5 million doses,[89] which had been approved for emergency use on February 5.[90]

In February, Ecuador signed a deal for 2 million doses of CoronaVac which had been approved for emergency use.[91] Chile donated 20,000 doses of CoronaVac to Ecuador on March 6.[92]

In March, Paraguay received a donation of 20,000 doses of CoronaVac from Chile.[92] Paraguay began vaccinations with CoronaVac on March 10.[93]

In January, Uruguay announced the purchased of 1.75 million doses of CoronaVac.[94] The first 192,000 doses arrived on 25 February and vaccinations started on 1 March.[18]

Europe

In March, Albania received 192,000 doses of a first batch of 1 million doses purchased through Turkey.[95]

In November, Turkey signed a contract to buy 50 million doses of CoronaVac.[96] Turkey approved emergency use on 13 January[97] and President Recep Tayyip Erdoğan received his first dose at Ankara City Hospital.[98] In February, Turkey signed a deal for another 50 million doses for a total of 100 million doses.[21] By March 10.7 million doses had been administered, and 852 of the 1.3 million people who had received both doses were later diagnosed with the disease. 53 were hospitalized, but none of those hospitalized were intubated or died.[99]

In December, Ukraine signed a contract to purchase 1.8 million doses of CoronaVac. One dose of CoronaVac would cost 504 hryvnias (around $18).[100] On March 9, Ukraine granted approval for use of CoronaVac.[101]

Asia

On 19 January, Azerbaijan launched its vaccination campaign with CoronaVac. Azerbaijan plans to receive 4 million doses of the vaccine and aims to vaccinate 40% of the population.[102]

In February, Cambodia approved Coronavac[103] for emergency use and later ordered 1.5 million doses to arrive on March 26.[104]

In late August, China approved CoronaVac for emergency use to vaccinate high-risk groups such as medical staff.[105] In early February, China approved CoronaVac for general use.[15]

In December, Hong Kong ordered 7.5 million doses of CoronaVac.[106] The vaccination campaign with CoronaVac began on 26 February.[107]

In August, Indonesia’s Foreign Minister Retno Marsudi said an agreement was signed with Sinovac for 50 million doses,[108] which later increased to 140 million doses.[109] Indonesia approved emergency use authorization on 11 January and[35] President Joko Widodo received the first shot of the vaccine, which would be free for all Indonesian citizens.[13] By March, Indonesia had received 53.5 million doses of CoronaVac.[110]

On 26 January, Malaysia ordered 12 million doses.[57] CoronaVac was approved for emergency use on 2 March.[111] Malaysian Science, Technology and Innovation Minister Khairy Jamaluddin received the first dose with CoronaVac on 18 March as part of the vaccination campaign.[112]

In January, the Philippine’s announced the country had secured 25 million doses.[113] The vaccine was approved on 22 February but not for all health workers as it had lower efficacy when used with health workers compared to healthy individuals aged 18-59. The first 600,000 doses of CoronaVac arrived on 28 February.[114]

Singapore has signed advance purchase agreements for CoronaVac.[115] In February, the first doses arrived in the country.[116]

In early January, Thailand’s Ministry of Public Health announced an order for 2 million doses of CoronaVac,[117] which was approved for emergency use on 22 February.[118] Thailand started its vaccination program on 27 February.[14] In March, Thailand was in talks to purchase an additional 5 million doses.[119]

North America

By March 8, Dominican Republic had vaccinated 400,000 people and had reserved delivery for 10 million additional doses of CoronaVac.[19]

In February, Mexico approved emergency use of CoronaVac.[120] The country has ordered 20 million doses,[121] of which the first 200,000 doses arrived on 20 February.[122] It is currently used as part of the national vaccination campaign.[20]

Africa

In March, Benin received 203,000 doses of CoronaVac with vaccinations to start with health workers and the medically vulnerable.[123]

In March, South Africa’s drug regulator began assessing CoronaVac for use in the country.[124] South African firm Numolux said it could supply 5 million doses once it secured regulatory clearances.[125]

In March, Tunisia’s Ministry of Health approved marketing authorization of CoronaVac in the country.[126]

In March, Zimbabwe approved CoronaVac for emergency use.[127]

Oceania

In March, Fiji said it would be receiving a donation of CoronaVac.[128]

Controversies

Politicization

CoronaVac has been championed by the governor of São Paulo, João Doria, who many believe will challenge Jair Bolsonaro for the presidency in 2022.[129] A political showdown began in October 2020, when Bolsonaro vetoed a deal between the Brazilian health ministry and the São Paulo government for the purchase of 46 million doses of the vaccine.[130] After Instituto Butantan announced CoronaVac’s efficacy rate, Bolsonaro mocked the vaccine’s effectiveness against COVID-19.[131] Critics against the politicization of vaccines have warned that failure to follow international testing and safety protocols risks undermining public trust and can increase people’s hesitancy to inoculation.[129] Doctors in São Paulo said they were struggling to convince patients that CoronaVac would be safe.[132]

In March 2021, the Paraná Pesquisas opinion polling institute found that the vaccines preferred by Brazilians are CoronaVac and the Oxford–AstraZeneca vaccine, chosen by 23.6% and 21.2% of Brazilians interviewed, respectively, against 11.3% of those who would prefer the Pfizer–BioNTech vaccine.[133]

Delays in releasing results

On 23 December 2020, researchers in Brazil said the vaccine was more than 50% effective, but withheld full results at Sinovac’s request, raising questions again about transparency as it was the third delay in releasing results from the trials.[134] São Paulo Health Secretary Jean Gorinchteyn later said the vaccine didn’t reach 90% efficacy. Turkey said its trial showed an estimated efficacy rate of 91.25%, though that was based on only 29 infected cases.[32] When São Paulo state officials announced the protection rate, they declined to provide a more detailed breakdown of the trial, such as information about age groups and side effects of the vaccine.[32] Scientists said the lack of transparency about the data ran the risk of damaging CoronaVac’s credibility, with Brazilians and others world-wide already reluctant to take it.[30] Nikolai Petrovsky, a professor at the College of Medicine and Public Health at Flinders University said, “There is enormous financial and prestige pressure for these trials to massively overstate their results.”[135]

References

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External links

Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Routes of
administration		Intramuscular injection
ATC codeNone
Legal status
Legal statusEmergency authorization for use in China, Indonesia, Brazil and Turkey
Identifiers
DrugBankDB15806
Part of a series on the
COVID-19 pandemic
SARS-CoV-2 (virus)COVID-19 (disease)
showTimeline
showLocations
showInternational response
showMedical response
showImpact
 COVID-19 Portal
vte

Sinovac Biotech Ltd. (Chinese: 北京科兴生物制品有限公司, Nasdaq: SVA) is a Chinese biopharmaceutical company that focuses on the research, development, manufacture and commercialization of vaccines that protect against human infectious diseases. The company is based in Haidian District, Beijing.[2] The company is listed on the NASDAQ but the exchange halted Sinovac’s trading in February 2019 due to a proxy fight.[3][4]

Vaccines

Sinovac’s commercialized vaccines include Healive (hepatitis A), Bilive (combined hepatitis A and B), Anflu (influenza), Panflu (H5N1) and PANFLU.1 (H1N1). Sinovac is currently developing a Universal Pandemic Influenza vaccine and a Japanese encephalitis vaccine.[5][better source needed]

Sinovac is also developing vaccines for enterovirus 71 and human rabies. Its wholly owned subsidiary, Tangshan Yian, is conducting field trials for independently developed inactivated animal rabies vaccines.[citation needed]

COVID-19 vaccine development

Main article: CoronaVac

CoronaVac is an inactivated virus COVID-19 vaccine developed by Sinovac.[6] It has been in Phase III clinical trials in Brazil,[7] Chile,[8] Indonesia,[9] Malaysia,[10] Philippines,[11] and Turkey.[12]

It relies on traditional technology similar to BBIBP-CorV and BBV152, other inactivated-virus COVID-19 vaccines in Phase III trials.[13] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[14]

Brazil announced results on January 13, 2021 showing 50.4% effective at preventing symptomatic infections, 78% effective in preventing mild cases needing treatment, and 100% effective in preventing severe cases.[15] Final Phase III results from Turkey announced on 3 March 2021 showed an efficacy of 83.5%.[16] Interim results in Indonesia were announced on 11 January 2021 with an efficacy of 65.3%.[17]

CoronaVac is being used in vaccination campaigns by certain countries in Asia,[18][19][20] South America,[21][22] and Europe.[23] In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June 2021.[24] As of 27 February 36 million doses had been administered in total.[25]

See also

References

  1. ^ “China’s Vaccine Front-Runner Aims to Beat Covid the Old-Fashioned Way”. Bloomberg. 24 August 2020.
  2. ^ “Home (English)”. Sinovac. Retrieved 2021-03-06. Add: No. 39 Shangdi Xi Road, Haidian District, Beijing, P.R.C. 100085 – Chinese address: “地址：中国· 北京 海淀区上地西路39号北大生物城（100085）”
  3. ^ Dou, Eva (December 4, 2020). “As China nears a coronavirus vaccine, bribery cloud hangs over drugmaker Sinovac”. The Washington Post. ISSN 0190-8286. Archived from the original on December 4, 2020. Retrieved 2020-12-06.
  4. ^ Levine, Matt (May 22, 2020). “A Vaccine With a Poison Pill”. Bloomberg News. Archived from the original on June 21, 2020. Retrieved December 6, 2020.
  5. ^ Google Finance, url=https://www.google.com/finance?q=Sinovac
  6. ^ Nidhi Parekh (22 July 2020). “CoronaVac: A COVID-19 Vaccine Made From Inactivated SARS-CoV-2 Virus”. Retrieved 25 July2020.
  7. ^ “New coronavirus vaccine trials start in Brazil”. AP News. 21 July 2020. Retrieved 2020-10-07.
  8. ^ “Chile initiates clinical study for COVID-19 vaccine”. Chile Reports. 4 August 2020. Retrieved 2020-10-07.
  9. ^ “248 volunteers have received Sinovac vaccine injections in Bandung”. Antara News. 30 August 2020. Retrieved 2020-10-07.
  10. ^ “Malaysia Receives China’s Sinovac Vaccine For Regulatory Testing”. Bloomberg.com. 2021-02-27. Retrieved 2021-03-02.
  11. ^ “DOH eyes 5 hospitals for Sinovac vaccine Phase 3 clinical trial”. PTV News. 16 September 2020. Retrieved 2020-10-07.
  12. ^ “Turkey begins phase three trials of Chinese Covid-19 vaccine”. TRT World News. 1 September 2020. Retrieved 2020-10-07.
  13. ^ Zimmer, Carl; Corum, Jonathan; Wee, Sui-Lee. “Coronavirus Vaccine Tracker”. The New York Times. ISSN 0362-4331. Retrieved 2021-02-12.
  14. ^ “CoronaVac: Doses will come from China on nine flights and can…” AlKhaleej Today (in Arabic). 2020-11-01. Retrieved 2021-02-12.
  15. ^ “Sinovac: Brazil results show Chinese vaccine 50.4% effective”. BBC News. 2021-01-13. Retrieved 2021-02-12.
  16. ^ AGENCIES, DAILY SABAH WITH (25 December 2020). “Turkey set to receive ‘effective’ COVID-19 vaccine amid calls for inoculation”. Daily Sabah. Retrieved 12 February 2021.
  17. ^ hermesauto (11 January 2021). “Indonesia grants emergency use approval to Sinovac’s vaccine, local trials show 65% efficacy”. The Straits Times. Retrieved 12 February 2021.
  18. ^ TARIGAN, EDNA; MILKO, VICTORIA (13 January 2021). “Indonesia starts mass COVID vaccinations over vast territory”. Associated Press. Retrieved 15 January 2021.
  19. ^ Aliyev, Jeyhun (19 January 2021). “Azerbaijan kicks off COVID-19 vaccination”. Anadolu Agency.
  20. ^ “China approves Sinovac vaccines for general public use”. South China Morning Post. 6 February 2021. Retrieved 6 February2021.
  21. ^ Fonseca, Jamie McGeever, Pedro (17 January 2021). “Brazil clears emergency use of Sinovac, AstraZeneca vaccines, shots begin”. Reuters. Retrieved 17 January 2021.
  22. ^ Miranda, Natalia A. Ramos (28 January 2021). “Chile receives two million-dose first delivery of Sinovac COVID-19 vaccine”. Reuters. Retrieved 30 January 2021.
  23. ^ “Turkey aims to vaccinate 60 percent of population: Minister – Turkey News”. Hürriyet Daily News. Retrieved 12 February 2021.
  24. ^ Liu, Roxanne (2021-03-03). “Sinovac eyes two billion doses in annual capacity of virus vaccine by June”. Reuters. Retrieved 2021-03-03.
  25. ^ “Malaysia receives first batch of Sinovac Covid-19 vaccine today”. Bernama. 27 February 2021. Retrieved 27 February 2021– via The Malay Mail.

External links

TypePublic
Traded asNasdaq: SVA
(American Depository Receipts)
Founded1999; 22 years ago
FounderYin Weidong[1]
HeadquartersBeijing,China
Websitehttp://www.sinovac.com/
Sinovac Biotech
Simplified Chinese北京科兴生物制品有限公司
Traditional Chinese北京科興生物製品有限公司
hideTranscriptionsStandard MandarinHanyu PinyinBěijīng Kē Xìng Shēngwù Zhìpǐn Yǒuxiàn Gōngsī

/////////Sinovac COVID-19 vaccine, CoronaVac, corona virus, covid 19, vaccine, china, Sinovac Biotech, PiCoVacc

#Sinovac COVID-19 vaccine, #CoronaVac, #corona virus, #covid 19, #vaccine, #china, #Sinovac Biotech, #PiCoVacc

Sputnik V, Gam-COVID-Vac, Gamaleya

March 24, 2021 9:36 am / 1 Comment on Sputnik V, Gam-COVID-Vac, Gamaleya


sputnik-5

Sputnik V 

Gam-COVID-Vac

Gamaleya

SARS-CoV-2

  • Gam-COVID-Vac Lyo
Chart: How Effective Are The Covid-19 Vaccines? | Statista

Gam-COVID-Vac was created by Gamaleya Research Institute of Epidemiology and MIcrobiology in Russia. The vaccine candidate is a heterologous COVID-19 vaccine containing two components, recombinant adenovirus type 26 (rAd26) vector and recombinant adenovirus type 5 (rAd5) vector which both carry the SARS-CoV-2 spike glycoprotein. The vaccine is offered in both a frozen (Gam-COVID-Vac) and freeze-dried formulation (lyophilizate; Gam-COVID-Vac Lyo). Phase 1/2 human trials with 76 participants evaluated the safety, tolerability, and immunogenicity of both frozen (Gam-COVID-Vac;NCT04436471) and freeze-dried (Gam-COVID-Vac Lyo;NCT04437875) vaccine candidates in June 2020, and were completed in early August 2020. Preliminary results suggested that all participants developed antibodies to the SARS-CoV-2 glycoproteins with a good safety profile in both trials.

Sputnik V (Russian: Спутник V, literally Traveler V) is a COVID-19 vaccine developed by the Gamaleya Research Institute of Epidemiology and Microbiology. Registered on 11 August 2020 by the Russian Ministry of Health as Gam-COVID-Vac (Russian: Гам-КОВИД-Вак, romanized: Gam-KOVID-Vak),[2][3] Sputnik V is an adenovirus viral vector vaccine. The “V” in the name is the letter V, not the Roman numeral for five.[4]

Gam-COVID-Vac was initially approved for distribution in Russia on the preliminary results of Phase I–II studies eventually published on 4 September 2020.[5] The quick approval in early August of Gam-COVID-Vac was met with criticism in mass media and precipitated discussions in the scientific community whether this decision was justified in the absence of robust scientific research confirming the safety and efficacy of the vaccine.[2][3][6][7][8] On 2 February 2021, an interim analysis from the trial was published in The Lancet, indicating 91.6% efficacy without unusual side effects.[9]

Emergency mass-distribution of the vaccine began in December 2020 in multiple countries including Russia, Argentina, Belarus, Hungary, Serbia and the United Arab Emirates. As of February 2021, over a billion doses of the vaccine were ordered for immediate distribution globally.[10]

Infographic: What we know about Russia's Sputnik-V vaccine | Dhaka Tribune

NEW DRUG APPROVALS

ONE TIME

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Technology

 President Putin‘s meeting with government members, on 11 August 2020 via videoconference, at which he announced a conditionally registered vaccine against COVID-19.[2][3] Medical worker in Moscow with the vaccineSee also: COVID-19 vaccine

Gam-COVID-Vac is a viral two-vector vaccine based on two human adenoviruses – a common cold virus – containing the gene that encodes the full-length spike protein (S) of SARS-CoV-2 to stimulate an immune response.[5][11][12] The Gam-COVID-Vac vaccine was developed by a cellular microbiologists team of the government-backed Gamaleya Research Institute of Epidemiology and Microbiology. The group was led by MD and RAS associate member Denis Logunov, who also worked on vaccines for the Ebolavirus and the MERS-coronavirus.[13]

The recombinant adenovirus types 26 and 5 are both used as vectors in the vaccine. They were biotechnology-derived and contain the SARS-CoV-2 S protein cDNA. Both of them are administered into the deltoid muscle: the Ad26-based vaccine is used on the first day and the Ad5 vaccine is used on the 21st day to boost immune response.[11][14][15]

The vaccine can be formulated as frozen (storage temperature must be −18 °C or 0 °F or lower) and freeze-dried (“Gam-COVID-Vac-Lyo”, storage temperature is 2–8 °C or 36–46 °F) dosage forms.[16] The first formulation was developed for large-scale use, it is cheaper and easier to manufacture. The production of a lyophilized formulation takes much more time and resources, although it is more convenient for storage and transportation. Gam-COVID-Vac-Lyo was developed especially for vaccine delivery to hard-to-reach regions of Russia.[17] The head of the Gamaleya Research Institute Alexander Ginzburg estimates that it will take 9–12 months to vaccinate the vast majority of the Russian population, assuming in-country resources are adequate.[18][19] A single-dose version is also being developed to speed up vaccination outside Russia. It will offer less protection than the two-dose versions, but it is still expected to reach an efficacy of 85%.[20][21]

COVID-19 vaccines: where we stand and challenges ahead | Cell Death & Differentiation

Clinical research

Phase I–II

A phase I safety trial began on 18 June.[2] On 4 September, data on 76 participants in a phase I–II trial were published, indicating preliminary evidence of safety and an immune response.[5] The results were challenged by international vaccine scientists as being incomplete, suspicious, and unreliable when identical data were reported for many of the trial participants,[22] but the authors responded that there was a small sample size of nine, and the measured results of titration could only take discrete values (800, 1600, 3200, 6400). Coupled with the observation that values tended to reach a plateau after three to four weeks, they contend that it is not unlikely that several participants would show identical results for days 21 to 28.[23]

Phase III

 Sputnik V, efficacy for different conditions. The error bars indicate the confidence interval containing the efficacy with 95% probability

In early November 2020, Israel Hadassah Medical Center director-general Prof. Zeev Rotstein stated that Hadassah’s branch in Moscow’s Skolkovo Innovation Center was collaborating on a phase III clinical trial.[24]

The ongoing phase III study is a randomised, double-blind, placebo-controlled, multi-centre clinical trial involving 40,000 volunteers in Moscow, and is scheduled to run until May 2021.[25] In 2020–2021, phase III clinical studies were also being conducted in Belarus,[26] UAE,[27] India[28] and Venezuela.[29]

On 2 February 2021, an interim analysis from the Moscow trial was published in The Lancet, indicating 91.6% efficacy (95% CI 85.6–95.2) after the second vaccination, without unusual side effects.[30] The trial started on 7 September 2020 using the frozen liquid form of the vaccine, and data was analysed up to the second database lock on 24 November 2020. The over-60-years-old group in the trial (oldest participant was 87) had essentially the same efficacy (91.8%) as for all ages. The lowest age participants were 18 years old.[9][31]

SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates | npj Vaccines

Sputnik–AstraZeneca COVID-19 vaccine trials

On 21 December 2020 the Russian Direct Investment Fund (RDIF), the Gamaleya National Center, AstraZeneca and R-Pharm have signed an agreement aimed at the development and implementation of a clinical research program to assess the immunogenicity and safety of the combined use of one of the components of the Sputnik V vaccine developed by the Gamaleya Center, and one of the components of the AZD1222 vaccine, developed by AstraZeneca and the University of Oxford.[32] The study program will last 6 months in several countries, and it is planned to involve 100 volunteers in each study program. On 9 February 2021, the Ministry of Health of the Republic of Azerbaijan allowed clinical studies in the country for the combined use of the Sputnik V vaccine and the vaccine developed by AstraZeneca, stating that the trials would begin before the end of February 2021.[33][34]

Composition

The Gam-COVID-Vac is a two-vector vaccine.[1] The active component for both vectors is a modified (recombinant) replication-defective adenovirus of a different serotype (Serotype 26 for the first vaccination and serotype 5 for the second vaccination), which has been modified to include the protein S-expressing gene of SARS-CoV-2.[1]

The other ingredients (excipients) are the same, both quantitatively and qualitatively, in the two components.[35]

As per the official datasheet, no further components or ingredients, including other adjuvants, should be included in the vaccine.[1]

History

In May 2020, the Gamaleya Research Institute of Epidemiology and Microbiology announced that it had developed the vaccine without serious side effects. By August 2020, phases I and II of two clinical trials (involving 38 patients each) were completed. Only one of them used the formulation which later obtained marketing authorization under limited conditions.[36][37] This vaccine was given the trade name “Sputnik V”, after the world’s first artificial satellite.[3][7][38]

During preclinical and clinical trials, 38 participants who received one or two doses of the Gam-COVID-Vac vaccine had produced antibodies against SARS-CoV-2’s spike protein, including potent neutralizing antibodies that inactivate viral particles.[2] On 11 August 2020, the Russian minister of Health Mikhail Murashko announced at a government briefing with the participation of President Vladimir Putin regulatory approval of the vaccine for widespread use. The state registration of the vaccine was carried out “conditionally” with post-marketing measures according to the decree of the Government of the Russian Federation. The registration certificate for the vaccine stated that it could not be used widely in Russia until 1 January 2021, and before that, it may be provided to “a small number of citizens from vulnerable groups”, such as medical staff and the elderly, according to a Ministry of Health spokesperson.[3] The license under register number No. ЛП-006395 (LP-006395) was issued on 11 August by the Russian Ministry of Health. Although the announcement was made even before the vaccine candidate had been entered into Phase III trials, the practice of marketing authorization “on conditions” also exists in other countries.[39][40] On 26 August, certificate No. ЛП-006423 (LP-006423) was issued for the lyophilized formulation “Gam-COVID-Vac-Lyo”.[2][3][7][41][5]

The commercial release of the Gam-COVID-Vac was first scheduled for September 2020. In October, Mikhail Murashko said that the Gam-COVID-Vac will be free for all Russian citizens after the launching of mass production.[42][43] Later on, Russian Ministry of Health registered maximum ex-factory price equal to 1,942 rubles for two components and included them into The National List of Essential medicines.[44] There were also suggestions to include the vaccine in the National Immunisation Calendar of Russia.[44]

According to Russian media, the mass production of the Gam-COVID-Vac was launched by 15 August. By that moment, the Russian Federation has already received applications from 20 countries for the supply of 1 billion doses of vaccine. Three facilities were able to produce about a million doses per month at each with a potential doubling of capacity by winter. By the end of 2020, Gamaleya Research Institute’s production, according to an interview with the organization’s spokesperson, was planned to produce 3–5 million doses.[45][46]

On 9 March 2021, an agreement was signed by the RDIF sovereign wealth fund and Swiss-based pharmaceutical company Adienne to produce the vaccine in Italy. Kirill Dmitriev, RDIF’s head, told Russian state TV his fund had also struck deals with production facilities in Spain, France and Germany for local manufacturing of the vaccine.[47]

Scientific assessment

Balram Bhargava, director of the Indian Council of Medical Research, said that Russia had managed to fast-track a COVID-19 vaccine candidate through its early phases.[48]

On 11 August 2020, a World Health Organization (WHO) spokesperson said, “… prequalification of any vaccine includes the rigorous review and assessment of all required safety and efficacy data”.[8]

  • A WHO assistant director said, “You cannot use a vaccine or drugs or medicines without following through all of these stages, having complied with all of these stages”.[49]
  • Francois Balloux, a geneticist at University College London, called the Russian government’s approval of Gam-COVID-Vac a “reckless and foolish decision”.[2] Professor Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia, characterized the announcement was a “political stunt”, and stated that the untested vaccine could be very harmful.[8]

Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said “that we can be cautiously optimistic that SARS-CoV2 vaccines targeting the spike protein are effective.” Moreover, as the Sputnik antigen is delivered via a different modality, namely using a disabled Adenovirus rather than formulated RNA, this provides flexibility in terms of perhaps one or other method providing better responses in certain age-groups, ethnicities, etc., plus the storage of this vaccine ought to be more straightforward.[50][failed verification][51]

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said “the data [is] compatible with the vaccine being reasonably effective … These results are consistent with what we see with other vaccines, because the really big message for global health scientists is that this disease [COVID-19] is able to be addressed by vaccines.”[50]

Julian Tang, clinical virologist at the University of Leicester, said: “Despite the earlier misgivings about the way this Russian Sputnik V vaccine was rolled out more widely – ahead of sufficient Phase 3 trial data – this approach has been justified to some extent now.”[52]

Ian Jones, a professor of virology at the University of Reading, and Polly Roy, professor and Chair of Virology at The London School of Hygiene and Tropical Medicine, commenting on phase III results published in the Lancet in February 2021, said “The development of the Sputnik V vaccine has been criticised for unseemly haste, corner cutting, and an absence of transparency. But the outcome reported here is clear and the scientific principle of vaccination is demonstrated, which means another vaccine can now join the fight to reduce the incidence of COVID-19.”[53]

Hildegund C. J. Ertl, a vaccine scientist at the Wistar Institute, called the phase-III results published on 2 February 2021 “great”: “Good safety profile, more than 90% efficacy across all age groups, 100% efficacy against severe disease or death, can be stored in the fridge and low cost. What more would we want?”[54]

According to preliminary review by experts,[who?] the lyophilized formulation of Gam-COVID-Vac is similar to the smallpox vaccine, circumventing the need for continuous “colder chain” or cold-chain storage – as required for the Pfizer–BioNTech and Moderna vaccines respectively – and allowing transportation to remote locations with reduced risk of vaccine spoilage.[55][56]

On 6 March 2021, Director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), Anthony Fauci, said that the data from Sputnik V “looked pretty good” to him.[57]

Distribution, vaccination and public perception

Early perception

An opinion poll of Canadians conducted by Léger in August 2020 found that a majority (68%) would not take the Russian vaccine if offered a free dose, compared to 14% who said they would take it. When Americans were asked the same question, 59% would not take the Russian vaccine if offered a free dose, compared to 24% who said they would take it.[58][59]

  • At that time, British and American officials stated that the Gam-COVID-Vac vaccine would likely be rejected due to concerns that the normally rigorous process of vaccine clinical testing was not followed.[60] One public health expert said the quick approval of Gam-COVID-Vac by the Russian government was “cutting corners”, and may harm public confidence if the vaccine proves to be unsafe or ineffective.[7] “There is a huge risk that confidence in vaccines would be damaged by a vaccine that received approval and was then shown to be harmful”, said immunologist Peter Openshaw.[7]


As for early September 2020, according to public opinion polls, only half of the Russian population would take the vaccine voluntarily.[61]

In Russia

 Vaccination of military personnel and civilian specialists of the Northern Fleet with the second component of the drug “Gam-COVID-Vac” (“Sputnik V”).

In the beginning of December 2020, Russian authorities announced the start of a large-scale free of charge vaccination with Gam-COVID-Vac for Russian citizens: the “immunization” program was launched on 5 December 2020 (with 70 Moscow-based medical centers providing vaccinations).[62]

Doctors and other medical workers, teachers, and social workers were given priority due to their highest risk of exposure to the disease.[63] The age for those receiving shots was initially capped at 60, later this restriction was lifted.[64]

Potential recipients were notified via text messaging, which says “You are working at an educational institution and have top-priority for the COVID-19 vaccine, free of charge”. Patients are asked a few general health questions before getting the vaccine. Program’s leaflet is handed to the patient, which warns of possible side effects, suggesting those are most likely to be mild and last a couple of days at most.[65][66][67] People with certain underlying health conditions, pregnant women, and those who have had a respiratory illness for the past two weeks are barred from vaccination.[63] Vaccine vial is removed from medical centre’s freezer about 15 minutes before use.

In early December 2020, the Minister of Health, Mikhail Murashko, said that Russia had already vaccinated more than 100,000 high-risk people.[68] Forty thousand of those are volunteers in Sputnik V’s Phase 3 trials, another 60,000 medics and doctors have also taken the vaccine.[69] The head of the Russian Direct Investment Fund, Kirill Dmitriev, said in an interview with the BBC that Russian medics expect to give about 2 million people coronavirus vaccinations in December.[70]

Up to the beginning of December 2020, Generium (which is supervised by Pharmstandard) and Binnopharm (which is supervised by AFK Sistema) companies produced Gam-COVID-Vac on a large scale.

On 10 December, Deputy Prime Minister Tatyana Golikova announced that approximately 6.9 million doses of the Sputnik V vaccine will enter civilian circulation in Russia before the end of February 2021.[71] Moscow Mayor Sergei Sobyanin announced that the newly-opened Moscow-based “R-Pharm” will become a leading manufacturer of Russia’s Sputnik V coronavirus vaccine. Working at full capacity, the factory will produce up to 10 million doses a month.[72]

Outside of Russia

 In dark green are the countries that ordered (Russian or licensed domestic production; China also plans to produce Sputnik V on its territory.) or approved Sputnik V vaccine against COVID-19 (w/disputed Crimea). In light green are the countries that have shown interest in obtaining the vaccine.

According to the Russian Direct Investment Fund, they had received orders for more than 1.2 billion doses of the vaccine as of December 2020. Over 50 countries had made requests for doses, with supplies for the global market being produced by partners in India, Brazil, China, South Korea, Hungary, and other countries.[73][74] In August 2020, according to the Russian authorities, there were at least 20 countries that wanted to obtain the vaccine.[75]

While free in Russia, the cost per dose would be less than US$10 (or less than US$20 for the two doses needed to vaccinate one person) on international markets, which makes it much more affordable compared to mRNA vaccines from other manufacturers. Kirill Dmitriev, head of the fund, told reporters that over 1 billion doses of the vaccine are expected to be produced in 2021 outside of Russia.[76][77]

The Israeli Hadassah Medical Center has signed a commercial memorandum of understanding to obtain 1.5–3 million doses.[78]

  • According to The New York Times’ sources,[79] to secure the release of an Israeli civilian held in Syria, Israel agreed to finance a supply of Russian-made Covid-19 vaccines for Damascus.

Argentina had agreed to buy 25 million doses of Russia’s Covid-19 vaccine.[80] The vaccine was registered and approved in Argentina in late December 2020.[81] The Brazilian state of Bahia has also signed an agreement to conduct Phase III clinical trials of the Sputnik V vaccine and plans to buy 50 million doses to market in northeastern Brazil.[82]

On 21 January 2021, the Argentine president Alberto Fernández became the first Latin American leader to be inoculated against the disease via the then recently approved Sputnik V.[83][84]

Due to the delay in shipping of doses from Italy and the European Union, San Marino imported doses of the Sputnik V vaccine (not approved by the E.M.A.) and started a mass vaccination on 28 February of its healthcare workers.[85]

EMA’s human medicines committee (CHMP) has started a rolling review of Sputnik V (Gam-COVID-Vac), a COVID-19 vaccine developed by Russia’s Gamaleya National Centre of Epidemiology and Microbiology. [86] Asked about the prospect of Austria taking the same step (as some other European countries chose to do), EMA management board chair Christa Wirthumer-Hoche told Austria’s ORF broadcaster: “It’s somewhat comparable to Russian roulette. I would strongly advise against a national emergency authorisation,” she said, pointing to the fact that there was not yet sufficient safety data about those who had already been given the vaccine. “We could have Sputnik V on the market in future, when we’ve examined the necessary data,” she said, adding that the vaccine needed to match up to European criteria on quality control and efficacy.[87]

Although vaccination rates in Russia are below those of other developed nations (as of March 2021),[88] Russia is pursuing deals to supply its vaccine abroad.[89]

Emergency use authorization

 show  Full authorizationshow  Emergency authorizationshow  Ordered doses  Eligible COVAX recipient (assessment in progress)[143]  EMA review in progress[144]

As of December 2020, Belarus and Argentina granted emergency use authorization for the vector-based vaccine.[145] On 21 January 2021, Hungary became the first European Union country to register the shot for emergency use, as well as the United Arab Emirates in the Gulf region.[146][147][148][149][150]

On 19 January 2021, the Russian authorities applied for the registration of Sputnik V in the European Union, according to the RDIF.[151] On 10 February, the European Medicines Agency (EMA) said that they had “not received an application for a rolling review or a marketing authorisation for the vaccine”. The developers have only expressed their interest that the vaccine be considered for a rolling review, but EMA’s Human Medicines Committee (CHMP) and the COVID-19 EMA pandemic Task Force (COVID-ETF) need to give their agreement first before developers can submit their application for initiation of the rolling review process.[152] On 4 March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the EMA started a rolling review of Sputnik V.[153] The EU applicant is R-Pharm Germany GmbH.[153]

Emergency use has also been authorized in Algeria, Bolivia, Serbia, the Palestinian territories,[154] and Mexico.[155]

On 25 January 2021, Iran approved the vaccine, with Foreign Minister Mohammad Javad Zarif saying the country hopes to begin purchases and start joint production of the shot “in the near future”, after Supreme Leader Ayatollah Ali Khamenei banned the government from importing vaccines from the United States and United Kingdom.[156][157]

On 1 March 2021, Slovakia bought two million Sputnik V vaccines. Slovakia received the first batch of 200,000 vaccines, and expects to receive another 800,000 doses in March and April. Another 1 million vaccines are set to arrive in May and June.[158] The Czech Republic is also considering buying Sputnik V.[159]

On 18 March 2021, German regional leaders including State Premiers and the major of Berlin called for the swift approval of the Russian vaccine by the European Medicines Agency to counteract the acute shortages of effective vaccines in Europe. German medical experts have recommended its approval also, and consider the Sputnik Vaccine “clever” and “highly safe”.[160]

On 19 March 2021, the Philippine Food and Drug Administration granted emergency use authorization for Sputnik V, the fourth COVID-19 vaccine to be given authorization. The Philippine government is planning to buy 20 million doses of the vaccine.[161][162]

As of March 23, 2021, 56 countries have granted Sputnik V emergency use authorization.[163]

Production

As of March 2021, RDIF has licensed production in India, China, South Korea and Brazil. In the EU, RDIF has signed production agreements, subject to European Medicines Agency approval, with companies in Germany, Spain and France, and is in negotiations with a Swiss/Italian company. By the end of March 2021 RDIF anticipates 33 million doses will have been manufactured in Russia, less than 5% of which will have been exported.[164]

An agreement for the production of over 100 million doses of vaccine in India has been made with Dr. Reddy’s Laboratories, who on 11 January 2021 submitted mid-stage trial data to the Indian regulator and recommended moving onto late-stage trials.[154] The RDIF announced plans to sell 100 million doses to India, 35 million to Uzbekistan, and 32 million to Mexico, as well as 25 million each to Nepal and Egypt.[165]

In March 2021, the Italian-Russian Chamber of Commerce announced that Italy would be the first EU country to manufacture the two-dose COVID-19 vaccine under license. From July to the end of 2021, the Italian-Swiss pharmaceutical company Adienne in Caponago will manufacture 10 million doses. The announcement came in a time of acute vaccine shortages in Europe while the Sputnik V vaccine was still under review by the European Medicines Agency. Russian authorities said they would be able to provide a total of 50 million doses to European countries beginning in June 2021.[166]

The Sputnik V doses to be manufactured in South Korea are not for domestic use. The vaccine is to be exported to Russia, Algeria, Argentina, Hungary, Iran and the United Arab Emirates.[167]

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  35. ^ “ИНСТРУКЦИЯ ПО МЕДИЦИНСКОМУ ПРИМЕНЕНИЮ ЛЕКАРСТВЕННОГО ПРЕПАРАТА Гам-КОВИД-Вак, Комбинированная векторная вакцина для профилактики коронавирусной инфекции, вызываемой вирусом SARS-CoV-2” (PDF). МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ.
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  92. ^ Jump up to:a b c “Sputnik V vaccine registered in Bosnia and Herzegovina’s Republika Srpska”. TASS. 5 February 2021. Retrieved 8 February2021.
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  95. ^ “Turkmenistan is the first in Central Asia to have registered “Sputnik V” vaccine”. Orient. 18 January 2021.
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  98. ^ “Argentina has registered the Sputnik V vaccine based on Russian clinical trial data” (Press release). Gamaleya Center. Retrieved 1 January 2021.
  99. ^ “Armenia approves Russia’s Sputnik V coronavirus vaccine -Russia’s RDIF”. Reuters. 1 February 2021. Retrieved 1 February2021.
  100. ^ “Bahrain authorises Sputnik V COVID-19 vaccine for emergency use – Bahrain TV”. Reuters. 10 February 2021. Retrieved 19 February 2021.
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  106. ^ “Guatemala to receive Russia’s Sputnik vaccine in coming weeks”. Reuters. 24 February 2021.
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  108. ^ “Russia’s Sputnik V vaccine expands its reach in Latin America”. CNN. 3 March 2021.
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  110. ^ “Iran approves Russian coronavirus vaccine Sputnik V”. Reuters. 26 January 2021.
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  118. ^ “Mongolia Approves Russia’s Sputnik V Coronavirus Vaccine – RDIF”. Urdu Point. 9 February 2021.
  119. ^ “Montenegro and St. Vincent approve Russia’s Sputnik V vaccine – RDIF”. Reuters. 12 February 2021.
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  121. ^ “Myanmar registers Russia’s Sputnik V COVID-19 vaccine”. TASS. Retrieved 19 February 2021.
  122. ^ “Namibia becomes the 50th country to authorize Sputnik V”(Press release). Moscow: Gamaleya Research Institute of Epidemiology and Microbiology. 11 March 2021. Retrieved 15 March 2021.
  123. ^ “Nicaragua approves Russian COVID-19 vaccine”. wsoctv. 3 February 2021.
  124. ^ “NRussia’s Sputnik V COVID 19 vaccine registered in North Macedonia”. TASS. 7 March 2021.
  125. ^ “Govt okays Russian vaccine for ’emergency use'”. Dawn. 24 January 2021.
  126. ^ “Palestine has become the first country in the Middle East to register Sputnik V vaccine”. RFID. 11 January 2021.
  127. ^ “Paraguay approves Russia’s Sputnik V vaccine: RDIF”. Reuters. 15 January 2021. Retrieved 15 January 2021.
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External links

Scholia has a profile for Gam-COVID-Vac (Q98270627).
Russian Ministry of Health image of Gam-COVID-Vac vials
Vaccine description
TargetSARS-CoV-2
Vaccine typeViral vector
Clinical data
Trade namesSputnik V[1]Спутник V
Other namesGam-COVID-VacГам-КОВИД-Вак
Routes of
administration		Intramuscular
ATC codeNone
Legal status
Legal statusRegistered in Russia on 11 August 2020
AE, AG, DZ, BO, BY, HU, IR, PS, RS: EUA only
Identifiers
DrugBankDB15848

////////SARS-CoV-2, corona virus, covid 19, Gam-COVID-Vac Lyo, Sputnik V, Gam-COVID-Vac, Gamaleya, russia

#SARS-CoV-2, #corona virus, #covid 19, #Gam-COVID-Vac Lyo, #Sputnik V, #Gam-COVID-Vac, #Gamaleya, #russia, #vaccine

NOVAWAX, NVX-CoV2373,

March 23, 2021 1:25 pm / Leave a comment


NOVAWAX

NVX-CoV2373

SARS-CoV-2 rS Nanoparticle Vaccine

MCDC OTA agreement number W15QKN-16-9-1002

Novavax COVID-19 vaccine, Coronavirus disease 19 infection

SARS-CoV-2 rS,  TAK 019

Novavax, Inc. is an American vaccine development company headquartered in Gaithersburg, Maryland, with additional facilities in Rockville, Maryland and Uppsala, Sweden. As of 2020, it had an ongoing Phase III clinical trial in older adults for its candidate vaccine for seasonal influenza, NanoFlu and a candidate vaccine (NVX-CoV2373) for prevention of COVID-19.

NVX-CoV2373 is a SARS-CoV-2 rS vaccine candidate and was shown to have high immunogenicity in studies. The vaccine is created from the genetic sequence of COVID-19 and the antigen derived from the virus spike protein is generated using recombinant nanoparticle technology. The vaccine was developed and tested by Novavax. As of May 2020, the company is pursuing a Phase 1 clinical trial (NCT04368988) to test the vaccine.

History

Novavax was founded in 1987. It focused principally on experimental vaccine development, but did not achieve a successful launch up to 2021.[4]

In June 2013, Novavax acquired the Matrix-M adjuvant platform with the purchase of Swedish company Isconova AB and renamed its new subsidiary Novavax AB.[5]

In 2015, the company received an $89 million grant from the Bill & Melinda Gates Foundation to support the development of a vaccine against human respiratory syncytial virus for infants via maternal immunization.[6][7][8][9]

In March 2015 the company completed a Phase I trial for its Ebola vaccine candidate,[10] as well as a phase II study in adults for its RSV vaccine, which would become ResVax.[11] The ResVax trial was encouraging as it showed significant efficacy against RSV infection.[11]

2016 saw the company’s first phase III trial, the 12,000 adult Resolve trial,[11] for its respiratory syncytial virus vaccine, which would come to be known as ResVax, fail in September.[3] This triggered an eighty-five percent dive in the company’s stock price.[3] Phase II adult trial results also released in 2016 showed a stimulation of antigencity, but failure in efficacy.[11] Evaluation of these results suggested that an alternative dosing strategy might lead to success, leading to plans to run new phase II trials.[3] The company’s difficulties in 2016 led to a three part strategy for 2017: cost reduction through restructuring and the termination of 30% of their workforce; pouring more effort into getting ResVax to market; and beginning clinical trials on a Zika virus vaccine.[3]

Alongside the adult studies of ResVax, the vaccine was also in 2016 being tested against infant RSV infection through the route of maternal immunization.[11]

In 2019, late-stage clinical testing of ResVax, failed for a second time, which resulted in a major downturn in investor confidence and a seventy percent reduction in capital value for the firm.[12][13] As a secondary result, the company was forced to conduct a reverse stock split in order to maintain Nasdaq minimum qualification, meaning it was in risk of being delisted.[13]

The company positions NanoFlu for the unmet need for a more effective vaccine against influenza, particularly in the elderly who often experience serious and sometimes life-threatening complications. In January 2020, it was granted fast track status by the U.S. Food and Drug Administration (FDA) for NanoFlu.

External sponsorships

In 2018, Novavax received a US$89 million research grant from the Bill and Melinda Gates Foundation for development of vaccines for maternal immunization.[14]

In May 2020, Novavax received US$384 million from the Coalition for Epidemic Preparedness Innovations to fund early-stage evaluation in healthy adults of the company’s COVID-19 vaccine candidate NVX-CoV2373 and to develop resources in preparation for large-scale manufacturing, if the vaccine proves successful.[15] CEPI had already invested $4 million in March.[15]

Drugs in development

ResVax is a nanoparticle-based treatment using a recombinant F lipoprotein or saponin, “extracted from the Quillaja saponaria [or?] Molina bark together with cholesterol and phospholipid.”[16] It is aimed at stimulating resistance to respiratory syncytial virus infection, targeting both adult and infant populations.[11]

In January 2020, Novavax was given Fast Track status by the FDA to expedite the review process for NanoFlu, a candidate influenze vaccine undergoing a Phase III clinical trial scheduled for completion by mid-2020.[17]

COVID-19 vaccine candidate

See also: NVX-CoV2373 and COVID-19 vaccine

In January 2020, Novavax announced development of a vaccine candidate, named NVX-CoV2373, to establish immunity to SARS-CoV-2.[18] NVX-CoV2373 is a protein subunit vaccine that contains the spike protein of the SARS-CoV-2 virus.[19] Novavax’s work is in competition for vaccine development among dozens of other companies.

In January 2021, the company released phase 3 trials showing that it has 89% efficacy against Covid-19, and also provides strong immunity against new variants.[20] It has applied for emergency use in the US and UK but will be distributed in the UK first.Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 TrialJan 28, 2021 at 4:05 PM ESTDownload PDF

First to Demonstrate Clinical Efficacy Against COVID-19 and Both UK and South Africa Variants

  • Strong efficacy in Phase 3 UK trial with over 50% of cases attributable to the now-predominant UK variant and the remainder attributable to COVID-19 virus
  • Clinical efficacy demonstrated in Phase 2b South Africa trial with over 90% of sequenced cases attributable to prevalent South Africa escape variant
  • Company to host investor conference call today at 4:30pm ET

GAITHERSBURG, Md., Jan. 28, 2021 (GLOBE NEWSWIRE) — Novavax, Inc. (Nasdaq: NVAX), a biotechnology company developing next-generation vaccines for serious infectious diseases, today announced that NVX-CoV2373, its protein-based COVID-19 vaccine candidate, met the primary endpoint, with a vaccine efficacy of 89.3%, in its Phase 3 clinical trial conducted in the United Kingdom (UK). The study assessed efficacy during a period with high transmission and with a new UK variant strain of the virus emerging and circulating widely. It was conducted in partnership with the UK Government’s Vaccines Taskforce. Novavax also announced successful results of its Phase 2b study conducted in South Africa.

“With today’s results from our UK Phase 3 and South Africa Phase 2b clinical trials, we have now reported data on our COVID-19 vaccine from Phase 1, 2 and 3 trials involving over 20,000 participants. In addition, our PREVENT-19 US and Mexico clinical trial has randomized over 16,000 participants toward our enrollment goal of 30,000. NVX-CoV2373 is the first vaccine to demonstrate not only high clinical efficacy against COVID-19 but also significant clinical efficacy against both the rapidly emerging UK and South Africa variants,” said Stanley C. Erck, President and Chief Executive Officer, Novavax. “NVX-CoV2373 has the potential to play an important role in solving this global public health crisis. We look forward to continuing to work with our partners, collaborators, investigators and regulators around the world to make the vaccine available as quickly as possible.”

NVX-CoV2373 contains a full-length, prefusion spike protein made using Novavax’ recombinant nanoparticle technology and the company’s proprietary saponin-based Matrix-M™ adjuvant. The purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike (S) protein and is produced in insect cells. It can neither cause COVID-19 nor can it replicate, is stable at 2°C to 8°C (refrigerated) and is shipped in a ready-to-use liquid formulation that permits distribution using existing vaccine supply chain channels.

UK Phase 3 Results: 89.3% Efficacy

The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65. The primary endpoint of the UK Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline.

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].

The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.

“These are spectacular results, and we are very pleased to have helped Novavax with the development of this vaccine. The efficacy shown against the emerging variants is also extremely encouraging. This is an incredible achievement that will ensure we can protect individuals in the UK and the rest of the world from this virus,” said Clive Dix, Chair, UK Vaccine Taskforce.

Novavax expects to share further details of the UK trial results as additional data become available. Additional analysis on both trials is ongoing and will be shared via prepublication servers as well as submitted to a peer-reviewed journal for publication. The company initiated a rolling submission to the United Kingdom’s regulatory agency, the MHRA, in mid-January.

South Africa Results:   Approximately 90% of COVID-19 cases attributed to South Africa escape variant

In the South Africa Phase 2b clinical trial, 60% efficacy (95% CI: 19.9 – 80.1) for the prevention of mild, moderate and severe COVID-19 disease was observed in the 94% of the study population that was HIV-negative. Twenty-nine cases were observed in the placebo group and 15 in the vaccine group. One severe case occurred in the placebo group and all other cases were mild or moderate. The clinical trial also achieved its primary efficacy endpoint in the overall trial population, including HIV-positive and HIV-negative subjects (efficacy of 49.4%; 95% CI: 6.1 – 72.8).

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa. Preliminary sequencing data is available for 27 of 44 COVID-19 events; of these, 92.6% (25 out of 27 cases) were the South Africa escape variant.

Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (i.e., non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.

“The 60% reduced risk against COVID-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the first COVID-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” says Professor Shabir Maddi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits, and principal investigator in the Novavax COVID-19 vaccine trial in South Africa. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically targeted to the variant, which together with the current vaccine is likely to form the cornerstone of the fight against COVID-19.”

Novavax initiated development of new constructs against the emerging strains in early January and expects to select ideal candidates for a booster and/or combination bivalent vaccine for the new strains in the coming days. The company plans to initiate clinical testing of these new vaccines in the second quarter of this year.

“A primary benefit of our adjuvanted platform is that it uses a very small amount of antigen, enabling the rapid creation and large-scale production of combination vaccine candidates that could potentially address multiple circulating strains of COVID-19,” said Gregory M. Glenn, M.D., President of Research and Development, Novavax. “Combined with the safety profile that has been observed in our studies to-date with our COVID-19 vaccine, as well as prior studies in influenza, we are optimistic about our ability to rapidly adapt to evolving conditions.”

The Coalition for Epidemic Preparedness Innovations (CEPI) funded the manufacturing of doses of NVX-CoV2373 for this Phase 2b clinical trial, which was supported in part by a $15 million grant from the Bill & Melinda Gates Foundation.

Significant progress on PREVENT-19 Clinical Trial in US and Mexico

To date, PREVENT-19 has randomized over 16,000 participants and expects to complete our targeted enrollment of 30,000 patients in the first half of February.  PREVENT-19 is being conducted with support from the U.S. government partnership formerly known as Operation Warp Speed, which includes the Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) at HHS. BARDA is also providing up to $1.75 billion under a Department of Defense agreement.

PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial | COVID-19) is a Phase 3, randomized, placebo-controlled, observer-blinded study in the US and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 30,000 subjects 18 years of age and older compared with placebo. The trial design has been harmonized to align with other Phase 3 trials conducted under the auspices of Operation Warp Speed, including the use of a single external independent Data and Safety Monitoring Board to evaluate safety and conduct an unblinded review when predetermined interim analysis events are reached.

The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Conference Call

Novavax will host a conference call today at 4:30pm ET. The dial-in numbers for the conference call are (877) 212-6076 (Domestic) or (707) 287-9331 (International), passcode 7470222. A replay of the conference call will be available starting at 7:30 p.m. ET on January 28, 2021 until 7:30 p.m. ET on February 4, 2021. To access the replay by telephone, dial (855) 859-2056 (Domestic) or (404) 537-3406 (International) and use passcode 7470222.

A webcast of the conference call can also be accessed on the Novavax website at novavax.com/events. A replay of the webcast will be available on the Novavax website until April 28, 2021.

About NVX-CoV2373

NVX-CoV2373 is a protein-based vaccine candidate engineered from the genetic sequence of SARS-CoV-2, the virus that causes COVID-19 disease. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and is adjuvanted with Novavax’ patented saponin-based Matrix-M™ to enhance the immune response and stimulate high levels of neutralizing antibodies. NVX-CoV2373 contains purified protein antigen and can neither replicate, nor can it cause COVID-19. Over 37,000 participants have participated to date across four different clinical studies in five countries. NVX-CoV2373 is currently being evaluated in two pivotal Phase 3 trials: a trial in the U.K that completed enrollment in November and the PREVENT-19 trial in the U.S. and Mexico that began in December.

About Matrix-M™

Novavax’ patented saponin-based Matrix-M™ adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune response.

About Novavax

Novavax, Inc. (Nasdaq: NVAX) is a biotechnology company that promotes improved health globally through the discovery, development and commercialization of innovative vaccines to prevent serious infectious diseases. The company’s proprietary recombinant technology platform combines the power and speed of genetic engineering to efficiently produce highly immunogenic nanoparticles designed to address urgent global health needs. Novavax is conducting late-stage clinical trials for NVX-CoV2373, its vaccine candidate against SARS-CoV-2, the virus that causes COVID-19. NanoFlu™, its quadrivalent influenza nanoparticle vaccine, met all primary objectives in its pivotal Phase 3 clinical trial in older adults and will be advanced for regulatory submission. Both vaccine candidates incorporate Novavax’ proprietary saponin-based Matrix-M™ adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.

For more information, visit www.novavax.com and connect with us on Twitter and LinkedIn.

Candidate: NVX-CoV2373

Category: VAX

Type: Stable, prefusion protein made using Novavax’ proprietary nanoparticle technology, and incorporating its proprietary saponin-based Matrix-M™ adjuvant.

2021 Status: Novavax on March 11 announced final efficacy of 96.4% against mild, moderate and severe disease caused by the original COVID-19 strain in a pivotal Phase III trial in the U.K. of NVX–CoV2373. The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65.

The company also announced the complete analysis of its Phase IIb trial in South Africa, showing the vaccine had an efficacy of 55.4% among a cohort of HIV-negative trial participants, and an overall efficacy of 48.6% against predominantly variant strains of SARS-CoV-2 among 147 PCR-positive cases (51 cases in the vaccine group and 96 in the placebo group). Across both trials, NVX-CoV2373 demonstrated 100% protection against severe disease, including all hospitalization and death.

Philippines officials said March 10 that they secured 30 million doses of NVX-CoV2373 through an agreement with the Serum Institute of India, the second vaccine deal signed by the national government, according to Agence France-Presse. The first was with AstraZeneca for 2.6 million doses of its vaccine, developed with Oxford University.

The Novavax vaccine will be available from the third quarter, at a price that has yet to be finalized. The government hopes to secure 148 million doses this year from seven companies—enough for around 70% of its population.

In announcing fourth quarter and full-year 2020 results on March 1, Novavax said it could file for an emergency use authorization with the FDA in the second quarter of 2021. Novavax hopes it can use data from its Phase III U.K. clinical trial in its FDA submission, and expects the FDA to examine data in May, a month after they are reviewed by regulators in the U.K., President and CEO Stanley C. Erck said on CNBC. Should the FDA insist on waiting for U.S. data, the agency may push the review timeline by one or two months, he added.

The company also said that NVX-CoV2373 showed 95.6% efficacy against the original strain of COVID-19 and 85.6% against the UK variant strain, and re-stated an earlier finding that its vaccine met the Phase III trial’s primary endpoint met with an efficacy rate of 89.3%.

Novavax said February 26 that it signed an exclusive license agreement with Takeda Pharmaceutical for Takeda to develop, manufacture, and commercialize NVX-CoV2373 in Japan.

Novavax agreed to transfer the technology for manufacturing of the vaccine antigen and will supply its Matrix-M™ adjuvant to Takeda. Takeda anticipated the capacity to manufacture over 250 million doses of the COVID-19 vaccine per year. Takeda agreed in return to pay Novavax undisclosed payments tied to achieving development and commercial milestones, plus a portion of proceeds from the vaccine.

Takeda also disclosed that it dosed the first participants in a Phase II clinical trial to test the immunogenicity and safety of Novavax’ vaccine candidate in Japanese participants.

Novavax on February 18 announced a memorandum of understanding with Gavi, the Vaccine Alliance (Gavi), to provide 1.1 billion cumulative doses of NVX-CoV2373 for the COVAX Facility. Gavi leads the design and implementation of the COVAX Facility, created to supply vaccines globally, and has committed to working with Novavax to finalize an advance purchase agreement for vaccine supply and global distribution allocation via the COVAX Facility and its partners.

The doses will be manufactured and distributed globally by Novavax and Serum Institute of India (SII), the latter under an existing agreement between Gavi and SII.

Novavax and SK Bioscience said February 15 that they expanded their collaboration and license agreement, with SK finalizing an agreement to supply 40 million doses of NVX-CoV2373 to the government of South Korea beginning in 2021, for an undisclosed price. SK also obtained a license to manufacture and commercialize NVX-CoV2373 for sale to South Korea, as a result of which SK said it will add significant production capacity.

The agreement also calls on Novavax to facilitate technology transfer related to the manufacturing of its protein antigen, its Matrix M adjuvant, and support to SK Bioscience as needed to secure regulatory approval.

Rolling review begins—On February 4, Novavax announced it had begun a rolling review process for authorization of NVX-CoV2373 with several regulatory agencies worldwide, including the FDA, the European Medicines Agency, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), and Health Canada. The reviews will continue while the company completes its pivotal Phase III trials in the U.S. and U.K., and through initial authorization for emergency use granted under country-specific regulations, and through initial authorization for emergency use.

A day earlier, Novavax executed a binding Heads of Terms agreement with the government of Switzerland to supply 6 million doses of NVX-CoV2373, to the country. Novavax and Switzerland plan to negotiate a final agreement, with initial delivery of vaccine doses slated to ship following successful clinical development and regulatory review.

On January 28, Novavax electrified investors by announcing that its COVID-19 vaccine NVX-CoV2373 showed efficacy of 89.3% in the company’s first analysis of data from a Phase III trial in the U.K., where a variant strain (B.1.1.7) accounted for about half of all positive cases.

However, NVX-CoV2373 achieved only 60% efficacy in a Phase IIb trial in South Africa, where that country’s escape variant of the virus (B.1.351, also known as 20H/501Y.V2) was seen in 90% of cases, Novavax said.

Novavax said January 7 it executed an Advance Purchase Agreement with the Commonwealth of Australia for 51 million doses of NVX-CoV2373 for an undisclosed price, with an option to purchase an additional 10 million doses—finalizing an agreement in principle announced in November 2020. Novavax said it will work with Australia’s Therapeutics Goods Administration (TGA), to obtain approvals upon showing efficacy in clinical studies. The company aims to deliver initial doses by mid-2021.

2020 Status: Phase III trial launched—Novavax said December 28 that it launched the pivotal Phase III PREVENT-19 trial (NCT04611802) in the U.S. and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373. The randomized, placebo-controlled, observer-blinded study will assess the efficacy, safety and immunogenicity of NVX-CoV2373 in up to 30,000 participants 18 years of age and older compared with placebo. The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Two thirds of the participants will be assigned to randomly receive two intramuscular injections of the vaccine, administered 21 days apart, while one third of the trial participants will receive placebo. Trial sites were selected in locations where transmission rates are currently high, to accelerate the accumulation of positive cases that could show efficacy. Participants will be followed for 24 months following the second injection

PREVENT-19 is being conducted with support from federal agencies involved in Operation Warp Speed, the Trump administration’s effort to promote development and distribution of COVID-19 vaccines and drugs. Those agencies include the Department of Defense (DoD), the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA)—which has committed up to $1.6 billion to Novavax under a DoD agreement (identifier MCDC OTA agreement number W15QKN-16-9-1002).

Novavax is also conducting a pivotal Phase III study in the United Kingdom, a Phase IIb safety and efficacy study in South Africa, and an ongoing Phase I/II trial in the U.S. and Australia. Data from these trials are expected as soon as early first quarter 2021, though timing will depend on transmission rates in the regions, the company said.

Novavax said November 9 that the FDA granted its Fast Track designation for NVX-CoV2373. By the end of November, the company expected to finish enrollment in its Phase III U.K. trial, with interim data in that study expected as soon as early first quarter 2021.

Five days earlier, Novavax signed a non-binding Heads of Terms document with the Australian government to supply 40 million doses of NVX-CoV2373 to Australia starting as early as the first half of 2021, subject to the successful completion of Phase III clinical development and approval of the vaccine by Australia’s Therapeutic Goods Administration (TGA). The vaccine regimen is expected to require two doses per individual, administered 21 days apart.

Australia joins the U.S., the U.K., and Canada in signing direct supply agreements with Novavax. The company is supplying doses in Japan, South Korea, and India through partnerships. Australian clinical researchers led the global Phase I clinical trial in August, which involved 131 Australians across two trial sites (Melbourne and Brisbane). Also, approximately 690 Australians have participated in the Phase II arm of the clinical trial, which has been conducted across up to 40 sites in Australia and the U.S.

Novavax joined officials in its headquarters city of Gaithersburg, MD, on November 2 to announce expansion plans. The company plans to take 122,000 square feet of space at 700 Quince Orchard Road, and has committed to adding at least 400 local jobs, nearly doubling its current workforce of 450 worldwide. Most of the new jobs are expected to be added b March 2021.

Maryland’s Department of Commerce—which has prioritized assistance to life sciences companies—approved a $2 million conditional loan tied to job creation and capital investment. The state has also approved a $200,000 Partnership for Workforce Quality training grant, and the company is eligible for several tax credits, including the Job Creation Tax Credit and More Jobs for Marylanders.

Additionally, Montgomery County has approved a $500,000 grant tied to job creation and capital investment, while the City of Gaithersburg said it will approve a grant of up to $50,000 from its Economic Development Opportunity Fund. The city accelerated its planning approval process to accommodate Novavax’ timeline, given the company’s role in fighting COVID-19 and resulting assistance from Operation Warp Speed, the Trump administration’s effort to accelerate development of COVID-19 vaccines.

On October 27, Novavax said that it had enrolled 5,500 volunteers in the Phase III U.K. trial, which has been expanded from 10,000 to 15,000 volunteers. The increased enrollment “is likely to facilitate assessment of safety and efficacy in a shorter time period,” according to the company.

The trial, which is being conducted with the U.K. Government’s Vaccines Taskforce, was launched in September and is expected to be fully enrolled by the end of November, with interim data expected by early first quarter 2021, depending on the overall COVID-19 attack rate. Novavax has posted the protocol for the Phase III U.K. trial online. The protocol calls for unblinding of data once 152 participants have achieved mild, moderate or severe endpoints. Two interim analyses are planned upon occurrence of 66 and 110 endpoints.

Novavax also said it expects to launch a second Phase III trial designed to enroll up to 30,000 participants in the U.S. and Mexico by the end of November—a study funded through the U.S. government’s Operation Warp Speed program. The patient population will reflect proportional representation of diverse populations most vulnerable to COVID-19, across race/ethnicity, age, and co-morbidities.

The company cited progress toward large-scale manufacturing while acknowledging delays from original timeframe estimates. Novavax said it will use its contract manufacturing site at FUJIFILM Diosynth Biotechnologies’ Morrisville, NC facility to produce material for the U.S. trial.

On September 25, Novavax entered into a non-exclusive agreement with Endo International subsidiary Par Sterile Products to provide fill-finish manufacturing services at its plant in Rochester, MI, for NVX-CoV2373. Under the agreement, whose value was not disclosed, the Rochester facility has begun production of NVX-CoV2373 final drug product, with initial batches to be used in Novavax’ Phase III clinical trial in the U.S. Par Sterile will also fill-finish NVX-CoV2373 vaccine intended for commercial distribution in the U.S.

A day earlier, Novavax launched the U.K. trial. The randomized, placebo-controlled, observer-blinded study to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 10,000 subjects 18-84 years of age, with and without “relevant” comorbidities, over the following four to six weeks, Novavax said. Half the participants will receive two intramuscular injections of vaccine comprising 5 µg of protein antigen with 50 µg Matrix‑M adjuvant, 21 days apart, while half of the trial participants will receive placebo. At least 25% of the study population will be over age 65.

The trial’s first primary endpoint is first occurrence of PCR-confirmed symptomatic COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2. The second primary endpoint is first occurrence of PCR-confirmed symptomatic moderate or severe COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2

“The data from this trial is expected to support regulatory submissions for licensure in the UK, EU and other countries,” stated Gregory M. Glenn, M.D., President, Research and Development at Novavax.

Maryland Gov. Larry Hogan joined state Secretary of Commerce Kelly M. Schulz and local officials in marking the launch of Phase III studies with a tour of the company’s facilities in Gaithersburg: “The coronavirus vaccine candidate that’s been developed by Novavax is one of the most promising in the country, if not the world.”

On August 31, Novavax reached an agreement in principle with the government of Canada to supply up to 76 million doses of NVX-CoV2373. The value was not disclosed. Novavax and Canada did say that they expect to finalize an advance purchase agreement under which Novavax will agree to supply doses of NVX-CoV2373 to Canada beginning as early as the second quarter of 2021.

The purchase arrangement will be subject to licensure of the NVX-CoV2373 by Health Canada, Novavax said. The vaccine is in multiple Phase II clinical trials: On August 24, Novavax said the first volunteers had been enrolled in the Phase II portion of its ongoing Phase I/II clinical trial (NCT04368988), designed to evaluate the immunogenicity and safety of two doses of of NVX-CoV2373 (5 and 25 µg) with and without 50 µg of Matrix‑M™ adjuvant in up to 1,500 volunteers ages 18-84.

The randomized, placebo-controlled, observer-blinded study is designed to assess two dose sizes (5 and 25 µg) of NVX-CoV2373, each with 50 µg of Matrix‑M. Unlike the Phase I portion, the Phase II portion will include older adults 60-84 years of age as approximately half of the trial’s population. Secondary objectives include preliminary evaluation of efficacy. The trial will be conducted at up to 40 sites in the U.S. and Australia, Novovax said.

NVX-CoV2373 is in a pair of Phase II trials launched in August—including a Phase IIb study in South Africa to assess efficacy, and a Phase II safety and immunogenicity study in the U.S. and Australia.

On August 14, the U.K. government agreed to purchase 60 million doses of NVX-CoV2373 from the company, and support its planned Phase III clinical trial in the U.K., through an agreement whose value was not disclosed. The doses are set to be manufactured as early as the first quarter of 2021.

The trial will be designed to evaluate the ability of NVX-CoV2373 to protect against symptomatic COVID-19 disease as well as evaluate antibody and T-cell responses. The randomized, double-blind, placebo-controlled efficacy study will enroll approximately 9,000 adults 18-85 years of age in the U.K., and is expected to start in the third quarter.

Novavax also said it will expand its collaboration with FUJIFILM Diosynth Biotechnologies (FDB), which will manufacture the antigen component of NVX-CoV2373 from its Billingham, Stockton-on-Tees site in the U.K., as well as at U.S. sites in Morrisville, NC, and College Station, TX. FDB’s U.K. sitevis expected to produce up to 180 million doses annually.

On August 13, Novavax said it signed a development and supply agreement for the antigen component of NVX-CoV2373 with Seoul-based SK bioscience, a vaccine business subsidiary of SK Group. The agreement calls for supply to global markets that include the COVAX Facility, co-led by Gavi, the Coalition for Epidemic Preparedness Innovations (CEPI) and the World Health Organization.

Novavax and SK signed a letter of intent with South Korea’s Ministry of Health and Welfare to work toward broad and equitable access to NVX-CoV2373 worldwide, as well as to make the vaccine available in South Korea. SK bioscience agreed to manufacture the vaccine antigen component for use in the final drug product globally during the pandemic, at its vaccine facility in Andong L-house, South Korea, beginning in August. The value of the agreement was not disclosed.

On August 7, Novavax licensed its COVID-19 vaccine technology to Takeda Pharmaceutical through a partnership by which Takeda will develop, manufacture, and commercialize NVX‑CoV2373 in Japan, using Matrix-M adjuvant to be supplied by Novavax. Takeda will also be responsible for regulatory submission to Japan’s Ministry of Health, Labour and Welfare (MHLW).

MHLW agreed to provide funding to Takeda—the amount was not disclosed in the companies’ announcement—for technology transfer, establishment of infrastructure, and scale-up of manufacturing. Takeda said it anticipated the capacity to manufacture over 250 million doses of NVX‑CoV2373 per year.

Five days earlier, Serum Institute of India agreed to license rights from Novavax to NVX‑CoV2373 for development and commercialization in India as well as low- and middle-income countries (LMIC), through an agreement whose value was not disclosed. Novavax retains rights to NVX-CoV2373 elsewhere in the world.

Novavax and Serum Institute of India agreed to partner on clinical development, co-formulation, filling and finishing and commercialization of NVX-CoV2373. Serum Institute will oversee regulatory submissions and marketing authorizations in regions covered by the collaboration. Novavax agreed to provide both vaccine antigen and Matrix‑M adjuvant, while the partners said they were in talks to have the Serum Institute manufacture vaccine antigen in India. Novavax and Seerum Institute plan to split the revenue from the sale of product, net of agreed costs.

A day earlier, Novavax announced positive results from the Phase I portion of its Phase I/II clinical trial (NCT04368988), designed to evaluate two doses of NVX-CoV2373 (5 and 25 µg) with and without Matrix‑M™ adjuvant in 131 healthy adults ages 18-59. NVX-CoV2373, adjuvanted with Matrix-M, elicited robust antibody responses numerically superior to human convalescent sera, according to data submitted for peer-review to a scientific journal.

All participants developed anti-spike IgG antibodies after a single dose of vaccine, Novavax said, many also developing wild-type virus neutralizing antibody responses. After the second dose, all participants developed wild-type virus neutralizing antibody responses. Both anti-spike IgG and viral neutralization responses compared favorably to responses from patients with clinically significant COVID‑19 disease, the company said—adding that IgG antibody response was highly correlated with neutralization titers, showing that a significant proportion of antibodies were functional.

For both dosages of NVX‑CoV2373 with adjuvant, the 5 µg dose performed “comparably” with the 25 µg dose, Novavax said. NVX‑CoV2373 also induced antigen-specific polyfunctional CD4+ T cell responses with a strong bias toward the Th1 phenotype (IFN-g, IL-2, and TNF-a).

Based on an interim analysis of Phase I safety and immunogenicity data, the trial was expanded to Phase II clinical trials in multiple countries, including the U.S. The trial—which began in Australia in May—is being funded by up-to $388 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI). If the Phase I/II trial is successful, CEPI said, it anticipates supporting further clinical development that would advance NVX-CoV2373 through to licensure.

On July 23, Novavax joined FDB to announce that FDB will manufacture bulk drug substance for NVX-CoV2373, under an agreement whose value was not disclosed. FDB’s site in Morrisville, NC has begun production of the first batch of NVX-CoV2373. Batches produced at FDB’s Morrisville site will be used in Novavax’s planned pivotal Phase III clinical trial, designed to assess NVX-CoV2373 in up to 30,000 participants, and set to start this fall.

The Phase III trial is among R&D efforts to be funded through the $1.6 billion awarded in July to Novavax through President Donald Trump’s “Operation Warp Speed” program toward late-stage clinical trials and large-scale manufacturing to produce 100 million doses of its COVID-19 vaccine by year’s end. Novavax said the funding will enable it to complete late-stage clinical studies aimed at evaluating the safety and efficacy of NVX-CoV2373.

In June, Novavax said biotech investor and executive David Mott was joining its board as an independent director, after recently acquiring nearly 65,000 shares of the company’s common stock. Also, Novavax was awarded a $60 million contract by the U.S. Department of Defense (DoD) for the manufacturing of NVX‑CoV2373. Through the Defense Health Program, the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense Enabling Biotechnologies (JPEO-CBRND-EB) agreed to support production of several vaccine components to be manufactured in the U.S.  Novavax plans to deliver this year for DoD 10 million doses of NVX‑CoV2373 that could be used in Phase II/III trials, or under an Emergency Use Authorization (EUA) if approved by the FDA.

Also in June, AGC Biologics said it will partner with Novavax on large-scale GMP production of Matrix-M– significantly increasing Novavax’ capacity to deliver doses in 2020 and 2021—through an agreement whose value was not disclosed. And Novavax joined The PolyPeptide Group to announce large-scale GMP production by the global CDMO of two unspecified key intermediate components used in the production of Matrix-M.

In May, Novavax acquired Praha Vaccines from the India-based Cyrus Poonawalla Group for $167 million cash, in a deal designed to ramp up Novavax’s manufacturing capacity for NVX-CoV2373. Praha Vaccines’ assets include a 150,000-square foot vaccine and biologics manufacturing facility and other support buildings in Bohumil, Czech Republic. Novavax said the Bohumil facility is expected to deliver an annual capacity of over 1 billion doses of antigen starting in 2021 for the COVID-19 vaccine.

The Bohumil facility is completing renovations that include the addition of Biosafety Level-3 (BSL-3) capabilities. The site’s approximately 150 employees with “significant experience” in vaccine manufacturing and support have joined Novavax, the company said.

On May 11, Novavax joined CEPI in announcing up to $384 million in additional funding for the company toward clinical development and large-scale manufacturing of NVX-CoV2373. CEPI agreed to fund preclinical as well as Phase I and Phase II studies of NVX-CoV2373. The funding multiplied CEPI’s initial $4 million investment in the vaccine candidate, made two months earlier. Novavax’s total $388 million in CEPI funding accounted for 87% of the total $446 million awarded by the Coalition toward COVID-19 vaccine R&D as of that date.

Novavax identified its COVID-19 vaccine candidate in April. The company said NVX-CoV2373 was shown to be highly immunogenic in animal models measuring spike protein-specific antibodies, antibodies that block the binding of the spike protein to the receptor, and wild-type virus neutralizing antibodies. High levels of spike protein-specific antibodies with ACE-2 human receptor binding domain blocking activity and SARS-CoV-2 wild-type virus neutralizing antibodies were also seen after a single immunization.

In March, Emergent Biosolutions disclosed it retained an option to allocate manufacturing capacity for an expanded COVID-19 program under an agreement with Novavax to provide “molecule-to-market” contract development and manufacturing (CDMO) services to produce Novavax’s NanoFlu™, its recombinant quadrivalent seasonal influenza vaccine candidate.

Earlier in March, Emergent announced similar services to support clinical development of Novavax’s COVID-19 vaccine candidate, saying March 10 it agreed to produce the vaccine candidate and had initiated work, anticipating the vaccine candidate will be used in a Phase I study within the next four months. In February, Novavax said it had produced and was assessing multiple nanoparticle vaccine candidates in animal models prior to identifying an optimal candidate for human testing.

References

  1. ^ “Company Overview of Novavax, Inc”. Bloomberg.com. Archived from the original on 24 February 2017. Retrieved 2 June2019.
  2. ^ https://www.globenewswire.com/news-release/2021/03/01/2184674/0/en/Novavax-Reports-Fourth-Quarter-and-Full-Year-2020-Financial-Results-and-Operational-Highlights.html
  3. ^ Jump up to:a b c d e Bell, Jacob (November 14, 2016). “Novavax aims to rebound with restructuring, more trials”. BioPharma Dive. Washington, D.C.: Industry Dive. Archived from the original on 2017-03-29. Retrieved 2017-03-28.
  4. ^ Thomas, Katie; Twohey, Megan (2020-07-16). “How a Struggling Company Won $1.6 Billion to Make a Coronavirus Vaccine”. The New York Times. ISSN 0362-4331. Retrieved 2021-01-29.
  5. ^ Taylor, Nick Paul (3 June 2013). “Novavax makes $30M bid for adjuvant business”. FiercePharma. Archived from the original on 14 September 2016. Retrieved 9 September 2016.
  6. ^ “Gaithersburg Biotech Receives Grant Worth up to $89 million”. Bizjournals.com. Archived from the original on 2017-04-01. Retrieved 2017-03-28.
  7. ^ “With promising RSV data in hand, Novavax wins $89M Gates grant for PhIII | FierceBiotech”. Fiercebiotech.com. Archivedfrom the original on 2017-04-14. Retrieved 2017-03-28.
  8. ^ “Novavax RSV vaccine found safe for pregnant women, fetus”. Reuters. 2016-09-29. Archived from the original on 2016-10-07. Retrieved 2017-03-28.
  9. ^ Herper, Matthew. “Gates Foundation Backs New Shot To Prevent Babies From Dying Of Pneumonia”. Forbes. Archived from the original on 2016-09-21. Retrieved 2017-03-28.
  10. ^ “Novavax’s Ebola vaccine shows promise in early-stage trial”. Reuters. 2017-07-21. Archived from the original on 2016-10-02. Retrieved 2017-03-28.
  11. ^ Jump up to:a b c d e f Adams, Ben (September 16, 2016). “Novavax craters after Phase III RSV F vaccine failure; seeks path forward”. FierceBiotech. Questex. Archived from the original on 18 August 2020. Retrieved 25 Jan 2020.
  12. ^ Shtrubel, Marty (December 12, 2019). “3 Biotech Stocks That Offer the Highest Upside on Wall Street”. Biotech. Nasdaq. Archived from the original on 2020-01-26. Retrieved 25 Jan 2020.
  13. ^ Jump up to:a b Budwell, George (January 20, 2020). “3 Top Biotech Picks for 2020”. Markets. Nasdaq. Novavax: A catalyst awaits. Archivedfrom the original on 2020-01-25. Retrieved 25 Jan 2020.
  14. ^ Mark Terry (February 16, 2018). “Why Novavax Could be a Millionaire-Maker Stock”. BioSpace. Archived from the original on 22 November 2020. Retrieved 6 March 2020.
  15. ^ Jump up to:a b Eric Sagonowsky (2020-05-11). “Novavax scores $384M deal, CEPI’s largest ever, to fund coronavirus vaccine work”. FiercePharma. Archived from the original on 2020-05-16. Retrieved 2020-05-12.
  16. ^ “Novavax addresses urgent global public health needs with innovative technology”. novavax.com. Archived from the original on 10 September 2020. Retrieved 30 August 2020.
  17. ^ Sara Gilgore (January 15, 2020). “Novavax earns key FDA status for its flu vaccine. Wall Street took it well”. Washington Business Journal. Archived from the original on 10 November 2020. Retrieved 6 March 2020.
  18. ^ Sara Gilgore (February 26, 2020). “Novavax is working to advance a potential coronavirus vaccine. So are competitors”. Washington Business Journal. Archived from the original on March 16, 2020. Retrieved March 6, 2020.
  19. ^ Nidhi Parekh (July 24, 2020). “Novavax: A SARS-CoV-2 Protein Factory to Beat COVID-19”. Archived from the original on November 22, 2020. Retrieved July 24, 2020.
  20. ^ “Covid-19: Novavax vaccine shows 89% efficacy in UK trials”. BBC news. Retrieved 1 February 2021.

Further reading

External links

General References

  1. Novavax Pipeline Page [Link]
  2. Novavex News Release [Link]
TypePublic
Traded asNasdaq: NVAX
Russell 2000 Component
IndustryBiotechnology
Founded1987; 34 years ago [1]
HeadquartersGaithersburg, Maryland,United States
Area servedWorldwide
Key peopleStanley Erck (CEO)
ProductsVaccines
RevenueIncrease $475.2 Million (2020)[2]
Number of employees500+[3]
Websitewww.novavax.com 

The Novavax COVID-19 vaccine, codenamed NVX-CoV2373, and also called SARS-CoV-2 rS (recombinant spike) protein nanoparticle with Matrix-M1 adjuvant, is a COVID-19 vaccine candidate developed by Novavax and Coalition for Epidemic Preparedness Innovations (CEPI). It requires two doses[1] and is stable at 2 to 8 °C (36 to 46 °F) (refrigerated).[2]

Description

NVX-CoV2373 has been described as both a protein subunit vaccine[3][4][5] and a virus-like particle vaccine,[6][7] though the producers call it a “recombinant nanoparticle vaccine”.[8]

The vaccine is produced by creating an engineered baculovirus containing a gene for a modified SARS-CoV-2 spike protein. The baculovirus then infects a culture of Sf9 moth cells, which create the spike protein and display it on their cell membranes. The spike proteins are then harvested and assembled onto a synthetic lipid nanoparticle about 50 nanometers across, each displaying up to 14 spike proteins.[3][4][8]

The formulation includes a saponin-based adjuvant.[3][4][8]

Development

In January 2020, Novavax announced development of a vaccine candidate, codenamed NVX-CoV2373, to establish immunity to SARS-CoV-2.[9] Novavax’s work is in competition for vaccine development among dozens of other companies.[10]

In March 2020, Novavax announced a collaboration with Emergent BioSolutions for preclinical and early-stage human research on the vaccine candidate.[11] Under the partnership, Emergent BioSolutions will manufacture the vaccine at large scale at their Baltimore facility.[12] Trials have also taken place in the United Kingdom, and subject to regulatory approval, at least 60 million doses will be manufactured by Fujifilm Diosynth Biotechnologies in Billingham for purchase by the UK government.[13][14] They also signed an agreement with Serum Institute of India for mass scale production for developing and low-income countries.[15] It has also been reported, that the vaccine will be manufactured in Spain.[16] The first human safety studies of the candidate, codenamed NVX-CoV2373, started in May 2020 in Australia.[17][18]

In July, the company announced it might receive $1.6 billion from Operation Warp Speed to expedite development of its coronavirus vaccine candidate by 2021—if clinical trials show the vaccine to be effective.[19][20] A spokesperson for Novavax stated that the $1.6 billion was coming from a “collaboration” between the Department of Health and Human Services and Department of Defense,[19][20] where Gen. Gustave F. Perna has been selected as COO for Warp Speed. In late September, Novavax entered the final stages of testing its coronavirus vaccine in the UK. Another large trial was announced to start by October in the US.[21]

In December 2020, Novavax started the PREVENT-19 (NCT04611802) Phase III trial in the US and Mexico.[22][full citation needed][23]

On 28 January 2021, Novavax reported that preliminary results from the United Kingdom trial showed that its vaccine candidate was more than 89% effective.[24][2] However, interim results from a trial in South Africa showed a lower effectiveness rate against the 501.V2 variant of the virus, at around 50-60%.[1][25]

On 12 March 2021, they announced their vaccine candidate was 96.4% effective in preventing the original strain of COVID-19 and 86% effective against the U.K variant. It proved 55% effective against the South African variant in people without HIV/AIDS. It was also 100% effective at preventing severe illness.[citation needed]

Deployment

On 2 February 2021, the Canadian Prime Minister Justin Trudeau announced that Canada has signed a tentative agreement for Novavax to produce millions of doses of its COVID-19 vaccine in Montreal, Canada, once it’s approved for use by Health Canada, making it the first COVID-19 vaccine to be produced domestically.[26]

References

  1. ^ Jump up to:a b Wadman M, Jon C (28 January 2021). “Novavax vaccine delivers 89% efficacy against COVID-19 in UK—but is less potent in South Africa”. Science. doi:10.1126/science.abg8101.
  2. ^ Jump up to:a b “New Covid vaccine shows 89% efficacy in UK trials”. BBC News. 28 January 2021. Retrieved 28 January 2021.
  3. ^ Jump up to:a b c Wadman M (November 2020). “The long shot”. Science. 370 (6517): 649–653. Bibcode:2020Sci…370..649W. doi:10.1126/science.370.6517.649. PMID 33154120.
  4. ^ Jump up to:a b c Wadman M (28 December 2020). “Novavax launches pivotal U.S. trial of dark horse COVID-19 vaccine after manufacturing delays”. Science. doi:10.1126/science.abg3441.
  5. ^ Parekh N (24 July 2020). “Novavax: A SARS-CoV-2 Protein Factory to Beat COVID-19”. Archived from the original on 22 November 2020. Retrieved 24 July 2020.
  6. ^ Chung YH, Beiss V, Fiering SN, Steinmetz NF (October 2020). “COVID-19 Vaccine Frontrunners and Their Nanotechnology Design”. ACS Nano. 14 (10): 12522–12537. doi:10.1021/acsnano.0c07197. PMC 7553041. PMID 33034449.
  7. ^ Medhi R, Srinoi P, Ngo N, Tran HV, Lee TR (25 September 2020). “Nanoparticle-Based Strategies to Combat COVID-19”. ACS Applied Nano Materials. 3 (9): 8557–8580. doi:10.1021/acsanm.0c01978. PMC 7482545.
  8. ^ Jump up to:a b c “Urgent global health needs addressed by Novavax”. Novavax. Retrieved 30 January 2021.
  9. ^ Gilgore S (26 February 2020). “Novavax is working to advance a potential coronavirus vaccine. So are competitors”. Washington Business Journal. Archived from the original on 16 March 2020. Retrieved 6 March 2020.
  10. ^ “COVID-19 vaccine tracker (click on ‘Vaccines’ tab)”. Milken Institute. 11 May 2020. Archived from the original on 6 June 2020. Retrieved 12 May 2020. Lay summary.
  11. ^ Gilgore S (10 March 2020). “Novavax’s coronavirus vaccine program is getting some help from Emergent BioSolutions”. Washington Business Journal. Archived from the original on 9 April 2020. Retrieved 10 March 2020.
  12. ^ McCartney R. “Maryland plays an outsized role in worldwide hunt for a coronavirus vaccine”. Washington Post. Archived from the original on 7 May 2020. Retrieved 8 May 2020.
  13. ^ Boseley S, Davis N (28 January 2021). “Novavax Covid vaccine shown to be nearly 90% effective in UK trial”. The Guardian. Retrieved 29 January 2021.
  14. ^ Brown M (14 August 2020). “60m doses of new covid-19 vaccine could be made in Billingham – and be ready for mid-2021”. TeesideLive. Reach. Retrieved 29 January 2021.
  15. ^ “Novavax signs COVID-19 vaccine supply deal with India’s Serum Institute”. Reuters. 5 August 2020.
  16. ^ “Spain, again chosen to produce the vaccine to combat COVID-19”. This is the Real Spain. 18 September 2020.
  17. ^ Sagonowsky E (11 May 2020). “Novavax scores $384M deal, CEPI’s largest ever, to fund coronavirus vaccine work”. FiercePharma. Archived from the original on 16 May 2020. Retrieved 12 May 2020.
  18. ^ “Novavax starts clinical trial of its coronavirus vaccine candidate”. CNBC. 25 May 2020. Archived from the original on 26 May 2020. Retrieved 26 May 2020.
  19. ^ Jump up to:a b Thomas K (7 July 2020). “U.S. Will Pay $1.6 Billion to Novavax for Coronavirus Vaccine”. The New York Times. Archived from the original on 7 July 2020. Retrieved 7 July 2020.
  20. ^ Jump up to:a b Steenhuysen J (7 July 2020). “U.S. government awards Novavax $1.6 billion for coronavirus vaccine”. Reuters. Archived from the original on 14 September 2020. Retrieved 15 September 2020.
  21. ^ Thomas K, Zimmer C (24 September 2020). “Novavax Enters Final Stage of Coronavirus Vaccine Trials”. The New York Times. ISSN 0362-4331. Archived from the original on 28 September 2020. Retrieved 28 September 2020.
  22. ^ Clinical trial number NCT04611802 for “A Study Looking at the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults at Risk for SARS-CoV-2” at ClinicalTrials.gov
  23. ^ “Phase 3 trial of Novavax investigational COVID-19 vaccine opens”. National Institutes of Health (NIH). 28 December 2020. Retrieved 28 December 2020.
  24. ^ Lovelace B (28 January 2020). “Novavax says Covid vaccine is more than 89% effective”. CNBC.
  25. ^ Facher L, Joseph A (28 January 2021). “Novavax says its Covid-19 vaccine is 90% effective in late-stage trial”. Stat. Retrieved 29 January 2021.
  26. ^ “Canada signs deal to produce Novavax COVID-19 vaccine at Montreal plant”. CP24. 2 February 2021. Retrieved 2 February2021.
Vaccine description
TargetSARS-CoV-2
Vaccine typeSubunit
Clinical data
Other namesNVX-CoV2373
Routes of
administration		Intramuscular
ATC codeNone
Identifiers
DrugBankDB15810
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COVID-19 pandemic
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showInternational response
showMedical response
showImpact
 COVID-19 Portal
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UPDATE

SARS-CoV-2 Spike glycoprotein vaccine antigen nvx-cov2373

SARS-CoV-2 rS;
Novavax Covid-19 vaccine (TN);
Nuvaxovid (TN)

SARS-CoV-2 rS;
組換えコロナウイルス (SARS-CoV-2) ワクチン;
コロナウイルス(SARS-CoV-2)スパイク糖タンパク質抗原nvx-cov2373ワクチン;
SARS-CoV-2 Spike glycoprotein vaccine antigen nvx-cov2373;
SARS-CoV-2 rS

APPROVED JAPAN Nuvaxovid, 2022/4/19

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BBIBP-CorV, Sinopharm COVID-19 vaccine

March 23, 2021 2:54 am / Leave a comment


Sinopharm COVID-19 vaccine (2021) K (cropped).jpeg

BBIBP-CorV, Sinopharm COVID-19 vaccine

 
CAS Number2503126-65-4
  • Inactivated novel coronavirus (2019-CoV) vaccine (Vero cells)
  • Purified inactivated SARS-CoV-2 Vaccine

ref Lancet Infectious Diseases (2021), 21(1), 39-51.

BBIBP-CorV, also known as the Sinopharm COVID-19 vaccine,[1] is one of two inactivated virus COVID-19 vaccines developed by Sinopharm. In late December 2020, it was in Phase III trials in Argentina, Bahrain, Egypt, Morocco, Pakistan, Peru, and the United Arab Emirates (UAE) with over 60,000 participants.[2]

On December 9, the UAE announced interim results from Phase III trials showing BBIBP-CorV had a 86% efficacy against COVID-19 infection.[3] In late December, Sinopharm announced that its internal analysis indicated a 79% efficacy.[4] While mRNA vaccines like the Pfizer–BioNTech COVID-19 vaccine and mRNA-1273 showed higher efficacy of +90%, those present distribution challenges for some nations as they require deep-freeze facilities and trucks. BIBP-CorV could be transported and stored at normal refrigerated temperatures.[5]

BBIBP-CorV shares similar technology with CoronaVac and BBV152, other inactivated virus vaccines for COVID-19 being developed in Phase III trials.[6][7]

BBIBP-CorV is being used in vaccination campaigns by certain countries in Asia,[8][9][10] Africa,[11][12][13] South America,[14][15] and Europe.[16][17][18] Sinopharm expects to produce one billion doses of BBIBP-CorV in 2021.[19] By February 21, Sinopharm said more than 43 million doses of the vaccine had been administered in total.[20]

BBIBP-CorV vaccine contains a SARS-CoV-2 strain inactivated inside Vero Cells. Investigation shows this vaccine induces neutralizing antibodies in several mammalian species while also showing protective efficacy with SARS-CoV-2 challenge in rhesus macaques2. As of August 2020, this vaccine is being tested for prophylaxis against COVID-19 in human clinical trials.

A vaccination certificate of BBIBP-CorV (Beijing Institute of Biological Products, Sinopharm).

Clinical research

Main article: COVID-19 vaccine

Phases I and II

In April 2020, China approved clinical trials for a candidate COVID-19 vaccine developed by Sinopharm‘s Beijing Institute of Biological Products[21] and the Wuhan Institute of Biological Products.[22] Both vaccines are chemically-inactivated whole virus vaccines for COVID-19.

On October 15, the Beijing Institute of Biological Products published results of its Phase I (192 adults) and Phase II (448 adults) clinical studies for the BBIBP-CorV vaccine, showing BBIBP-CorV to be safe and well-tolerated at all tested doses in two age groups. Antibodies were elicited against SARS-CoV-2 in all vaccine recipients on day 42. These trials included individuals older than 60.[21]

On August 13, the Wuhan Institute of Biological Products published interim results of its Phase I (96 adults) and Phase II (224 adults) clinical studies. The report noted the inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy would require Phase III trials.[22]

BIBP-CorV may have characteristics favorable for vaccinating people in the developing world. While mRNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine showed higher efficacy of +90%, mRNA vaccines present distribution challenges for some nations, as some may require deep-freeze facilities and trucks. By contrast, BIBP-CorV can be transported and stored at normal refrigeration temperatures.[23] While Pfizer and Moderna are among developers relying on novel mRNA technology, manufacturers have decades of experience with the inactivated virus technology Sinopharm is using.[23]

Phase III

Africa and Asia

On July 16, Sinopharm began conducting a Phase III vaccine trial of 31,000 volunteers in the UAE in collaboration with G42 Healthcare, an Abu Dhabi-based company.[24] By August, all volunteers had received their first dose and were to receive the second dose within the next few weeks.[25] On December 9, UAE’s Ministry of Health and Prevention announced the official registration of BBICP-CorV, after an interim analysis of the Phase III trial showed BBIBP-CorV to have a 86% efficacy against COVID-19 infection.[26] The vaccine had a 99% sero-conversion rate of neutralizing antibodies and 100% effectiveness in preventing moderate and severe cases of the disease.[27]

On September 2, Sinopharm began a Phase III trial in Casablanca and Rabat on 600 people.[28][29] In September, Egypt opened registration for a Phase III trial to last one year and enroll 6,000 people.[30]

In August 2020, Sinopharm began a Phase III clinical trial in Bahrain on 6,000 citizens and resident volunteers.[31][32] In a November update, 7,700 people had volunteered in the trials.[33] Also in late August, Sinopharm began a Phase III clinical trial in Jordan on 500 volunteers at Prince Hamzah Hospital.[34][35]

In Pakistan, Sinopharm began working with the University of Karachi on a trial with 3,000 volunteers.[36]

South America

On September 10, Sinopharm began a Phase III trial in Peru with the long-term goal of vaccinating a total of 6,000 people between the ages of 18 and 75.[37] In October, the trials were expanded to include an additional 6,000 volunteers.[38] On January 26, a volunteer in the placebo group of the vaccine trials had died.[39]

On September 16, Argentina began a Phase III trial with 3,000 volunteers.[40]

Manufacturing

Sinopharm’s Chariman Yang Xioyun has said the company could produce one billion doses in 2021.[19]

In October, Dubai’s G42 Healthcare reached manufacturing agreements to provide UAE and other regional states with BBIBP-CorV, with the UAE producing 75 to 100 million doses in 2021.[41]

In December, Egypt announced an agreement between Sinopharm and Egyptian Holding Company for Biological Products & Vaccines (VACSERA) for the vaccine to be manufactured locally,[42] which would also be exported to other African countries.[43]

In December, AP reported Morocco plans to produce BBIBP-CorV locally.[44]

In March, Serbia announced plans to produce 24 million doses of BBIBP-CorV annually starting in October. The production volume would be sufficient to meet the needs of Serbia and all of its neighbors, deputy prime minister Branislav Nedimović noted.[45]

In March, Belarus was looking to produce BBIBP-CorV locally.[18]

Marketing and Distribution

 
show  Full authorizationshow  Emergency authorizationshow  Received donated doses  Eligible COVAX recipient (assessment in progress)[86]

On February 21, 2021 Sinopharm said more than 43 million doses of BBIBP-CorV had been administered so far, including more than 34 million administered in China and the rest internationally.[20]

Asia

In February, Afghanistan was pledged 400,000 doses of BBIBP-CorV by China.[82]

In November 3, 2020 Bahrain granted emergency use authorization of BBIBP-CorV for frontline workers.[33] In December, Bahrain approved Sinopharm’s vaccine, citing data from Phase III clinical trials that showed an 86% efficacy rate.[87]

In February, Brunei received the first batch of Sinopharm vaccines donated by China.[84]

In January, Cambodia said China would provide a million doses.[88] Cambodia granted emergency use authorization on February 4[89] and started the vaccination campaign on February 10 with the first 600,000 doses.[90]

In China, Sinopharm obtained an EUA in July.[91] In October, it began offering the vaccine for free to students going abroad for higher studies.[92] On December 30, China‘s National Medical Products Administration approved BBIBP-CorV for general use.[93][8] In February, Macau received the first 100,000 doses of 400,000 doses.[94]

In October, Indonesia reached an agreement with Sinopharm to deliver 15 million dual-dose vaccines in 2020.[95]

In February, Iran approved emergency use of BBIBP-CorV,[96] and received the first batch of 250,000 doses on February 28.[97]

In January, Iraq approved BBIBP-CorV for emergency use[98] and has signed agreements for 2 million doses. The first doses arrived on March 2.[99]

In January, Jordan approved BBIBP-CorV for emergency use[100] and started its vaccination campaign on January 13.[101]

In March, Kyrgyzstan received a donation of 150,000 doses of the vaccine.[102]

In January, Laos began vaccinating medical workers at hospitals in Vientiane [103] and received another 300,000 doses in early February.[104]

In March, Lebanon received a donation of 50,000 doses at its request,[105] for which it granted emergency use authorization on March 2.[106]

In March, Maldives granted emergency approval for use. At the time of approval, the country had received 18,000 doses and was awaiting 200,000 additional doses.[107]

In February, Mongolia received a donation of 300,000 doses.[108] On March 10, Governor of Ulaanbaatar D. Sumiyabazar and Deputy Prime Minister S. Amarsaikhan received the first doses of BBIBP-CorV.[109]

In February, Nepal approved the vaccine for emergency use, allowing a donation of 500,000 doses to enter the country.[110]

In December, Pakistan‘s purchased 1.2 million doses,[111] which was approved for emergency use on January 18,[112] and began a vaccination campaign on February 2.[10]

In March, Palestine said it would receive 100,000 doses donated by China.[113]

In March 19, Sri Lanka approved the vaccine for emergency use, allowing a donation of 600,000 doses by China to enter the country.[114]

On 14 September 2020, the United Arab Emirates approved the vaccine for front-line workers following successful interim Phase III trials.[24] In December, the country registered BBIBP-CorV after it reviewed the results of the interim analysis.[26] In March, a small number of people who have reduced immunity against diseases, have chronic illnesses, or belong to high-risk groups have been given a 3rd booster shot.[115]

Africa

In February, Algeria received a donation of 200,000 doses.[83]

Egypt plans to buy 40 million doses of Sinpharm’s vaccine[116] which was approved for regulatory use on January 3.[116] President Abdel Fattah el-Sisi announced a vaccination campaign starting 24 January.[11]

In February, Equatorial Guinea received a donation of 100,000 doses which arrived on February 10. The country began vaccinations on February 15.[56]

In March, Gabon received a donation of 100,000 doses which was the second vaccine approved for use in the country.[117]

Morocco placed orders for 41 million vaccine doses from Sinopharm and 25 million from AstraZeneca, for a total of 66 million doses.[118] Morocco granted emergency use approval on January 23,[119] and the first 500,000 doses arrived on January 27.[12]

In February, Mozambique received a donation of 200,000 doses[120] and planned to start vaccinations on March 8.[121]

In March, Namibia received a donation of 100,000 doses and announced the start of vaccinations in the Khomas and Erongo regions.[122]

In March, Niger received a donation of 400,000 doses with vaccinations to begin on March 27.[123]

In February, Senegal received 200,000 doses in Dakar[124] and began vaccinating health workers on February 22.[125]

In February, Sierra Leone received a donation of 200,000 doses.[126] It was approved for emergency use and vaccinations began on March 15.[127]

In January, Seychelles said it would begin administering vaccinations on January 10 with 50,000 doses it had received as a gift from the UAE.[128]

In March, Republic of the Congo received 100,000 doses with vaccinations prioritizing the medically vulnerable and those over 50.[129]

In February, Zimbabwe purchased 600,000 doses on top of 200,000 doses donated by China,[130] and started vaccinations on February 18.[13] Zimbabwe later purchased an additional 1.2 million doses.[131]

North America

In February, the Dominican Republic ordered 768,000 doses of BBIBP-CorV.[132]

In March, Dominica received 20,000 doses of BBIBP-CorV which it began using in its vaccination campaign on March 4.[133]

In March, Mexico announced it would order 12 million doses of BBIBP-CorV pending approval by its health regulator.[134]

South America

In February, Argentina authorized emergency use of BBIBP-CorV[135] ahead of the arrival of 904,000 doses on February 26.[136]

In February, Bolivia purchased 400,000 doses on top of 100,000 doses donated by China,[137] and started its vaccination campaign on February 26.[15]

In March, Guyana received a donation of 20,000 doses of BBIBP-CorV.[138] Vaccinations were to start on March 7.[139]

In January, Peru purchased 38 million doses of BBIBP-CorV.[140] Peru granted emergency approval for BBIBP-CorV on January 27[141] and started vaccinations on February 9 with the first 300,000 doses.[14]

In March, Venezuela granted approval for BBIBP-CorV to be used in the country.[142] The first 500,000 doses arrived on March 2.[143]

Europe

In February, Belarus received a donation of 100,000 doses[144] and began using the vaccine on March 15.[18]

In January, Hungary became first EU member to approve BBIBP-CorV, signing a deal for 5 million doses.[145] The first 550,000 doses arrived in Budapest on February 16[146] and vaccinations started on February 24.[17] Prime Minister Viktor Orbán was vaccinated with BBIBP-CorV on February 28.[147]

In March, Moldova received 2,000 doses donated by the UAE[148] which will be used to vaccinate doctors at the State University of Mediecne and Pharmacy starting on March 22.[149]

In March 3, Montenegro received a donation of 30,000 doses of BBIBP-CorV.[85]

In February, North Macedonia signed an agreement for 200,000 doses of BBIBP-CorV, with which they hoped to launch their vaccination program later that month.[150]

In January, Serbia received one million doses, making it the first country in Europe to receive BBIBP-CorV.[151] On January 19, Serbia approved the vaccine and Health Minister Zlatibor Lončar became the first person to receive a shot.[16]

Controversies

Lack of public data

Unlike Moderna‘s MRNA-1273, Oxford–AstraZeneca‘s AZD1222, and Johnson & Johnson‘s Ad26.COV2.S, there is little public information about the Chinese vaccine’s safety or efficacy.[152] The UAE said it had reviewed Sinopharm’s interim data analysis which showed the vaccine was 100% effective to prevent moderate and severe instances of COVID-19, but did not say whether it had independently analyzed the case data in its review. It was unclear how Sinopharm drew conclusions, since the UAE announcement of the approval for BBIBP-CorV noticeably lacked details such as the number of COVID-19 cases in the placebo or active group or the volunteers ages.[153]

As of December 30, 2020, no detailed efficacy data of the vaccine has been released to the public. A Sinopharm executive said detailed data would be released later and published in scientific journals in China and internationally.[8]

Sinopharm president Wu Yonglin said the trial results exceeded the WHO’s requirements, but a director at a large pharmaceutical company in Shanghai expressed skepticism over the trials and the expectation that drug regulators in Bahrain and the UAE would not hold the same standard as the U.S. Food and Drug Administration.[154]

Unauthorized use in Asia

On December 30, Philippine Defense Secretary Delfin Lorenzana said in an interview that at least one minister and president Rodrigo Duterte‘s bodyguards were provided BBIBP-CorV which were “smuggled” but that he felt what happened was “justified”. Brigadier General Jesus Durante, head of the Presidential Security Guard (PSG), said he felt compelled and “took the risk” to have some of his men vaccinated because they provide close-in security to Duterte, who at 75 is highly vulnerable to COVID-19.[155] Ingming Aberia, an author at The Manila Times commented that FDA director-general Enrique Domingo had reason to believe Sinopharm may cause harm to the consuming public given that no COVID-19 vaccine license was issued, but out of “self-preservation”, he would not initiate charges against PSG.[156]

On January 1, Mainichi Shimbun reported that 18 wealthy people, including several owners of leading Japanese companies, have been vaccinated with Sinopharm vaccines since November 2020. The vaccines were brought in by a Chinese consultant close to a senior member of the Chinese Communist Party.[157] The Chinese embassy in Japan later expressed its dissatisfaction at the unverified claims by Japanese news media.[158]

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  133. ^ “Dominica: Melissa Skerrit receives the Sinopharm COVID-19 vaccine”. WIC News. 2021-03-04. Retrieved 2021-03-05.
  134. ^ Jorgic, Drazen (2021-03-10). “Mexico leans on China after Biden rules out vaccines sharing in short term”. Reuters. Retrieved 2021-03-10.
  135. ^ Biannchi, Walter (2021-02-21). “Argentina approves Sinopharm COVID-19 vaccine for emergency use”. Reuters. Retrieved 2021-02-22.
  136. ^ “Buenos Aires Times | Shipment of 900,000 Sinopharm vaccine doses arrives in Argentina”. http://www.batimes.com.ar. Retrieved 2021-02-26.
  137. ^ Ramos, Danny (2021-02-11). “Bolivia signs deal with China´s Sinopharm for coronavirus vaccine”. Reuters. Retrieved 2021-02-11.
  138. ^ “China-donated Sinopharm vaccine received”. Guyana Chronicle. 2021-03-03. Retrieved 2021-03-03.
  139. ^ “Sinopharm vaccine rollout starts this weekend”. Stabroek News. 2021-03-06. Retrieved 2021-03-07.
  140. ^ Reuters Staff (2021-01-06). “Peru inks deals with Sinopharm, AstraZeneca for coronavirus vaccines -president”. Reuters. Retrieved 2021-01-07.
  141. ^ Aquino, Marco (2021-01-27). “Peru grants ‘exceptional’ approval for Sinopharm COVID-19 vaccine – government sources”. Reuters. Retrieved 2021-01-28.
  142. ^ Sequera, Vivian (2021-03-01). “Venezuela approves use of China’s Sinopharm coronavirus vaccine”. Reuters. Retrieved 2021-03-02.
  143. ^ Sequera, Vivian (2021-03-02). “Venezuela receives donated coronavirus vaccine from China”. Reuters. Retrieved 2021-03-02.
  144. ^ “China sends 100,000 coronavirus vaccines to Belarus”. eng.belta.by. 2021-02-19. Retrieved 2021-02-19.
  145. ^ “Hungary signs deal for Chinese Sinopharm’s COVID-19 vaccine, first in EU”. nationalpost. Retrieved 2021-01-29.
  146. ^ Staff, Reuters (2021-02-16). “First 550,000 doses of Chinese Sinopharm’s vaccine arrive in Hungary”. Reuters. Retrieved 2021-02-18.
  147. ^ “Hungary’s PM Viktor Orbán vaccinated against COVID with Chinese Sinopharm vaccine”. euronews. 2021-02-28.
  148. ^ “Emiratele Arabe Unite au donat Republicii Moldova un lot de vaccin împotriva COVID-19”. TV8 (in Romanian). 13 March 2021.
  149. ^ Cristina (2021-03-19). “O mie de studenți și medici-rezidenți din cadrul USMF vor fi imunizați anti-COVID cu vaccinul BBIBP-CorV, produs de către Sinopharm Beijing Institute of Biological Products”. Ziarul de Gardă (in Romanian). Retrieved 2021-03-19.
  150. ^ “Vaccine delay in North Macedonia stirs political tension”. ABC News. Retrieved 2021-02-12.
  151. ^ Reuters Staff (2021-01-16). “Serbia receives million doses of China’s Sinopharm COVID-19 vaccine”. Reuters. Retrieved 2021-01-16.
  152. ^ “Abu Dhabi starts COVID-19 vaccinations”. Arab News. 2020-12-14. Retrieved 2020-12-17.
  153. ^ Wee SL (9 December 2020). “Chinese Covid-19 Vaccine Gets Key Push, but Doubts Swirl”. The New York Times. Retrieved 21 December 2020.
  154. ^ Yu, Sun (December 31, 2020). “China approves first domestic Covid-19 vaccine for general use”. Financial Times. Retrieved January 12, 2021.
  155. ^ Dancel R. “Philippine officials under fire from critics, health authorities for unsanctioned Covid-19 vaccinations”. The Straits Times.
  156. ^ Aberia, Ingming (6 January 2021). “Did Sinopharm forget that Duque exists?”. The Manila Times. Retrieved 9 January 2021.
  157. ^ “水面下で出回る中国ワクチン 富裕層から永田町へ？ 狙われる日本市場”. Mainichi Daily News (in Japanese). 2020-12-31. Retrieved 2021-01-02.
  158. ^ Elmer, Keegan (January 3, 2021). “Beijing responds to claims Japanese were given unapproved Sinopharm jabs”. South China Morning Post. Retrieved January 9, 2021.

External links

A vial of the BBIBP-CorV COVID‑19 vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Routes of
administration		Intramuscular
ATC codeNone
Legal status
Legal statusAuthorization for use in Bahrain, China, Egypt, Iraq, Pakistan, Serbia, United Arab Emirates, Iran (emergency use)
Identifiers
CAS Number2503126-65-4
DrugBankDB15807
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How the Sinopharm Vaccine Works

By Jonathan Corum and Carl ZimmerUpdated March 22, 2021Leer en español

In early 2020, the Beijing Institute of Biological Products created an inactivated coronavirus vaccine called BBIBP-CorV. Clinical trials run by the state-owned company Sinopharm showed that it had an efficacy rate of 79 percent. China approved the vaccine and soon began exporting it to other countries.

A Vaccine Made From Coronaviruses

BBIBP-CorV works by teaching the immune system to make antibodies against the SARS-CoV-2 coronavirus. The antibodies attach to viral proteins, such as the so-called spike proteins that stud its surface.

Spikes

Spike

protein

gene

CORONAVIRUS

To create BBIBP-CorV, the Beijing Institute researchers obtained three variants of the coronavirus from patients in Chinese hospitals. They picked one of the variants because it was able to multiply quickly in monkey kidney cells grown in bioreactor tanks.

Killing the Virus

Once the researchers produced large stocks of the coronaviruses, they doused them with a chemical called beta-propiolactone. The compound disabled the coronaviruses by bonding to their genes. The inactivated coronaviruses could no longer replicate. But their proteins, including spike, remained intact.

Beta-

propiolactone

INACTIVATED

CORONAVIRUS

Inactivated

genes

The researchers then drew off the inactivated viruses and mixed them with a tiny amount of an aluminum-based compound called an adjuvant. Adjuvants stimulate the immune system to boost its response to a vaccine.

Inactivated viruses have been used for over a century. Jonas Salk used them to create his polio vaccine in the 1950s, and they’re the bases for vaccines against other diseases including rabies and hepatitis A.

Prompting an Immune Response

Because the coronaviruses in BBIBP-CorV are dead, they can be injected into the arm without causing Covid-19. Once inside the body, some of the inactivated viruses are swallowed up by a type of immune cell called an antigen-presenting cell.

INACTIVATED

CORONAVIRUS

Engulfing

the virus

ANTIGEN-

PRESENTING

CELL

Digesting

virus proteins

Presenting

virus protein

fragments

HELPER

T CELL

The antigen-presenting cell tears the coronavirus apart and displays some of its fragments on its surface. A so-called helper T cell may detect the fragment. If the fragment fits into one of its surface proteins, the T cell becomes activated and can help recruit other immune cells to respond to the vaccine.

Making Antibodies

Another type of immune cell, called a B cell, may also encounter the inactivated coronavirus. B cells have surface proteins in a huge variety of shapes, and a few might have the right shape to latch onto the coronavirus. When a B cell locks on, it can pull part or all of the virus inside and present coronavirus fragments on its surface.

A helper T cell activated against the coronavirus can latch onto the same fragment. When that happens, the B cell gets activated, too. It proliferates and pours out antibodies that have the same shape as their surface proteins.

ACTIVATED

HELPER

T CELL

INACTIVATED

CORONAVIRUS

Activating

the B cell

Matching

surface proteins

B CELL

SECRETED

ANTIBODIES

Stopping the Virus

Once vaccinated with BBIBP-CorV, the immune system can respond to an infection of live coronaviruses. B cells produce antibodies that stick to the invaders. Antibodies that target the spike protein can prevent the virus from entering cells. Other kinds of antibodies may block the virus by other means.

ANTIBODIES

LIVE

VIRUS

Remembering the Virus

Sinopharm’s clinical trials have demonstrated that BBIBP-CorV can protect people against Covid-19. But no one can yet say how long that protection lasts. It’s possible that the level of antibodies drops over the course of months. But the immune system also contains special cells called memory B cells that might retain information about the coronavirus for years or even decades.

Vaccine Timeline

January, 2020 Sinopharm begins developing an inactivated vaccine against the coronavirus.

June Researchers report the vaccine produces promising results in monkeys. A Phase 1/2 trial shows that the vaccine doesn’t cause any serious side effects and enables people to make antibodies against the coronavirus.

A Sinopharm production plant in Beijing.Zhang Yuwei/Xinhua, via Associated Press

July A Phase 3 trial begins in the United Arab Emirates.

August Phase 3 trials begin in Morocco and Peru.

Preparing a Sinopharm dose in Lima, Peru.Ernesto Benavides/Agence France-Presse

Sept. 14 The U.A.E. gives emergency approval for Sinopharm’s vaccine to use on health care workers. Government officials and others begin to receive it.

November The chairman of Sinopharm says almost a million people in China have received Sinopharm vaccines.

Nov. 3 The ruler of Dubai, Sheikh Mohammed bin Rashid al-Maktoum, announces he received the vaccine.

Sheikh Mohammed before receiving the vaccine.Agence France-Presse

Dec. 9 The U.A.E. gives full approval to BBIBP-CorV, announcing it has an efficacy rate of 86 percent. But the government did not release any details with their announcement, leaving it unclear how they had come to their conclusions.

Dec. 13 Bahrain also approves the vaccine.

Vials of the Sinopharm vaccine at a packaging plant.Zhang Yuwei/Xinhua, via Associated Press

Dec. 30 Sinopharm announces that the vaccine has an efficacy of 79.34 percent, leading the Chinese government to approve it. The company has yet to publish detailed results of their Phase 3 trial.

Jan. 3, 2021 Egypt authorizes the vaccine for emergency use.

Sources: National Center for Biotechnology Information; Science; The Lancet; Lynda Coughlan, University of Maryland School of Medicine; Jenna Guthmiller, University of Chicago.

Data

/////////////BBIBP-CorV, Sinopharm,  COVID-19 vaccine, china, covid 19, corona virus, vaccine

#BBIBP-CorV, #Sinopharm,  #COVID-19 vaccine, #china, #covid 19, #corona virus, #vaccine

COVAXIN, BBV 152

March 17, 2021 2:40 am / 1 Comment on COVAXIN, BBV 152


covid vaccine india, corona vaccine, corona virus vaccine, first covid vaccine in inida

COVAXIN

CAS 2501889-19-4

  • Whole-Virion Inactivated SARS-CoV-2 Vaccine
  • UNII76JZE5DSN6
  • BBV 152
  • A whole virion inactivated COVID-19 vaccine candidate derived from SARS-CoV-2 strain NIV-2020-770

REF

medRxiv (2020), 1-21.

bioRxiv (2020), 1-32.

BBV152 (also known as Covaxin) is an inactivated virus-based COVID-19 vaccine being developed by Bharat Biotech in collaboration with the Indian Council of Medical Research.

BBV152 is a vaccine candidate created by the Indian Council of Medical Research (ICMR). The candidate, a whole virion inactivated SARS-CoV-2 vaccine, was developed from a well-known SARS-CoV-2 strain and a vero cell platform (CCL-81) with adjuncts of either aluminum hydroxide gel (Algel) or a novel TLR7/8 agonist adsorbed gel. The components of the vaccine include BBV152A, BBV152B, and BBV152C. Animal studies in mice, rats, and rabbits reported BBV152 immunogenicity at two separate antigen concentrations with both types of adjuvants. The formulation with the TLR7/8 adjuvant specifically induced significant Th1 biased antibody responses and increased SARS-CoV-2 lymphocyte responses. Thus, as of July 2020, BBV152 is in Phase 1/2 clinical trials assessing safety and immunogenicity in humans (NCT04471519).

Clinical research

Phase I and II trials

In May 2020, Indian Council of Medical Research’s (ICMR‘s) National Institute of Virology approved and provided the virus strains for developing a fully indigenous COVID-19 vaccine.[1][2] In June 2020, the company got permission to conduct Phase I and Phase II human trials of a developmental COVID-19 vaccine named Covaxin, from the Drugs Controller General of India (DCGI), Government of India.[3] A total of 12 sites were selected by the Indian Council for Medical Research for Phase I and II randomised, double-blind and placebo-controlled clinical trials of vaccine candidate.[4][5][6]

In December 2020, the company announced the report for Phase I trials and presented the results through medRxiv preprint;[7][8] the report was later published in the The Lancet.[9]

On March 8, 2021, Phase II results were published in The Lancet. The study showed that Phase II trials had a higher immune response and induced T-cell response due to the difference in dosing regime from Phase I. The doses in Phase II were given at 4 weeks interval as opposed to 2 weeks in Phase I. Neutralization response of the vaccine were found significantly higher in Phase II.[10]

Phase III trials[edit]

In November 2020, Covaxin received the approval to conduct Phase III human trials[11] after completion of Phase I and II.[12] The trial involves a randomised, double-blinded, placebo-controlled study among volunteers of age group 18 and above and started on 25 November.[13] The Phase III trials involved around 26,000 volunteers from across India.[14] The phase III trials covered a total of 22 sites consisting several states in the country, including Delhi, Karnataka and West Bengal.[15] Refusal rate for Phase III trials was much higher than that for Phase I and Phase II. As a result only 13,000 volunteers had been recruited by 22 December with the number increasing to 23,000 by 5 January. [16][17]

As on March 2021, the stated interim efficacy rate for phase III trial is 81%.[18][10]

B.1.1.7 (United Kingdom) variant

In December 2020, a new SARS‑CoV‑2 variant, B.1.1.7, was identified in the UK.[19] A study on this variant was carried and preliminary results presented in biorxiv have shown Covaxin to be effective in neutralizing this strain.[20]

Manufacturing

The vaccine candidate is produced with Bharat Biotech’s in-house vero cell manufacturing platform[21] that has the capacity to deliver about 300 million doses.[22] The company is in the process of setting up a second plant at its Genome Valley facility in Hyderabad to make Covaxin. The firm is in talks with other state governments like Odisha[23] for another site in the country to make the vaccine. Beside this, they are also exploring global tie-ups for Covaxin manufacturing.[24]

In December 2020, Ocugen Inc entered a partnership with Bharat Biotech to co-develop Covaxin for the U.S. market.[25][26] In January 2021, Precisa Med entered an agreement with Bharat Biotech to supply Covaxin in Brazil[27]

Emergency use authorisation

 
show  Full authorizationshow  Emergency authorization

See also: COVID-19 vaccine § Trial and authorization status

Bharat Biotech has applied to the Drugs Controller General of India (DCGI), Government of India seeking an emergency use authorisation (EUA).[31] It was the third firm after Serum Institute of India and Pfizer to apply for emergency use approval.[32]

On 2 January 2021, the Central Drugs Standard Control Organisation (CDSCO) recommended permission for EUA,[33] which was granted on 3 January.[34] The emergency approval was given before Phase III trial data was published. This was criticized in some sections of the media.[35][36]

The vaccine was also approved for Emergency Use in Iran and Zimbabwe.[30][29]

References

  1. ^ “ICMR teams up with Bharat Biotech to develop Covid-19 vaccine”. Livemint. 9 May 2020.
  2. ^ Chakrabarti A (10 May 2020). “India to develop ‘fully indigenous’ Covid vaccine as ICMR partners with Bharat Biotech”. ThePrint.
  3. ^ “India’s First COVID-19 Vaccine Candidate Approved for Human Trials”. The New York Times. 29 June 2020.
  4. ^ “Human clinical trials of potential Covid-19 vaccine ‘COVAXIN’ started at AIIMS”. DD News. Prasar Bharati, Ministry of I & B, Government of India. 25 July 2020.
  5. ^ Press, Associated (25 July 2020). “Asia Today: Amid new surge, India tests potential vaccine”. Washington Post. Retrieved 17 December 2020.
  6. ^ “Delhi: 30-year-old is first to get dose of trial drug Covaxin”. The Indian Express. 25 July 2020.
  7. ^ Perappadan, Bindu Shajan (16 December 2020). “Coronavirus | Covaxin phase-1 trial results show promising results”. The Hindu. Retrieved 17 December 2020.
  8. ^ Sabarwal, Harshit (16 December 2020). “Covaxin’s phase 1 trial result shows robust immune response, mild adverse events”. Hindustan Times. Retrieved 17 December 2020.
  9. ^ Ella, Raches; Vadrevu, Krishna Mohan; Jogdand, Harsh; Prasad, Sai; Reddy, Siddharth; Sarangi, Vamshi; Ganneru, Brunda; Sapkal, Gajanan; Yadav, Pragya; Abraham, Priya; Panda, Samiran; Gupta, Nivedita; Reddy, Prabhakar; Verma, Savita; Rai, Sanjay Kumar; Singh, Chandramani; Redkar, Sagar Vivek; Gillurkar, Chandra Sekhar; Kushwaha, Jitendra Singh; Mohapatra, Satyajit; Rao, Venkat; Guleria, Randeep; Ella, Krishna; Bhargava, Balram (21 January 2021). “Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial”. The Lancet Infectious Diseases. doi:10.1016/S1473-3099(20)30942-7. PMC 7825810. PMID 33485468.
  10. ^ Jump up to:a b Ella, Raches; Reddy, Siddhart; Jogdand, Harsh; Sarangi, Vamsi; Ganneru, Brunda; Prasad, Sai; Das, Dipankar; Dugyala, Raju; Praturi, Usha; Sakpal, Gajanan; Yadav, Pragya; Reddy, Prabhakar; Verma, Savita; Singh, Chandramani; Redkar, Sagar Vivek; Singh, Chandramani; Gillurkar, Chandra Sekhar; Kushwaha, Jitendra Singh; Mohapatra, Satyajit; Mohapatra, Satyajit; Bhate, Amit; Rai, Sanjay; Panda, Samiran; Abraham, Priya; Gupta, Nivedita; Ella, Krishna; Bhargav, Balram; Vadrevu, Krishna Mohan (8 March 2021). “Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial”. The Lancet Infectious Diseases. doi:10.1016/S1473-3099(21)00070-0.
  11. ^ “Coronavirus | Covaxin Phase III trial from November”. The Hindu. 23 October 2020.
  12. ^ Ganneru B, Jogdand H, Daram VK, Molugu NR, Prasad SD, Kannappa SV, et al. (9 September 2020). “Evaluation of Safety and Immunogenicity of an Adjuvanted, TH-1 Skewed, Whole Virion InactivatedSARS-CoV-2 Vaccine – BBV152”. doi:10.1101/2020.09.09.285445. S2CID 221635203.
  13. ^ “An Efficacy and Safety Clinical Trial of an Investigational COVID-19 Vaccine (BBV152) in Adult Volunteers”. clinicaltrials.gov(Registry). United States National Library of Medicine. NCT04641481. Retrieved 26 November 2020.
  14. ^ “Bharat Biotech begins Covaxin Phase III trials”. The Indian Express. 18 November 2020.
  15. ^ Sen M (2 December 2020). “List of states that have started phase 3 trials of India’s first Covid vaccine”. mint.
  16. ^ “70%-80% Drop In Participation For Phase 3 Trials Of Covaxin: Official”. NDTV. 17 December 2020.
  17. ^ “Bharat Biotech’s Covaxin given conditional nod based on incomplete Phase 3 trial results data”. The Print. 3 January 2021.
  18. ^ Kumar, N. Ravi (3 March 2021). “Bharat Biotech says COVID-19 vaccine Covaxin shows 81% efficacy in Phase 3 clinical trials”. The Hindu.
  19. ^ “Inside the B.1.1.7 Coronavirus Variant”. The New York Times. 18 January 2021. Retrieved 29 January 2021.
  20. ^ Sapkal, Gajanan N.; Yadav, Pragya D.; Ella, Raches; Deshpande, Gururaj R.; Sahay, Rima R.; Gupta, Nivedita; Mohan, V. Krishna; Abraham, Priya; Panda, Samiran; Bhargava, Balram (27 January 2021). “Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum”. bioRxiv: 2021.01.26.426986. doi:10.1101/2021.01.26.426986. S2CID 231777157.
  21. ^ Hoeksema F, Karpilow J, Luitjens A, Lagerwerf F, Havenga M, Groothuizen M, et al. (April 2018). “Enhancing viral vaccine production using engineered knockout vero cell lines – A second look”. Vaccine. 36 (16): 2093–2103. doi:10.1016/j.vaccine.2018.03.010. PMC 5890396. PMID 29555218.
  22. ^ “Coronavirus vaccine update: Bharat Biotech’s Covaxin launch likely in Q2 of 2021, no word on pricing yet”. http://www.businesstoday.in. India Today Group. Retrieved 13 December2020.
  23. ^ “Odisha fast tracks coronavirus vaccine manufacturing unit”. The New Indian Express. 7 November 2020.
  24. ^ Raghavan P (24 September 2020). “Bharat Biotech exploring global tie-ups for Covaxin manufacturing”. The Indian Express.
  25. ^ Reuters Staff (22 December 2020). “Ocugen to co-develop Bharat Biotech’s COVID-19 vaccine candidate for U.S.” Reuters. Retrieved 5 January 2021.
  26. ^ “Bharat Biotech, Ocugen to co-develop Covaxin for US market”. The Economic Times. Retrieved 5 January 2021.
  27. ^ “Bharat Biotech inks pact with Precisa Med to supply Covaxin to Brazil”. mint. 12 January 2021.
  28. ^ Schmall E, Yasir S (3 January 2021). “India Approves Oxford-AstraZeneca Covid-19 Vaccine and 1 Other”. The New York Times. Retrieved 3 January 2021.
  29. ^ Jump up to:a b “Iran issues permit for emergency use for three other COVID-19 vaccines: Official”. IRNA English. 17 February 2021.
  30. ^ Jump up to:a b Manral, Karan (4 March 2021). “Zimbabwe approves Covaxin, first in Africa to okay India-made Covid-19 vaccine”. Hindustan Times. Retrieved 6 March 2021.
  31. ^ Ghosh N (7 December 2020). “Bharat Biotech seeks emergency use authorization for Covid-19 vaccine”. Hindustan Times.
  32. ^ “Coronavirus | After SII, Bharat Biotech seeks DCGI approval for Covaxin”. The Hindu. 7 December 2020.
  33. ^ “Expert panel recommends granting approval for restricted emergency use of Bharat Biotech’s Covaxin”. The Indian Express. 2 January 2021.
  34. ^ “Coronavirus: India approves vaccines from Bharat Biotech and Oxford/AstraZeneca”. BBC News. 3 January 2021. Retrieved 3 January 2021.
  35. ^ “Disputes Mount, but Heedless Govt Intent on Rolling Vaccine Candidates Out”. The Wire. 12 January 2021.
  36. ^ “AIPSN urges govt to reconsider emergency approval for Covaxin till Phase 3 data is published – Health News , Firstpost”. Firstpost. 8 January 2021.

External links

Scholia has a profile for Covaxin / BBV152 (Q98703813).

COVAXIN®, India‘s indigenous COVID-19 vaccine by Bharat Biotech is developed in collaboration with the Indian Council of Medical Research (ICMR) – National Institute of Virology (NIV).

The indigenous, inactivated vaccine is developed and manufactured in Bharat Biotech’s BSL-3 (Bio-Safety Level 3) high containment facility.

The vaccine is developed using Whole-Virion Inactivated Vero Cell derived platform technology. Inactivated vaccines do not replicate and are therefore unlikely to revert and cause pathological effects. They contain dead virus, incapable of infecting people but still able to instruct the immune system to mount a defensive reaction against an infection.

Why develop Inactivated Vaccine? Conventionally, inactivated vaccines have been around for decades. Numerous vaccines for diseases such as Seasonal Influenza, Polio, Pertussis, Rabies, and Japanese Encephalitis use the same technology to develop inactivated vaccines with a safe track record of >300 million doses of supplies to date. It is the well-established, and time-tested platform in the world of vaccine technology.

Key Attributes:

  • COVAXIN® is included along with immune-potentiators, also known as vaccine adjuvants, which are added to the vaccine to increase and boost its immunogenicity.
  • It is a 2-dose vaccination regimen given 28 days apart.
  • It is a vaccine with no sub-zero storage, no reconstitution requirement, and ready to use liquid presentation in multi-dose vials, stable at 2-8oC.
  • Pre-clinical studies: Demonstrated strong immunogenicity and protective efficacy in animal challenge studies conducted in hamsters & non-human primates. For more information about our animal study, please visit our blog page on Non-Human Primates.
  • The vaccine received DCGI approval for Phase I & II Human Clinical Trials in July, 2020.
  • A total of 375 subjects have been enrolled in the Phase 1 study and generated excellent safety data without any reactogenicity. Vaccine-induced neutralizing antibody titers were observed with two divergent SARS-CoV-2 strains. Percentage of all the side-effects combined was only 15% in vaccine recipients. For further information, visit our blog page on phase 1 study.
  • In Phase 2 study, 380 participants of 12-65 years were enrolled. COVAXIN® led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. Know more about our phase 2 study.
Covaxin phase 3 trials
  • A total of 25,800 subjects have been enrolled and randomized in a 1:1 ratio to receive the vaccine and control in a Event-Driven, randomized, double-blind, placebo-controlled, multicentre phase 3 study.

The purpose of this study is to evaluate the efficacy, safety, and immunogenicity of COVAXIN® in volunteers aged ≥18 years.

Of the 25,800 participants, >2400 volunteers were above 60 years of age and >4500 with comorbid conditions.

COVAXIN® demonstrated 81% interim efficacy in preventing COVID-19 in those without prior infection after the second dose.

COVAXIN® effective against UK variant strain:

Analysis from the National Institute of Virology indicates that vaccine-induced antibodies can neutralize the UK variant strains and other heterologous strains.

Global Acceptance of COVAXIN®:

Bharat biotech has been approached by several countries across the world for the procurement of COVAXIN®.

  • Clinical trials in other countries to commence soon.
  • Supplies from government to government in the following countries to take place: Mongolia, Myanmar, Sri Lanka, Philippines, Bahrain, Oman, Maldives and Mauritius.
Covaxin world map
A person holding a vial of the Covaxin vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Trade namesCovaxin
Routes of
administration		Intramuscular
ATC codeNone
Legal status
Legal statusEUA : IND, IRN, ZBW
Identifiers
DrugBankDB15847
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COVID-19 pandemic
SARS-CoV-2 (virus)COVID-19 (disease)
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showMedical response
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 COVID-19 Portal
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////////COVAXIN, BBV152, BBV 152, INDIA 2021, APPROVALS 2021, COVID 19, CORONA VIRUS, bharat biotech

#COVAXIN, #BBV152, #BBV 152, #INDIA 2021, #APPROVALS 2021, #COVID 19, #CORONA VIRUS, #bharat biotech

Desidustat

July 9, 2020 4:52 am / Leave a comment


Desidustat.svg

Ranjit Desai

Inventor of Oxemia (Desidustat), a breakthrough PHD inhibitor approved for Chronic Kidney Diseases (CKD) / Accomplished pharma executive / 4 INDs in 4 years, ZYDUS LIFESCIENCES

DESIDUSTAT

Formal Name
N-[[1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl]carbonyl]-glycine
CAS Number 1616690-16-4
Molecular Formula   C16H16N2O6
Formula Weight 332.3
FormulationA crystalline solid
λmax233, 291, 335

2-(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid

desidustat

Glycine, N-((1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl)carbonyl)-

N-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine

ZYAN1 compound

BCP29692

EX-A2999

ZB1514

CS-8034

HY-103227

A16921

(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) +. 1H NMR (DMSO-d 6): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Desidustat | C16H16N2O6 - PubChem

Oxemia (Desidustat) has received approval from the Drug Controller General of India. This was an incredible team effort by Zydans across the organization and I am so proud of what we have accomplished. Oxemia is a breakthrough treatment for Anemia associated with Chronic Kidney Disease in Patients either on Dialysis or Not on Dialysis, and will help improve quality of life for CKD patients. Team #zydus , on to our next effort!

Desidustat (INN, also known as ZYAN1) is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences.[1] The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India,based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP.[2] Clinical trials on desidustat have been done in India and Australia.[3] In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed.[4] The Phase 3 clinical trials were conducted at additional lower doses as of 2019.[5] Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization.[6][7] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.[8] In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China.[9] It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress [10] A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of Covid-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6.[11] Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).[12]. Desidustat has met the primary endpoints in the phase 3 clinical trials and Zydus had filed the New Drug Application (NDA) to DCGI in November, 2021.[13]\

CLIP

https://www.businesstoday.in/industry/pharma/story/zydus-receives-dcgi-approval-for-new-drug-oxemia-what-you-need-to-know-324966-2022-03-07

Zydus receives DCGI approval for new drug Oxemia; what you need to know

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, Zydus said in a statement.

Gujarat-based pharma company Zydus Lifesciences on Monday received the Drugs Controller General of India (DCGI) approval for its new drug application for a first-of-its-kind oral treatment for anemia associated with Chronic Kidney Disease (CKD) – Oxemia (Desidustat).

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, the drug firm said in a statement.

Desidustat showed good safety profile, improved iron mobilization and LDL-C reduction in CKD patients in DREAM-D and DREAM-ND Phase III clinical trials, conducted in approximately 1,200 subjects. Desidustat provides CKD patients with an oral convenient therapeutic option for the treatment of anemia. The pharma major did not, however, declare the cost per dose if the drug is available in the market.

“After more than a decade of research and development into the science of HIF-PH inhibitors, results have demonstrated that Oxemia addresses this unmet need and additionally reduces hepcidin, inflammation and enables better iron mobilization. This advancement offers ease of convenience for the patient and will also reduce the disease burden by providing treatment at an affordable cost, thereby improving the quality of life for patients suffering from Chronic Kidney Disease,” Chairman of Zydus Lifesciences Pankaj Patel said.

Chronic Kidney Disease (CKD) is a progressive medical condition characterised by a gradual loss of kidney function and is accompanied by comorbidities like anemia, cardiovascular diseases (hypertension, heart failure and stroke), diabetes mellitus, eventually leading to kidney failure.

PATENT

US277539705

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C922CC7937C0B6D7F987FE395E8B6F34.wapp2nB?docId=US277539705&_cid=P21-KCEB8C-83913-1

      Patent applications WO 2004041818, US 20040167123, US 2004162285, US 20040097492 and US 20040087577 describes the utility of N-arylated hydroxylamines of formula (IV), which are intermediates useful for the synthesis of certain quinolone derivatives (VI) as inhibitors of hepatitis C (HCV) polymerase useful for the treatment of HCV infection. In these references, the compound of formula (IV) was prepared using Scheme 1 which involves partial reduction of nitro group and subsequent O-alkylation using sodium hydride as a base.

 (MOL) (CDX)

      The patent application WO 2014102818 describes the use of certain quinolone based compound of formula (I) as prolyl hydroxylase inhibitors for the treatment of anemia. Compound of formula (I) was prepared according to scheme 2 which involved partial reduction of nitro group and subsequent O-alkylation using cesium carbonate as a base.

 (MOL) (CDX)

      The drawback of process disclosed in WO 2014102818 (Scheme 2) is that it teaches usage of many hazardous reagents and process requires column chromatographic purification using highly flammable solvent at one of the stage and purification at multi steps during synthesis, which is not feasible for bulk production.
Scheme 3:

 (MOL) (CDX)

 Scheme 4.

 (MOL) (CDX)

      The process for the preparation of compound of formula (I-a) comprises the following steps:

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)


 (MOL) (CDX)
      In a 5 L fixed glass assembly, Ethanol (1.25 L) charged at room temperature. 2-iodobenzoic acid (250 g, 1.00 mol) was added in one lot at room temperature. Sulphuric acid (197.7 g, 2.01 mol) was added carefully in to reaction mixture at 20 to 35° C. The reaction mixture was heated to 80 to 85° C. Reaction mixture was stirred for 20 hours at 80 to 85° C. After completion of reaction distilled out ethanol at below 60° C. The reaction mixture was cooled down to room temperature. Water (2.5 L) was then added carefully at 20 to 35° C. The reaction mixture was then charged with Ethyl acetate (1.25 L). After complete addition of ethyl acetate, reaction mixture turned to clear solution. At room temperature it was stirred for 5 to 10 minutes and separated aqueous layer. Aqueous layer then again extracted with ethyl acetate (1.25 L) and separated aqueous layer. Combined organic layer then washed with twice 10% sodium bicarbonate solution (2×1.25 L) and twice process water (2×1.25L) and separated aqueous layer. Organic layer then washed with 30% brine solution (2.5 L) and separated aqueous layer. Concentrated ethyl acetate in vacuo to get ethyl 2-iodobenzoate in 95% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 248.75 (M+H). 1H NMR (CDCl 3): 1.41-1.37 (t, 3H), 4.41-4.35 (q, 2H), 7.71-7.09 (m, 1H), 7.39-7.35 (m, 1H), 7.94-7.39 (m, 1H), 7.96-7.96 (d, 1H). HPLC Purity: 99.27%

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)


 (MOL) (CDX)
      In a 5 L fixed glass assembly, toluene (1.5 L) was charged at room temperature. Copper (I) iodide (15.3 g, 0.08 mol) was added in one lot at room temperature. Glycine (39.1 g, 0.520 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Ethyl 2-iodobenzoate (221.2 g, 0.801 mol) was added in one lot at room temperature. Tert-butyl (cyclopropylmethoxy)carbamate (150 g, 0.801 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Potassium carbonate (885.8 g, 6.408 mol) and ethanol (0.9 L) were added at 25° C. to 35° C. Reaction mixture was stirred for 30 minutes. The reaction mixture was refluxed at 78 to 85° C. for 24 hours. Reaction mixture was cooled to room temperature and stirred for 30 minutes. The reaction mixture was then charged with ethyl acetate (1.5 L). After complete addition of ethyl acetate, reaction mixture turned to thick slurry. At room temperature it was stirred for 30 minutes and the solid inorganic material was filtered off through hyflow supercel bed. Inorganic solid impurity was washed with ethyl acetate (1.5 L), combined ethyl acetate layer was washed with twice water (2×1.5 L) and separated aqueous layer. Organic layer washed with 30% sodium chloride solution (1.5 L) and separated aqueous layer. Ethyl acetate was concentrated in vacuo to get ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate in 89% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 357.93 (M+Na). 1H NMR (CDCl 3): 0.26-0.23 (m, 2H), 0.52-0.48 (m, 2H), 1.10-1.08 (m, 1H), 1.38-1.35 (t, 3H), 1.51 (s, 9H), 3.78-3.76 (d, J=7.6 Hz, 2H), 4.35-4.30 (q, J=6.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.49-7.47 (m, 2H), 7.78-7.77 (d, 1H). HPLC Purity: 88.07%

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)


 (MOL) (CDX)
      In a 10 L fixed glass assembly, dichloromethane (2.4 L) was charged at room temperature. Ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate (200 g, 0.596 mol) was charged and cooled externally with ice-salt at 0 to 10° C. Methanolic HCl (688.3 g, 3.458 mol, 18.34% w/w) solution was added slowly drop wise, over a period of 15 minutes, while maintaining internal temperature below 10° C. Reaction mixture was warmed to 20 to 30° C., and stirred at 20 to 30° C. for 3 hours. The reaction mixture was quenched with addition of water (3.442 L). Upon completion of water addition, the reaction mixture turn out to light yellow coloured solution. At room temperature it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with Dichloromethane (0.8 L). Combined dichloromethane layer then washed with 20% sodium chloride solution (1.0 L) and separated aqueous layer. Concentrated dichloromethane vacuo to get Ethyl 2-((cyclopropylmethoxy)amino)benzoate in 92% yield, as an oil. MS (ESI-MS): m/z 235.65 (M+H) +. 1H NMR (CDCl 3): 0.35-0.31 (m, 2H), 0.80-0.59 (m, 2H), 0.91-0.85 (m, 1H), 1.44-1.38 (t, 3H), 3.76-3.74 (d, 2H), 4.36-4.30 (q, 2H), 6.85-6.81 (t, 1H), 7.36-7.33 (d, 1H), 7.92-7.43 (m, 1H), 7.94-7.93 (d, 1H), 9.83 (s, 1H). HPLC Purity: 87.62%

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)


 (MOL) (CDX)
      In a 2 L fixed glass assembly, Acetonitrile (0.6 L) was charged at room temperature. Ethyl 2-((cyclopropylmethoxy)amino)benzoate (120 g, 0.510 mol) was charged at room temperature. Ethyl hydrogen malonate (74.1 g, 0.561 mol) was charged at room temperature. Pyridine (161.4 g, 2.04 mol) was added carefully in to reaction mass at room temperature and cooled externally with ice-salt at 0 to 10° C. Phosphorous oxychloride (86.0 g, 0.561 mol) was added slowly drop wise, over a period of 2 hours, while maintaining internal temperature below 10° C. Reaction mixture was stirred at 0 to 10° C. for 45 minutes. The reaction mixture was quenched with addition of water (1.0 L). Upon completion of water addition, the reaction mixture turns out to dark red coloured solution. Dichloromethane (0.672 L) was charged at room temperature and it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with dichloromethane (0.672 L). Combined dichloromethane layer then washed with water (0.400 L) and 6% sodium chloride solution (0.400 L) and separated aqueous layer. Mixture of acetonitrile and dichloromethane was concentrated in vacuo to get Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate in 95% yield, as an oil. MS (ESI-MS): m/z 350.14 (M+H) l. 1H NMR (DMSO-d 6): 0.3-0.2 (m, 2H), 0.6-0.4 (m, 2H), 1.10-1.04 (m, 1H), 1.19-1.15 (t, 3H), 1.29-1.25 (t, 3H), 3.72-3.70 (d, 2H), 3.68 (s, 2H), 4.17-4.12 (q, 2H), 4.25-4.19 (q, 2H), 7.44-7.42 (d, 1H), 7.50-7.46 (t, 1H), 7.68-7.64 (m, 1H), 7.76-7.74 (d, 1H). HPLC Purity: 86.74%

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)


 (MOL) (CDX)
      In a 10 L fixed glass assembly under Nitrogen atmosphere, Methanol (0.736 L) was charged at room temperature. Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate (160 g, 0.457 mol) was charged at room temperature. Sodium methoxide powder (34.6 g, 0.641 mol) was added portion wise, over a period of 30 minutes, while maintaining internal temperature 10 to 20° C. Reaction mixture was stirred at 10 to 20° C. for 30 minutes. The reaction mixture was quenched with addition of ˜1N aqueous hydrochloric acid solution (0.64 L) to bring pH 2, over a period of 20 minutes, while maintaining an internal temperature 10 to 30° C. Upon completion of aqueous hydrochloric acid solution addition, the reaction mixture turned to light yellow coloured slurry. Diluted the reaction mass with water (3.02 L) and it was stirred for another 1 hour. Solid material was filtered off and washed twice with water (2×0.24 L). Dried the compound in fan dryer at temperature 50 to 55° C. for 6 hours to get crude ethyl 1-(cyclopropylmetboxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a solid.

Purification

      In a 10 L fixed glass assembly, DMF (0.48 L) was charged at room temperature. Crude ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (120 g) was charged at room temperature. Upon completion of addition of crude compound, clear reaction mass observed. Reaction mixture stirred for 30 minutes at room temperature. Precipitate the product by addition of water (4.8 L), over a period of 30 minutes, while maintaining an internal temperature 25 to 45° C. Upon completion of addition of water, the reaction mixture turned to light yellow colored slurry. Reaction mixture was stirred at 25 to 45° C. for 30 minutes. Solid material was filtered off and washed with water (0.169 L). Dried the product in fan dryer at temperature 50 to 55° C. for 6 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 81% yield, as a solid. MS (ESI-MS): m/z 303.90 (M+H) +. 1H NMR (DMSO-d 6): 0.37-0.35 (m, 2H), 0.59-0.55 (m, 2H), 1.25-1.20 (m, 1H), 1.32-1.29 (t, 3H), 3.97-3.95 (d, 2H), 4.36-4.31 (q, 2H), 7.35-7.31 (in, 1H), 7.62-7.60 (dd, 1H), 7.81-7.77 (m, 1H), 8.06-7.04 (dd, 1H). HPLC Purity: 95.52%

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)


 (MOL) (CDX)
      In a 5 L fixed glass assembly, tetrahydrofuran (0.5 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (100 g, 0.329 mol) was charged at room temperature. Glycine ethyl ester HCl (50.7 g, 0.362 mol) was charged at room temperature. N,N-Diisopropylethyl amine (64 g, 0.494 mol) was added carefully in to reaction mass at room temperature and heated the reaction mass at 65 to 70° C. Reaction mixture was stirred at 65 to 70° C. for 18 hours. The reaction mixture was quenched with addition of water (2.5 L).
      Upon completion of water addition, the reaction mixture turns out to off white to yellow coloured slurry. Concentrated tetrahydrofuran below 55° C. in vacuo and reaction mixture was stirred at 25 to 35° C. for 1 hour. Solid material was filtered off and washed with water (3×0.20 L). Dried the compound in fan dryer at temperature 55 to 60° C. for 8 hours to get crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate as a solid.

Purification

      In a 2 L fixed glass assembly, Methanol (1.15 L) was charged at room temperature. Crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (100 g) was charged at room temperature. The reaction mass was heated to 65 to 70° C. Reaction mass was stirred for 1 h at 65 to 70° C. Removed heating and cool the reaction mass to 25 to 35° C. Reaction mass stirred for 1 h at 25 to 35° C. Solid material was filtered off and washed with methanol (0.105 L). The product was dried under fan dryer at temperature 55 to 60° C. for 8 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 80% yield, as a solid. MS (ESI-MS): m/z 360.85 (M+H) +. 1H NMR (DMSO-d 6): 0.39 (m, 2H), 0.60-0.54 (m, 2H), 1.23-1.19 (t, 3H), 1.31-1.26 (m, 1H), 4.04-4.02 (d, 2H), 4.18-4.12 (q, 2H), 4.20-4.18 (d, 2H), 7.40-7.36 (m, 1H), 7.70-7.68 (d, 1H), 7.87-7.83 (m, 1H), 8.08-8.05 (dd, 1H), 10.27-10.24 (t, 1H). HPLC Purity: 99.84%

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)


 (MOL) (CDX)
      In a 5 L fixed glass assembly, methanol (0.525 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (75 g, 0.208 mol) was charged at room temperature. Water (0.30 L) was charged at room temperature. Sodium hydroxide solution (20.8 g, 0.520 mol) in water (0.225 L) was added carefully at 30 to 40° C. Upon completion of addition of sodium hydroxide solution, the reaction mass turned to clear solution. Reaction mixture stirred for 30 minutes at 30 to 40° C. Diluted the reaction by addition of water (2.1 L). Precipitate the solid by addition of hydrochloric acid solution (75 mL) in water (75 mL). Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4×0.375 L). The compound was dried under fan dryer at temperature 25 to 35° C. for 6 hours and then dried for 4 hours at 50 to 60° C. to get (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) +. 1H NMR (DMSO-d 6): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Polymorphic Data (XRPD):

References[edit]

  1. ^ “Zydus receives DCGI approval for new drug Oxemia; what you need to know”.
  2. ^ CDSCO, SEC Committee. “SEC meeting to examine IND proposals, dated 29.12.2021”. CDSCO website Govt of India. CDSCO. Retrieved 19 January 2022.
  3. ^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). “Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers”. Clinical Pharmacokinetics. 57 (1): 87–102. doi:10.1007/s40262-017-0551-3. PMC 5766731. PMID 28508936.
  4. ^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
  5. ^ “Zydus Cadila announces phase III clinical trials of Desidustat”. 17 April 2019. Retrieved 20 April 2019 – via The Hindu BusinessLine.
  6. ^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). “Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia”. Drug Research. 66 (2): 107–12. doi:10.1055/s-0035-1554630. PMID 26367279.
  7. ^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). “Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases”. Journal of Medicinal Chemistry. 61 (16): 6964–6982. doi:10.1021/acs.jmedchem.7b01686. PMID 29712435.
  8. ^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). “Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation”. European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID 30458168. S2CID 53943666.
  9. ^ Market, Capital (20 January 2020). “Zydus enters into licensing agreement with China Medical System Holdings”. Business Standard India. Retrieved 20 January 2020 – via Business Standard.
  10. ^ Joharapurkar, Amit; Patel, Vishal; Kshirsagar, Samadhan; Patel, Maulik; Savsani, Hardikkumar; Jain, Mukul (22 January 2021). “Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress”. Drug Development Research. 82 (6): 852–860. doi:10.1002/ddr.21792. PMID 33480036. S2CID 231680317.
  11. ^ “Zydus’ trials of Desidustat shows positive results for Covid-19 management”. The Hindu Business Line. The Hindu. Retrieved 25 January 2021.
  12. ^ “Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy”. PipelineReview.com. La Merie Publishing. Retrieved 22 January 2021.
  13. ^ “Stock Share Price | Get Quote | BSE”.

 

 

ANALYSIS

https://patentscope.wipo.int/search/en/result.jsf?inchikey=IKRKQQLJYBAPQT-UHFFFAOYSA-N

Publication Dates
20141
20153
20160
20170
20180
20192
2020
1.WO/2020/086736RGMC-SELECTIVE INHIBITORS AND USE THEREOF
WO – 30.04.2020
Int.Class A61P 7/06Appl.No PCT/US2019/057687Applicant SCHOLAR ROCK, INC.Inventor NICHOLLS, Samantha
Selective inhibitors of repulsive guidance molecule C (RGMc), are described. Related methods, including methods for making, as well as therapeutic use of these inhibitors in the treatment of disorders, such as anemia, are also provided.
2.WO/2020/058882METHODS OF PRODUCING VENOUS ANGIOBLASTS AND SINUSOIDAL ENDOTHELIAL CELL-LIKE CELLS AND COMPOSITIONS THEREOF
WO – 26.03.2020
Int.Class C12N 5/071Appl.No PCT/IB2019/057882Applicant UNIVERSITY HEALTH NETWORKInventor KELLER, Gordon
Disclosed herein are methods of producing a population of venous angioblast cells from stem cells using a venous angioblast inducing media and optionally isolating a CD34+ population from the cell population comprising the venous angioblast cells, for example using a CD34 affinity reagent, CD31 affinity reagent and/or CD144 affinity reagent, optionally with or without a CD73 affinity reagent as well as methods of further differentiating the venous angioblasts in vitro to produce SEC-LCs and/or in vivo to produce SECs. Uses of the cells and compositions comprising the cells are also described.
3.110876806APPLICATION OF HIF2ALPHA AGONIST AND ACER2 AGONIST IN PREPARATION OF MEDICINE FOR TREATING ATHEROSCLEROSIS
CN – 13.03.2020
Int.Class A61K 45/00Appl.No 201911014253.3Applicant PEKING UNIVERSITYInventor JIANG CHANGTAO
The invention discloses application of an HIF2alpha agonist and an ACER2 agonist in preparation of a medicine for treating and/or preventing atherosclerosis. Wherein the HIF2alpha agonist can be an adipose cell HIF2alpha agonist, and the ACER2 agonist can be a visceral fat ACER2 enzyme activator. The invention also discloses an application of Roxadustat in preparing a medicine for treating and/orpreventing atherosclerosis. The HIF2alpha agonist, the ACER2 agonist and the Roxadustat can be used for inhibiting or alleviating the occurrence and development of atherosclerosis.
4.20190359574PROCESS FOR THE PREPARATION OF QUINOLONE BASED COMPOUNDS
US – 28.11.2019
Int.Class C07D 215/58Appl.No 16421671Applicant CADILA HEALTHCARE LIMITEDInventor Ranjit C. Desai

The present invention relates to an improved process for the preparation of quinolone based compounds of general formula (I) using intermediate compound of general formula (XII). Invention also provides an improved process for the preparation of compound of formula (I-a) using intermediate compound of formula (XII-a) and some novel impurities generated during process. Compounds prepared using this process can be used to treat anemia.
5.WO/2019/169172SYSTEM AND METHOD FOR TREATING MEIBOMIAN GLAND DYSFUNCTION
WO – 06.09.2019
Int.Class A61F 9/00Appl.No PCT/US2019/020113Applicant THE SCHEPENS EYE RESEARCH INSTITUTEInventor SULLIVAN, David, A.
Systems and methods of treating meibomian and sebaceous gland dysfunction. The methods include reducing oxygen concentration in the environment of one or more dysfunctional meibomian and sebaceous glands, thereby restoring a hypoxic status of one or more dysfunctional meibomian and sebaceous glands. The reducing of the oxygen concentration is accomplished by restricting blood flow to the one or more dysfunctional meibomian and sebaceous glands and the environment of one or more dysfunctional meibomian sebaceous glands. The restricting of the blood flow is accomplished by contracting or closing one or more blood vessels around the one or more dysfunctional meibomian or sebaceous glands. The methods also include giving local or systemic drugs that lead to the generation of hypoxia-inducible factors in one or more dysfunctional meibomian and sebaceous glands.
6.201591195ХИНОЛОНОВЫЕ ПРОИЗВОДНЫЕ
EA – 30.10.2015
Int.Class C07D 215/58Appl.No 201591195Applicant КАДИЛА ХЕЛЗКЭР ЛИМИТЕДInventor Десаи Ранджит К.

Настоящее изобретение относится к новым соединениям общей формулы (I), фармацевтическим композициям, содержащим указанные соединения, применению этих соединений для лечения состояний, опосредованных пролилгидроксилазой HIF, и к способу лечения анемии, включающему введение заявленных соединений
7.2935221QUINOLONE DERIVATIVES
EP – 28.10.2015
Int.Class C07D 215/58Appl.No 13828997Applicant CADILA HEALTHCARE LTDInventor DESAI RANJIT C
The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. [Formula should be inserted here].
8.20150299193QUINOLONE DERIVATIVES
US – 22.10.2015
Int.Class C07D 215/58Appl.No 14652024Applicant Cadila Healthcare LimitedInventor Ranjit C. Desai

The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

embedded image
9.WO/2014/102818NOVEL QUINOLONE DERIVATIVES
WO – 03.07.2014
Int.Class C07D 215/58Appl.No PCT/IN2013/000796Applicant CADILA HEALTHCARE LIMITEDInventor DESAI, Ranjit, C.
The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. [Formula should be inserted here].

 

1 / 1

 

Desidustat
Desidustat.svg
Clinical data
Other names ZYAN1
Identifiers
CAS Number
UNII
Chemical and physical data
Formula C16H16N2O6
Molar mass 332.312 g·mol−1
3D model (JSmol)

Date

CTID Title Phase Status Date
NCT04215120 Desidustat in the Treatment of Anemia in CKD on Dialysis Patients Phase 3 Recruiting 2020-01-02
NCT04012957 Desidustat in the Treatment of Anemia in CKD Phase 3 Recruiting 2019-12-24

////////// DESIDUSTAT, ZYDUS CADILA, COVID 19, CORONA VIRUS, PHASE 3, ZYAN 1,  OXEMIA, APPROVALS 2022, INDIA 2022

breakingnewspharma hashtag on Twitter

AZITHROMYCIN, アジスロマイシン;

March 29, 2020 3:32 am / 1 Comment on AZITHROMYCIN, アジスロマイシン;


Azithromycin

Azithromycin structure.svg

ChemSpider 2D Image | Azithromycin | C38H72N2O12

AZITHROMYCIN

C38H72N2O12,

748.9845

アジスロマイシン;

CAS: 83905-01-5
PubChem: 51091811
ChEBI: 2955
ChEMBL: CHEMBL529
DrugBank: DB00207
PDB-CCD: ZIT[PDBj]
LigandBox: D07486
NIKKAJI: J134.080H
CAS Registry Number: 83905-01-5
CAS Name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one
Additional Names: N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A
Molecular Formula: C38H72N2O12
Molecular Weight: 748.98
Percent Composition: C 60.94%, H 9.69%, N 3.74%, O 25.63%
Literature References: Semi-synthetic macrolide antibiotic; related to erythromycin A, q.v. Prepn: BE 892357; G. Kobrehel, S. Djokic, US 4517359 (1982, 1985 both to Sour Pliva); of the crystalline dihydrate: D. J. M. Allen, K. M. Nepveux, EP 298650; eidem, US 6268489 (1989, 2001 both to Pfizer). Antibacterial spectrum: S. C. Aronoff et al., J. Antimicrob. Chemother. 19, 275 (1987); and mode of action: J. Retsema et al., Antimicrob. Agents Chemother. 31, 1939 (1987). Series of articles on pharmacology, pharmacokinetics, and clinical experience: J. Antimicrob. Chemother. 31, Suppl. E, 1-198 (1993). Clinical trial in prevention of Pneumocystis carinii pneumonia in AIDS patients: M. W. Dunne et al., Lancet 354, 891 (1999). Review of pharmacology and clinical efficacy in pediatric infections: H. D. Langtry, J. A. Balfour, Drugs 56, 273-297 (1998).
Properties: Amorphous solid, mp 113-115°. [a]D20 -37° (c = 1 in CHCl3).
Melting point: mp 113-115°
Optical Rotation: [a]D20 -37° (c = 1 in CHCl3)
 
Derivative Type: Dihydrate
CAS Registry Number: 117772-70-0
Manufacturers’ Codes: CP-62993; XZ-450
Trademarks: Azitrocin (Pfizer); Ribotrex (Fabre); Sumamed (Pliva); Trozocina (Sigma-Tau); Zithromax (Pfizer); Zitromax (Pfizer)
Properties: White crystalline powder. mp 126°. [a]D26 -41.4° (c = 1 in CHCl3).
Melting point: mp 126°
Optical Rotation: [a]D26 -41.4° (c = 1 in CHCl3)
 
Therap-Cat: Antibacterial.

Azithromycin is an antibiotic used for the treatment of a number of bacterial infections.[3] This includes middle ear infections, strep throat, pneumonia, traveler’s diarrhea, and certain other intestinal infections.[3] It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections.[3] Along with other medications, it may also be used for malaria.[3] It can be taken by mouth or intravenously with doses once per day.[3]

Common side effects include nausea, vomiting, diarrhea and upset stomach.[3] An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible.[3] No harm has been found with its use during pregnancy.[3] Its safety during breastfeeding is not confirmed, but it is likely safe.[4] Azithromycin is an azalide, a type of macrolide antibiotic.[3] It works by decreasing the production of protein, thereby stopping bacterial growth.[3]

Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988.[5][6] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] The World Health Organization classifies it as critically important for human medicine.[8] It is available as a generic medication[9] and is sold under many trade names worldwide.[2] The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose.[10] In the United States, it is about US$4 for a course of treatment as of 2018.[11] In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.[12]

Medical uses

Azithromycin is used to treat many different infections, including:

  • Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.[13]
  • Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae[14]
  • Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
  • Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.[15]
  • Trachoma due to C. trachomatis[16]
  • Genital ulcer disease (chancroid) in men due to H. ducrey
  • Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.[17][18]
  • Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.[19]
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy[20]

Bacterial susceptibility

Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.

A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin,[21] but the drug is not widely used as monotherapy due to a low barrier to resistance development.[15] Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.[22]

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Pregnancy and breastfeeding

No harm has been found with use during pregnancy.[3] However, there are no adequate well-controlled studies in pregnant women.[23]

Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects.[4] Nevertheless, it is recommended that the drug be used with caution during breastfeeding.[3]

Airway diseases

Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes.[24] And potentially useful in asthma and sinusitis via this mechanism.[25] Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.[26][27]

Adverse effects

Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported.[28] Clostridium difficile infection has been reported with use of azithromycin.[3] Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.[29]

Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[30][31]

In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.[32][33][34]

Pharmacology

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.[23]

Pharmacokinetics

Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility.[citation needed] Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.[35]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[35] Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.

History

A team of researchers at the pharmaceutical company Pliva in Zagreb, SR Croatia, Yugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980.[6] It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991.[36] Patent protection ended in 2005.[37]

Society and culture

 

Zithromax (azithromycin) 250 mg tablets (CA)

Cost

It is available as a generic medication.[9] The wholesale cost is about US$0.18 to US$2.98 per dose.[10] In the United States it is about US$4 for a course of treatment as of 2018.[11] In India, it is about US$1.70 for a course of treatment.[citation needed]

Available forms

Azithromycin is commonly administered in film-coated tablet, capsule, oral suspension, intravenous injection, granules for suspension in sachet, and ophthalmic solution.[2]

Usage

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[38] whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[39]

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References

  1. ^ Jump up to:ab “Azithromycin Use During Pregnancy”. Drugs.com. 2 May 2019. Retrieved 24 December 2019.
  2. ^ Jump up to:abcdef “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
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  9. ^ Jump up to:ab Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN9781284057560.
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  11. ^ Jump up to:ab “NADAC as of 2018-05-23”. Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
  12. ^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December2018.
  13. ^ Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med. 128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032. PMID26291905.
  14. ^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID17278083.
  15. ^ Jump up to:ab “Gonococcal Infections – 2015 STD Treatment Guidelines”. Archived from the original on 1 March 2016.
  16. ^ Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”. Cochrane Database Syst Rev. 11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3. PMC4661324. PMID26568232.
  17. ^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg. 152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097. PMID25832968.
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  19. ^ Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician. 69 (11): 2713–5. PMID15202704.
  20. ^ Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician. 88 (5): 338–40. PMID24010402.
  21. ^ The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015Archived 18 September 2015 at the Wayback Machine
  22. ^ Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
  23. ^ Jump up to:ab “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
  24. ^ Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine. 107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019. PMID23352223.
  25. ^ Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”. CHEST. 125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52S. ISSN0012-3692. PMID14872001.
  26. ^ Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology. 68 (5): 479–503. doi:10.1007/s00228-011-1161-x. ISSN1432-1041. PMID22105373.
  27. ^ Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”. Mediators of Inflammation. 2012: 584262. doi:10.1155/2012/584262. PMC3388425. PMID22778497.
  28. ^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol. 27 (1): 121–6. doi:10.1177/039463201402700116. PMID24674687.
  29. ^ Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
  30. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy. 26 (1): 147–50. doi:10.1592/phco.2006.26.1.147. PMID16506357.
  31. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
  32. ^ Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”. The New York Times. Archived from the original on 17 May 2012. Retrieved 18 May 2012.
  33. ^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”. New England Journal of Medicine. 366(20): 1881–90. doi:10.1056/NEJMoa1003833. PMC3374857. PMID22591294.
  34. ^ “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
  35. ^ Jump up to:ab “Archived copy”. Archived from the original on 14 October 2014. Retrieved 10 October 2014.
  36. ^ Banić Tomišić, Z. (2011). “The Story of Azithromycin”. Kemija U Industriji. 60 (12): 603–617. ISSN0022-9830. Archived from the original on 8 September 2017.
  37. ^ “Azithromycin: A world best-selling Antibiotic”. http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
  38. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 368 (15): 1461–1462. doi:10.1056/NEJMc1212055. PMID23574140.
  39. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 369 (12): 1175–1176. doi:10.1056/NEJMc1306863. PMID24047077.

External links

Keywords: Antibacterial (Antibiotics); Macrolides.

Azithromycin
Azithromycin structure.svg
Azithromycin 3d structure.png
Clinical data
Trade names Zithromax, Azithrocin, others[2]
Other names 9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
AHFS/Drugs.com Monograph
MedlinePlus a697037
License data
Pregnancy
category
  • AU: B1 [1]
  • US: B (No risk in non-human studies) [1]
Routes of
administration		 By mouth (capsule, tablet or suspension), intravenous, eye drop
Drug class Macrolide antibiotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism Liver
Elimination half-life 11–14 h (single dose) 68 h (multiple dosing)
Excretion Biliary, kidney (4.5%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.126.551 Edit this at Wikidata
Chemical and physical data
Formula C38H72N2O12
Molar mass 748.984 g·mol−1 g·mol−1
3D model (JSmol)

/////////AZITHROMYCIN, Antibacterial, Antibiotics,  Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,

Substances Referenced in Synthesis Path
CAS-RN Formula Chemical Name CAS Index Name
76801-85-9 C37H70N2O12 2-deoxo-9a-aza-9a-homoerythromycin A 1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-eth- yl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-, [2R-(2
R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,1
4R*)]-

90503-04-1 C37H70N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
13S*,14R*)]-13-[(2,6-dideoxy-3-C-methyl3-O-methyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,6,10-tetrahydroxy3,5,8,10,12,14-hexamethyl-13-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-
β-D-xylo-hexopyranosyl] oxy]-1-oxa-6-azacyclopentadecan-15-one
1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-Omethyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,6,10-tetrahydroxy3,5,8,10,12,14-hexamethyl-13-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-β-Dxylo-hexopyranosyl]oxy]-, [2R-(2R*,3S*,4R
*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-

90503-05-2 C38H72N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
13S*,14R*)]-13-[(2,6-dideoxy-3-C-methyl3-O-methyl-α-L-ribo-hexopyranosyl) oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-
β-D-xylo-hexopyranosyl]
oxy]-1-oxa-6-azacyclopentadecan-15-one
6-oxide
1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-Omethyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-βD-xylo-hexopyranosyl]oxy]-, 6-oxide,
[2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,1
3S*,14R*)]-

50-00-0 CH2O formaldehyde Formaldehyde
74-88-4 CH3I methyl iodide Methane, iodoTrade Names

Country Trade Name Vendor Annotation
D Ultreon Pfizer
Zithromax Pfizer Pharma/Gödecke/Parke-Davis
numerous generic preparations
F Azadose Pfizer
Monodose Pfizer
Zithromax Pfizer
GB Zithromax Pfizer
I Azitrocin Bioindustria
Ribotrex Pierre Fabre
Trocozina Sigma-Tau
Zithromax Pfizer
J Zithromac Pfizer
USA Azasite InSite Vision
Zithromax Pfizer as dihydrate

Formulations
cps. 100 mg, 250 mg; Gran. 10%; susp. 200 mg (as dihydrate); tabl. 250 mg
References
Djokic, S. et al.: J. Antibiot. (JANTAJ) 40, 1006 (1987).
a DOS 3 140 449 (Pliva; appl. 12.10.1981; YU-prior. 6.3.1981).
US 4 517 359 (Pliva; 14.5.1985; appl. 22.9.1981; YU-prior. 6.3.1981).
b EP 101 186 (Pliva; appl. 14.7.1983; USA-prior. 19.7.1982, 15.11.1982).
US 4 474 768 (Pfizer; 2.10.1984; prior. 19.7.1982, 15.11.1982).
educt by ring expansion of erythromycin A oxime by Beckmann rearrangement:
Djokic, S. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1986, 1881-1890.
Bright, G.M. et al.: J. Antibiot. (JANTAJ) 41, 1029 (1988). US 4 328 334 (Pliva; 4.5.1982; YU-prior. 2.4.1979).
stable, non-hygroscopic dihydrate: EP 298 650 (Pfizer; appl. 28.6.1988).
medical use for treatment of protozoal infections:
US 4 963 531 (Pfizer; 16.10.1990; prior. 16.8.1988, 10.9.1987).

Molnupiravir, EIDD 2801

March 28, 2020 3:49 am / 7 Comments on Molnupiravir, EIDD 2801


CID 145996610.png

EIDD 2801

Molecular Formula: C13H19N3O7
Molecular Weight: 329.31 g/mol

[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate

UNII YA84KI1VEW

CAS 2349386-89-4

Molnupiravir (development codes MK-4482 and EIDD-2801) is an experimental antiviral drug which is orally active (can be taken orally) and was developed for the treatment of influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication.[1][2] Activity has also been demonstrated against coronaviruses including SARS, MERS and SARS-CoV-2.[3]

The drug was developed at Emory University by the university’s drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop the drug further.

 

Safety Controversy

In April 2020, a whistleblower complaint by former Head of US Biomedical Advanced Research and Development Authority (BARDA) Rick Bright revealed concerns over providing funding for the further development of molnupiravir due to similar drugs having mutagenic properties (producing birth defects).[4] A previous company, Pharmasset, that had investigated the drug’s active ingredient had abandoned it. These claims were denied by George Painter, CEO of DRIVE, noting that toxicity studies on molnupiravir had been carried out and data provided to regulators in the US and UK, who permitted safety studies in humans to move forward in the spring of 2020. Also at this time, DRIVE and Ridgeback Biotherapeutics stated they planned future safety studies in animals.[5]

COVID-19

After being found to be active against SARS-CoV-2 in March 2020, molnupiravir was tested in a preliminary human study for “Safety, Tolerability, and Pharmacokinetics” in healthy volunteers in the UK and US.[6] In June 2020, Ridgeback Biotherapeutics announced it was moving to Phase II trials to test the efficacy of the drug as a treatment for COVID-19.[7] Two trials of small numbers of hospitalized and non-hospitalized patients in the US and the UK were underway in July.[8][9] In late July 2020, and without yet releasing any medical data, Merck, which had been partnering with Ridgeback Biotherapeutics on developing the drug, announced its intention to move molnupiravir to late stage trials beginning in September 2020.[10] On October 19 2020, Merck began a one year Stage 2/3 trial focused on hospitalized patients.[11]

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PATENT

WO 2019113462

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019113462

Example 10: Synthesis of EIDD-2801

A 1L round bottom flask was charged with uridine (25 g, 102.38 mmol) and acetone (700 mL). The reaction mixture was allowed to stir at rt. The slurry was then treated with sulfuric acid (0.27 mL, 5.12 mmol). Stirring was allowed to continue at rt for 18 hours. The reaction was quenched with 100 mL of trimethylamine and was used in the next step without further pruficication.

A 1L round bottom flask was charged with the reaction mixture from the previous reaction. Triethylamine (71.09 mL, 510.08 mmol) and 4-dimethylaminopyridine (0.62 g, 5.1 mmol) were then added. The flask was cooled using an ice bath and then 2-methylpropanoyl 2-methylpropanoate (17.75 g, 112.22 mmol) was slowly added. The reaction mixture was allowed to stir at rt until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 600 mL ethyl acetate and washed with saturated aqueous bicarbonate solution x 2, water x 2 and brine x 2. The organics were dried over sodium sulfate and concentrated under reduced pressure to yield a clear colorless oil. The crude product was used in the next step without further purification.

A 1L round bottom flask was charged with the crude product from above (36 g, 101.59 mmol) and MeCN (406.37 mL). The reaction mixture was allowed to stir until all the starting material was dissolved. Next, 1,2, 4-triazole (50.52 g, 731.46 mmol) was added followed by the addition of N,N-diethylethanamine (113.28 mL, 812.73 mmol). The reaction mixture was allowed to stir at rt until all solids dissolved. The reaction was then cooled to 0°C using an ice bath. Phosphorous oxychloride (24.44 mL, 152.39 mmol) was added slowly. The slurry that formed was allowed to stir under argon while slowly warming to rt. The reaction was then allowed to stir until complete by TLC (EtOAc). The reaction was then quenched by the addition of lOOmL of water. The slurry then became a dark colored solution, which was

then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (2 x 330 g columns). All fractions containing product were collected and concentrated under reduced pressure.

A 500 mL round bottom flask was charged with the product from the previous step (11.8 g, 29.11 mmol) and isopropyl alcohol (150 mL). The reaction mixture was allowed to stir at rt until all solids dissolved. Next, hydroxylamine (1.34 mL, 43.66 mmol) was added and stirring continued at ambient temperature. When the reaction was complete (HPLC) some solvent was removed under high vacuum at ambient temperature. The remaining solvent was removed under reduced pressure at 45°C. The resulting residue was dissolved in EtOAc and was washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield oil. Crystals formed upon standing at rt. The crystals were collected by filtration, washed with ether x 3, and dried in vacuo to provide the product as a white solid.

A 200 mL round bottom flask was charged with the product from the previous step (6.5 g, 17.6 mmol) and formic acid (100 mL, 2085.6 mmol). The reaction mixture was allowed to stir at rt overnight. The progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure at 42°C to yield a clear, pale pink oil. Next, 30 mL of ethanol was added. Solvent was then removed under reduced pressure. MTBE (50 mL) was added to the solid and heated. Next, isopropyl alcohol was added and heating was continued until all solid material dissolved (5 mL). The solution was then allowed to cool and stand at rt.

A solid started to form after about lhr. The solids were collected by filtration, washed with MTBE, and dried in vacuo to yield the EIDD-2801 as a white solid. The filtrate was concentrated under reduced pressure to yield a sticky solid, which was dissolved in a small amount of isopropyl alcohol with heating. The solution was allowed to stand at rt overnight. A solid formed in the flask, which was collected by filtration, rinsed with isopropyl alcohol and MTBE, and dried in vacuo to an additional crop of desired product.

EIDD-2801 (25 g) was dissolved in 250 mL of isopropyl alcohol by heating to 70°C to give a clear solution. The warm solution was polish filtered and filtrate transferred to 2L three neck flask with overhead stirrer. It was warmed back to 70°C and MTBE (250 mL) was slowly added into the flask. The clear solution was seeded and allowed to cool slowly to rt with stirring for 18 hrs. The EIDD-2801 solid that formed was filtered and washed with MTBE and dried at 50°C under vacuum for l8hours. The filtrate was concentrated, redissolved in 50 mL isopropyl alcohol and 40 mL MTBE by warming to give clear solution and allowed to stand at rt to give a second crop of EIDD-2801.

Example 11: General synthesis for Deuteration

389 390

The lactone 389 (0.0325 mol) was added to a dry flask under an argon atmosphere and was then dissolved in dry THF (250 mL). The solution as then cooled to -78°C and a DIBAL-D solution in toluene (0.065 mol) was dropwise. The reaction was allowed to stir at -78°C for 3-4 hours. The reaction was then quenched with the slow addition of water (3 mL). The reaction was then allowed to stir while warming to rt. The mixture was then diluted with two volumes of diethyl ether and was then poured into an equal volume of saturated sodium potassium tartrate solution. The organic layer was separated, dried over MgSCri. filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with hexanes/ethyl acetate. The resulting lactol 390 was then converted to an acetate or benzolyate and subjected to cytosine coupling conditions and then further elaborated to N-hydroxycytidine.

PATENT

WO 2019173602

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019173602

PAPER

ChemRxiv (2020), 1-3.

AND

ChemRxiv (2020), 1-2

PAPER

A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2
Synlett (2020), Ahead of Print.

https://www.thieme-connect.de/media/synlett/EFirst/supmat/sup_st-2020-v0498-l_10-1055_a-1275-2848.pdf

 

A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

To a 20 mL vial was added N-hydroxycytidine acetonide ester 5 (0.25 g, 96% purity) followed by formic acid (4 mL). The resultant solution was stirred at room temperature for 4 h 20 min. Solvent was removed under reduced pressure and fresh EtOH (5 mL) was added. The resultant solution was again concentrated under vacuum to afford an oil. Methyl tert-butyl ether and IPA (5 mL each) were successively added as described earlier for preparation of compound 4 and concentrated to give 0.205 g of crude material (77% assay yield, 79% purity). This material was purified by silica gel column chromatography in 8 % MeOH/ Chloroform to afford 130 mg of EIDD-2801 as a solid (60% isolated yield corrected for purity, 98% purity) 1H NMR (600 MHz, CD3OD): δ 6.91 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.8 Hz, 1H), 5.61 (d, J = 8.2 Hz, 1H), 4.29 (d, J = 3.6 Hz, 2H), 4.14 (t, J = 4.9 Hz, 1H), 4.08 (p, J = 4.9 Hz, 2H), 2.62 (septet, J = 7.0 Hz, 1H), 1.19 (d, J = 7.0 Hz, 6H); 13C NMR (151 MHz, CD3OD): δ 178.6, 151.81, 146.44, 132.04, 99.84, 90.74, 82.88, 74.67, 71.80, 65.23, 35.45, 27.49, 19.65, 19.61.

One-Pot Transamination/Deprotection of 4 to EIDD-2801: To acetonide ester 4 (1.03 g, 77% Purity) in a 100 mL single neck round bottom flask was added hydroxylamine sulfate (1.09 g, 3.2 equiv.) followed by 40% IPA (20 mL prepared by mixing 12 mL of water and 8 mL of 99.5% IPA. The resultant solution was heated to 78˚C (internal temperature 72-73 ˚C) for 23 h upon which time HPLC showed the formation of EIDD-2801. Solvent was removed on a rotary evaporator and isopropanol (20 mL) was then added. The resulting slurry was sonicated for 5 minutes. The insoluble residue was then filtered and the filtrate concentrated under reduced pressure to afford crude material. (1.34 g, 38% purity, 69% assay yield). The resultant material was purified by silica gel chromatography (5-6% MeOH/DCM) to provide pure EIDD-2801 as two fractions (0.26 g, >99% purity, 36% corrected yield) as an yellow solid and 0.27 g (69.5% purity, 26% corrected yield) as a pinkish solid. The lower purity material was subjected to a second column purification again using 7% MeOH/ DCM to afford 0.137 g of material with 90% purity by NMR. The combined yield thus was estimated to be 53%. The 1H NMR spectrum of the product thus obtained matched the one obtained in the sequential approach as outlined above.

SYN

image

image

image

A High‐Yielding Synthesis of EIDD‐2801 from Uridine** - Steiner - - European Journal of Organic Chemistry - Wiley Online Library

A High‐Yielding Synthesis of EIDD‐2801 from Uridine** - Steiner - - European Journal of Organic Chemistry - Wiley Online Library

EIDD-2801 was isolated in 69% yield (307 mg) and ≥99% purity as a white
solid.
1H-NMR (300 MHz, MeOH-d4) δ 6.91 (d, J= 8.3 Hz, 1H), 5.82 (d, J= 4.8 Hz, 1H), 5.61 (d, J= 8.2 Hz, 1H), 4.29
(d, J= 3.6 Hz, 2H), 4.15-4.07 (m, 3H), 2.62 (sept, J= 7.0 Hz, 1H), 1.18 (d, J= 7.0 Hz 6H);

13C-NMR (75 MHz,
MeOH-d4Ϳ δ 178.2, 151.5, 146.1, 131.7, 99.5, 90.4, 82.5, 74.3, 71.5, 64.9, 35.1, 19.3, 19.3. The NMR data
is in agreement with previously published values.[2] HRMS (ESI, positive mode): m/z [M + H]+
Calcd for
[C13H20N3O7 +H]+
: 330.1296, found: 330.1297.

SYN

https://www.chemistryviews.org/details/ezine/11278339/High-Yielding_Synthesis_of_Antiviral_Drug_Candidate.html

C. Oliver Kappe, Doris Dallinger, University of Graz, Austria, and colleagues have developed an improved synthesis of EIDD-2801 from uridine (pictured below) by strategically reordering the synthetic steps. The reaction sequence starts with the activation of uridine with 1,2,4-triazole and continues with a telescoped acetonide protection/esterification and a telescoped hydroxyamination/acetonide deprotection. Telescoped reaction sequences consist of two or more than one one-pot procedures that are performed back-to-back without a work-up step in-between. A continuous flow process was used for the final acetonide deprotection, which improved selectivity and reproducibility.

SYN

https://www.frontiersin.org/articles/10.3389/fphar.2020.01013/full

Frontiers | Turning the Tide: Natural Products and Natural-Product-Inspired Chemicals as Potential Counters to SARS-CoV-2 Infection | Pharmacology

 

SYN

http://www.rsc.org/suppdata/d0/cc/d0cc05944g/d0cc05944g1.pdf

To a solution of 5’-O-isobutyrylcytidine 4 (1.0 g, 90% purity, 2.87 mmol, 1.0 eq) in 2-propanol (15 ml), hydroxylamine sulphate (2.12 g, 12.93 mmol, 4.5 eq.) was added and reaction was stirred for 20 h at 78 C. Upon completion, the reaction was cooled to room temperature. The organic layer (upper layer) was separated from biphasic reaction mixture. The aqueous layer was washed with 2-propanol (2 X 5 mL). The combined organic layer was concentrated using rotary evaporation and the crude was purified by column chromatography with a gradient of 2-15% methanol in dichloromethane to yield EIDD-2801 (1) as a white solid (963 mg, 94% purity, 96% yield). 1H NMR (600 MHz, D2O) δ 6.98 (d, J = 8.3 Hz, 1H), 5.87 (d, J = 5.0 Hz, 1H), 5.78 (d, J = 8.2 Hz, 1H), 4.39 – 4.33 (m, 3H), 4.28 (dd, J = 6.6, 3.4 Hz, 2H), 2.69 (hept, J = 7.0 Hz, 1H), 1.17 (d, J = 3.7 Hz, 3H), 1.16 (d, J = 3.7 Hz, 3H). 13C NMR (126 MHz, D2O) δ 18.1, 18.2, 33.9, 48.8, 63.6, 69.6, 72.5, 81.0, 88.5, 98.8, 131.1, 151.1, 179.8 ppm; LRMS: 330.1 [M+H]+ ; HRMS (ESI): calcd. for C13H19N3O7 [M+H]+ 330.1296, found 330.1302; Purity: 94% (assessed by qNMR).

https://pubs.rsc.org/en/content/articlehtml/2020/cc/d0cc05944g

A concise route to MK-4482 (EIDD-2801) from cytidine,Chemical Communications - X-MOL

A concise route to MK-4482 (EIDD-2801) from cytidine - Chemical Communications (RSC Publishing) DOI:10.1039/D0CC05944G

image file: d0cc05944g-f2.tif
  Fig. 2 A new route to MK-4482 from cytidine.

References

  1. ^ Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. (October 2019). “Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia”. Science Translational Medicine. 11 (515): eaax5866. doi:10.1126/scitranslmed.aax5866. PMC 6848974. PMID 31645453.
  2. ^ Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK (April 2020). “Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model”. Translational Research. 218: 16–28. doi:10.1016/j.trsl.2019.12.002. PMID 31945316.
  3. ^ Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, et al. (April 2020). “An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice”. Science Translational Medicine. 12 (541): eabb5883. doi:10.1126/scitranslmed.abb5883. PMC 7164393. PMID 32253226.
  4. ^ Halford, Bethany. “An emerging antiviral takes aim at COVID-19”. Retrieved 1 August 2020.
  5. ^ Cohen, Jon; Piller, Charles (13 May 2020). “Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug”. Science. Retrieved 1 August 2020.
  6. ^ “COVID-19 First In Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers”. ClinicalTrials.gov. Retrieved 1 June 2020.
  7. ^ “Ridgeback Biotherapeutics Announces Launch of Phase 2 Trials Testing EIDD-2801 as Potential Treatment for COVID-19”. Business Wire. Retrieved 4 July 2020.
  8. ^ “A Safety, Tolerability and Efficacy of EIDD-2801 to Eliminate Infectious Virus Detection in Persons With COVID-19”. ClinicalTrials.gov. Retrieved 4 July 2020.
  9. ^ “The Effect of EIDD-2801 on Viral Shedding of SARS-CoV-2 (COVID-19)”. ClinicalTrials.gov. Retrieved 4 July 2020.
  10. ^ Court, Emma (31 July 2020). “Merck pushes ahead on COVID-19 treatment, vaccines”. Retrieved 31 July 2020.
  11. ^ ClinicaL trials register : Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)

Story image

Electron microscope image of SARS virus in a tissue culture isolate, courtesy of CDC Public Health Image Library.

The drug EIDD-1931 was effective against SARS and MERS viruses in the laboratory, and a modified version (EIDD-2801) could potentially be valuable against 2019-nCoV.

https://news.emory.edu/stories/2020/02/coronavirus_eidd/index.html

Emory, collaborators testing antiviral drug as potential treatment for coronaviruses

09812-buscon5-emory.jpg

An antiviral compound discovered at Emory University could potentially be used to treat the new coronavirus associated with the outbreak in China and spreading around the globe. Drug Innovation Ventures at Emory (DRIVE), a non-profit LLC wholly owned by Emory, is developing the compound, designated EIDD-2801.

In testing with collaborators at the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center, the active form of EIDD-2801, which is called EIDD-1931, has shown efficacy against the related coronaviruses SARS (Severe Acute Respiratory Syndrome)- and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). Some of the data was recently published in Journal of Virology.

EIDD-2801 is an oral ribonucleoside analog that inhibits the replication of multiple RNA viruses, including respiratory syncytial virus, influenza, chikungunya, Ebola, Venezuelan equine encephalitis virus, and Eastern equine encephalitis viruses.

“We have been planning to enter human clinical tests of EIDD-2801 for the treatment of influenza, and recognized that it has potential activity against the current novel coronavirus,” says George Painter, PhD, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “Based on the drug’s broad-spectrum activity against viruses including influenza, Ebola and SARS-CoV/MERS-CoV, we believe it will be an excellent candidate.”

“Our studies in the Journal of Virology show potent activity of the EIDD-2801 parent compound against multiple coronaviruses including SARS and MERS,” says Mark Denison, MD, the Stahlman Professor of Pediatrics and director of pediatric infectious diseases at Vanderbilt University School of Medicine.  “It also has a strong genetic barrier to development of viral resistance, and its oral bioavailability makes it a candidate for use during an outbreak.”

“Generally speaking, seasonal flu is still a much more common threat than this coronavirus, however, novel emerging coronaviruses represent a considerable threat to global health as evidenced by the new 2019-nCoV,” said Ralph Baric, PhD, an epidemiology professor at the University of North Carolina’s Gillings School of Global Public Health. “But the reason the new coronavirus is so concerning is that it’s much more likely to be deadly than the flu – fatal for about one in 25 people versus one in 1,000 for the flu.”

The development of EIDD-2801 has been funded in whole or in part with Federal funds from  the National Institute of Allergy and Infectious Diseases (NIAID), under contract numbers HHSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA), under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075, for the treatment of Influenza, coronavirus, chikungunya,  and Venezuelan equine encephalitis virus.

About DRIVE:  DRIVE is a non-profit LLC wholly owned by Emory started as an innovative approach to drug development.  Operating like an early stage biotechnology company, DRIVE applies focus and industry development expertise to efficiently translate discoveries to address viruses of global concern. Learn more at: http://driveinnovations.org/

Emory-discovered antiviral is poised for COVID-19 clinical trials

The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans

https://cen.acs.org/biological-chemistry/infectious-disease/Emory-discovered-antiviral-poised-COVID/98/i12?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN&fbclid=IwAR1yIuxNNrelRhKBdPp2hz3oRlqFrDtFYgTPEEORPf1G2R30RIhPIYD9Iwg

Asmall-molecule antiviral discovered by Emory University chemists could soon start human testing against COVID-19, the respiratory disease caused by the novel coronavirus. That’s the plan of Ridgeback Biotherapeutics, which licensed the compound, EIDD-2801, from an Emory nonprofit.

EIDD-2801 works similarly to Gilead Sciences’ remdesivir, an unapproved drug that was developed for the Ebola virus and is being studied in five Phase III trials against COVID-19. Both molecules are nucleoside analogs that metabolize into an active form that blocks RNA polymerase, an essential component of viral replication.

But remdesivir can only be given intravenously, meaning it would be difficult to deploy widely. In contrast, EIDD-2801 can be taken in pill form, says Mark Denison, a coronavirus expert and director of the infectious diseases division at Vanderbilt Medical School. Denison partnered with Emory and researchers at the University of North Carolina to test the compound against coronaviruses.

 

EIDD-2801 has other promising features. Many antivirals work by introducing errors into the viral genome, but, unlike other viruses, coronaviruses can fix some mistakes. In lab experiments, EIDD-2801 “was able to overcome the coronavirus proofreading function,” Denison says.

He also notes that while remdesivir and EIDD-2801 both block RNA polymerase, they appear to do it in different ways, meaning they could be complementary.

Unlike remdesivir, EIDD-2801 lacks human safety data. Ridgeback founder and CEO Wendy Holman says she expects the US Food and Drug Administration to give the green light for a Phase I study in COVID-19 infections within “weeks, not months.”

“weeks, not months.”

Molnupiravir
MK-4482.svg
Clinical data
Other names MK-4482, EIDD-2801
Legal status
Legal status
  • US: Investigational drug
Identifiers
CAS Number
PubChem CID
UNII
Chemical and physical data
Formula C13H19N3O7
Molar mass 329.31 g·mol−1
3D model (JSmol)

////////EIDD 2801, EMORY, CORONA VIRUS,  COVID 19, mk 4482, molnupiravir, merck

CC(C)C(=O)OC[C@H]2O[C@@H](N1C=CC(=NC1=O)NO)[C@H](O)[C@@H]2O

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Application IdApplication NumberApplication DateCountryTitle
US3338280141717017208.02.2021USN4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
US3052515951675577907.12.2018USN4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
WO2021159044PCT/US2021/01698407.02.2021WON4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
WO2021137913PCT/US2020/05485708.10.2020WO4′-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين

March 25, 2020 8:44 am / 1 Comment on CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين


Chloroquine

Chloroquine.svg

CHLOROQUINE

N4-(7-Chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine
Хлорохин [Russian] [INN]
クロロキン [Japanese]
كلوروكين [Arabic] [INN]
Formula
C18H26ClN3
CAS
54-05-7
Mol weight
319.8721
CAS Registry Number: 54-05-7
CAS Name: N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine
Additional Names: 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
Manufacturers’ Codes: SN-7618; RP-3377
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87
Percent Composition: C 67.59%, H 8.19%, Cl 11.08%, N 13.14%
Literature References: Prepd by the condensation of 4,7-dichloroquinoline with 1-diethylamino-4-aminopentane: DE 683692 (1939); H. Andersag et al., US 2233970 (1941 to Winthrop); Surrey, Hammer, J. Am. Chem. Soc. 68, 113 (1946). Review: Hahn in Antibiotics vol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 58-78. Comprehensive description: D. D. Hong, Anal. Profiles Drug Subs. 5, 61-85 (1976). Comparative clinical trial with dapsone in rheumatoid arthritis: P. D. Fowler et al., Ann. Rheum. Dis. 43, 200 (1984); with penicillamine: T. Gibson et al., Br. J. Rheumatol. 26, 279 (1987).
Properties: mp 87°.
Melting point: mp 87°
Image result for CHLOROQUINE
Derivative Type: Diphosphate
CAS Registry Number: 50-63-5
Trademarks: Arechin (Polfa); Avloclor (AstraZeneca); Malaquin (Ahn Gook); Resochin (Bayer)
Molecular Formula: C18H26ClN3.2H3PO4
Molecular Weight: 515.86
Percent Composition: C 41.91%, H 6.25%, Cl 6.87%, N 8.15%, P 12.01%, O 24.81%
Properties: Bitter, colorless crystals. Dimorphic. One modification, mp 193-195°; the other, mp 215-218°. Freely sol in water; pH of 1% soln about 4.5; less sol at neutral and alkaline pH. Stable to heat in solns of pH 4.0 to 6.5. Practically insol in alcohol, benzene, chloroform, ether.
Melting point: mp 193-195°; mp 215-218°
Derivative Type: Sulfate
CAS Registry Number: 132-73-0
Trademarks: Aralen (Sanofi-Synthelabo); Nivaquine (Aventis)
Molecular Formula: C18H26ClN3.H2SO4
Molecular Weight: 417.95
Percent Composition: C 51.73%, H 6.75%, Cl 8.48%, N 10.05%, S 7.67%, O 15.31%
Therap-Cat: Antimalarial; antiamebic; antirheumatic. Lupus erythematosus suppressant.
Keywords: Antiamebic; Antiarthritic/Antirheumatic; Antimalarial; Lupus Erythematosus Suppressant.

Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects.[1] A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection).[1] Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.[verification needed][1][2] However, the agent is not without the possibility of serious side effects at standard doses,[1][3] and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication.[1] Chloroquine is also used as a medication for rheumatoid arthritis, lupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines).[1] Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.[4]

Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs.[1] As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell.[1] In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism.[1] Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms.[5] Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,[clarification needed] loss of appetite, diarrhea, and skin rash.[clarification needed][1] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.[1][6]

Chloroquine was discovered in 1934 by Hans Andersag.[7][8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[9] It is available as a generic medication.[1] The wholesale cost in the developing world is about US$0.04.[10] In the United States, it costs about US$5.30 per dose.[1]

Medical uses

Malaria

Distribution of malaria in the world:[11]
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.[12][13]

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.[14] In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.[15]

Amebiasis

In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.[1]

Side effects

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.[17][18]

  • Unwanted/uncontrolled movements (including tongue and face twitching) [17]
  • Deafness or tinnitus.[17]
  • Nausea, vomiting, diarrhea, abdominal cramps[18]
  • Headache.[17]
  • Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)[17][18]
  • Signs of serious infection (such as high fever, severe chills, persistent sore throat)[17]
  • Skin itchiness, skin color changes, hair loss, and skin rashes.[18][19]
    • Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.[20]
  • Unpleasant metallic taste
    • This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.[21]
  • Chloroquine retinopathy
  • Electrocardiographic changes[22]
    • This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
  • Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis.[24] Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body.[23][25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.[24]

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.[23]

Drug interactions

Chloroquine has a number of drug-drug interactions that might be of clinical concern:[citation needed]

Overdose

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small.[26] One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.[23]

An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg).[27] The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.[27]

Pharmacology

Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.

Mechanism of action

Medical quinolines

Malaria

Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases,[28][29] autophagy, and apoptosis.[30]

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.[citation needed]

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.[citation needed]

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. [31] Parasites that do not form hemozoin are therefore resistant to chloroquine.[32]

Resistance in malaria[edit source]

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole.[33] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.[34] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.[citation needed]

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.[35]

Antiviral

Chloroquine has antiviral effects.[36] It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.[37][38]

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.[39][40]

Other

Chloroquine inhibits thiamine uptake.[41] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru the indigenous people extracted the bark of the Cinchona plant[42] trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria.[43] The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”.[44] It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.[45]

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.[46]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.[47]

Other animals

Chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum.[48]

Research

COVID-19

See also: Coronavirus disease 2019 § Research, and COVID-19 drug repurposing research

In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted.[49] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.[50][51]

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.[52][53] These agencies noted contraindications for people with heart disease or diabetes.[54] Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.[55] Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.”[56] Self-medication with chloroquine has caused one known fatality.[57]

On 24 March 2020, NBC News reported[58] a fatality due to misuse of a chloroquine product used to control fish parasites.[59]

Other viruses

In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.[60]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.[61]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.[62][63] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

 

 

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  36. ^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases. 3(11): 722–7. doi:10.1016/s1473-3099(03)00806-5. PMID 14592603.
  37. ^ Al-Bari MA (February 2017). “Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases”. Pharmacology Research & Perspectives. 5 (1): e00293. doi:10.1002/prp2.293. PMC 5461643. PMID 28596841.
  38. ^ Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV (November 2002). “Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus”. Journal of Virology. 76 (22): 11440–6. doi:10.1128/JVI.76.22.11440-11446.2002. PMC 136743. PMID 12388705.
  39. ^ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (1 October 2014). “Chloroquine is a zinc ionophore”. PloS One. 9(10): e109180. doi:10.1371/journal.pone.0109180. PMC 4182877. PMID 25271834.
  40. ^ te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (November 2010). “Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture”. PLoS Pathogens. 6 (11): e1001176. doi:10.1371/journal.ppat.1001176. PMC 2973827. PMID 21079686.
  41. ^ Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, et al. (2012). “Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy”. PLOS Genetics. 8 (11): e1003083. doi:10.1371/journal.pgen.1003083. PMC 3510038. PMID 23209439.
  42. ^ Fern, Ken (2010–2020). “Cinchona officinalis – L.” Plans for a Future. Archived from the original on 25 August 2017. Retrieved 2 February 2020.
  43. ^ V. Kouznetsov, Vladímir (2008). “Antimalarials: construction of molecular hybrids based on chloroquine” (PDF). Universitas Scientiarum: 1. Archived (PDF) from the original on 22 February 2020. Retrieved 22 February 2020 – via scielo.
  44. ^ Krafts K, Hempelmann E, Skórska-Stania A (July 2012). “From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy”. Parasitology Research. 111 (1): 1–6. doi:10.1007/s00436-012-2886-x. PMID 22411634.
  45. ^ “The History of Malaria, an Ancient Disease”. Centers for Disease Control. 29 July 2019. Archived from the original on 28 August 2010.
  46. ^ “Chloroquine”. nih.gov. National Institutes of Health. Retrieved 24 March 2020.
  47. ^ “Ipca Laboratories: Formulations – Branded”. Archived from the original on 6 April 2019. Retrieved 14 March 2020.
  48. ^ Francis-Floyd, Ruth; Floyd, Maxine R. “Amyloodinium ocellatum, an Important Parasite of Cultured Marine Fish” (PDF). agrilife.org.
  49. ^ “Could an old malaria drug help fight the new coronavirus?”. asbmb.org. Archived from the original on 6 February 2020. Retrieved 6 February 2020.
  50. ^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications. 323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085. PMID 15351731.
  51. ^ Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 11:105938. doi:10.1016/j.ijantimicag.2020.105938 PMID 32171740
  52. ^ “Physicians work out treatment guidelines for coronavirus”. m.koreabiomed.com (in Korean). 13 February 2020. Archivedfrom the original on 17 March 2020. Retrieved 18 March 2020.
  53. ^ “Azioni intraprese per favorire la ricerca e l’accesso ai nuovi farmaci per il trattamento del COVID-19”. aifa.gov.it (in Italian). Retrieved 18 March 2020.
  54. ^ “Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions… from PDR.net”. http://www.pdr.net. Archivedfrom the original on 18 March 2020. Retrieved 19 March 2020.
  55. ^ Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. (March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseases. doi:10.1093/cid/ciaa237. PMID 32150618.
  56. ^ Gao J, Tian Z, Yang X (February 2020). “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies”. Bioscience Trends. 14: 72–73. doi:10.5582/bst.2020.01047. PMID 32074550. Archived from the original on 19 March 2020. Retrieved 19 March 2020.
  57. ^ Edwards, Erika; Hillyard, Vaughn (23 March 2020). “Man dies after ingesting chloroquine in an attempt to prevent coronavirus”. NBC News. Retrieved 24 March 2020.
  58. ^ “A man died after ingesting a substance he thought would protect him from coronavirus”. NBC News. Retrieved 25 March 2020.
  59. ^ “Banner Health experts warn against self-medicating to prevent or treat COVID-19”. Banner Health (Press release). 23 March 2020. Retrieved 25 March 2020.
  60. ^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications. 323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085. PMID 15351731.
  61. ^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases. 3(11): 722–7. doi:10.1016/S1473-3099(03)00806-5. PMID 14592603.
  62. ^ Savarino A, Lucia MB, Giordano F, Cauda R (October 2006). “Risks and benefits of chloroquine use in anticancer strategies”. The Lancet. Oncology. 7 (10): 792–3. doi:10.1016/S1470-2045(06)70875-0. PMID 17012039.
  63. ^ Sotelo J, Briceño E, López-González MA (March 2006). “Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial”. Annals of Internal Medicine. 144 (5): 337–43. doi:10.7326/0003-4819-144-5-200603070-00008. PMID 16520474.
    “Summaries for patients. Adding chloroquine to conventional chemotherapy and radiotherapy for glioblastoma multiforme”. Annals of Internal Medicine. 144 (5): I31. March 2006. doi:10.7326/0003-4819-144-5-200603070-00004. PMID 16520470.

External links

“Chloroquine”. Drug Information Portal. U.S. National Library of Medicine.

Chloroquine
Chloroquine.svg
Chloroquine 3D structure.png
Clinical data
Pronunciation /ˈklɔːrəkwɪn/
Trade names Aralen, other
Other names Chloroquine phosphate
AHFS/Drugs.com Monograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 1-2 months
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.175 Edit this at Wikidata
Chemical and physical data
Formula C18H26ClN3
Molar mass 319.872 g·mol−1
3D model (JSmol)

//////////////CHLOROQUINE,, クロロキン, ANTIMALARIAL, COVID 19, CORONA VIRUS, Хлорохин , クロロキン , كلوروكين

Niclosamide, ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , 

March 24, 2020 4:02 am / Leave a comment


 

Niclosamide.svg

Niclosamide

ChemSpider 2D Image | Niclosamide | C13H8Cl2N2O4

Niclosamide

ニクロサミド;

Formula
C13H8Cl2N2O4
cas
50-65-7
Mol weight
327.1196
никлосамид [Russian] [INN]
نيكلوساميد [Arabic] [INN]
氯硝柳胺 [Chinese] [INN]
Niclosamide [BSI] [INN] [ISO] [USAN] [Wiki]
1532
2′,5-Dichlor-4′-nitro-salizylsaeureanilid [German]
2′,5-Dichloro-4′-nitrosalicylanilide
200-056-8 [EINECS]
2820605
50-65-7 [RN]
]
5-Chlor-N-(2-chlor-4-nitrophenyl)-2-hydroxybenzolcarboxamid
5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

CAS Registry Number: 50-65-7

CAS Name: 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
Additional Names: 2¢,5-dichloro-4¢-nitrosalicylanilide; 5-chloro-N-(2¢-chloro-4¢-nitrophenyl)salicylamide; 5-chlorosalicyloyl-(o-chloro-p-nitranilide); N-(2¢-chloro-4¢-nitrophenyl)-5-chlorosalicylamide
Manufacturers’ Codes: Bayer 2353
Trademarks: Cestocide (Bayer); Niclocide (Miles); Ruby (Spencer); Trédémine (RPR); Yomesan (Bayer)
Molecular Formula: C13H8Cl2N2O4
Molecular Weight: 327.12
Percent Composition: C 47.73%, H 2.47%, Cl 21.68%, N 8.56%, O 19.56%
Literature References: Prepn: GB 824345 (1959 to Bayer), C.A. 54, 15822b (1960). See also: E. Schraufstätter, R. Gönnert, US 3079297; R. Strufe et al., US 3113067 (both 1963 to Bayer); Bekhli et al., Med. Prom. SSSR 1965, 25.
Properties: Pale yellow crystals, mp 225-230°. Practically insol in water. Sparingly sol in ethanol, chloroform, ether.
Melting point: mp 225-230°
Derivative Type: Ethanolamine salt
CAS Registry Number: 1420-04-8
Additional Names: Clonitrilide
Trademarks: Bayluscid (Bayer)
Molecular Formula: C13H8Cl2N2O4.C2H7NO
Molecular Weight: 388.20
Percent Composition: C 46.41%, H 3.89%, Cl 18.27%, N 10.82%, O 20.61%
Properties: Yellow-brown solid, mp 204°.
Melting point: mp 204°
Use: The ethanolamine salt as a molluscicide.
Therap-Cat: Anthelmintic (Cestodes).
Therap-Cat-Vet: Anthelmintic (Cestodes).
Keywords: Anthelmintic (Cestodes).

Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations.[2] This includes diphyllobothriasis, hymenolepiasis, and taeniasis.[2] It is not effective against other worms such as pinworms or roundworms.[3] It is taken by mouth.[2]

Side effects include nausea, vomiting, abdominal pain, and itchiness.[2] It may be used during pregnancy and appears to be safe for the baby.[2] Niclosamide is in the anthelmintic family of medications.[3] It works by blocking the uptake of sugar by the worm.[4]

Niclosamide was discovered in 1958.[5] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] The wholesale cost in the developing world is about 0.24 USD for a course of treatment.[7] It is not commercially available in the United States.[3] It is effective in a number of other animals.[4]

Side effects

Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness.[2] Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.[citation needed]

Mechanism of action

Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the tapeworm.[8]

Other applications

Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae,[9][10] as a molluscide,[11] and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population.[11] Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.[12]

Research

Niclosamide is being studied in a number of types of cancer.[13] Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.[14]

syn

https://www.sciencedirect.com/science/article/pii/S0099542805320028

Image result for niclosamide

References

  1. ^ Jump up to:a b c d e f World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 81, 87, 591. hdl:10665/44053. ISBN 9789241547659.
  2. ^ Jump up to:a b c “Niclosamide Advanced Patient Information – Drugs.com”. http://www.drugs.com. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. ^ Jump up to:a b Jim E. Riviere; Mark G. Papich (13 May 2013). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 1096. ISBN 978-1-118-68590-7. Archived from the original on 10 September 2017.
  4. ^ Mehlhorn, Heinz (2008). Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 483. ISBN 9783540489948. Archived from the original on 2016-12-20.
  5. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ^ “Niclosamide”. International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 1 December 2016.
  7. ^ Weinbach EC, Garbus J (1969). “Mechanism of action of reagents that uncouple oxidative phosphorylation”. Nature. 221 (5185): 1016–8. doi:10.1038/2211016a0. PMID 4180173.
  8. ^ Boogaard, Michael A. Delivery Systems of Piscicides “Request Rejected”(PDF). Archived (PDF) from the original on 2017-06-01. Retrieved 2017-05-30.
  9. ^ Verdel K.Dawson (2003). “Environmental Fate and Effects of the Lampricide Bayluscide: a Review”. Journal of Great Lakes Research. 29 (Supplement 1): 475–492. doi:10.1016/S0380-1330(03)70509-7.
  10. ^ Jump up to:a b “WHO Specifications And Evaluations. For Public Health Pesticides. Niclosamide” (PDF).[dead link]
  11. ^ “Researchers find new methods to combat invasive zebra mussels”. The Minnesota Daily. Retrieved 2018-11-19.
  12. ^ “Clinical Trials Using Niclosamide”. NCI. Retrieved 20 March 2019.
  13. ^ Rajamuthiah R, Fuchs BB, Conery AL, Kim W, Jayamani E, Kwon B, Ausubel FM, Mylonakis E (April 2015). Planet PJ (ed.). “Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus”. PLoS ONE. 10 (4): e0124595. doi:10.1371/journal.pone.0124595. ISSN 1932-6203. PMC 4405337. PMID 25897961.

External links

 

Niclosamide

Niclosamide
Niclosamide.svg
Clinical data
Trade names Niclocide, Fenasal, Phenasal, others[1]
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration		 By mouth
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.052 Edit this at Wikidata
Chemical and physical data
Formula C13H8Cl2N2O4
Molar mass 327.119 g/mol g·mol−1
3D model (JSmol)
Melting point 225 to 230 °C (437 to 446 °F)

//////////Niclosamide ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , covid 19, corona virus

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