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ORGANIC SPECTROSCOPY

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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 GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 year tenure till date Dec 2017, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

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Colchicine


Skeletal formula of colchicine

Colchicine

CAS Registry Number: 64-86-8CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44

CSIR-Laxai Life Sciences get DCGI nod for clinical trials Colchicine on Covid patients

laxai

https://www.thehindubusinessline.com/news/csir-laxai-life-sciences-get-dcgi-nod-for-clinical-trials-colchicine-on-covid-patients/article34795126.ece?fbclid=IwAR21MOLpbdhdTR-owHYYWC-xG1DZEECOg1PcYRoMICoAwVkV7TWO2CgZQWA

It is an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines

The Council of Scientific & Industrial Research (CSIR), and Laxai Life Sciences Pvt. Ltd. Hyderabad, have obtained approval from the Drug Controller General of India (DCGI) to undertake a two-arm phase-II clinical trial of the drug Colchicine for Covid-19 treatment.

The partner CSIR institutes in this important clinical trial are the CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad and CSIR-Indian Institute of Integrative Medicine (IIIM), Jammu.

According to Ram Vishwakarma, advisor to DG-CSIR, colchicine, in combination with standard of care, will be an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines, leading to faster recovery.

A number of global studies have confirmed now that cardiac complications during the course of Covid-19 infections and post-covid syndrome are leading to the loss of many lives, and it is essential to look for new or repurposed drugs.

laxai

VAMI MADDIPATLA

CHAIRMAN AND MD,  LAXAI

A visionary & an entrepreneur with 17 years of experience in technology and bio-pharma industries. Founder and ex-CEO of LAXAI Pharma Ltd – a clinical data services company based in NJ, USA. Past employment: Pfizer, Wyeth Pharmaceuticals, Johnson & Johnson and Deloitte.

Vamsi provides a unique blend of operational and financial experience – along with a strong and expansive network of key influencers, industry experts and financial partners. He delivers a visionary understanding of client challenges and opportunities, and the instinctive ability to facilitate collaboration between the right people to turn strategic concepts into actionable plans – and, ultimately, into business results.

Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad) and Dr. DS Reddy (Director, CSIR-IIIM, Jammu), the two partner institutes from CSIR said that they were looking forward to the outcome of this Phase II clinical efficacy trial on Colchicine, which may lead to life-saving intervention in the management of hospitalised patients.

srivari

Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad)

ds-reddy

Dr. DS Reddy (Director, CSIR-IIIM, Jammu)

India is one of the largest producers of this key drug and if successful, it will be made available to the patients at an affordable cost.

According to Ram Upadhayay, CEO, Laxai the enrollment of patients has already begun at multiple sites across India and the trial is likely to be completed in the next 8-10 weeks.

The drug can be made available to the large population of India based on the results of this trial and regulatory approval, he added.

Recent clinical studies have reported in leading medical journals about colchicine being associated with a significant reduction in the rates of recurrent pericarditis, post-pericardiotomy syndrome, and peri-procedural atrial fibrillation following cardiac surgery and atrial fibrillation ablation, according to a release.

laxai

Ram Upadhayaya, PhD

Chief Executive Officer, LAXAI

Ram Upadhayaya, CEO of Laxai Life Sciences, brings with him more than two decades of R&D experience spanning both academia and industry. A Ph. D in synthetic organic Chemistry, Ram has held key positions with leading international drug discovery organizations such as Bioimics AB Sweden, and Lupin India. Apart from his industrial background, Ram has been deeply associated with academic research. He was associated with Institute of Molecular Medicine, India as Principal Scientist as well as Uppsala University, Sweden in the capacity of Assistant Professor (Forskare). During these stints he significantly contributed to the development of novel therapeutics against infectious diseases such as AIDS and TB.

Ram has 10 international patents to his credit and has authored 25 peer reviewed publications. He is concurrently a consultant to the scientific advisory committee of the Principal Scientific Advisor, Government of India.

laxai
Raghava Reddy Kethiri, PhD, LAXAI
Chief Scientific Officer

25+ years of experience at various leadership positions in Biotech, CRO and Universities; Ex Karlsruhe Institute of Technology (KIT), Technical University of Dresden (TUD), JADO Technologies , Dresden, Germany, Jubilant Biosys, India

Delivered several leads, optimised leads and PCCs/DCs across Oncology, Pain, CNS, MD and Antibacterial therapeutics areas for global pharmaceutical companies. Co-Inventor of two clinical candidates ASN-001 ( NCT 02349139) for Metastatic Castration Resistant Prostrate Cancer & ASN-007 (NCT 03415126) for metastatic KRAS, NRAS & HRAS mutated solid tumors. Co-authored over 60 publications/patents (US/EU/Indian)

Colchicine

CAS Registry Number: 64-86-8

CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44Percent Composition: C 66.15%, H 6.31%, N 3.51%, O 24.03%

Literature References: A major alkaloid of Colchicum autumnale L., Liliaceae. Extraction procedure: Chemnitius, J. Prakt. Chem. [II] 118, 29 (1928); F. E. Hamerslag, Technology and Chemistry of Alkaloids (New York, 1950) pp 66-80. Structure: Dewar, Nature155, 141 (1945); King et al.,Acta Crystallogr.5, 437 (1952); Horowitz, Ullyot, J. Am. Chem. Soc.74, 487 (1952). Crystal structure: L. Lessinger, T. N. Margulis, Acta Crystallogr.B34, 578 (1978). 
Total synthesis: Schreiber et al.,Helv. Chim. Acta44, 540 (1961); Van Tamelen et al.,Tetrahedron14, 8 (1961); Nakamura, Chem. Pharm. Bull.8, 843 (1960); Sunagawa et al.,ibid.9, 81 (1961); 10, 281 (1962); Scott et al.,Tetrahedron21, 3605 (1965); Woodward, Harvey Lectures, Ser. 59 (Academic Press, New York, 1965) p 31; Kotani et al.,Chem. Commun.1974, 300; D. A. Evans et al.,J. Am. Chem. Soc.103, 5813 (1981). 
Biosynthesis: Leete, Tetrahedron Lett.1965, 333; Battersby et al.,J. Chem. Soc.1964, 4257; Hill, Unrau, Can. J. Chem.43, 709 (1965). Tubulin-binding activity: J. M. Andreu, S. N. Timasheff, Proc. Natl. Acad. Sci. USA79, 6753 (1982). Toxicity: S. J. Rosenbloom, F. C. Ferguson, Toxicol. Appl. Pharmacol.13, 50 (1968); R. P. Beliles, ibid.23, 537 (1972). Clinical evaluations in cirrhosis of the liver: M. M. Kaplan et al.,N. Engl. J. Med.315, 1448 (1986); D. Kershenobich et al.,ibid.318, 1709 (1988). Bibliography of early literature: Eigsti, Lloydia10, 65 (1947). 
Monograph: O. J. Eigsti, P. Dustin, Jr., Colchicine in Agriculture, Medicine, Biology and Chemistry (Iowa State College Press, Ames, Iowa, 1955). Reviews: Fleming, Selected Organic Syntheses (John Wiley, London, 1973) pp 183-207; G. Lagrue et al.,Ann. Med. Interne132, 496-500 (1981); F. D. Malkinson, Arch. Dermatol.118, 453-457 (1982). Comprehensive description: D. K. Wyatt et al.,Anal. Profiles Drug Subs.10, 139-182 (1981). 
Properties: Pale yellow scales or powder, mp 142-150°. Darkens on exposure to light. Has been crystallized from ethyl acetate, pale yellow needles, mp 157°. [a]D17 -429° (c = 1.72). [a]D17 -121° (c = 0.9 in chloroform). pK at 20°: 12.35; pH of 0.5% soln: 5.9. uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47). One gram dissolves in 22 ml water, 220 ml ether, 100 ml benzene; freely sol in alcohol or chloroform. Practically insol in petr ether. Forms two cryst compds with chloroform, B.CHCl3 or B.2CHCl3, which do not give up their chloroform unless heated between 60 and 70° for considerable time. LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles).

Melting point: mp 142-150°; mp 157°pKa: pK at 20°: 12.35; pH of 0.5% soln: 5.9Optical Rotation: [a]D17 -429° (c = 1.72); [a]D17 -121° (c = 0.9 in chloroform)Absorption maximum: uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47)

Toxicity data: LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles)Use: In research in plant genetics (for doubling chromosomes).Therap-Cat: Gout suppressant. Treatment of Familial Mediterranean Fever.Therap-Cat-Vet: Has been used as an antineoplastic.Keywords: Antigout.

SYN

DOI: 10.1039/C39740000300

DOI: 10.1002/hlca.19610440225 DOI: 10.1021/ja00409a032

http://www.druglead.com/cds/Colchicine.html

File:Colchicine synthesis.svg

SYN

https://pubs.rsc.org/en/content/articlelanding/2017/sc/c7sc01341h#!divAbstract

Here, we describe a concise, enantioselective, and scalable synthesis of (−)-colchicine (9.2% overall yield, >99% ee). Moreover, we have also achieved the first syntheses of (+)-demecolcinone and metacolchicine, and determined their absolute configurations. The challenging tricyclic 6-7-7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. Notably, the synthesized colchicinoid 23 exhibited potent inhibitory activity toward the cell growth of human cancer cell lines (IC50 = ∼3.0 nM), and greater inhibitory activity towards microtubule assembly than colchicine, making it a promising lead in the search for novel anticancer agents.

Graphical abstract: Enantioselective total synthesis of (−)-colchicine, (+)-demecolcinone and metacolchicine: determination of the absolute configurations of the latter two alkaloids

Enantioselective total synthesis of (−)- and (+)-colchicine

The synthesis began with the transition-metal-catalyzed C–H bond functionalization of 7 with 14 (Scheme 1). Inspired by Li’s seminal work,18 we applied the strategy to compound 7. Pleasingly, after optimization, we successfully generated the N-sulfonyl imine in situ by reaction of 7 with TsNH2 (15) in the presence of anhydrous CuSO4 in THF. Furthermore, subsequent treatment of this imine with [RhCp*Cl2]2 (1 mol%), AgSbF6 (4 mol%), NaOAc (2.0 equiv.), and 14 (2.0 equiv.) at 80 °C afforded ortho-olefinated benzaldehyde 16 in good yield (90% on a 0.5 g scale; 70% on a 5.0 g scale). This modified catalytic C–H bond activation involved a transient directing group.19

Scheme 1 Enantioselective synthesis of (−)-colchicine and (+)-colchicine.

SYN

https://chemistry.stackexchange.com/questions/67473/synthesis-of-colchicine

Recently one of my relatives have fallen ill and was prescribed with some colchicine. Looking at the structure of the molecule, and with nothing much to do, I decided to put my retrosynthetic skills to the test. Here is a picture of my thought process: 

Is there a better way to design a synthesis for this compound using the disconnection method.

From 11b, a Birch reduction is carried out to give the qunione 10b. A rearrangement of the ketone with methanediazonium gives 9b. A dihydroxylation with a peroxy acid and subsequent addition of water gives 8b. A double dehydration reaction with sulfuric acid, coupled with the protection of the ketone with propan-1,3-diol gives the seven-membered quinone 7b. A Heck reaction (or Ullmann reaction) with 7a with a palladium catalyst yields 6. (The protection group is thereafter labelled “PG”) Friedel-Crafts acylation with ethanoyl chloride yields 5 (although on second thoughts, I should have done the acylation from 7a from the start). A Michael addition is then carried out with BuLiBuLi to lithiate the ketone to give the terminal imine 4. Since this terminal imine is unstable, a mild reducing agent converts the imine to the amine 3. The ketone is then removed by addition of dithiol and subsequently reduced by Raney nickel to form 2. Finally, a simple condensation reaction between the amine and acetic anhydride, followed by deprotection of the ketone using an acid, yields the final product colchicine, 1.

Colchicine is a medication used to treat gout[1][2] and Behçet’s disease.[3] In gout, it is less preferred to NSAIDs or steroids.[1] Other uses for colchicine include the management of pericarditis and familial Mediterranean fever.[1][4] Colchicine is taken by mouth.[1]

Colchicine has a narrow therapeutic index and overdosing is therefore a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses.[5] Severe side effects may include low blood cells and rhabdomyolysis, and the medication can be deadly in overdose.[1] It is not clear whether colchicine is safe for use during pregnancy, but its use during breastfeeding appears to be safe.[1][6] Colchicine works by decreasing inflammation via multiple mechanisms.[7]

Colchicine, in the form of the autumn crocus (Colchicum autumnale), has been used as early as 1500 BC to treat joint swelling.[8] It was approved for medical use in the United States in 1961.[9] It is available as a generic medication in the United Kingdom.[6] In 2017, it was the 201st-most commonly prescribed medication in the United States, with more than two million prescriptions.[10][11]

Medical uses

Gout

Colchicine is an alternative for those unable to tolerate NSAIDs in gout.[12] At high doses, side effects (primarily gastrointestinal upset) limit its use.[13][14] At lower doses, it is well tolerated.[13][15][16][17] One review found low-quality evidence that low-dose colchicine (1.8 mg in one hour or 1.2 mg per day) reduced gout symptoms and pain, whereas high-dose colchicine (4.8 mg over 6 hours) was effective against pain, but caused more severe side effects, such as diarrhea, nausea or vomiting.[16]

For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear.[18] Subsequent doses may be needed if symptoms worsen.[18][16] There is preliminary evidence that daily colchicine (0.6 mg twice daily) was effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares,[2] although adverse gastrointestinal effects may occur.[19]

Other conditions

Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet’s disease.[20] It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms.[21] It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathies, calcinosis, scleroderma, and amyloidosis.[20][22][23] Research regarding the efficacy of colchicine in many of these diseases has not been performed.[23] It is also used in the treatment of familial Mediterranean fever,[20] in which it reduces attacks and the long-term risk of amyloidosis.[24]

Colchicine is effective for prevention of atrial fibrillation after cardiac surgery.[25] Potential applications for the anti-inflammatory effect of colchicine have been studied with regard to atherosclerosis and chronic coronary disease (e.g., stable ischemic heart disease).[26] In people with recent myocardial infarction (recent heart attack), it has been found to reduce risk of future cardiovascular events. Its clinical use may grow to include this indication.[27][28]

Colchicine is also being studied in clinical trials for possible effects on COVID-19.[29][30]

Contraindications

Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advanced kidney failure (including those on dialysis).[18] About 10-20 percent of a colchicine dose is excreted unchanged by the kidneys; it is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting, and a severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs.[18]

Adverse effects

Deaths – both accidental and intentional – have resulted from overdose of colchicine.[18] Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia.[13] High doses can also damage bone marrow, lead to anemia, and cause hair loss. All of these side effects can result from inhibition of mitosis,[31] which may include neuromuscular toxicity and rhabdomyolysis.[18]

Toxicity

According to one review, colchicine poisoning by overdose (range of acute doses of 7 to 26 mg) begins with a gastrointestinal phase occurring 10–24 hours after ingestion, followed by multiple organ dysfunction occurring 24 hours to 7 days after ingestion, after which the affected person either declines into multi-organ failure or recovers over several weeks.[32]

Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes.[13] Colchicine can cause a temporary clouding of the cornea and be absorbed into the body, causing systemic toxicity. Symptoms of colchicine overdose start 2 to 24 hours after the toxic dose has been ingested and include burning in the mouth and throat, fevervomitingdiarrhea, and abdominal pain.[18] This can cause hypovolemic shock due to extreme vascular damage and fluid loss through the gastrointestinal tract, which can be fatal.[32][33]

If the affected person survives the gastrointestinal phase of toxicity, they may experience multiple organ failure and critical illness. This includes kidney damage, which causes low urine output and bloody urinelow white blood cell counts that can last for several days; anemia; muscular weakness; liver failurehepatomegalybone marrow suppressionthrombocytopenia; and ascending paralysis leading to potentially fatal respiratory failure. Neurologic symptoms are also evident, including seizuresconfusion, and delirium; children may experience hallucinations. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal.[32][31]

Long-term exposure to colchicine can lead to toxicity, particularly of the bone marrowkidney, and nerves. Effects of long-term colchicine toxicity include agranulocytosis, thrombocytopenia, low white blood cell counts, aplastic anemia, alopecia, rashpurpuravesicular dermatitiskidney damageanuriaperipheral neuropathy, and myopathy.[31]

No specific antidote for colchicine is known, but supportive care is used in cases of overdose. In the immediate period after an overdose, monitoring for gastrointestinal symptoms, cardiac dysrhythmias, and respiratory depression is appropriate,[31] and may require gastrointestinal decontamination with activated charcoal or gastric lavage.[32][33]

Mechanism of toxicity

With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin.[32] Cells so affected undergo impaired protein assembly with reduced endocytosisexocytosiscellular motility, and interrupted function of heart cells, culminating in multi-organ failure.[7][32]

Epidemiology

In the United States, there are several hundred recorded cases of colchicine toxicity annually; approximately 10% of which end with serious morbidity or mortality. Many of these cases are intentional overdoses, but others were accidental; for example, if the drug was not dosed appropriately for kidney function. Most cases of colchicine toxicity occur in adults. Many of these adverse events resulted from the use of intravenous colchicine.[23]

Drug interactions

Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism.[18][32] Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.[18]

People taking macrolide antibioticsketoconazole or cyclosporine, or those who have liver or kidney disease, should not take colchicine, as these drugs and conditions may interfere with colchicine metabolism and raise its blood levels, potentially increasing its toxicity abruptly.[18][32] Symptoms of toxicity include gastrointestinal upset, fever, muscle painlow blood cell counts, and organ failure.[13][18] People with HIV/AIDS taking atazanavirdarunavirfosamprenavirindinavirlopinavirnelfinavirritonavir, or saquinavir may experience colchicine toxicity.[18] Grapefruit juice and statins can also increase colchicine concentrations.[18]

In gout, inflammation in joints results from the precipitation of circulating uric acid, exceeding its solubility in blood and depositing as crystals of monosodium urate in and around synovial fluid and soft tissues of joints.[7] These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines.[7] Colchicine accumulates in white blood cells and affects them in a variety of ways: decreasing motility, mobilization (especially chemotaxis) and adhesion.[23]

Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:

Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators.[7] Apart from inhibiting mitosis, colchicine inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect, which has efficacy for inhibiting or preventing gout inflammation.[7][18]

The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (circa 1500 BC), an Egyptian medical papyrus.[34] It is a toxic alkaloid and secondary metabolite.[13][35][18] Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides, in the first century AD. Use of the bulb-like corms of Colchicum to treat gout probably dates to around 550 AD, as the “hermodactyl” recommended by Alexander of TrallesColchicum corms were used by the Persian physician Avicenna, and were recommended by Ambroise Paré in the 16th century, and appeared in the London Pharmacopoeia of 1618.[36][23] Colchicum use waned over time, likely due to the severe gastrointestinal side effects preparations caused. In 1763, Colchicum was recorded as a remedy for dropsy (now called edema) among other illnesses.[23] Colchicum plants were brought to North America by Benjamin Franklin, who had gout himself and had written humorous doggerel about the disease during his stint as United States Ambassador to France.[37]

Colchicine was first isolated in 1820 by the French chemists P. S. Pelletier and J. B.Caventou.[38] In 1833, P. L. Geiger purified an active ingredient, which he named colchicine.[39] It quickly became a popular remedy for gout.[23] The determination of colchicine’s structure required decades, although in 1945, Michael Dewar made an important contribution when he suggested that, among the molecule’s three rings, two were seven-member rings.[40] Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

An unintended consequence of the 2006 U.S. Food and Drug Administration (FDA) safety program called the Unapproved Drugs Initiative—through which the FDA sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs[41]—was a price increase of 2000 percent [42] for “a gout remedy so old that the ancient Greeks knew about its effects.”[42] Under Unapproved Drugs Initiative small companies like URL Pharma, a Philadelphia drugmaker, were rewarded with licenses for testing of medicines like colchicine. In 2009, the FDA reviewed a New Drug Application for colchicine submitted by URL Pharma. URL Pharma did the testing, gained FDA formal approval, and was granted rights over colchicine. With this monopoly pricing power, the price of colchicine increased.

In 2012 Asia’s biggest drugmaker, Takeda Pharmaceutical Co., acquired URL Pharma for $800 million including the rights to colchicine (brand name Colcrys) earning $1.2 billion in revenue by raising the price even more.[42]

Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.[43] On July 30, 2009, the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares[43]), and gave URL Pharma a three-year marketing exclusivity agreement[44] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010, both in oral and intravenous forms, but allowed pharmacies to buy up the older unapproved colchicine.[45] Colchicine in combination with probenecid has been FDA-approved before 1982.[44]

July 29, 2009, colchicine won FDA approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.[46][47] It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses (1.2 mg and 0.6 mg) an hour apart were as effective as higher doses in combating the acute flare of gout.[17]

As a drug antedating the FDA, colchicine was sold in the United States for many years without having been reviewed by the FDA for safety and efficacy. The FDA reviewed approved colchicine for gout flares, awarding Colcrys a three-year term of market exclusivity, prohibiting generic sales, and increasing the price of the drug from $0.09 to $4.85 per tablet.[48][49][50]

Numerous consensus guidelines, and previous randomized controlled trials, had concluded that colchicine is effective for acute flares of gouty arthritis. However, as of 2006, the drug was not formally approved by the FDA, owing to the lack of a conclusive randomized control trial (RCT). Through the Unapproved Drugs Initiative, the FDA sought more rigorous testing of the efficacy and safety of colchicine and other unapproved drugs.[41] In exchange for paying for the costly testing, the FDA gave URL Pharma three years of market exclusivity for its Colcrys brand,[51] under the Hatch-Waxman Act, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout.

In April 2010, an editorial in the New England Journal of Medicine said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that no evidence of meaningful improvement to public health was seen, and that it would be less expensive for the FDA, the National Institutes of Health or large insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers.[52] In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.[53]

Colchicine patents expire on February 10, 2029.[54]

URL Pharma also received seven years of market exclusivity for Colcrys in the treatment of familial Mediterranean fever, under the Orphan Drug Law. URL Pharma then raised the price per tablet from $0.09 to $4.85 and sued to remove other versions from the market, increasing annual costs for the drug to U.S. state Medicaid programs from $1 million to $50 million. Medicare also paid significantly higher costs, making this a direct money-loser for the government. (In a similar case, thalidomide was approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)[52]

Regulation

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.[55]

Formulations and dosing

Trade names for colchicine are Colcrys or Mitigare which are manufactured as a dark– and light-blue capsule having a dose of 0.6 mg.[18][56] Colchicine is also prepared as a white, yellow, or purple pill (tablet) having a dose of 0.6 mg.[56]

Colchicine is typically prescribed to mitigate or prevent the onset of gout, or its continuing symptoms and pain, using a low-dose prescription of 0.6 to 1.2 mg per day, or a high-dose amount of up to 4.8 mg in the first 6 hours of a gout episode.[5][18][16] With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.[35] For treating gout, the initial effects of colchicine occur in a window of 12 to 24 hours, with a peak within 48 to 72 hours.[18] It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.[18] Colchicine is not a general pain relief drug, and is not used to treat pain in other disorders.[18]

Biosynthesis

According to laboratory research, the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Giving radioactive phenylalanine-2-14C to C. byzantinum, another plant of the family Colchicaceae, resulted in its incorporation into colchicine.[57] However, the tropolone ring of colchicine resulted from the expansion of the tyrosine ring. Radioactive feeding experiments of C. autumnale revealed that colchicine can be synthesized biosynthetically from (S)-autumnaline. That biosynthesic pathway occurs primarily through a phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-adenosylmethionine. Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. N-formyldemecolcine hydrolyzes then to generate the molecule demecolcine, which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-coenzyme A to deacetylcolchicine.[58][59]

A

Purification

Colchicine may be purified from Colchicum autumnale (autumn crocus) or Gloriosa superba (glory lily). Concentrations of colchicine in C. autumnale peak in the summer, and range from 0.1% in the flower to 0.8% in the bulb and seeds.[23]

Colchicine is widely used in plant breeding by inducing polyploidy in plant cells to produce new or improved varieties, strains and cultivars.[60] When used to induce polyploidy in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Seeds can be presoaked in a colchicine solution before planting. Since chromosome segregation is driven by microtubules, colchicine alters cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes, therefore, contain no chromosomes, while the other half contains double the usual number of chromosomes (i.e., diploid instead of haploid, as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e., tetraploid instead of diploid).[60] While this would be fatal in most higher animal cells, in plant cells it is not only usually well-tolerated, but also frequently results in larger, hardier, faster-growing, and in general more desirable plants than the normally diploid parents. For this reason, this type of genetic manipulation is frequently used in breeding plants commercially.[60]

When such a tetraploid plant is crossed with a diploid plant, the triploid offspring are usually sterile (unable to produce fertile seeds or spores), although many triploids can be propagated vegetatively. Growers of annual triploid plants not readily propagated vegetatively cannot produce a second-generation crop from the seeds (if any) of the triploid crop and need to buy triploid seed from a supplier each year. Many sterile triploid plants, including some trees, and shrubs, are becoming increasingly valued in horticulture and landscaping because they do not become invasive species and will not drop undesirable fruit and seed litter. In certain species, colchicine-induced triploidy has been used to create “seedless” fruit, such as seedless watermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually require cross-pollination with a diploid parent to induce seedless fruit production.

The ability of colchicine to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding triticale (× Triticosecale) from wheat (Triticum spp.) and rye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.[61]

References

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  29. ^ Kaul S, Gupta M, Bandyopadhyay D, Hajra A, Deedwania P, Roddy E, et al. (December 2020). “Gout Pharmacotherapy in Cardiovascular Diseases: A Review of Utility and Outcomes”American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventionsdoi:10.1007/s40256-020-00459-1PMC 7768268PMID 33369719.
  30. ^ Reyes, Aaron Z; Hu, Kelly A; Teperman, Jacob; Wampler Muskardin, Theresa L; Tardif, Jean-Claude; Shah, Binita; Pillinger, Michael H (2020-12-08). “Anti-inflammatory therapy for COVID-19 infection: the case for colchicine”Annals of the Rheumatic Diseases: annrheumdis–2020–219174. doi:10.1136/annrheumdis-2020-219174ISSN 0003-4967PMID 33293273.
  31. Jump up to:a b c d “CDC – The Emergency Response Safety and Health Database: Biotoxin: Cochicine”. Centers for Disease Control and Prevention, US Department of Health and Human Services. Retrieved 31 December 2015.
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  33. Jump up to:a b Matt Doogue (2014). “Colchicine – extremely toxic in overdose” (PDF). Christchurch and Canterbury District Health Board, New Zealand. Retrieved 23 August 2018.
  34. ^ Graham W, Roberts JB (March 1953). “Intravenous colchicine in the management of gouty arthritis”Annals of the Rheumatic Diseases12 (1): 16–9. doi:10.1136/ard.12.1.16PMC 1030428PMID 13031443.
  35. Jump up to:a b “Colcrys (colchicine). Summary review for regulatory action”(PDF). Center for Drug Evaluation and Research, US Food and Drug Administration. 30 July 2009. Retrieved 19 August 2018.
  36. ^ Hartung EF (September 1954). “History of the use of colchicum and related medicaments in gout; with suggestions for further research”Annals of the Rheumatic Diseases13 (3): 190–200. doi:10.1136/ard.13.3.190PMC 1006735PMID 13198053.(free BMJ registration required)
  37. ^ Ebadi MS (2007). Pharmacodynamic basis of herbal medicineISBN 978-0-8493-7050-2.
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  39. ^ Geiger, Ph. L. (1833) “Ueber einige neue giftige organische Alkalien” (On some new poisonous organic alkalis) Annalen der Pharmacie7 (3) : 269-280; colchicine is discussed on pages 274-276.
  40. ^ Dewar MJ (February 3, 1945). “Structure of colchicine”. Letters to Editor. Nature155 (3927): 141–142. Bibcode:1945Natur.155..141Ddoi:10.1038/155141d0S2CID 4074312. Dewar did not prove the structure of colchicine; he merely suggested that it contained two seven-membered rings. Colchicine’s structure was determined by X-ray crystallography in 1952 King MV, de Vries JL, Pepinsky R (July 1952). “An x-ray diffraction determination of the chemical structure of colchicine”Acta Crystallographica5 (4): 437–440. doi:10.1107/S0365110X52001313. Its total synthesis was first accomplished in 1959 Eschenmoser A (1959). “Synthese des Colchicins”. Angewandte Chemie71 (20): 637–640. doi:10.1002/ange.19590712002.
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Further reading

  • Dowd, Matthew J. (April 30, 1998). “Colchicine”. Virginia Commonwealth University. Archived from the original on 2010-06-10.
  • EXT LINKS
Clinical data
Trade namesColcrys, Mitigare, others
AHFS/Drugs.comMonograph
MedlinePlusa682711
License dataUS DailyMedColchicine
Pregnancy
category
AU: D
Routes of
administration
By mouth
ATC codeM04AC01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability45%
Protein binding35-44%
MetabolismMetabolism, partly by CYP3A4
Elimination half-life26.6-31.2 hours
ExcretionFaeces (65%)
Identifiers
showIUPAC name
CAS Number64-86-8 
PubChem CID6167
IUPHAR/BPS2367
DrugBankDB01394 
ChemSpider5933 
UNIISML2Y3J35T
KEGGD00570 
ChEBICHEBI:27882 
ChEMBLChEMBL107 
CompTox Dashboard (EPA)DTXSID5024845 DTXSID20274387, DTXSID5024845 
ECHA InfoCard100.000.544 
Chemical and physical data
FormulaC22H25NO6
Molar mass399.437 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
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///////////Colchicine, CSIR, Laxai Life Sciences, DCGI, clinical trials,  Covid patients, covid 19, corona virus 

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Corbevax, BioE COVID-19, BECOV2D


Corbevax

BioE COVID-19, BECOV2D

the Baylor College of Medicine in Houston, United States,

Dynavax Technologies

Adjuvanted protein subunit vaccine

Corbevax is a “recombinant protein sub-unit” vaccine, which means it is made up of a specific part of SARS-CoV-2 — the spike protein on the virus’s surface.

The spike protein allows the virus to enter the cells in the body so that it can replicate and cause disease. However, when this protein alone is given to the body, it is not expected to be harmful as the rest of the virus is absent. The body is expected to develop an immune response against the injected spike protein. Therefore, when the real virus attempts to infect the body, it will already have an immune response ready that will make it unlikely for the person to fall severely ill.

Although this technology has been used for decades to make hepatitis B vaccines, Corbevax will be among the first Covid-19 vaccines to use this platform. Novavax has also developed a protein-based vaccine, which is still waiting for emergency use authorisation from various regulators.

How Corbevax was made

While it is indigenously produced, Corbevax’s beginnings can be traced to the Baylor College of Medicine’s National School of Tropical Medicine. The School had been working on recombinant protein vaccines for coronaviruses SARS and MERS for a decade.

“We knew all the techniques required to produce a recombinant protein (vaccine) for coronaviruses at high levels of efficiency and integrity,” said Dr Peter Hotez, Professor and Dean at the School.

When the genetic sequence for SARS-CoV-2 was made available in February 2020, researchers at the School pulled out the sequence for the gene for the spike protein, and worked on cloning and engineering it. The gene was then put into yeast, so that it could manufacture and release copies of the protein. “It’s actually similar to the production of beer. Instead of releasing alcohol, in this case, the yeast is releasing the recombinant protein,” Dr Hotez said.

After this, the protein was purified to remove any remnants of the yeast “to make it pristine”. Then, the vaccine was formulated using an adjuvant to better stimulate the immune response.

Most of these ingredients are cheap and easy to find.

In August, BCM transferred its production cell bank for this vaccine to Biological E, so that the Hyderabad-based company could take the candidate through trials. The vaccine has received approval for phase 3 trials, which the government expects will be over by July.

Biological E is also expected to scale up production for the world.

How Corbevax is different

Other Covid-19 vaccines approved so far are either mRNA vaccines (Pfizer and Moderna), viral vector vaccines (AstraZeneca-Oxford/Covishield, Johnson & Johnson and Sputnik V) or inactivated vaccines (Covaxin, Sinovac-CoronaVac and Sinopharm’s SARS-CoV-2 Vaccine–Vero Cell).

Inactivated vaccines, which include killed particles of the whole SARS-CoV-2 virus, attempt to target the entire structure of the virus. On the other hand, Corbevax, like the mRNA and viral vector Covid-19 vaccines, targets only the spike protein, but in a different way.

Viral vector and mRNA and vaccines use a code to induce our cells to make the spike proteins against which the body have to build immunity. “In this case (Corbevax), we’re actually giving the protein,” said Dr Hotez.

Like most other Covid-19 vaccines, Corbevax is administered in two doses. However, as it is made using a low-cost platform, it is also expected to be among the cheapest available in the country.

Why Corbevax matters

This is the first time the Indian government has placed an order for a vaccine that has not received emergency use authorisation, paying Rs 1,500 crore in advance to block an order that could vaccinate 15 crore Indian citizens. The Centre has provided major pre-clinical and clinical trial support towards the vaccine’s development, including a grant-in-aid of Rs 100 crore from the Department of Biotechnology.

A major reason for India placing such a big order is the difficulties it is facing in enhancing vaccine supplies. While the US, UK and the EU had made advance payments and at-risk investments into vaccines like Pfizer, AstraZeneca and Moderna, India waited until after its first two vaccines were approved before placing limited orders. Even after the government eased regulatory requirements for foreign vaccines, it did not receive a speedy response from companies like Pfizer and Moderna, their supplies already blocked through orders from other countries. India is currently in negotiations for a limited supply of Pfizer’s vaccine, and expecting to secure up to two billion doses of Covid vaccines by December this year. Given the ease with which it can be mass produced, Corbevax could make up a sizeable portion of this expected supply.

Biological E, the manufacturer of Corbevax

Biological E, headquartered in Hyderabad, was founded by Dr D V K Raju in 1953 as a biological products company that pioneered the production of heparin in India. By 1962, it forayed into the vaccines space, producing DPT vaccines on a large-scale. Today, it is among the major vaccine makers in India and, by its own claim, the “largest” tetanus vaccine producer in the world.

It has seven WHO-prequalified shots, including a five-in-one vaccine against diphtheria, tetanus, pertussis, hepatitis B and haemophilus influenza type-b infections. Its vaccines are supplied to over 100 countries and it has supplied more than two billion doses in the last 10 years alone.

Since 2013, the company has been under the management of Mahima Datla — the third generation of the founding family. During her time as managing director, the company has received WHO prequalification of its Japanese encephalitis, DTwP and Td as well as measles and rubella vaccines and also commenced commercial operations in the US.

REF

https://indianexpress.com/article/explained/corbevax-vaccine-biological-e-india-7344928/

Corbevax[1] or BioE COVID-19, is a COVID-19 vaccine candidate developed by Indian biopharmacutical firm Biological E. Limited (BioE), the Baylor College of Medicine in Houston, United States, and Dynavax Technologies. It is a protein subunit vaccine.[2][3][4][5]

Clinical research

Phase I and II trials

In phase I clinical trial was carried to evaluate the safety and immunogenicity of the vaccine candidate in about 360 participants.[5]The phase II concluded in April 2021.[6][7]

Phase III trials

In April 2021, the Drugs Controller General of India permitted the vaccine candidate to start phase III clinical trials. A total of 1,268 healthy participants between the age of 18 and 80 years to be selected from 15 sites across India for the trial and intended to be part of a larger global Phase III study.[8][7]

Manufacturing and Orders

In April 2021, the U.S. International Development Finance Corporation (DFC) announced that it would fund the expansion of BioE’s manufacturing capabilities, so that it could produce at least 1 billion doses by end of 2022.[9]

On 3 June, India’s Ministry of Health and Family Welfare pre-ordered 300 million doses of Corbevax.[10]

References

  1. ^ Bharadwaj, Swati (3 June 2021). “Telangana: Biological E starts at risk manufacturing of Corbevax”The Times of India. Retrieved 3 June 2021.
  2. ^ “A prospective open label randomised phase-I seamlessly followed by phase-II study to assess the safety, reactogenicity and immunogenicity of Biological E’s novel Covid-19 vaccine containing Receptor Binding Domain of SARS-CoV-2 for protection against Covid-19 disease when administered intramuscularly in a two dose schedule (0, 28D) to healthy volunteers”ctri.nic.inClinical Trials Registry India. 13 January 2021. CTRI/2020/11/029032. Archived from the original on 12 November 2020.
  3. ^ “CEPI partners with Biological E Limited to advance development and manufacture of COVID-19 vaccine candidate”cepi.netCEPI. Retrieved 5 March 2021.
  4. ^ Chui M (16 November 2020). “Biological E. Limited and Baylor COVID-19 vaccine begins clinical trial in India”Baylor College of Medicine.
  5. Jump up to:a b Leo L (16 November 2020). “Biological E initiates human trials of vaccine”Mint.
  6. ^ “Coronavirus | Biological E gets nod to start Phase III trials of COVID-19 vaccine”The Hindu. 24 April 2021.
  7. Jump up to:a b Leo, Leroy (24 April 2021). “Biological E completes phase-2 covid vaccine trial, gets SEC nod for phase-3”mint.
  8. ^ “A Prospective, multicentre, Phase II Seamlessly Followed by Phase III Clinical Study to Evaluate the Immunogenicity and Safety of Biological E’s CORBEVAX Vaccine for Protection Against COVID-19 Disease When Administered to COVID-19-Negative Adult Subjects”ctri.nic.inClinical Trials Registry India. 5 June 2021. CTRI/2021/06/034014.
  9. ^ Basu, Nayanima (25 April 2021). “US assures export of raw materials to India for Covid vaccines as Doval speaks to Sullivan”ThePrint.
  10. ^ “Health ministry buys 300 mn doses of Biological-E’s Covid vaccine in advance”Hindustan Times. 3 June 2021. Retrieved 4 June 2021.

External links

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PTX-COVID19-B



PTX-COVID19-B

mRNA-based vaccine

Providence Therapeutics; Canadian government

bioRxiv (2021), 1-50.

https://www.biorxiv.org/content/10.1101/2021.05.11.443286v1

Safe and effective vaccines are needed to end the COVID-19 pandemic caused by SARS-CoV-2. Here we report the preclinical development of a lipid nanoparticle (LNP) formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351 and P.1 lineages. No adverse effects were induced by PTX-COVID19-B in both mice and hamsters. These preclinical results indicate that PTX-COVID19-B is safe and effective. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 1 clinical trial ongoing (ClinicalTrials.gov number: NCT04765436).

PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine, a vaccine for the prevention of the COVID-19 disease caused by an infection of the SARS-CoV-2 coronavirus, created by Providence Therapeutics—a private Canadian drug company co-founded by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson.[1] in 2013. A team of eighteen working out of Sunnybrook Research Institute in Toronto, Ontario developed PTX-COVID19-B[2] in less than four weeks, according to the Calgary Herald.[3] Human trials with sixty volunteers began on January 26, 2021 in Toronto.[4][5][6]

Providence, which has no manufacturing facilities, partnered with Calgary-based Northern mRNA—the “anchor tenant” in their future manufacturing facilities pending financing.[2]

On 30 April 2021, Sorenson announced that Providence Therapeutics would be leaving Canada and any vaccine that it developed would not be manufactured in Canada.[2]

Overview

Providence Therapeutics Holdings Inc. was co-founded in Toronto, Ontario[7][8] by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson Ph.D, who was also the Chief Scientific Officer.[9][3]

PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine. In an interview with CTV news, Sorenson said they were “building some of the important building blocks for the messenger RNA … that provides instructions to cells … to build proteins that may treat or prevent disease”.

As of January 2021, Northern RNA’s Calgary lab was proposed as the site where manufacturing of PTX-COVID19-B would take place.[10] Providence Therapeutics’ partner, Northern RNA, which located at 421 7 Avenue SW in Calgary, has been described as Providence Therapeutics northern division.[7][8]

A February 2021 Manitoba government press release said that the Winnipeg-based Emergent BioSolutions would be manufacturing the vaccine.[11]

Human trials

Phase 1

Human trials began on January 26, 2021 with 60 volunteers between the ages of 18 to 65 in Toronto.[12][13][3] Of these, 15 would receive a placebo and 3 groups of 15 would receive different doses of the vaccine.[10] The volunteers will be monitored for 13 months. The company said that enough data would be available in May which could result in a Phase 2 clinical testing beginning soon after that, pending regulatory approval. If the results of a subsequent larger human trial are positive, the vaccine could enter a commercialization phase in 2022.[14] The Phase 1 clinical trial lead was Piyush Patel. At the 29 April meeting with the House of Commons, Sorenson estimated that PTX-COVID19-B could be approved by Health Canada by “January or February 2022”.[15]:8

Provincial funding

Shortly after the first human trials on PTX-COVID19-B began in late January, on 11 February 2021, Manitoba Premier Brian Pallister announced a “term sheet” between the province and Providence Therapeutics through which Manitoba would receive 2 million doses of PTX-COVID19-B pending its approval by Health Canada.[11] The term sheet includes “best-price guarantee” PTX-COVID19-B.[13] According to a provincial statement released by the Manitoba government, pending approval of the vaccine, the actual manufacturing would take place in Winnipeg by Emergent BioSolutions.[11] Pallister said that, “Building a secure, made-in-Canada vaccine supply will put Canadians at the head of the line to get a COVID vaccine, where we belong.”[11] The down payment would be 20% with a subsequent 40% to be paid when the vaccine was approved by Health Canada; the balance would be paid on delivery of the doses.[13] Specifics about the contract were released in April 2021: the total cost was estimated as CAD $36 million and the agreement included a clause for a non-refundable advance payment of CAD $7.2 million.[2] Sorenson made this comment to Global News: “Under no circumstances is Manitoba going to be on the hook for $7.2 million unless they get real value out of it”.

Federal funding

Canada’s National Research Council (NRC) provided Providence Therapeutics with CAD $5 million for the launch of January 2021 first phase of PTX-COVID19-B clinical trials.[2]

As part of the federal government’s “next generation manufacturing supercluster” program, Providence and Northern mRNA had also been “cleared to access up to $5 million” towards the manufacturing start up process, according to a federal government spokesperson.[2]

The CBC report in late April 2021 also stated that “it could be eligible for a slice of $113 million in additional funding from the National Research Council of Canada Industrial Research Assistance Program”. The federal government had provided funding to some other companies in Canada that were also working to develop a COVID-19 vaccine.[2]

Sorenson as Providence Therapeutics CEO posted an open letter to Prime Minister Justin Trudeau, in which he requested $CDN 150 million upfront to be used to pay for clinical trial and material costs.[16][9]

On 29 April 2021, Sorenson appeared before the House of Commons standing committee on international trade, to ask the Minister of ProcurementAnita Anand, to consider PTX-COVID19-B as an alternative to Moderna and Pfizer for the “2022 booster vaccines”.[15] Sorenson said that the NRC had approached Providence Therapeutics in 2020 after the company had announced their Phase I trial PTX-COVID19-B. Sorenson told the Standing Committee that, “We’ve had really good dialogue ever since phase I started. That process has gone on. That started probably [in February], as we geared up to conclude our phase I trial and release data. Although the NRC is capped at $10 million, which is certainly not sufficient to carry out phase II and phase III trials, the NRC has, through the bureaucracy, elevated us back up to the strategic innovation fund. That occurred about three weeks ago. We’re now working with the strategic innovation fund.”[15]:7

He later said that no reply had been received from the government.[17]

In a meeting with the federal COVID-19 vaccine task force and Sorenson, task force members expressed concerns that “Providence might not be able to scale up production fast enough”.[2]

Clinical trials

PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64… https://clinicaltrials.gov/ct2/show/NCT04765436

Hyderabad Drugmaker To Make Canada Firm’s mRNA Covid Vaccine In India.. https://www.ndtv.com/india-news/hyderabad-drugmaker-biological-e-to-make-canada-firms-mrna-covid-vaccine-in-india-2454000

Biological E., will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement

Hyderabad-based Biological E said on Tuesday it has entered into a licensing agreement with Providence Therapeutics Holdings to manufacture the Canadian company’s mRNA COVID-19 vaccine in India.

Biological E., which also has a separate deal to produce about 600 million doses of Johnson & Johnson’s COVID-19 shot annually, will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement.

Providence will sell up to 30 million doses of its mRNA vaccine, PTX-COVID19-B, to Biological E, and will also provide the necessary technology transfer of the shot, with a minimum production capacity of 600 million doses in 2022 and a target capacity of 1 billion doses.

Financial details of the transaction were not disclosed.

India has been struggling with a devastating second wave of the pandemic and has managed to fully vaccinate only about 3% of its population. On Monday, the Serum Institute of India said it will increase production of AstraZeneca’s shot by nearly 40% in June, a step towards bridging the shortfall in the country.

“The mRNA platform has emerged as the front runner in delivering the first vaccines for emergency use to combat the COVID-19 pandemic,” said Mahima Datla, Biological E.’s managing director.

Messenger ribonucleic acid (mRNA) vaccines prompt the body to make a protein that is part of the virus, triggering an immune response. US companies Pfizer and Moderna use mRNA technology in their COVID-19 shots.

The drug regulator has approved clinical trials of another mRNA vaccine developed by local firm Gennova Biopharmaceuticals, and the government has said it will fund the studies.

Providence Therapeutics Announces Very Favorable Interim Phase 1 Trial Data for PTX-COVID19-B, its mRNA Vaccine Against COVID-19

https://www.providencetherapeutics.com/providence-therapeutics-announces-very-favorable-interim-phase-1-trial-data-for-ptx-covid19-b-its-mrna-vaccine-against-covid-19May 12, 2021

CALGARY, AB, May 12, 2021 / – Providence Therapeutics Holdings Inc. (“Providence”) announced today very favorable interim clinical data of PTX-COVID19-B, its vaccine candidate against SARS-CoV-2 (“COVID-19”), from its Phase 1 study entitled “PRO-CL-001, A Phase 1, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” (the “Phase 1 Study”), which found that PTX-COVID19-B met Providence’s target results for safety, tolerability, and immunogenicity in the participants of the Phase 1 Study.

Highlights from Providence Therapeutics’ “Phase 1 Study”:

  • PTX-COVID19-B was generally safe and well tolerated
  • PTX-COVID19-B exhibited strong virus neutralization capability across the 16µg, 40µg and 100µg dose cohorts
  • PTX-COVID19-B 40µg dose was selected for Phase 2 study
  • PTX-COVID19-B will be evaluated in additional Phase 1 population cohorts

The Phase 1 Study was designed with dose-escalations and was performed in seronegative adult subjects without evidence of recent exposure to COVID-19. The subjects were randomized to receive either the PTX-COVID19-B vaccine or a placebo in a 3:1 ratio. A total of 60 subjects participated in the Phase 1 Study.

The overall results of the Phase 1 Study are that PTX-COVID19-B was safe and well tolerated at the three dose levels of 16µg, 40µg and 100µg. Adverse events identified in the Phase 1 Study were generally mild to moderate in severity, self-resolving and transient. There were no serious adverse events reported in the Phase 1 Study. The most common adverse event reported in the Phase 1 Study was redness and pain at the injection site. Systemic reactions reported in the Phase 1 Study were generally mild to moderate and well tolerated with headache being the most common reaction reported. The reported adverse events of the Phase 1 Study were in line with the expectations of management of Providence as they compare very favorably to the adverse events data published on other mRNA vaccines for COVID-19 that have been approved for use by various health authorities around the world.

Based on the results of the Phase 1 Study, Providence intends to use a 40µg dose for the Phase 2 study of PTX-COVID19-B that is anticipated to be initiated in June 2021. Additional Phase 1 studies in adolescent and elderly populations are also planned to be undertaken by Providence.

PTX-COVID19-B vaccination induced high anti-S IgG antibodies:

Participants in the Phase 1 Study were vaccinated on day zero and day twenty-eight. Plasma samples were collected on day 1, day 8, day 28 (prior to the participant receiving the second dose), and day 42 to determine levels of IgG anti-S protein using electrochemiluminescence (“ECL”) assays from Meso Scale Discovery (“MSD”). Study participants in all three vaccine dose cohorts of the Phase 1 Study developed a strong IgG antibody response against Spike protein that was detected by day 28 and enhanced by day 42. No antibodies against S protein were detected in participants in the Phase 1 Study injected with placebo. The highest levels of antibodies were found in the 40 and 100 µg doses. By day 42, PTX-COVID19-B vaccinated participants had more than one log higher antibody levels than convalescent subjects-plasma (indicated in the dotted line) which was evaluated in the same assay.

Based on the interim data of the Phase 1 Study, the level of antibodies produced in participants by PTX-COVID19-B compare favorably to the levels of antibodies produced by other mRNA vaccines that have been approved for use against COVID-19 based on the recently published report from Stanford University, where IgG responses in individuals vaccinated with the COVID-19 mRNA vaccine compared to COVID-19 infected patients were evaluated[1].

PTX-COVID19-B vaccination induced high neutralizing antibody levels:

Neutralizing activity from the Phase 1 Study participants’ plasma was evaluated by S-ACE2 MSD assay. The results indicate that the antibodies block the interaction between S protein with the ACE2 receptor and the decrease in ECL signal is used to calculate percentage inhibition of the plasma at the same dilution. All participants in the Phase 1 Study from the 16, 40 and 100 µg dose levels showed blocking activity by day 28 and all of them reached 100% blocking activity by day 42 with samples diluted 1:100 or greater. Moreover, the quantification of the antibody levels in ng/mL with a reference standard showed that all participants in the Phase 1 Study produced neutralizing antibodies by day 28 with the first immunization and increase ten-fold by day 42, two weeks after the administration of the second dose. These results indicate that PTX-COVID19-B induced a strong neutralizing antibody response which compares very favorably to the published results of other mRNA vaccines. Further studies are being conducted by Providence to determine neutralization activity using a pseudo-virus assay.

Providence intends to advance a Phase 2 clinical trial in early June 2021, with multiple trial sites in Canada. The Phase 2 clinical trial is anticipated to be structured as a comparator trial using Pfizer/BioNTech vaccine as the positive control.

About Providence Therapeutics

Providence is a leading Canadian clinical stage biotechnology company pioneering mRNA therapeutics and vaccines with operations in Calgary, Alberta and Toronto, Ontario. In response to a worldwide need for a COVID-19 vaccine, Providence expanded its focus beyond oncology therapies and devoted its energy and resources to develop a world-class mRNA vaccine for COVID-19. Providence is focused on serving the needs of Canada, and other countries that may be underserved by large pharmaceutical programs. For more information, please visit providencetherapeutics.com.

References

  1. ^ “Canadian company urges human trials after COVID-19 vaccine results in mice”Lethbridge News Now. 5 August 2020. Retrieved 19 March 2021.
  2. Jump up to:a b c d e f g h Tasker, John Paul (30 April 2021). “COVID-19 vaccine maker Providence says it’s leaving Canada after calls for more federal support go unanswered”CBC News. Retrieved 1 May 2021.
  3. Jump up to:a b c Stephenson, Amanda (26 January 2021). “Made-in-Canada COVID vaccine to be manufactured in Calgary”Calgary Herald. Retrieved 22 March 2021.
  4. ^ Clinical trial number NCT04765436 for “PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” at ClinicalTrials.gov
  5. ^ “Providence Therapeutics Holdings Inc: PTX-COVID19-B”. Montreal: McGill University. Retrieved 19 March 2021.
  6. ^ “Made-in-Canada coronavirus vaccine starts human clinical trials”. Canadian Broadcasting Corporation. 26 January 2021.
  7. Jump up to:a b “Company Profile”PitchBook.
  8. Jump up to:a b “Company Profile”DNB.
  9. Jump up to:a b Code, Jillian (5 February 2021). “‘Do something’ Made-In-Canada vaccine CEO pleads for federal government to respond”CTV News. Calgary, Alberta. Retrieved 22 March 2021.
  10. Jump up to:a b Fieldberg, Alesia (26 January 2021). “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”CTV. Retrieved 2 May 2021.
  11. Jump up to:a b c d “Manitoba Supports Made-In-Canada COVID-19 Vaccine to Protect Manitobans” (Press release). 11 February 2021. Retrieved 3 May 2021.
  12. ^ Providence Therapeutics Holdings Inc.: a Phase I, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64 (Report). Clinical Trials via U.S. National Library of Medicine. 19 February 2021. Retrieved 1 May2021.
  13. Jump up to:a b c Gibson, Shane (11 February 2021). “Manitoba agrees to purchase 2M doses of Providence Therapeutics coronavirus vaccine”Global News. Retrieved 2 May 2021.
  14. ^ “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”CTV. Retrieved 2 May 2021.
  15. Jump up to:a b c Evidence (PDF), 43rd Parliament, 2nd Session. Standing Committee on International Trade, 29 April 2021, retrieved 2 May2021
  16. ^ Sorenson, Brad (5 February 2021). “An Open Letter to the Government of Canada”. Retrieved 3 May 2021.
  17. ^ Dyer, Steven. “‘Canada had an opportunity’, Calgary company explores taking vaccine development out of Canada”CTV. Retrieved 2 May 2021.
Vaccine description
TargetSARS-CoV-2
Vaccine typemRNA
Clinical data
Routes of
administration
Intramuscular
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////////PTX-COVID19-B, canada, hyderabad, providence, Gennova Biopharmaceuticals, biological e, COVID-19, SARS-CoV-2 , corona virus, covid 19, phase 1

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Casirivimab


(Heavy chain)
QVQLVESGGG LVKPGGSLRL SCAASGFTFS DYYMSWIRQA PGKGLEWVSY ITYSGSTIYY
ADSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCARDR GTTMVPFDYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
DIQMTQSPSS LSASVGDRVT ITCQASQDIT NYLNWYQQKP GKAPKLLIYA ASNLETGVPS
RFSGSGSGTD FTFTISGLQP EDIATYYCQQ YDNLPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H147-H203, H223-L214, H229-H’229, H232-H’232, H264-H324, H370-H428, H’22-H’96, H’147-H’203, H’223-L’214, H’264-H’324, H’370-H’428, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Casirivimab

カシリビマブ;

  • Immunoglobulin G1, anti-​(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10933 γ1-​chain)​, disulfide with human monoclonal REGN10933 κ-​chain, dimer
FormulaC6454H9976N1704O2024S44
CAS2415933-42-3
Mol weight145233.3296

Monoclonal antibody
Treatment and prophylaxis of SARS-CoV-2 infection (COVID-19)

SARS-CoV-2 spike glycoprotein

  • Protein Sequence
  • Sequence Length: 1328, 450, 450, 214, 214
  • REGN 10933
  • RG 6413

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19 November 21, 2020

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms [about 88 pounds]) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19. This includes those who are 65 years of age or older or who have certain chronic medical conditions.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.

Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.

Casirivimab and imdevimab are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. A benefit of casirivimab and imdevimab treatment has not been shown in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

“The FDA remains committed to advancing the nation’s public health during this unprecedented pandemic. Authorizing these monoclonal antibody therapies may help outpatients avoid hospitalization and alleviate the burden on our health care system,” said FDA Commissioner Stephen M. Hahn, M.D. “As part of our Coronavirus Treatment Acceleration Program, the FDA uses every possible pathway to make new treatments available to patients as quickly as possible while continuing to study the safety and effectiveness of these treatments.” 

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. Casirivimab and imdevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.

“The emergency authorization of these monoclonal antibodies administered together offers health care providers another tool in combating the pandemic,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “We will continue to facilitate the development, evaluation and availability of COVID-19 therapies.”

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that casirivimab and imdevimab administered together may be effective in treating patients with mild or moderate COVID-19. When used to treat COVID-19 for the authorized population, the known and potential benefits of these antibodies outweigh the known and potential risks. There are no adequate, approved and available alternative treatments to casirivimab and imdevimab administered together for the authorized population.

The data supporting this EUA for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms. Of these patients, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline. Viral load reduction in patients treated with casirivimab and imdevimab was larger than in patients treated with placebo at day seven. However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment. For patients at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated patients on average compared to 9% in placebo-treated patients. The effects on viral load, reduction in hospitalizations and ER visits were similar in patients receiving either of the two casirivimab and imdevimab doses.

Under the EUA, fact sheets that provide important information about using casirivimab and imdevimab administered together in treating COVID-19 as authorized must be made available to health care providers and to patients and caregivers. These fact sheets include dosing instructions, potential side effects and drug interactions. Possible side effects of casirivimab and imdevimab include: anaphylaxis and infusion-related reactions, fever, chills, hives, itching and flushing.

The EUA was issued to Regeneron Pharmaceuticals Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Related Information

Casirivimab/imdevimab, sold under the brand name REGEN-COV,[1] is an experimental medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial “antibody cocktail” designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic.[3][4] It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together.[1][5][6] The combination of two antibodies is intended to prevent mutational escape.[7]

Trials

In a clinical trial of people with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in people at high risk for disease progression within 28 days after treatment when compared to placebo.[2] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.[2]

The data supporting the emergency use authorization (EUA) for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms.[2] Of these participants, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.[2]

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline.[2] Viral load reduction in participants treated with casirivimab and imdevimab was larger than in participants treated with placebo at day seven.[2] However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment.[2] For participants at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated participants on average compared to 9% in placebo-treated participants.[2] The effects on viral load, reduction in hospitalizations and ER visits were similar in participants receiving either of the two casirivimab and imdevimab doses.[2]

As of September 2020, REGEN-COV is being evaluated as part of the RECOVERY Trial.[8]

On 12 April 2021, Roche and Regeneron announced that the Phase III clinical trial REGN-COV 2069 met both primary and secondary endpoints, reducing risk of infection by 81% for the non-infected patients, and reducing time-to-resolution of symptoms for symptomatic patients to one week vs. three weeks in the placebo group.[9]

Authorization

On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19.[2][10][11] This includes those who are 65 years of age or older or who have certain chronic medical conditions.[2] Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.[2]

Casirivimab and imdevimab are not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.[2] A benefit of casirivimab and imdevimab treatment has not been shown in people hospitalized due to COVID-19.[2] Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized people with COVID-19 requiring high flow oxygen or mechanical ventilation.[2]

The EUA was issued to Regeneron Pharmaceuticals Inc.[2][10][12]

On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.[13][14] In February 2021, the CHMP concluded that the combination, also known as REGN-COV2, can be used for the treatment of confirmed COVID-19 in people who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.[15]

The Central Drugs Standards Control Organisation (CDSCO) in India, on 5 May 2021, granted an Emergency Use Authorisation to Roche (Genentech)[16] and Regeneron[17] for use of the casirivimab/imdevimab cocktail in the country. The announcement came in light of the second wave of the COVID-19 pandemic in India. Roche India maintains partnership with Cipla, thereby permitting the latter to market the drug in the country.[18]

Deployment

Although Regeneron is headquartered in Tarrytown, New York (near New York City), REGEN-COV is manufactured at the company’s primary U.S. manufacturing facility in Rensselaer, New York (near the state capital at Albany).[19] In September 2020, to free up manufacturing capacity for REGEN-COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.[20]

Regeneron has a deal in place with Roche (Genentech)[21]to manufacture and market REGEN-COV outside the United States.[10][22]

On 2 October 2020, Regeneron Pharmaceuticals announced that US President Donald Trump had received “a single 8 gram dose of REGN-COV2” after testing positive for SARS-CoV-2.[23][24] The drug was provided by the company in response to a “compassionate use” (temporary authorization for use) request from the president’s physicians.[23]

References

  1. Jump up to:a b c “REGEN-COV- casirivimab and imdevimab kit”DailyMed. Retrieved 18 March 2021.
  2. Jump up to:a b c d e f g h i j k l m n o p q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”Reuters. Retrieved 14 September 2020.
  4. ^ “Regeneron’s COVID-19 Response Efforts”Regeneron Pharmaceuticals. Retrieved 14 September 2020.
  5. ^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”BBC News Online. Retrieved 14 September2020.
  6. ^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
  7. ^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”Science369 (6506): 1014–1018. Bibcode:2020Sci…369.1014Bdoi:10.1126/science.abd0831PMC 7299283PMID 32540904.
  8. ^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”Recovery Trial. Retrieved 14 September 2020.
  9. ^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”streetinsider.comArchived from the original on 2021-04-12. Retrieved 2021-04-12.
  10. Jump up to:a b c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
  11. ^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
  12. ^ “Casirivimab and Imdevimab”Regeneron Pharmaceuticals. Retrieved 19 March 2021.
  13. ^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. ^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
  15. ^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  16. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  17. ^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
  18. ^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”http://www.cipla.com. Retrieved 2021-05-06.
  19. ^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”The Daily Gazette.
  20. ^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”BioProcess International.
  21. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  22. ^ “Roche and Regeneron link up on a coronavirus antibody cocktail”CNBC. 19 August 2020. Retrieved 14 September 2020.
  23. Jump up to:a b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”The New York TimesISSN 0362-4331. Retrieved 2 October 2020.
  24. ^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”http://www.precisionvaccinations.comArchived from the original on 3 October 2020.

External links

REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB6VSB6XDG.
Combination of
CasirivimabMonoclonal antibody against spike protein of SARS-CoV-2
ImdevimabMonoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade namesREGEN-COV
Other namesREGN-COV2
AHFS/Drugs.comMonograph
License dataUS DailyMedCasirivimab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: Unapproved (Emergency Use Authorization)[1][2]
Identifiers
DrugBankDB15691
KEGGD11938

//////////// Casirivimab, ANTI VIRAL, PEPTIDE, SARS-CoV-2, MONOCLONAL ANTIBODY, FDA 2020, 2020APPROVALS, CORONA VIRUS, COVID 19, カシリビマブ, REGN-COV2, REGN10933+REGN10987 combination therapy, REGN 10933, RG 6413

wdt-7

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Casirivimab with Imdevimab

ZyCoV-D


Zydus Cadila Hopes To Get Clearance To Its Covid Vaccine ZyCoV-D From Indian Authorities Soon - YouTube

ZyCoV-D

CAS 2541524-47-2 

DNA vaccine construct encoding a spike protein antigen of SARS-CoV-2 virus (Zydus-Cadila)

http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=51254&EncHid=&userName=ZyCoV-D

bioRxiv (2021), 1-26. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423510/

ZyCoV-D | (CTRI/2020/07/026352, 2020CTRI/2020/07/026352, 2020Myupchar, 2020)ZYDUS CADILA

ZyCoV-D is a genetically engineered DNA plasmid based vaccine encoding for the membrane proteins of the virus. The clinical trials to study the immunogenicity, and safety of the vaccine, will administer three doses at an interval of 28 days in 1048 individuals.

Phase 1/2: CTRI/2020/07/026352

Vaccine description
TargetSARS-CoV-2
Vaccine typeDNA
Clinical data
Routes of
administration
Intradermal
ATC codeNone
Identifiers
DrugBankDB15892
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

ZyCoV-D is a DNA plasmid based COVID-19 vaccine being developed by Cadila Healthcare with support from the Biotechnology Industry Research Assistance Council.

The ZYCOV-D vaccine candidate was developed by Cadila Healthcare Ltd. based in India1. The vaccine was developed using a DNA vaccine platform with a non-replicating and non-integrating plasmid carrying the gene of interest3. Once the plasmid DNA is introduced into host cells and the viral protein is translated, it elicits a strong immune response, stimulating the humoral and cellular components of the immune system3. The DNA vaccine platform offers minimal biosafety requirements, more improved vaccine stability, and lower cold chain requirements3. Phase I clinical trials of this vaccine candidate were completed in July 2020, with the company reporting successful dosing and tolerance1,2. As of August, 2020 the candidate is in Phase II clinical trials1.

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Clinical research

Phase I and II trials

In February 2020, Cadila Healthcare decided to develop a DNA plasmid based COVID-19 vaccine at their Vaccine Technology Centre (VTC) in Ahmedabad.[1] The vaccine candidate was able to pass the pre-clinical trials on animal models successfully. A report of the study was made available via bioRxiv.[2] Thereafter, human trials for Phase I and II were approved by the regulator.[3]

The Phase II trials of the vaccine candidate were conducted in over 1,000 volunteers as part of the adaptive Phase I/II multi-centric, dose escalation, randomised, double-blind placebo controlled method.[4][5]

Phase III trials

In November 2020, the company announced it would test the vaccine candidate on 30,000 patients in Phase III trials.[6] The vaccine would be given out in three doses at five sites across four cities of India.[7] In January 2021, the Drugs Controller General of India (DCGI) granted permission to conduct the Phase III clinical trials for 28,216 Indian participants.[8][9]

In April 2021, the company reported that they expected to have initial data for the Phase III trials by May 2021.[10]

Production

On 23 April 2021, production of the ZyCoV-D vaccine was started, with a yearly capacity of 240 million doses. It is expected to get emergency use authorization in May or June.[11]

References

  1. ^ “Zydus Cadila launches a fast tracked programme to develop vaccine for the novel coronavirus, 2019-nCoV (COVID-19)”(PDF). http://www.zyduscadila.comCadila Healthcare.
  2. ^ Dey A, Rajanathan C, Chandra H, Pericherla HP, Kumar S, Choonia HS, et al. (26 January 2021). “Immunogenic Potential of DNA Vaccine candidate, ZyCoV-D against SARS-CoV-2 in Animal Models”. bioRxiv: 2021.01.26.428240. doi:10.1101/2021.01.26.428240S2CID 231777527.
  3. ^ “A prospective, randomized, adaptive, phase I/II clinical study to evaluate the safety and immunogenicity of Novel Corona Virus −2019-nCov vaccine candidate of M/s Cadila Healthcare Limited by intradermal route in healthy subjects”ctri.nic.inClinical Trials Registry India. 15 December 2020. CTRI/2020/07/026352. Archived from the original on 22 November 2020.
  4. ^ “Zydus Cadila’s ZyCov-D vaccine found to be ‘safe and immunogenic'”@businesslineThe Hindu. 24 December 2020.
  5. ^ Rawat K, Kumari P, Saha L (February 2021). “COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies”European Journal of Pharmacology892: 173751. doi:10.1016/j.ejphar.2020.173751PMC 7685956PMID 33245898.
  6. ^ Thacker T (7 November 2020). “Zydus Cadila to test ZyCoV-D on 30,000 patients in Phase-3 trials”The Economic Times.
  7. ^ “Covid 19 vaccine in India: Zydus Cadila begins enrolment for Phase 3 trial of ZyCoV-D in 4 cities”The Financial Express. 22 January 2021.
  8. ^ “DBT-BIRAC supported indigenously developed DNA Vaccine Candidate by Zydus Cadila, approved for Phase III clinical trials”pib.gov.inPress Information Bureau. 3 January 2021.
  9. ^ “Novel Corona Virus-2019-nCov vaccine by intradermal route in healthy subjects”ctri.nic.in. Clinical Trials Registry – India. Retrieved 10 April 2021.
  10. ^ Das, Sohini (22 April 2021). “Cadila Healthcare testing two-shot regimen for ZyCoV-D, data likely by May”Business Standard India.
  11. ^ Writer, Staff (24 April 2021). “Cadila Healthcare starts production of Covid vaccine candidate”mint. Retrieved 27 April 2021.

Zydus Cadila Covid vaccine close to getting approved in India, says MD Sharvil Patel

https://www.indiatoday.in/coronavirus-outbreak/vaccine-updates/story/zydus-cadila-covid-vaccine-close-to-getting-approved-in-india-says-md-sharvil-patel-1800132-2021-05-08

In an exclusive interview with India Today TV, Managing Director of Zydus Cadila Dr Sharvil Patel said the company’s Covid vaccine candidate ZyCoV-D against the Covid-19 infection is very close to getting approved in India. They are likely to apply for emergency use authorisation this month.

Ahmedabad-based pharmaceutical company Zydus Cadila is likely to submit the application for emergency use authorisation of its Covid-19 vaccine candidate ‘ZyCoV-D’ in India this month. The company is confident that the vaccine will be approved in May itself. The company plants to produce one crore doses of its ‘painless’ Covid-19 vaccine per month.

If approved, ZyCoV-D will be the fourth vaccine to be used in India’s Covid-19 vaccination drive. Made in India, the company plans to ramp up the vaccine’s production to 3-4 crore doses per month and is already in talks with two other manufacturing companies for the same

Although the vaccine should ideally be stored between 2 and 8 degrees Celsius, it remains stable even at room temperature conditions at 25 degrees Celsius. It is easy to administer, the developers said, and will be administered via intradermal injection.

If approved for emergency use, ZyCoV-D could help India fill the vacuum of vaccine doses currently being experienced in the country’s immunisation drive.

Earlier in April, Zydus Cadila announced that its drug Virafin had received restricted emergency use approval from the Drug Controller General of India for the treatment of mild cases of Covid-19.

In an exclusive interview with India Today TV, Sharvil Patel sheds details on all aspects of the Covid-19 vaccine ZyCoV-D.

When asked the status of Covid vaccine candidate ZyCoV-D and when exactly Zydus Cadila would apply for emergency use authorisation in India, Dr Sharvil Patel said the vaccine was getting very close to getting approved in the country.

“I am very happy to say that India’s first indigenously developed DNA vaccine candidate against Covid, which is our ZyCoV-D, is getting very close to approval,” he said.

“We have almost completed all our recruitment for the clinical trials. We have, by far, recruited the largest number of patients for a Covid vaccine trial in India. The number of volunteers who have been vaccinated as a part of the trial is 28,000,” Sharvil Patel said.

Sharvil Patel also said that his company has also included children in the 12-17 age group for the vaccine trials.

He said, “The recruitment holds very important milestones in terms of cohorts because not only have we included the elderly and those with co-morbidities, but also children in the age group of 12 to 17 years.”

Sharvil Patel said as soon as the efficacy data is obtained, Sydus Cadila will file for emergency use authorisation. As soon as the approval is granted, Zydus Cadila will start production of Covid-19 vaccines from July, he said.

“We hope to see our efficacy data in the middle of May. As soon as we see strong efficacy which correlates to the vaccine’s strong immunogenicity in Phase 2, we will file for emergency use authorization. We hope to produce a good quantity of the vaccine from July onwards to make sure it is available to the people. That is the need of the hour right now,” Sharvil Patel said.

He said by May the company will be in a position to talk to the regulators about the restricted use of the Covid-19 vaccine. “The regulatory process is a rolling one. I believe the regulators look at the data in a short period of time,” Sharvil Patel said.

“We have submitted a lot of data already so that it will aid the regulators once we provide them with the efficacy results. We are, hence, expecting to get the approval in May itself,” Sharvil Patel said.

///////////ZyCoV-D, COVID 19, CORONA VIRUS, VACCINE, INDIA 2021, APPROVALS 2021, SARS-CoV-2

2-Deoxy-D-glucose


2-Deoxy-D-glucose
ChemSpider 2D Image | 2-Deoxy-D-glucose | C6H12O5
Deoxyglucose.png

2-Deoxy-D-glucose

  • Molecular FormulaC6H12O5
  • Average mass164.156 Da

2-Deoxy-D-glucose

(4R,5S,6R)-6-(Hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol(4R,5S,6R)-6-(Hydroxyméthyl)tétrahydro-2H-pyran-2,4,5-triol

154-17-6[RN]

  • 2-Deoxy-D-arabino-hexose
  • 2 DG
  • 2-Deoxy-D-glucose
  • 2-Deoxy-D-mannose
  • 2-Deoxyglucose
  • 2-Desoxy-D-glucose
  • Ba 2758
  • D-Glucose, 2-deoxy-
  • NSC 15193

2-Deoxy-D-arabino-hexopyranose2-deoxy-D-glucopyranose2-deoxyglucose
2-DGD-arabino-2-DesoxyhexoseD-arabino-Hexopyranose, 2-deoxy- [(4R,5S,6R)-6-(Hydroxymethyl)oxane-2,4,5-triol2-deoxyglucopyranose2-deoxymannopyranose2-dGlc

61-58-5 [RN]77252-38-1 [RN]

D-arabino-2-Deoxyhexoseglucitol, 2,5-anhydro-
2-Deoxy-D-glucose

CAS Registry Number: 154-17-6

CAS Name: 2-Deoxy-D-arabino-hexose

Additional Names: D-arabino-2-desoxyhexose; 2-deoxyglucose; 2-DGManufacturers’ Codes: Ba-2758Molecular Formula: C6H12O5Molecular Weight: 164.16Percent Composition: C 43.90%, H 7.37%, O 48.73%Literature References: Antimetabolite of glucose, q.v., with antiviral activity.


Synthesis: M. Bergmann et al.,Ber.55, 158 (1922); 56, 1052 (1923); J. C. Sowden, H. O. L. Fischer, J. Am. Chem. Soc.69, 1048 (1947); H. R. Bolliger, Helv. Chim. Acta34, 989 (1954); H. R. Bolliger, M. D. Schmid, ibid. 1597, 1671; H. R. Bolliger, “2-Deoxy-D-arabino-hexose (2-Deoxy-D-glucose)” in Methods in Carbohydrate Chemistryvol. I, R. L. Whistler, M. L. Wolfrom, Eds. (Academic Press, New York, 1962) pp 186-189.
Inhibition of influenza virus multiplication: E. D. Kilbourne, Nature183, 271 (1959).
Effects on herpes simplex virus: R. J. Courtney et al.,Virology52, 447 (1973). Mechanism of action studies: M. R. Steiner et al.,Biochem. Biophys. Res. Commun.61, 745 (1974); E. K. Ray et al.,Virology58, 118 (1978). Use in human genital herpes infections: H. A. Blough, R. L. Giuntoli, J. Am. Med. Assoc.241, 2798 (1979); L. Corey, K. K. Holmes, ibid.243, 29 (1980). Effect vs respiratory syncytial viral infections in calves: S. B. Mohanty et al.,Am. J. Vet. Res.42, 336 (1981).

Properties: Cryst from acetone or butanone, mp 142-144°. [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine).

Melting point: mp 142-144°

Optical Rotation: [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine) Derivative Type: a-Form

Properties: Cryst from isopropanol, mp 134-136°. [a]D26 +156° ® +103° (c = 0.9 in pyridine).Melting point: mp 134-136°Optical Rotation: [a]D26 +156° ® +103° (c = 0.9 in pyridine) Use: Exptlly as an antiviral agent.

Source Temperature: 210 °C
   Sample Temperature: 150 °C
   Direct, 75 eV
14.0       2.2
      15.0      11.5
      17.0       3.9
      18.0      19.4
      19.0      13.7
      26.0       2.5
      27.0      12.1
      28.0      21.9
      29.0      31.2
      30.0       4.6
      31.0      41.3
      32.0      12.4
      39.0       5.9
      40.0       2.1
      41.0      10.9
      42.0      12.4
      43.0      46.3
      44.0      31.5
      45.0      34.3
      46.0       2.8
      47.0       4.1
      53.0       1.5
      54.0       2.0
      55.0      14.4
      56.0      35.3
      57.0      55.7
      58.0      11.4
      59.0       2.0
      60.0     100.0
      61.0      31.1
      62.0       2.3
      68.0       4.6
      69.0      12.2
      70.0       3.0
      71.0      34.9
      72.0       7.0
      73.0      25.3
      74.0      46.6
      75.0       5.1
      81.0       1.5
      82.0       2.4
      83.0       1.3
      84.0       1.3
      85.0      18.1
      86.0      55.3
      87.0       4.6
      89.0       1.2
      91.0       1.5
      97.0       3.6
      98.0       2.9
      99.0       1.7
     100.0       3.5
     102.0       1.1
     103.0      19.8
     104.0       1.4
     111.0       1.6
     115.0      25.2
     116.0       3.0
     117.0       2.1
     120.0       3.3
     128.0       1.0
     129.0       2.5
     133.0       1.8
     147.0       2.2

1H NMR DMSO D6

1H NMR D20

IR NUJOL MULL

IR KBR

PAPERCollection of Czechoslovak Chemical Communications (1955), 20, 42-5. http://cccc.uochb.cas.cz/20/1/0042/

Preparation of 2-​deoxy-​D-​glucose

By: Stanek, Jaroslav; Schwarz, Vladimir

Triacetyl-​D-​glucal (I) adds (BzO)​2IAg and (BzO)​2BrAg, to give 1-​benzoyl-​3,​4,​6-​triacetyl-​2-​deoxy-​2-​iodo-​α-​D-​glucopyranose (II) and 1-​benzoyl-​3,​4,​6-​triacetyl-​2-​deoxy-​2-​bromo-​α-​D-​glucopyranose (III)​, resp.  Both halogen derivs. give 2-​deoxy-​D-​glucose (IV) by reduction.  Adding a C6H6 soln. of 16.7 g. iodine into a suspension of 33.6 g. dry BzOAg in 200 ml. C6H6, treating the mixt. with a soln. of 20 g. I in 200 ml. C6H6, heating the mixt. 7 hrs. on the steam bath, removing the AgI, evapg. the solvent, and crystg. the residue from EtOH gave 20.8 g. (54.7​%) II, m. 129-​30°, [α]​21D 21.7°.  Analogous procedure with 13.4 g. BzOAg, 4.6 g. Br, and 8 g. I gave 3.9 g. (33​%) III, m. 139-​40°, [α]​17D 33.5°.  The same compd. (3 g.)​, m. 140°, [α]​18D 33.6°, was obtained by adding 3.2 g. Br to a soln. of 5.44 g. I in 50 ml. CCl4, by refluxing the mixt. 2 hrs. with 6 g. BzOAg, filtering off the AgBr, and evapg. the solvent.  Reducing 8 g. II or an equiv. III in 150 ml. MeOH with 60 g. Zn activated by 1 hr. immersion in a soln. of 60 g. CuSO4 in 1500 ml. H2O, removing Zn after 8 hrs., evapg. the MeOH, and sapong. the residue with Ba(OH)​2 yielded 0.42 g. (20​%) IV, m. 145°, [α]​18D 46.1°.

Wavlen: 589.3 nm; Temp: 18 °C, +46.1 °  ORD

PATENT

https://patents.google.com/patent/WO2004058786A1/enThe present invention relates to a process for the synthesis of 2-deoxy-D-glucose. Background of the invention 2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann, M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 989 (1951); Bolliger, H.R., Schmid, M.D., Helv. Chim. A a 34, 1597 (1951); Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 1671 (1951) and from D-arabhiose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J.C, Fisher, H.O.L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2- deoxy-D-glucose in low yield and of inferior purity due to the formation of several byproducts and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.Accordingly it is important to develop a process for synthesis of 2-deoxy-D-glucose which obviates the drawbacks as detailed above and results in good yield and good purity. Objects of the inventionThe main object of the present invention is to provide a process for the synthesis of 2- deoxy-D-glucose resulting in good yield and with good purity.Another object of the invention is to provide an economical process for the synthesis of 2-deoxy-D-glucose. Summary of the inventionA process that would produce 2-deoxy-D-glucose economically and with desired purity, is a welcome contribution to the art. This invention fulfills this need efficiently.Accordingly the present invention relates to a process for the synthesis of 2-deoxy- D-glucose comprising haloalkoxylation of R-D-Glucal wherein R is selected from H and 3, 4, 6-tri-O-benzyl, to obtain alkyl 2-deoxy-2-halo-R-α/ -D-gluco/mannopyranoside, converting alkyl 2-deoxy-2-halo-R-α/β-D-gluco/mannopyranoside by reduction to alkyl 2- deoxy-α/β-D-glucopyranoside, hydrolysing alkyl 2-deoxy-α/β-D-glucopyranoside to 2- deoxy-D-glucose.In one embodiment of the invention, the alkyl 2-deoxy-α/β-D-glucopyranoside is obtained by (a) haloalkoxylating 3,4,6,-tri-O-benzyl-D-glucal to alkyl 2-deoxy-2-halo-3,4,6-tri-O- benzyl-α/β-D-gluco-/mannopyranoside; (b) subjecting alkyl 2-deoxy-2-halo-3,4,6-tri-O-benzyl-α/β-D-gluco/mannopyranoside to reductive dehalogenation and debenzylation to obtain alkyl 2-deoxy -α/β-D- glucopyranoside. In another embodiment of the invention, in step (a) haloalkoxylation of 3,4,6-tri-O- benzyl-D-glucal is carried out by reaction with a haloalkoxylating agent selected from a N- halosuccinimide and a N-haloacetamide, and alcohol.The reaction scheme for the reactions involved in the process of the invention are also given below:

Figure imgf000005_0001

in R’=CH3I R=C6H5CH2 H R=C6H5CH2, X=Br, R’=CH3 IV R=H V R=CH3, C2HSJ C6H5CH3, iPr, X=Br

Figure imgf000005_0002

Such overall synthesis may be depicted as follows where R=H, CH3, C2H5, (CH3)2CH, C6H5CH ; RX-CH3; X-CL, Br.Example 1 To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mol) in dichloromethane (20ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDC13) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3xPhCH2O), 7.10-7.60 (m, 15H, Ar-H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside (50 g) in methanol (300) was charged into one litre autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50°C for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz, CDC13): δ 1.50-2.40 (m,2H,H-2,2′)5 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5H, H-3,4,5,6,6′), 4.30-5.00 (m, 7H, 3xPhCH2, H-l), 7.10-7.45 (m, 15H, Ar-H). The syrup of methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside (37.9g) was dissolved in methanol (200 ml). 1 g of 5%Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D- glucopyranoside obtained 10.5 g (70%). [ ]D + 25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H- 1,3,4,5,6,6′ – OCH3).Example 2 To a solution of D-glucal (64.6g, 0.44 mol) in methanol (325 ml) at 10°C was addedN-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15°C during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D- gluco/mannopyranoside (105 g) as a syrup. [α]D + 36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-23,4,5,6,6′), 4.48-5.13 (2s, 1H, H-l). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%. Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside: When solvent was ethanol instead of methanol the compound obtained was ethyl 2- bromo-2-deoxy-α/β-D-gluco-/mannopyranoside. 1HNMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-l α/β).Isopropyl 2-bromo-2-deoxy- /β-D-gluco-/mannopyranoside: When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2xCH3) 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.60-4.60 (m 8H,H- 2,3,4,5,6,6′, CH2) 4.40, 5.30 (2s, 1H, H-l, α/β).Example 3 A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15 C for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10°C. After 12 hours, the reaction mixture was diluted with CHC13 (500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D + 65.0° (c 1.0, CHC13) 1H NMR (200 MHz, CDC13): δ 1.55-1.90 (m, 2H, H-2,2′), 2.01, 2.04,2.11, 2.15, (4s, 9H, 3xOCOCH3), 2.18,3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) IN NaOMe in methanol (25ml) was added and left at room temperature. After 6-10 h, dry CO2 gas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).Example 4 A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (32.3 g) in methanol (175 ml), cooled to 15°C, N-bromosucci-t imide (NBS) (39.4 g) was added and stirred for 6 hours at 15°C. The reaction mixture was concentrated to half the volume, cooled to 0°C and separated succinimide was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β- D-glucopyranoside (85%).Example 5 To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2C12 (3×150 ml). The organic phase was separated, washed with saturated NaHCO3 solution, H2O dried over Na2SO and concentrated to obtain 2-deoxy- 1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound, mp. 115-118°C. Quantity obtained 44.5 g (86%). [α]D + 21.5° (c 1.0, CHC13). 1H NMR (200 MHz, CDC13): δ 1.50-2.45 (m, 14H, H-2,2′, 4xOCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-l,α/ β). To a heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D- glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80°C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad. Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2O5 to obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5°C crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149°C.Example 6 A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO (0.3 ml) was stirred at 85°C for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)2 solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2O5 to obtain 2-deoxy- D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149°C.Example 7A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(25g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean- Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. The filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2- deoxy-D-glucose (7.33 g, 59%). mp. 148-151°C.Example 8 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (lOg) (from example 5), H2O (200 ml) cone. HC1 (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85°C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 2.75 g. mp. 147-148°C.Example 9 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(lOg) (from example 3) water (100 ml) and cone. HCI (0.5ml) was heated to 80°C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue andcrystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15g mp. 148-151°C.Example 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water(15 ml) and cone. HCI (1.5 ml) was heated to 80-85°C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151°C.Example 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water (195 ml) and cone. H2SO (5.9 ml) was heated to 80°C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)2 and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154°C.Example 12 A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24g) (from example 2) water(125 ml) and IR 120 H+ resin (7.5 ml) was heated to 90-95°C for 2h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D- glucose (8.8 g), mp. 150-152°C. The main advantages of the present invention are:-1). It does not involve the use of toxic mercaptans like ethane thiol. 2). This process does not involve reaction of D-glucal with mineral acid, thereby avoiding the formation of Ferrier by-products.

2-Deoxy-d-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level (step 2 of glycolysis).[2] In most cells, glucose hexokinase phosphorylates 2-deoxyglucose, trapping the product 2-deoxyglucose-6-phosphate intracellularly (with exception of liver and kidney)[; thus, labelled forms of 2-deoxyglucose serve as a good marker for tissue glucose uptake and hexokinase activity. Many cancers have elevated glucose uptake and hexokinase levels. 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.

2-DG is uptaken by the glucose transporters of the cell. Therefore, cells with higher glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is in clinical trials. [3] A recent clinical trial showed 2-DG can be tolerated at a dose of 63 mg/kg/day, however the observed cardiac side-effects (prolongation of the Q-T interval) at this dose and the fact that a majority of patients’ (66%) cancer progressed casts doubt on the feasibility of this reagent for further clinical use.[4] However, it is not completely clear how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to be sufficient to explain why 2-DG treated cells stop growing.[5] Because of its structural similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR) pathway.[6][7][8]

Clinicians have noted that 2-DG is metabolised in the pentose phosphate pathway in red blood cells at least, although the significance of this for other cell types and for cancer treatment in general is unclear.

Work on the ketogenic diet as a treatment for epilepsy have investigated the role of glycolysis in the disease. 2-Deoxyglucose has been proposed by Garriga-Canut et al. as a mimic for the ketogenic diet, and shows great promise as a new anti-epileptic drug.[9][10] The authors suggest that 2-DG works, in part, by increasing the expression of Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Arc (protein) (ARC), and Basic fibroblast growth factor (FGF2).[11] Such uses are complicated by the fact that 2-deoxyglucose does have some toxicity.

A study found that by combining the sugar 2-deoxy-D-glucose (2-DG) with fenofibrate, a compound that has been safely used in humans for more than 40 years to lower cholesterol and triglycerides, an entire tumor could effectively be targeted without the use of toxic chemotherapy.[12][13]

2-DG has been used as a targeted optical imaging agent for fluorescent in vivo imaging.[14][15] In clinical medical imaging (PET scanning), fluorodeoxyglucose is used, where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to be imaged by external gamma camera(s). This is increasingly done in tandem with a CT function which is part of the same PET/CT machine, to allow better localization of small-volume tissue glucose-uptake differences.

Resistance to 2-DG has been reported in HeLa cells [16] and in yeast;[17][8] in the latter, it involves the detoxification of a metabolite derived from 2-DG (2DG-6-phosphate) by a phosphatase. Despite the existence of such a phosphatase in human (named HDHD1A) However it is unclear whether it contributes to the resistance of human cells to 2DG or affects FDG-based imaging.

SYN

Indian Pat. Appl., 2004DE02075,

SYN

CN 106496288,

STARTING MATERIAL CAS 69515-91-9

C14 H20 O9, 332.30

D-​arabino-​Hexopyranose, 2-​deoxy-​, 1,​3,​4,​6-​tetraacetate

SYN

Bioorganic & Medicinal Chemistry Letters, 22(10), 3540-3543; 2012

https://www.sciencedirect.com/science/article/abs/pii/S0960894X12004258

PATENT

https://patents.google.com/patent/US6933382B2/en2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H. R. Schmid, M. D., Helv. Chim. Acta 34, 989 (1951); Bolliger, H. R., Schmid, M. D., Helv, Chim. Acta 34, 1597 (1951); Bolliger, H. R Schmid, M. D., Helv. Chim. Acta 34, 1671 (1951) and from D-arabinose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J. C., Fisher, H. O. L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2-deoxy-D-glucose in low yield and of inferior purity due to the formation of several by-products and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.

Figure US06933382-20050823-C00001

EXAMPLE 1To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mmol) in dichloromethane (20 ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco-/mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDCl3) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3×PhCH2O), 7.10-7.60 (m 15H, Ar—H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl/α/β-D-gluco-/mannopyranoside (50 g) in methanol (300) was charged into one liter autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50° C. for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz CDCl3): δ 1.50-2.40 (m,2H,H-2,2′), 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5, H-3,4,5,6,6′) 4.30-5.00 (M 7H, 3×PhCH2, H-1), 7.10-7.45 (m, 15H, Ar—H). The syrup of methyl 2-deoxy-3,4, 6-tri-O-benzyl-α/β-D-glucopyranoside (37.9 g) was dissolved in methanol (200 ml). 1 g of 5% Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D-glucopyranoside obtained 10.5 g (70%). [α]D+25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H-1,3,4,5,6,6′—OCH3).EXAMPLE 2To a solution of D-glucal (64.6 g, 0.44 mmol) in methanol (325 ml) at 10° C. was added N-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15° C. during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside (105 g) as a syrup. [α]D+36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-2,3,4,5,6,6′), 4.48-5.13 (28, 1H, 1H, H-1). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%.Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside:When solvent was ethanol instead of methanol the compound obtained was ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-1, α/β).Isopropyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside:When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside, 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2×CH3) 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.60-4.60 (m 8H,H-2,3,4,5,6,6′, CH2) 4.40, 5,30 (2s, 1H, H-1, α/β.EXAMPLE 3A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15° C. for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10° C. After 12 hours, the reaction mixture was diluted with CHCl(500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D+65.0° (c 1.0, CHCl31H NMR (200 MHz, CDCl3): δ 1.55-1.90 (m, 2H, H-22′), 2.01, 2.04, 2.11, 2.15, (4s, 9H, 3×OCOCH3), 2.18, 3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) 1N NaOMe in methanol (25 ml) was added and left at room temperature. After 6-10 h, dry COgas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).EXAMPLE 4A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (323 g) in methanol (175 ml), cooled to 15° C., N-bromosuccinimide (NIBS) (39.4 g) was added and stirred or 6 hours at 15° C., The reaction mixture was concentrated to half the volume, cooled to 0° C. and separated succinimide, was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in Methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside (85%).EXAMPLE 5To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2Cl(3×150 ml). The organic phase was separated, washed with saturated NaHCOsolution H2O dried over Na2SOand concentrated to obtain 2-deoxy-1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound. mp. 115-118° C. Quantity obtained 44.5 g (86%). [α]D+21.5° (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ 1.50-2.45 (m, 14H, H-2,2′, 4×OCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-1, α/β). To a heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80° C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad, Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2Oto obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5° C. crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149° C.EXAMPLE 6A heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO(0.3 ml) was stirred at 85° C. for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2Oto obtain 2-deoxy-D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149° C.,EXAMPLE 7A heterogeneous mixture of 1,3,4,tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (25 g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean-Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. Be filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2-deoxy-D-glucose (7.33 g, 59%). mp. 148-151° C.EXAMPLE 8A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (tom example 5), H2O (200 ml) conc. HCl (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85° C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 275 g. mp. 147-148° C.EXAMPLE 9A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (from example 3) water (100 ml) and conc. HCl (0.5 ml) was heated to 80° C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue and crystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15 g mp. 148-151° C.,EXAMPLE 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (from example 2) water (15 ml) and conc. HCl (1.5 ml) was heated to 80-85° C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralize with aq. Ba(OH)and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151° C.EXAMPLE 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (form example 2) water (195 ml) and conc. H2SO(5.9 ml) was heated to 80° C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154° C.EXAMPLE 12A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24 g) (from example 2) water (125 ml) and IR 120H+resin (7.5 ml) was heated to 90-95° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D-glucose (8.8 g), mp. 150-152° C.CLIP

References

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The Drugs Controller General of India (DCGI) has given permission for the emergency use of drug 2-deoxy-D-glucose (2-DG) as an adjunct therapy in moderate to severe Covid-19 cases, said Defence Research and Development Organisation on Saturday.

“Being a generic molecule and analogue of glucose, it can be easily produced and made available in plenty,” said the DRDO in a statement.

An adjunct therapy refers to an alternative treatment that is used together with the primary treatment. Its purpose is to assist the primary treatment.

“The drug has been developed by DRDO lab Institute of Nuclear Medicine and Allied Sciences in collaboration with Dr Reddy’s Laboratories. Clinical trial have shown that this molecule helps in faster recovery of hospitalized patients and reduces supplemental oxygen dependence,” the statement read.

According to DRDO, the patients treated with 2-DG showed faster symptomatic cure than Standard of Care (SoC) on various endpoints in the efficacy trends.

“A significantly favourable trend (2.5 days difference) was seen in terms of the median time to achieving normalization of specific vital signs parameters when compared to SOC,” it said.

The drug comes in powder form in sachets, which is taken orally by dissolving it in water.

“It accumulates in the virus-infected cells and prevents virus growth by stopping viral synthesis and energy production,” said the DRDO.

In April 2020, during the first wave of the Covid-19 pandemic, INMAS-DRDO scientists conducted laboratory experiments of 2-DG with the help of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad.

They found that this molecule works effectively against the SARS-CoV-2 virus and inhibits viral growth.

Based on the results, the DCGI had in May 2020 permitted Phase-II clinical trial of 2-DG in Covid-19 patients.

In Phase-II trials (including dose-ranging) conducted from May to October 2020, the drug was found to be safe and showed significant improvement in the patients’ recovery.

“Phase IIa was conducted in 6 hospitals and Phase IIb (dose-ranging) clinical trial was conducted at 11 hospitals all over the country. Phase-II trial was conducted on 110 patients,” said the DRDO.

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Names
IUPAC name(4R,5S,6R)-6-(hydroxymethyl)oxane-2,4,5-triol
Other names2-Deoxyglucose
2-Deoxy-d-mannose
2-Deoxy-d-arabino-hexose
2-DG
Identifiers
CAS Number154-17-6 
3D model (JSmol)Interactive image
ChEMBLChEMBL2074932
ChemSpider388402 
EC Number205-823-0
IUPHAR/BPS4643
PubChem CID108223
UNII9G2MP84A8W 
showInChI
showSMILES
Properties
Chemical formulaC6H12O5
Molar mass164.16 g/mol
Melting point142 to 144 °C (288 to 291 °F; 415 to 417 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////2-Deoxy-D-glucose,  2 dg, 2-dg, 2 DEOXY D GLUCOSE, COVID 19, CORONA VIRUS, INDIA 2021, DCGI, DRDO, DR REDDYS

C(C=O)C(C(C(CO)O)O)O

Pegylated Interferon alpha-2b, (PegIFN), Virafin


DB00022 sequence CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMI QQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE

CDLPQTHSLG SRRTLMLLAQ MRRISLFSCL KDRHDFGFPQ EEFGNQFQKA ETIPVLHEMI
QQIFNLFSTK DSSAAWDETL LDKFYTELYQ QLNDLEACVI QGVGVTETPL MKEDSILAVR
KYFQRITLYL KEKKYSPCAW EVVRAEIMRS FSLSTNLQES LRSKE

2D chemical structure of 215647-85-1
Chemical structure of peginterferon α-2a and α-2b. Abbreviations: PeG-IFN, peginterferon; IFN, interferon; Lys, lysine; His, histidine; Cys, cysteine; Ser, serine. 

Chemical structure of peginterferon α-2a and α-2b. Abbreviations: PeG-IFN, peginterferon; IFN, interferon; Lys, lysine; His, histidine; Cys, cysteine; Ser, serine.

Pegylated Interferon alpha-2b

(PegIFN), Virafin

Zydus seeks DCGI approval for the use of Pegylated Interferon alpha-2b in  treating COVID-19 - The Indian Practitioner
FormulaC860H1353N229O255S9
CAS99210-65-8, 98530-12-2, 215647-85-1
Mol weight19268.9111
  • Interferon α2b, pegylated
  • PegIFN a-2b
  • PegIFN a-2b (biologics)
  • PegIFN α-2b
  • PegIntron
  • Pegaferon
  • PegiHep
  • Peginterferon alfa-2b
  • Peginterferon α-2b
  • Pegylated interferon alfa-2b
  • Pegylated interferon α-2b
  • Pegylated interferons, PegIFN a-2b
  • Proteinaceous biopharmaceuticals, PegIFN a-2b
  • Sch 54031
  • Sylatron
  • ViraferonPeg

Active Moieties

NAMEKINDUNIICASINCHI KEY
Interferon alfa-2bunknown43K1W2T1M698530-12-2Not applicable
Clinical data
Trade namesPegIntron, Sylatron, ViraferonPeg, others
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa605030
License dataEU EMAby INN
Routes of
administration
Subcutaneous injection
ATC codeL03AB10 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]EU: Rx-only
Pharmacokinetic data
Elimination half-life22–60 hrs
Identifiers
showIUPAC name
CAS Number215647-85-1 
IUPHAR/BPS7462
DrugBankDB00022 
ChemSpidernone
UNIIG8RGG88B68
KEGGD02745 
ChEMBLChEMBL1201561 
ECHA InfoCard100.208.164 
Chemical and physical data
FormulaC860H1353N229O255S9
Molar mass19269.17 g·mol−1
wdt-19

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New Delhi: ,,,,,,https://www.ndtv.com/india-news/zydus-virafin-gets-emergency-use-approval-for-treating-moderate-covid-19-cases-2420358

Zydus Cadila received emergency use approval from the Drugs Controller General of India (DGCI) on Friday for the use of “Virafin”, Pegylated Interferon alpha-2b (PegIFN) in treating moderate COVID-19 infection in adults.

A single-dose subcutaneous regimen of the antiviral Virafin will make the treatment more convenient for the patients. When administered early on during COVID-19, Virafin will help patients recover faster and avoid much of the complications, the company said.

In a release, Cadila Health highlighted that “the drug has also shown efficacy against other viral infections.”

Speaking on the development, Dr Sharvil Patel, Managing Director, Cadila Healthcare Limited said, “The fact that we are able to offer a therapy which significantly reduces the viral load when given early on can help in better disease management. It comes at a much-needed time for patients and we will continue to provide them access to critical therapies in this battle against COVID-19.”

In its Phase III clinical trials, the therapy had shown better clinical improvement in the patients suffering from COVID-19. During the trials, a higher proportion of patients administered with PegIFN arm were RT-PCR negative by day 7. The drug ensures faster viral clearance and has several add-on advantages compared to other anti-viral agents, the release further reads.

The development and the nod from DGCI come at a time when India is combating the second wave of coronavirus.

The central government in one of its major announcements decided to administer COVID-19 vaccines to all age above 18 years.

India recorded 3,32,730 new COVID-19 cases in the last 24 hours, the highest single-day spike since the pandemic broke out last year. India has crossed the mark of 3 lakh COVID-19 cases for two consecutive days now. This has taken the cumulative count of the COVID infection in the country to 1,62,63,695.

2CommentsThe country has recorded 2,263 new deaths due to COVID-19 in the last 24 hours. As many as 1,86,920 people have succumbed to the viral infection in India so far. There are 24,28,616 active COVID-19 cases in the country now.

PATENT

https://patents.google.com/patent/EP1562634B1/en

  • Interferon alpha-2a plays an important role for the treatment of chronic hepatitis C, but it is limited in its efficacy by the short in vivo half-life. To improve the half-life and efficacy, interferon alpha-2a was conjugated with a polyethylene glycol moiety. Pegylation changes physicochemical and biological properties of the protein. One effect is the decrease of the proteolytic degradation and the renal clearance. This increases the half-life of the pegylated protein in blood. Another effect is the altered distribution in the body, depending on the size of the PEG moiety of the protein. Interferon alpha 2a pegylated with a large polyethylene glycol moiety (PEG moiety) such as a 40 kDa branched polyethylene moietywherein R and R’ are independently lower alkyl; n and n’ are integers having a sum of from 600 to 1500; and the average molecular weight of the polyethylene glycol units in said conjugate is from about 26,000 daltons to about 66,000 daltons;
    has an improved biological activity and exhibits sustained adsorption and reduced renal clearance, resulting in a strong antiviral pressure throughout a once-weekly dosing schedule, see Perry M. C., et al. Drugs, 2001,15,2263-2288 and Lamb M. W., et al. The Annals of Pharmacotherapy, 2002, 36, 933-938.
  • [0003]See also Monkarsh et al. Analytical Biochemistry, 1997, 247, 434- 440 (Positional Isomers of Mono-pegylated Interferon α-2a) and Bailon et al. Bioconjugate Chemistry, 2001, 12, 195-202 (Rational Design of a Potent, Long-Lasting Form of interferon).
  • [0004]The method for the pegylation of interferon alpha-2a is described in EP A 809 996. Since this pegylation is performed by reaction of PEG2-NHS of formulawith primary amino groups on for example lysine or to the N-terminus of the interferon alpha.one or more PEG moieties may be attached and form a mixture of unpegylated, mono- and multiple-pegylated interferon. Monopegylated interferon alpha can be isolated from the mixture by methods known in the art. Furthermore, since interferon alpha-2a molecule exhibits 12 sites for pegylation (11 lysines and the N-terminus) it is a mixture of positional isomers. From these possible twelve isomers, nine were isolated and characterized, each of these being conjugated to the branched polyethylene glycol chain at a specific lysine, namely,
    at Lys(31) to form interferon alpha 2a pegylated at Lys(31) [referred to as PEG-Lys(31)],
    at Lys(49) to form interferon.alpha 2a pegylated at Lys(49) [referred to as PEG-Lys(49)],
    at Lys(70) to form interferon alpha 2a pegylated at Lys(70) [referred to as PEG-Lys(70)],
    at Lys(83) to form interferon alpha 2a pegylated at Lys(83) [referred to as PEG-Lys(83)],
    at Lys(112) to form interferon alpha 2a pegylated at Lys(112) [referred to as PEG-Lys(112)],
    at Lys(121) to form interferon alpha 2a pegylated at Lys(121) [referred to as PEG-Lys(121)],
    at Lys(131) to form interferon alpha 2a pegylated at Lys(131) [referred to as PEG-Lys(131)],
    at Lys(134) to form interferon alpha 2a pegylated at Lys(134) [referred to as PEG-Lys(134)],
    at Lys(164) to form interferon alpha 2a pegylated at Lys(164) [referred to as PEG-Lys(164)].
  • [0005]It has been found that PEG-Lys(31) and PEG-Lys(134) have higher activities in an antiviral assay than the mixture, the activity of PEG-Lys(164) was equal to the mixture, whereas the activities of PEG-Lys(49), PEG-Lys(70), PEG-Lys(83), PEG-Lys(112), PEG-Lys(121) and PEG-Lys(131) were lower.
  • The following examples will further illustrate the invention

Example 1A Separation of the positional isomers

  • [0035]A two-step isolation and purification scheme was used to prepare the monopegylated isoforms of PEG-interferon alpha 2a.
  • a) The first step was a separation of the positional isomers on a preparative low pressure liquid chromatography column with a weak-cation exchange matrix (TOSOH-BIOSEP, Toyopearl CM-650S, e.g. Resin Batch no. 82A the diameter of the column being 16 mm, the length 120 cm). A linear pH-gradient of increasing sodium acetate concentration (25 mM, pH 4.0 up 75 mM to pH 7.8) was applied at a flow rate of 0.7 mL/min. Detection was at 280 nm. With this chromatographic step species 1, 2, 5,6 and a mixture of 3, 4, 4a, 7 and 8 could be collected, see Table 1.
  • b) The fractions were further separated and purified in the second preparation step. A preparative column with the same matrix as the analytical strong-cation exchange column (Resin Batch no. 82A having a ion exchange capacity of 123 mEq/ml) as described above but larger dimensions (30 mm i.d. and 70 mm length), further a higher flow rate and an extended run time was used. As for the analytical method the column was pre-equilibrated with 3.4 mM sodium acetate, 10% ethanol and 1% diethylene glycol, adjusted to pH 4.4 (buffer A). After loading the PEG-IFN samples, the column was washed with buffer A, followed by an ascending linear gradient to 10 mM dibasic potassium phosphate, 10% ethanol and 1% diethylene glycol, adjusted to pH 6.6 (buffer B). The flow rate was 1.0 mL/min and the detection at 218 nm.
  • [0036]The protein concentration of the PEG-IFN alpha 2a isomer was determined by spectrophotometry, based on the 280 nm absorption of the.protein moiety of the PEG-IFN alpha 2a.
  • [0037]An analytical elution profile of 180 µg of PEG-IFN alpha 2a is shown in Figure 1. The result of this method is a separation into 8 peaks, 2 peaks with baseline separation and 6 with partial separation. The decrease of the baseline absorption towards the end of the chromatogram suggests that there were no other monopegylated species of IFN alpha 2a eluting at higher retention time.
  • [0038]In addition, looking carefully at the IEC-chromatogram a further peak close to the detection limit is visible between peaks 2 and 3 indicating the presence of additional positional isomers that should also contribute to the specific activity of the PEG-IFN alpha 2a mixture. Additional species were expected as the interferon alpha-2a molecule exhibits 12 sites for pegylation (11 lysines and the N-terminus). However, given the low abundance of the these species, they were not isolated and characterised.
  • [0039]Isomer samples derived from IEC optimisation runs were investigated directly after the isolation (t = 0) and after 2 of weeks of storage at 5°C (data not shown). No significant differences were observed for the protein derived from IEC-peaks with regard to the protein content as determined by spectrometric methods; nor were any changes to be detected in the monopegylation site, the content of oligo-PEG-IFN alpha 2a, the amount of aggregates and the bioassay activity. Taking into account the relative abundance of the individual isomers – as determined by the IEC method – as well as the specific activities – as determined in the anti-viral assay – almost the total specific bioactivity of the PEG-IFN alpha 2a mixture used for their isolation is recovered (approximately 93%).
  • [0040]The analytical IE-HPLC was used to check the purity of the individual isomers with respect to contamination with other positional isomers in the IEC fractions. The peaks 2, 3, 4, 4a, 5 and 7 had more than 98%, the peaks 1 and 8 had 93% and peak 6 had 88 % purity. Table 1:PEG-peptides identified by comparison of the Lys-C digest spectra of the isomers and the reference standard.Identified PEG Sites in the separated PEG-IFN SpeciesPeakmissing peaks in peptide mapPEG-IFNPEG siteMr (DA)SequencePeak 1K31A,E24-49Peak 2K134I, I’134-164Peak 3K131C122-131aPeak 4K121B, C113-131Peak 4aK164b134-164a,bPeak 5K70D, F50-83Peak 6K83D, H71-112Peak 7K49E, F32-70Peak 8K112B, H84-121a132-133 too small to detect.a,b RP-HPLC.
  • [0041]The fractions were characterised by the methods described in examples 2 to 6.

Example 1B Analytical separation of positional isomers of mono-pegylated interferon alpha 2a

  • [0042]HPLC Equipment:HP1100Column:SP-NPR, TosoH Bioscience, Particle size: 2.5µm, nonporous, Order#: 13076Injection:5-10 µg monopegylated IFNmobile Phase:Buffer A:  10% v/vEthanol 1% v/vDiethylenglycol 2.3 mMNa-Acetat 5.2 mMAcetic acid, in purified water, no pH adjustment Buffer B:  10% v/vEthanol 1% v/vDiethylenglycol 16.4 mMKH2PO4 4.4 mMK2HPO4, in purified water, no pH adjustmentGradient:0 Min40 %B 2 Min40 %B 2.1 Min48 %B 25 Min68 %B 27 Min75 %B 30 Min75 %B 34 Min40 %B 40 Min40 %BFlow:1.0 ml/min Column Temperature:25°C Detection:218 nm a typical Chromatogram is given in Figure 8.

Example 2 Analysis of the fractions by mass spectrometry peptide mapping

  • [0043]Mass spectra were recorded on a MALDI-TOF MS instrument (PerSeptive Biosystems Voyager-DE STR with delayed extraction). Each IEC fraction (Ion Exchange Chromatography) was desalted by dialysis, reduced with 0.02 M 1,4-dithio-DL-threitol (DTT) and alkylated with 0.2 M 4-vinyl pyridine. Then the proteins were digested with endoproteinase Lys-C (Wako Biochemicals) in 0.25 M Tris (tris(hydroxymethyl)-aminoethane) at pH 8.5 with an approximate enzyme to protein ratio of 1:30. The reaction was carried out over night at 37 °C.
  • [0044]A solution of 20 mg/ml α-cyano-4-hydroxycinnamic acid and 12 mg/ml nitrocellulose in acetone/isopropanol 40/60 (v/v) was used as matrix (thick-layer application). First, 0.5 µL of matrix was placed on the target and allowed to dry. Then, 1.0 µL of sample was added. The spectra were obtained in linear positive ionisation mode with an accelerating voltage of 20.000 V and a grid voltage of 95 %. At least 190 laser shots covering the complete spot were accumulated for each spectrum. Des-Arg1-bradykinin and bovine insulin were used for internal calibration.

Example 3 high-performance liquid chromatography (RP-HPLC) Peptide Mapping

  • [0045]The peptides were characterized by reverse-phase high-performance liquid chromatography (RP-HPLC) Peptide Mapping. The IEC fractions were reduced, alkylated and digested with endoproteinase Lys-C as described for the MALDI-TOF MS peptide mapping. The analysis of the digested isomers was carried out on a Waters Alliance HPLC system with a Vydac RP-C18 analytical column (5 µm, 2.1 × 250 mm) and a precolumn with the same packing material. Elution was performed with an acetonitrile gradient from 1 % to 95 % for 105 min in water with a flow rate of 0.2 mL/min. Both solvents contained 0.1 % (v/v) TFA. 100 µL of each digested sample were injected and monitored at 215 nm.

Example 4 MALDI-TOF spectra of undigested protein

  • [0046]An 18 mg/ml solution of trans-3-indoleacrylic acid in acetonitrile/0.1 % trifluoroacetic acid 70/30 (v/v) was premixed with the same volume of sample solution. Then 1.0 µL of the mixture was applied to the target surface. Typically 150 – 200 laser shots were averaged in linear positive ionisation mode. The accelerating voltage was set to 25.000 V and the grid voltage to 90 %. Bovine albumin M+ and M2+ were used for external calibration.

Example 5 SE-HPLC (size exclusion HPLC)

  • [0047]SE-HPLC was performed with a Waters Alliance 2690 HPLC system equipped with a TosoHaas TSK gel G 4000 SWXL column (7.8 × 300 mm). Proteins were eluted using a mobile phase containing 0.02 M NaH2PO4, 0.15 M NaCl, 1% (v/v) diethylene glycol and 10 % (v/v) ethanol (pH 6.8) at a flow rate of 0.4 mL/min and detected at 210 nm. The injection amounts were 20 µg of each isomers.
  • [0048]Size Exclusion HPLC and SDS-PAGE were used to determine the amount of oligo-PEG-IFN alpha 2a forms and aggregates in the different IEC fractions. The reference material contains 2.3 % aggregates and 2.2 % oligomers (Figure 4).
  • [0049]Peaks 1, 4, 4a, 5, 6 and 8 contain < 0.7 % of the oligopegylated IFN alpha 2a forms, whereas in,peaks 2, 3, and 7 the percentage of the oligopegylated IFN alpha 2a forms are under the detection limit (< 0.2 %). In the case of the aggregates a different trend could be seen. In all peaks the amount of aggregates is below 0.9 %.

Example 6 SDS-PAGE

  • [0050]SDS-PAGE was carried out both under non-reducing and under reducing conditions using Tris-Glycine gels of 16 % (1.5 mm, 10 well). Novex Mark 12 molecular weight markers with a mass range from 2.5 to 200 kDa were used for calibration, bovine serum albumin (BSA) was used as sensitivity standard (2 ng). Approximately 1 µg of all the samples and 0.5 µg of standard were applied to the gel. The running conditions were 125 V and 6 W for 120 min. The proteins were fixed and stained using the silver staining kit SilverXpress from Novex.
  • [0051]The gels that were recorded under non-reducing conditions for the IEC fractions 1- 8 (Figure 2) show a pattern that is comparable to that of the PEG-IFN alpha 2a reference standard.
  • [0052]Under reducing conditions, the gels show an increase in intensity of the minor bands at about 90 kDa as compared to the standard. Between 6 and 10 kDa protein fragments appear for peaks 6, 7 and 8 (Figure 3). Both bands together correspond to approximately 1 % of clipped material. In the lanes of isomer 1, 5, 6, 7, 8 additional bands with more than 100 kDa can be seen which are also present in the standard. These can be assigned to oligomers. Thus SDS-PAGE confirms the results of the SE-HPLC analysis.
  • [0053]Overall, RP-HPLC and SDS-PAGE experiments indicate that the purity of the IEC fractions can be considered comparable to the PEG-IFN alpha 2a reference standard.
  • [0054]The structure of the PEG-IFN alpha 2a species derived from the 9 IEC-fractions were identified based on the results of the methods described above using the strategy mentioned above.

Example 7 The antiviral activity (AVA)

  • [0055]The antiviral activity was estimated by its protective effect on Madin-Darby bovine kidney (MDBK) cells against the infection by vesticular stomatitis virus (VSV) and compared with a PEG-IFN alpha 2a standard. Samples and reference standard were diluted in Eagle’s Minimum Essential Medium (MEM) containing 10 % fetal bovine serum to a final concentration of 10 ng/mL (assay starting concentration). Each sample was assayed in quadruplicate.
  • [0056]The antiviral protection of Madin-Darby bovine kidney cells (MDBK) with vesicular stomatitis virus was tested according to the method described in Virol. 1981, 37, 755-758. All isomers induced an activity in the anti-viral assay as presented in Table 2. The activities range between 1061 and 339 U/µg, indicating that the difference in specific activities of the protein in the positional isomers is significant. The know-how and the results generated so far will allow the initiation of further investigations to establish this structure-function relationship between the positional isomers and the IFN alpha receptors. Table 2:In Vitro Antiviral Activities of PEG-IFN alpha 2a and individual PEG-IFN alpha 2a isomers. The Antiviral activity was determined in MDBK cells infected with vesicular stomatitis virus. The results present the averages of three assays performed independently.Antiviral Assay of PEG-IFNPeakU/µgPEG-IFN1061 ± 50Peak 11818 ± 127Peak 21358 ± 46Peak 3761197Peak 4339 ± 33Peak 4a966 ± 107Peak 5600 ± 27Peak 6463 ± 25Peak7513 ± 20Peak 8468 ± 23
  • [0057]The results are further illustrated by the following figures
  • Figure 1: Analytical IEC-HPLC of 180µg of PEG-IFN alpha 2a. An analytical strong-cation exchange column was used to check the purity of the separated positional isomers from each purification step (TOSOH-BIOSEP, SP-SPW,10 µm particle size, 7.5 mm diameter, 7.5 cm length).
  • Figure 2: A/B: SDS-PAGE analysis with Tris-glycine (16%), the samples were electrophoresed under non-reduced conditions. The gels were stained for protein with Silver Stain. Lanes: M, molecular weight marker proteins/ 2, Peak 1/ 3, Peak 2/ 4, Peak 3/ 5, Peak 4/ 6, Peak 4a/ 7, Peak 5/ 8, Peak 6/ 9, Peak 7/10, Peak 8/ 11, Ix PEG-IFN standard/ 12, 1.5x PEG-IFN standard/ C1, IFN standard.
  • Figure 3: A/B: SDS-PAGE analysis with Tris-glycine (16%), the samples were electrophoresed under reduced conditions. The gels were stained for protein with Silver Stain. Lanes: M, molecular weight marker proteins/ 2, Peak 1/ 3, Peak 2/ 4, Peak 3/ 5, Peak 4/ 6, Peak 4a/ 7, Peak 5/ 8, Peak 6/ 9, Peak 7/ 10, Peak 8/ 11, 1x PEG-IFN standard/ 12, 1.5x PEG-IFN standard/ C1, IFN standard.
  • Figure 4: Size Exclusion (SE-) HPLC was used to determine the amount of oligo PEG-IFN forms and aggregates in the different IEC fractions. SE-HPLC was performed with a TosoHaas TSK gel G 4000 SWXL column (7.8 × 300 mm).
  • Figure 5: MALDI-TOF spectrometry was used to determine the molecular weight of each isomer in order to ensure that the PEG-IFN molecules were still intact after IEC chromatography and to confirm the monopegylation.
  • Figure 6: MALDI-TOF Lys-C peptide maps of the PEG-IFN reference standard and the peaks 1, 2, 3, 4, 4a, 5, 6, 7, 8. Missing peaks compared to the standard are indicated by arrows.
  • Figure 7: RP-HPLC chromatograms of the Lys-C digests of the PEG-IFN reference and peak 4a
  • Figure 8: Analytical HPLC of 5-10µg of PEG-IFN alpha 2a mixture of positional isomers on a column charged with SP-NPR, TosoH Bioscience, Particle size: 2.5µm, nonporous as described in Example 1B..
  • Figure 9: Ribbon structure of interferon alpha-2a showing the pegylation sites. This is the high resolution structure of human interferon alpha-2a determined with NMR spectroscopy see JMol. Biol. 1997, 274, 661-675. The pegylation sites of pegylated interferon alpha-2a are coloured red and labelled with residue type and residue number.

Pegylated interferon alfa-2b, sold under the brand name PegIntron among others, is a medication used to treat hepatitis C and melanoma.[3] For hepatitis C it is typically used with ribavirin and cure rates are between 33 and 82%.[3][4] For melanoma it is used in addition to surgery.[3] It is given by injection under the skin.[3]

Side effects are common.[5] They may include headache, feeling tired, mood changes, trouble sleeping, hair loss, nausea, pain at the site of injection, and fever.[3] Severe side effects may include psychosisliver problemsblood clotsinfections, or an irregular heartbeat.[3] Use with ribavirin is not recommended during pregnancy.[3] Pegylated interferon alfa-2b is in the alpha interferon family of medications.[3] It is pegylated to protect the molecule from breakdown.[5]

Pegylated interferon alfa-2b was approved for medical use in the United States in 2001.[3] It is on the World Health Organization’s List of Essential Medicines.[6]

Peginterferon alfa-2b is a form of recombinant interferon used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 3. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) resulting in less use of Peginterferon alfa-2b. Peginterferon alfa-2b is derived from the alfa-2b moeity of recombinant human interferon and acts by binding to human type 1 interferon receptors. Activation and dimerization of this receptor induces the body’s innate antiviral response by activating the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Use of Peginterferon alfa-2b is associated with a wide range of severe adverse effects including the aggravation and development of endocrine and autoimmune disorders, retinopathies, cardiovascular and neuropsychiatric complications, and increased risk of hepatic decompensation in patients with cirrhosis. The use of Peginterferon alfa-2b has largely declined since newer interferon-free antiviral therapies have been developed.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) no longer recommend Peginterferon alfa-2b for the treatment of Hepatitis C 2. Peginterferon alfa-2b was used alongside Ribavirin(https://go.drugbank.com/drugs/DB00811) with the intent to cure, or achieve a sustained virologic response (SVR), after 48 weeks of therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 1.

Peginterferon alfa-2b is available as a variable dose injectable product (tradename Pegintron) used for the treatment of chronic Hepatitis C. Approved in 2001 by the FDA, Pegintron is indicated for the treatment of HCV with Ribavirin or other antiviral drugs Label. When combined together, Peginterferon alfa-2b and Ribavirin have been shown to achieve a SVR between 41% for genotype 1 and 75% for genotypes 2-6 after 48 weeks of treatment.

Medical uses

It is used to treat hepatitis C and melanoma. For hepatitis C it is typically used with ribavirin. For melanoma it is used in addition to surgery.[3]

For hepatitis C it may also be used with boceprevirtelaprevirsimeprevir, or sofosbuvir.[5]

In India, in 2021, DGCI approved emergency use of Zydus Cadila‘s Virafin in treating moderate COVID-19 infection.[7]

Host genetic factors

For genotype 1 hepatitis C treated with pegylated interferon-alfa-2a or pegylated interferon-alfa-2b combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature,[8] showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more likely to achieve sustained virological response after the treatment than others. A later report from Nature[9] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

Side effects

Common side effects include headache, feeling tired, mood changes, trouble sleeping, hair loss, nausea, pain at the site of injection, and fever. Severe side effects may include psychosisliver problemsblood clotsinfections, or an irregular heartbeat.[3] Use with ribavirin is not recommended during pregnancy.[3]

Mechanism of action

One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. The basic mechanism works such that PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in cell cycle control, cell differentiation, apoptosis, and immune response.[10][11]

PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present.[12]

Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines.[13]

A follow-up study researched to determine if the caspases were involved in the apoptosis seen in the previous study as well as to determine the role of mitochondrial cytochrome c release. The study confirmed that there was cleavage of caspase-3, -8, and -9. All three of these cysteine proteases play an important role in the initiation and activation of the apoptotic cascade. Furthermore, it was shown that IFNα induced a loss in the mitochondrial membrane potential which resulted in the release of cytochrome c from the mitochondria. Follow-up research is currently being conducted to determine the upstream activators of the apoptotic pathway that are induced by IFNα.[14]

History

It was developed by Schering-Plough. Merck studied it for melanoma under the brand name Sylatron. It was approved for this use in April 2011.

References

  1. ^ “PegIntron- peginterferon alfa-2b injection, powder, lyophilized, for solution PegIntron- peginterferon alfa-2b kit”DailyMed. Retrieved 28 September 2020.
  2. ^ “Sylatron- peginterferon alfa-2b kit”DailyMed. 28 August 2019. Retrieved 28 September 2020.
  3. Jump up to:a b c d e f g h i j k l “Peginterferon Alfa-2b (Professional Patient Advice) – Drugs.com”http://www.drugs.comArchived from the original on 16 January 2017. Retrieved 12 January 2017.
  4. ^ “ViraferonPeg Pen 50, 80, 100, 120 or 150 micrograms powder and solvent for solution for injection in pre-filled pen CLEAR CLICK – Summary of Product Characteristics (SPC) – (eMC)”http://www.medicines.org.uk. Archived from the original on 13 January 2017. Retrieved 12 January 2017.
  5. Jump up to:a b c “Peginterferon alfa-2b (PegIntron)”Hepatitis C OnlineArchived from the original on 23 December 2016. Retrieved 12 January 2017.
  6. ^ 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.
  7. ^ https://www.aninews.in/news/national/general-news/dgci-approves-emergency-use-of-zyduss-virafin-in-treating-moderate-covid-19-infection20210423163622/
  8. ^ Ge D, Fellay J, Thompson AJ, et al. (2009). “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance”. Nature461 (7262): 399–401. Bibcode:2009Natur.461..399Gdoi:10.1038/nature08309PMID 19684573S2CID 1707096.
  9. ^ Thomas DL, Thio CL, Martin MP, et al. (2009). “Genetic variation in IL28B and spontaneous clearance of hepatitis C virus”Nature461 (7265): 798–801. Bibcode:2009Natur.461..798Tdoi:10.1038/nature08463PMC 3172006PMID 19759533.
  10. ^ Ward AC, Touw I, Yoshimura A (January 2000). “The JAK-STAT pathway in normal and perturbed hematopoiesis”Blood95 (1): 19–29. doi:10.1182/blood.V95.1.19PMID 10607680. Archived from the original on 2014-04-26.
  11. ^ PATHWAYS :: IFN alpha[permanent dead link]
  12. ^ Thomas H, Foster G, Platis D (February 2004). “Corrigendum toMechanisms of action of interferon and nucleoside analogues J Hepatol 39 (2003) S93–8″J Hepatol40 (2): 364. doi:10.1016/j.jhep.2003.12.003.
  13. ^ Sangfelt O, Erickson S, Castro J, Heiden T, Einhorn S, Grandér D (March 1997). “Induction of apoptosis and inhibition of cell growth are independent responses to interferon-alpha in hematopoietic cell lines”Cell Growth Differ8 (3): 343–52. PMID 9056677Archived from the original on 2014-04-26.
  14. ^ Thyrell L, Erickson S, Zhivotovsky B, et al. (February 2002). “Mechanisms of Interferon-alpha induced apoptosis in malignant cells”Oncogene21 (8): 1251–62. doi:10.1038/sj.onc.1205179PMID 11850845.

External links

///////////Pegylated Interferon alpha-2b,  PegIFN, Virafin, COVID 19, CORONA VIRUS, INDIA 2021, APPROVALS 2021

Sinovac COVID-19 vaccine, CoronaVac,


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]

NEW DRUG APPROVALS

one time

$10.00

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 PauloJoão 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]

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  79. ^ “Covid-19: Zimbabwe authorises Sputnik V, Sinovac vaccines for emergency use”. news24.com. 9 March 2021.
  80. ^ “Regulation and Prequalification”World Health Organization. Retrieved 12 March 2021.
  81. ^ Simoes E (30 September 2020). “Brazil’s Sao Paulo signs agreement with Sinovac for COVID vaccine doses”ReutersArchived from the original on 1 October 2020. Retrieved 1 October 2020.
  82. ^ Fonseca I (30 October 2020). “CoronaVac May Be Four Times More Costly Than Flu Vaccine”The Rio TimesArchived from the original on 3 November 2020. Retrieved 30 October 2020.
  83. ^ “Em meio a críticas por atrasos, Pazuello diz que Brasil está preparado para iniciar vacinação em janeiro”Folha de S.Paulo(in Portuguese). 6 January 2021. Retrieved 7 January 2021.
  84. ^ Rochabrun, Marcelo. “Brazil health ministry says plans to order 30 million more Coronavac doses | The Chronicle Herald”http://www.thechronicleherald.ca. Retrieved 26 February 2021.
  85. ^ “Bolívia autoriza uso de vacinas Sputnik V e CoronaVac contra covid-19”noticias.uol.com.br (in Portuguese). Retrieved 7 January 2021.
  86. ^ “Government meets with Sinovac for first COVID-19 vaccine clinical trial in Chile”. Government of Chile. 13 October 2020. Archived from the original on 17 October 2020. Retrieved 8 November 2020.
  87. ^ Presse, AFP-Agence France. “Chile Approves Chinese Coronavirus Vaccine”barrons.com. Retrieved 21 January 2021.
  88. ^ “Fifth shipment with over two million Sinovac vaccines arrives to Chile”Chile Reports. Retrieved 12 March 2021.
  89. ^ “Colombia extends health state of emergency, seeks more Sinovac vaccines”Reuters. Retrieved 26 February 2021.
  90. ^ MENAFN. “Colombia declares emergency use of Sinovac vaccines”menafn.com. Retrieved 4 February 2021.
  91. ^ “Ecuador signs agreement with Sinovac for 2 million COVID-19 vaccine: minister”nationalpost. Retrieved 26 February 2021.
  92. Jump up to:a b Valencia, Alexandra (7 March 2021). “Chile donates 40,000 doses of Sinovac vaccine to Ecuador and Paraguay”Reuters. Retrieved 7 March 2021.
  93. ^ “CoronaVac, vacuna de alta eficacia”Ministerio de Salud Publica Y Bienestar Social.
  94. ^ “Uruguay will receive first batches of Pfizer and Sinovac vaccines late February or early March: US$ 120 million investment”MercoPress. Retrieved 24 January 2021.
  95. ^ “Albania gets 192,000 doses of Chinese Sinovac vaccine”CNA. Retrieved 25 March 2021.
  96. ^ “Turkey signs 50 million dose COVID-19 vaccine deal, health minister says”Reuters. 25 November 2020. Archived from the original on 1 December 2020. Retrieved 27 November 2020.
  97. ^ “Turkey grants emergency authorization to Sinovac’s CoronaVac: Anadolu”Reuters. 13 January 2021. Retrieved 15 January 2021.
  98. ^ “Turkish president gets COVID-19 vaccine”Anadolu Agency. 14 January 2021. Retrieved 20 January 2021.
  99. ^ SABAH, DAILY (12 March 2021). “Few virus infections reported among vaccinated people in Turkey”Daily Sabah. Retrieved 12 March 2021.
  100. ^ “Ukraine signs up for China’s Sinovac vaccine, with doses expected soon”Reuters. 30 December 2020. Retrieved 30 December 2020.
  101. ^ Zinets, Natalia (9 March 2021). “Ukraine approves China’s Sinovac COVID-19 vaccine”Reuters. Retrieved 9 March 2021.
  102. ^ Aliyev, Jeyhun (19 January 2021). “Azerbaijan kicks off COVID-19 vaccination”. Anadolu Agency.
  103. ^ “Cambodian PM okays two more Covid-19 vaccines – Sinovac and AstraZeneca – for emergency use | The Star”http://www.thestar.com.my. Retrieved 19 March 2021.
  104. ^ “Have no fear about shortage of vaccines, 1.5 million doses of Sinovac arriving on March 26”Khmer Times. 19 March 2021. Retrieved 19 March 2021.
  105. ^ “Sinovac’s coronavirus vaccine candidate approved for emergency use in China – source”Reuters. 29 August 2020. Archived from the original on 31 August 2020. Retrieved 30 August 2020.
  106. ^ “Government announces latest development of COVID-19 vaccine procurement” Archived 11 December 2020 at the Wayback Machine (Hong Kong Government Press Releases, 12 December 2020)
  107. ^ “Hong Kong kicks off COVID-19 vaccinations with Sinovac jab”AP NEWS. 26 February 2021. Retrieved 7 March 2021.
  108. ^ “Indonesia books 50 million coronavirus vaccine doses from Sinovac”Reuters. 21 August 2020. Archived from the original on 29 August 2020. Retrieved 21 August 2020.
  109. ^ “Sinovac vaccine has no critical side effects, BPOM says”The Jakarta Post. Retrieved 21 December 2020.
  110. ^ Arkyasa, Mahinda (25 March 2021). “16 Million Sinovac Vaccines Material Arrives in Indonesia”Tempo. Retrieved 25 March 2021.
  111. ^ “Malaysia’s NPRA Approves AstraZeneca, Sinovac Covid-19 Vaccines”. CodeBlue. 2 March 2021. Retrieved 2 March 2021.
  112. ^ Babulal, Veena (18 March 2021). “KJ gets first dose of Sinovac vaccine [NSTTV] | New Straits Times”NST Online. Retrieved 19 March 2021.
  113. ^ “Duque says deal sealed for 25M doses of Sinovac COVID-19 vaccine”GMA News Online. Retrieved 10 January 2021.
  114. ^ “Philippines receives COVID-19 vaccine after delays”AP NEWS. 28 February 2021. Retrieved 28 February 2021.
  115. ^ Chen F (24 December 2020). “Brazil joins ranks of Chinese vaccine backers”Asia Times Online. Retrieved 30 December2020.
  116. ^ “Singapore receives China’s Sinovac vaccine ahead of approval”The Star. 25 February 2021. Retrieved 26 February2021.
  117. ^ “Thailand to get 2 million shots of China’s Sinovac”Bangkok Post. Bangkok Post Public Company. Retrieved 4 January 2021.
  118. ^ “Thailand gives emergency use authorisation for Sinovac’s COVID-19 vaccine – official”Reuters. 22 February 2021. Retrieved 23 February 2021.
  119. ^ Limited, Bangkok Post Public Company. “Thailand in talks to buy another 5m Sinovac shots”Bangkok Post. Retrieved 20 March2021.
  120. ^ “Mexico approves China’s CanSino and Sinovac COVID-19 vaccines”Reuters. 11 February 2021. Retrieved 11 February2021.
  121. ^ Jorgic, Drazen (10 March 2021). “Mexico leans on China after Biden rules out vaccines sharing in short term”Reuters. Retrieved 10 March 2021.
  122. ^ Exteriores, Secretaría de Relaciones. “The Mexican Government receives 200,000 Sinovac COVID-19 vaccines”gob.mx (in Spanish). Retrieved 7 March 2021.
  123. ^ “Lutte contre la Covid-19 : 203.000 doses de vaccins s dont 100.000 offertes par la Chine au Bénin”Concentrées d’informations sur le Bénin et le monde à votre service depuis 2009(in French). 23 March 2021. Retrieved 25 March 2021.
  124. ^ Winning, Alexander. “South Africa’s drugs regulator to start assessing Sinovac COVID-19 vaccine”U.S. Retrieved 12 March2021.
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  126. ^ “Covid: Tunisia approva vaccino cinese Sinovac”Agenzia Nazionale Stampa Associata (in Italian). 5 March 2021. Retrieved 7 March 2021.
  127. ^ Dzirutwe, MacDonald (10 March 2021). “Zimbabwe authorises Sputnik V, Sinovac coronavirus vaccines for emergency use”Reuters. Retrieved 13 March 2021.
  128. ^ “China to donate Sinovac Vaccine to Fiji”Fiji Broadcasting Corporation. Retrieved 17 March 2021.
  129. Jump up to:a b Phillips, Tom (10 November 2020). “Jair Bolsonaro claims ‘victory’ after suspension of Chinese vaccine trial”The Guardian. Retrieved 18 January 2021.
  130. ^ Baptista, Eduardo (11 December 2020). “China-made coronavirus vaccine at heart of political showdown in Brazil”South China Morning Post. Retrieved 18 January 2021.
  131. ^ Carvalho, Daniel (14 January 2021). “‘Is 50% Good?’, Asks Bolsonaro, Mocking Coronavac’s Effectiveness”Folha de S.Paulo. Retrieved 18 January 2021.
  132. ^ Pearson, Samantha; Magalhaes, Luciana (10 November 2020). “Brazil’s Medical Experts Worry Politics Is Hampering Covid-19 Vaccine Progress”The Wall Street Journal. Retrieved 18 January 2021.
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  134. ^ Fonseca P. “Brazil institute says CoronaVac efficacy above 50%, but delays full results”Reuters. Retrieved 25 December 2020.
  135. ^ Hong, Jinshan (12 January 2021). “How Effective Is China’s Sinovac Vaccine? Data Confuse Experts”Bloomberg News. Retrieved 12 January 2021.

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
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COVID-19 pandemic
SARS-CoV-2 (virus)COVID-19 (disease)
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 COVID-19 Portal
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Sinovac Biotech Ltd. (Chinese: 北京科兴生物制品有限公司, NasdaqSVA) 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 DistrictBeijing.[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 PostISSN 0190-8286Archived from the original on December 4, 2020. Retrieved 2020-12-06.
  4. ^ Levine, Matt (May 22, 2020). “A Vaccine With a Poison Pill”Bloomberg NewsArchived 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 TimesISSN 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 asNasdaqSVA
(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


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, romanizedGam-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 III 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 RussiaArgentinaBelarusHungarySerbia 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 HealthMikhail 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 IndiaBrazilChinaSouth KoreaHungary, 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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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
AEAGDZBOBYHUIRPSRS: 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

BBIBP-CorV, Sinopharm COVID-19 vaccine


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 ArgentinaBahrainEgyptMoroccoPakistanPeru, 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-1273OxfordAstraZeneca‘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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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 BahrainChinaEgyptIraqPakistanSerbiaUnited Arab EmiratesIran (emergency use)
Identifiers
CAS Number2503126-65-4
DrugBankDB15807
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 COVID-19 Portal
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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

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