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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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FDA expands approval of Blincyto (blinatumomab) for treatment of a type of leukemia in patients who have a certain risk factor for relapse


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FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse

Blincyto (blinatumomab)

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.Continue reading.

 

March 29, 2018

Release

The U.S. Food and Drug Administration granted accelerated approval to Blincyto (blinatumomab) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

B-cell precursor ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The National Cancer Institute estimates that approximately 5,960 people in the United States will be diagnosed with ALL this year and approximately 1,470 will die from the disease.

Blincyto works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved Blincyto under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Philadelphia chromosome-positive ALL.

The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia).

Blincyto carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and difficulty breathing (cytokine release syndrome) at the start of the first treatment, experienced a short period of difficulty with thinking (encephalopathy) or other side effects in the nervous system. Serious risks of Blincyto include infections, effects on the ability to drive and use machines, inflammation in the pancreas (pancreatitis), and preparation and administration errors—instructions for preparation and administration should closely be followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative free saline should be used for patients weighing less than 22 kilograms.

This new indication for Blincyto was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL.

The FDA granted this application Priority Review and it received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Blincyto to Amgen Inc.

 

//////amgen, fda 2018,  Priority Review m  Orphan Drug designation, Blincyto, blinatumomab,

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Baloxavir marboxil, バロキサビルマルボキシル , балоксавир марбоксил , بالوكسافير ماربوكسيل , 玛巴洛沙韦 ,


Image result for japan animated flag

str1

1985606-14-1.pngBaloxavir marboxil.png

Image result for XofluzaChemSpider 2D Image | baloxavir marboxil | C27H23F2N3O7S

Baloxavir marboxil

バロキサビルマルボキシル

балоксавир марбоксил [Russian] [INN]

بالوكسافير ماربوكسيل [Arabic] [INN]
玛巴洛沙韦 [Chinese] [INN]

Carbonic acid, [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy]methyl methyl ester

({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate

  1. (((12aR)-12-((11S)-7,8-Difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl carbonate
  2. Carbonic acid, (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(b,E)thiepin-11-yl)-3,4,6,8,12,12a-hexahydro-6,8-dioxo-1H-(1,4)oxazino(3,4-C)pyrido(2,1-F)(1,2,4)triazin-7-yl)oxy)methyl methyl ester

Antiviral

In Japan the product is indicated for treatment influenza types A and B in adults and children

RG-6152

UNII-505CXM6OHG

  • Originator Shionogi
  • Developer Roche; Shionogi
  • Class Antivirals; Dibenzothiepins; Esters; Pyridines; Small molecules; Triazines
  • Mechanism of Action Endonuclease inhibitors

Highest Development Phases

  • Marketed Influenza A virus infections; Influenza B virus infections
  • Phase III Influenza virus infections
  • Preclinical Influenza A virus H5N1 subtype
Xofluza (TN)
Antiviral
Formula
C27H23F2N3O7S
Cas
1985606-14-1
Mol weight
571.5492
2018/2/23 PMDA JAPAN APPROVED Baloxavir marboxil Xofluza Shionogi

Image result for japan animated flag

バロキサビル マルボキシル
Baloxavir Marboxil

C27H23F2N3O7S : 571.55
[1985606-14-1]

Image result for ShionogiImage result for Xofluza

2D chemical structure of 1985606-14-1

https://chem.nlm.nih.gov/chemidplus/sid/1985606141

Baloxavir marboxil (trade name Xofluza, compound code S-033188/S-033447) is a medication being developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was in late-stage trials in Japan and the United States as of early 2018, with collaboration from Roche AG.[1].

It was approved for sale in Japan on February 23, 2018.[2]

Baloxavir marboxil is a medication developed by Shionogi Co., a Japanese pharmaceutical company, for treatment of influenza A and influenza B. The drug was approved for use in Japan in February 2018 and is in late phase trials in the United States as of early 2018. Roche, which makes Tamiflu, has acquired the license to sell Xofluza internationally, but it may not be until 2019 that it could be available in the United States [7]. Interestingly, a study has determined that administering Baloxavir marboxil with neuraminidase inhibitors leads to a synergistic effect in influenza treatment

Image result for Xofluza

It is an influenza therapeutic agent (cap-dependent endonuclease inhibitor), characterized by only taking one dose. Unlike neuraminidase inhibitors such as oseltamivir (Tamiflu) and zanamivir (Relenza) that inhibit the action of neuraminidase, which liberates viruses from the infected cells surface, baloxavir marboxil may prevent replication by inhibiting the cap-dependent endonuclease activity of the viral polymerase.[3]

In October 2015, the Japanese Ministry of Health, Labour and Welfare granted Sakigake status to Shionogi’s baloxavir marboxil for A type or B -type influenza virus infection . In October 2015, the drug was designated for Priority Review by the Ministry of Health, Labour and Welfare, presumably for the treatment of A type or B -type influenza virus infection .

This drug is a CAP endonuclease inhibitor [1]. The influenza endonuclease is an essential subdomain of the viral RNA polymerase enzyme. CAP endonuclease processes host pre-mRNAs to serve as primers for viral mRNA and therefore has been a common target for studies of anti-influenza drugs.

Viral gene transcription is primed by short-capped oligonucleotides that are cleaved from host cell pre mRNA by endonuclease activity. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription.The N-terminal domain of PA subunit (PAN) has been confirmed to accommodate the endonuclease activity residues, which is highly preserved among subtypes of influenza A virus and is able to fold functionally [4]. Translation of viral mRNAs by the host ribosome requires that they are capped at the 5′ end, and this is achieved in cells infected with influenza virus by a “cap-snatching” mechanism, whereby the endonuclease cleaves 5′ caps from host mRNA which then act as primers for transcription. The endonuclease domain binds the N-terminal half of PA (PAN) and contains a two-metal (Mn2+) active site that selectively cleaves the pre-mRNA substrate at the 3′ end of a guanine [3].

The administration of a CAP endonuclease inhibitor, such as Baloxavir marboxil, prevents the above process from occurring, exhibiting its action at the beginning of the pathway before CAP endonuclease may exert its action

Image result for Xofluza

It achieves this by inhibiting the process known as cap snatching[4], which is a mechanism exploited by viruses to hijack the host mRNA transcription system to allow synthesis of viral RNAs.

Image result for Xofluza

Shionogi, in collaboration with licensee Roche (worldwide except Japan and Taiwan), have developed and launched baloxavir marboxil

In March 2018, Shionogi launched baloxavir marboxil for the treatment of influenza types A and B in Japan . In September 2017, Shionogi was planning to file an NDA in the US; in February 2018, the submission remained in preparation

By September 2016, baloxavir marboxil had been awarded Qualified Infectious Disease Product (QIDP) designation in the US

In March 2017, a multicenter, randomized, double-blind, parallel-group, phase III study (NCT02954354; 1601T0831; CAPSTONE-1) was initiated in the US, Canada and Japan to compare a single dose of baloxavir marboxil versus placebo or oseltamivir bid for 5 days in influenza patients aged from 12 to 64 years of age (n = 1494). The primary endpoint was the time to alleviation of symptoms (TTAS).

PATENTS

JP 5971830

Kawai, Makoto; Tomita, Kenji; Akiyama, Toshiyuki; Okano, Azusa; Miyagawa, Masayoshi

PATENTS

WO 2017104691

Shishido, Takao; Noshi, Takeshi; Yamamoto, Atsuko; Kitano, Mitsutaka

In Japanese Patent Application No. 2015-090909 (Patent No. 5971830, issued on Aug. 17, 2016, Registered Publication), a compound having a CEN inhibitory action and represented by the formula:
[Chemical Formula 2]

is described. Anti-influenza agents of six mechanisms are enumerated as drugs that can be used together with the above compounds. However, no specific combinations are described, nor is it disclosed nor suggested about the combined effect.

Synthesis Example 2
[formula 39]

Compound III-1 (1.00g, 2.07mmol) to a suspension of DMA (5 ml) of chloromethyl methyl carbonate (0.483 g, 3.10 mmol) and potassium carbonate (0 .572 g, 4.14 mmol) and potassium iodide (0.343 g, 2.07 mmol) were added, the temperature was raised to 50 ° C. and the mixture was stirred for 6 hours. Further, DMA (1 ml) was added to the reaction solution, and the mixture was stirred for 6 hours. The reaction solution was cooled to room temperature, DMA (6 ml) was added, and the mixture was stirred at 50 ° C. for 5 minutes and then filtered. 1 mol / L hydrochloric acid water (10 ml) and water (4 ml) were added dropwise to the obtained filtrate under ice cooling, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure at 60 ° C. for 3 hours to obtain compound II-4 (1.10 g, 1.93 mmol, yield 93%).
1 H-NMR (DMSO-D 6) δ: 2.91-2.98 (1 H, m), 3.24-3.31 (1 H, m), 3.44 (1 H, t, J = 10.4 Hz) J = 10.8, 2.9 Hz), 4.06 (1 H, d, J = 14.3 Hz), 4.40 (1 H, dd, J = 11.5, 2.8 Hz), 3.73 (3 H, s), 4.00 , 5.67 (1 H, d, J = 6.5 Hz), 5.72 (1 H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9, 2.9 Hz), 5.42 J = 8.0, 1.1 Hz), 7.14 – 7.18 (1 H, m ), 7.23 (1 H, d, J = 7.8 Hz), 7.37 – 7.44 (2 H, m)

PATENTS

JP 6212678

PATENTS

JP 6249434

JP 5971830

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF KEY INTERMEDIATE

SYNTHESIS OF FINAL PRODUCT

Japan’s New Drug: One Pill May Stop The Flu in Just One Day

 Opinions expressed by Forbes Contributors are their own.

Isao Teshirogi, president and chief executive officer of Shionogi & Co., speaks during an interview in Tokyo, Japan. Photographer: Kiyoshi Ota/Bloomberg

One day, you may be able to stop flu viruses in your body in just one day with just one pill. Based on an announcement yesterday, that day may be someday very soon in May in Japan.

On Friday, Japanese pharmaceutical company Shionogi announced that the flu medication that they have developed, Xofluza, otherwise known as baloxavir marboxil (which sounds a bit like a Klingon General), has been approved to be manufactured and sold in Japan. Beginning in October 2015, the medication underwent priority review by Japan’s Ministry of Health, Labor, and Welfare. Shionogi filed for approval in the autumn of 2017. Compared to Tamiflu, which requires two doses each day for five days, apparently only a single dose of Xofluza will be needed to treat the flu. Even though Xofluza has received approval, people will have to wait until the Japanese national insurance sets a price for the medication, which according to Preetika Rana writing for the Wall Street Journal, may not occur until May.

Xofluza works via a different mechanism from neuroaminidase inhibitors like Tamiflu (oseltamivir) and Relenza (zanamivir). Flu viruses are like squatters in your home that then use the furniture and equipment in your home to reproduce. Yes, I know, that makes for a lovely picture. A flu infection begins when flu viruses reach your lungs. Each flu virus will enter a cell in your lungs and then use your cell’s genetic material and protein production machinery to make many, many copies of itself. In order to do this, the flu virus uses “cap-snatching”, which has nothing to do with bottle caps or Snapchat. The virus employs an endonuclease enzyme to clip off and steal the caps or ends of your messenger RNA and then re-purposes these caps to reproduce its own genetic material. After the virus has made multiple copies of itself, the resulting viruses implement another enzyme called a neuroaminidase to separate themselves from parts of the host cell and subsequently spread throughout the rest of your body to cause havoc. While Tamiflu, Relenza, and other neuroaminidase inhibitors try to prevent the neuroaminidase enzyme from working, Xofluza acts at an earlier step, stopping the “cap-snatching” by blocking the endonuclease enzyme.

In a clinical trial, Xofluza stopped an infected person from shedding flu virus sooner than Tamiflu. (Photo Illustration by Ute Grabowsky/Photothek via Getty Images)

By acting at an earlier step before the virus has managed to replicate, Xofluza could stop a flu virus infection sooner than neuroaminidase inhibitors. The results from Shionogi’s Phase III CAPSTONE-1 clinical trial compared Xofluza (then called Cap-dependent Endonuclease Inhibitor S-033188, which doesn’t quite roll off the tongue) with oseltamivir and placebo, with results being published in Open Forum Infectious Diseases. The study found that baloxavir marboxil (or Xofluza) stopped an infected person from shedding flu virus earlier (median 24 hours) than oseltamivir (median 72 hours). Those taking baloxavir marboxil also had lower measured amounts of viruses than those taking oseltamivir throughout the first 3 days of the infection. Baloxavir marboxil also seemed to shorten the duration of flu symptoms (median 53.7 hours compared to a median of 80.2 hours for those taking placebo). Since symptoms are largely your body’s reaction to the flu virus, you can begin shedding virus before you develop symptoms, and symptoms can persist even when you are no longer shedding the virus.

The key with any of these flu medications is early treatment, especially within the first 24 to 48 hours of infection, which may be before you notice any symptoms. Once the virus has replicated and is all over your body, your options are limited. The vaccine still remains the best way to prevent an infection.

In the words of Alphaville, this new drug could be big in Japan. While Xofluza won’t be available in time to help with the current flu season, this year’s particularly harsh flu season has highlighted the need for better ways to treat the flu. But will the United States see Xofluza anytime soon? Similar to Pokemon, Xofluza may need a year or two to reach the U.S. market. But one day, one pill and one day may be a reality in the U.S.

http://www.shionogi.co.jp/en/company/news/2018/pmrltj0000003nx1-att/e180223.pdf

XOFLUZA TM (Baloxavir Marboxil) Tablets 10mg/20mg Approved for the Treatment of Influenza Types A and B in Japan Osaka, Japan, February 23, 2018 – Shionogi & Co., Ltd. (Head Office: Osaka; President & CEO: Isao Teshirogi, Ph.D.; hereafter “Shionogi”) announced that XOFLUZATM (generic name: baloxavir marboxil) tablets 10mg/20mg was approved today by the Ministry of Health, Labour and Welfare for the treatment of Influenza Types A and B. As the cap-dependent endonuclease inhibitor XOFLUZATM suppresses the replication of influenza viruses by a mechanism different from existing anti-flu drugs, XOFLUZATM was designated for Sakigake procedure with priority review by the Ministry of Health, Labour, and Welfare of Japan in October 2015. Shionogi filed for approval to manufacture and sell XOFLUZATM in October 25, 2017. As the treatment with XOFLUZATM requires only a single oral dose regardless of age, it is very convenient, and is expected to improve adherence. XOFLUZATM is expected to be a new treatment option that can improve the quality of life in influenza patients. Shionogi will launch the product immediately after the National Health Insurance (NHI) price listing. Shionogi’s research and development targets infectious disease as one of its priority areas, and Shionogi have positioned “protecting people from the threat of infectious diseases” as one of its social mission targets. Shionogi strives constantly to bring forth innovative drugs for the treatment of infectious diseases, to protect the health of patients we serve.

References

  1. Jump up^ Rana, Preetika (10 February 2018). “Experimental Drug Promises to Kill the Flu Virus in a Day”. Wall Street Journal.
  2. Jump up^ “XOFLUZA (Baloxavir Marboxil) Tablets 10mg/20mg Approved For The Treatment Of Influenza Types A And B In Japan”. 23 February 2018 – via http://www.publicnow.com.
  3. Jump up^ Dias, Alexandre; Bouvier, Denis; Crépin, Thibaut; McCarthy, Andrew A.; Hart, Darren J.; Baudin, Florence; Cusack, Stephen; Ruigrok, Rob W. H. (2009). “The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit”. Nature458(7240): 914–918. doi:10.1038/nature07745ISSN 0028-0836.
  4. Jump up^ “Cap snatching”.
Baloxavir marboxil
Baloxavir marboxil.svg
Identifiers
CAS Number
PubChem CID
UNII
KEGG
Chemical and physical data
Formula C27H23F2N3O7S
Molar mass 571.55 g·mol−1
3D model (JSmol)

Shionogi & Company, Limited(塩野義製薬株式会社 Shionogi Seiyaku Kabushiki Kaisha) is a Japanesepharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi (“シオノギ”).

Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemiaantibiotics, and cancer medicines.

In Japan it is particularly known as a producer of antimicrobial and antibiotics. Because of antibiotic resistance and slow growth of the antibiotic market, it has teamed up with US based Schering-Plough to become a sole marketing agent for its products in Japan.

Shionogi had supported the initial formation of Ranbaxy Pharmaceuticals, a generic manufacturer based in India. In 2012 the company became a partial owner of ViiV Healthcare, a pharmaceutical company specialising in the development of therapies for HIV.[3]

The company is listed on the Tokyo Stock Exchange and Osaka Securities Exchange and is constituent of the Nikkei 225 stock index.[4]

Medicines
Media
  • Shionogi has a close relationship with Fuji Television Network, Inc., because Shionogi is the sponsor of “Music Fair” (as of 2018, aired on 17 TV stations including TV Oita System Co.) started in 1964.
  • Shionogi was a main sponsor of Team Lotus during the age 1991/1994.[5]
References
  1. “Shionogi Company Profile”. Retrieved March 18, 2014.
  2. “Shionogi Annual Report 2013” (PDF). Retrieved March 18, 2014.
  3. “Shionogi and ViiV Healthcare announce new agreement to commercialise and develop integrase inhibitor portfolio”. viivhealthcare.com. Retrieved 18 March 2014.
  4. “Components:Nikkei Stock Average”Nikkei Inc. Retrieved March 11,2014.
  5. Perry, Alan. “Sponsor Company Profiles”. Retrieved 25 April 2012.
External links

/////////Baloxavir marboxil, バロキサビルマルボキシル, JAPAN 2018,  Xofluza,  S-033188, S-033447, RG-6152, Qualified Infectious Disease Product, Priority Review, SAKIGAKE, балоксавир марбоксил بالوكسافير ماربوكسيل 玛巴洛沙韦 Shionogi, roche

COC(=O)OCOC1=C2C(=O)N3CCOCC3N(N2C=CC1=O)C4C5=C(CSC6=CC=CC=C46)C(=C(C=C5)F)F

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk) for patients who have limited treatment options


Image result for ibalizumab-uiykImage result for taiMed Biologics USA Corp

FDA approves new HIV treatment Trogarzo (ibalizumab-uiyk),for patients who have limited treatment options

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Continue reading.

 

 

March 6, 2018

Release

Today, the U.S. Food and Drug Administration approved Trogarzo (ibalizumab-uiyk), a new type of antiretroviral medication for adult patients living with HIV who have tried multiple HIV medications in the past (heavily treatment-experienced) and whose HIV infections cannot be successfully treated with other currently available therapies (multidrug resistant HIV, or MDR HIV).Trogarzo is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.

“While most patients living with HIV can be successfully treated using a combination of two or more antiretroviral drugs, a small percentage of patients who have taken many HIV drugs in the past have multidrug resistant HIV, limiting their treatment options and putting them at a high risk of HIV-related complications and progression to death,” said Jeff Murray, M.D., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Trogarzo is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options. New treatment options may be able to improve their outcomes.”

The safety and efficacy of Trogarzo were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with 10 or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after Trogarzo was added to their failing antiretroviral regimens. After 24 weeks of Trogarzo plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.

The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of Trogarzo in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the Trogarzo development program.

A total of 292 patients with HIV-1 infection have been exposed to Trogarzo IV infusion. The most common adverse reactions to Trogarzo were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The FDA granted this application Fast TrackPriority Review and Breakthrough Therapy designations. Trogarzo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Trogarzo to TaiMed Biologics USA Corp.

Theratechnologies Announces FDA Approval of Breakthrough Therapy, Trogarzo™ (ibalizumab-uiyk) Injection, the First HIV-1 Inhibitor and Long-Acting Monoclonal Antibody for Multidrug Resistant HIV-1


NEWS PROVIDED BY

Theratechnologies Inc. 


  •  First HIV treatment approved with a new mechanism of action in more than 10 years
  • Infused every two weeks, only antiretroviral treatment (ART) that does not require daily dosing
  • Trogarzo™ has no drug-drug interactions and no cross-resistance with other ARTs

MONTREALMarch 6, 2018 /PRNewswire/ – Theratechnologies Inc. (Theratechnologies) (TSX: TH) and its partner TaiMed Biologics, Inc. (TaiMed) today announced that the U.S. Food and Drug Administration (FDA) has granted approval of Trogarzo™ (ibalizumab-uiyk) Injection. In combination with other ARTs, Trogarzo™ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.1

Trogarzo™ represents a critical new treatment advance as the first HIV therapy with a new mechanism of action approved in 10 years and proven effectiveness in difficult-to-treat patients with limited options. Unlike all other classes of ARTs, Trogarzo™ is a CD4-directed post-attachment HIV-1 inhibitor that binds to CD4+ receptors on host cells and blocks the HIV virus from infecting the cells.1

“Today’s approval of Trogarzo™ by the FDA is great news for people infected with difficult-to-treat multidrug resistant HIV. We look forward to bringing this much-needed therapy to patients in the U.S within six weeks,” said Luc Tanguay, President and Chief Executive Officer, Theratechnologies Inc. “We are grateful to the patients, investigators, as well as the FDA who supported the clinical development of Trogarzo™, and are helping address this critical unmet medical need.”

Trogarzo™ previously received Breakthrough Therapy and Orphan Drug designations as well as Priority Review status from the FDA, underscoring the significance of the treatment for this patient population.

“I witnessed some of the earliest cases of HIV and AIDS, at a time when the diagnosis was terrifying to patients because in many cases it was a death sentence,” said David Ho, M.D., chief scientific advisor of TaiMed and scientific director and CEO of the Aaron Diamond AIDS Research Center. “Since then, treatment advances and the discovery that combinations of ARTs was the best way to bring viral load below the level of detection have allowed most people to manage HIV like a chronic condition and live long, healthy lives. However, this is not the reality for people whose HIV is resistant to multiple drugs and whose viral load is not controlled, which is why TaiMed dedicated the past decade to advancing ibalizumab in the clinic. For these patients, it represents the next breakthrough.”

Up to 25,000 Americans with HIV are currently multidrug resistant, of which 12,000 are in urgent need of a new treatment option because their current treatment regimen is failing them and their viral load has risen to detectable levels, jeopardizing their health and making HIV transmittable.2-13 The best way to prevent the transmission of multidrug resistant HIV is to control the virus in those living with it. According to new guidance from the Centers for Disease Control and Prevention (CDC), the HIV virus cannot be transmitted if it is being fully suppressed.13

“I’ve struggled with multidrug resistant HIV for almost 30 years and it was completely debilitating to feel like I had run out of options – I made no long-term plans,” said Nelson Vergel, founder of the Program for Wellness Restoration (PoWeR) and Trogarzo™ patient. “Since starting treatment with Trogarzo™ six years ago and getting my viral load to an undetectable level, I have been my happiest, most productive self. Trogarzo™ is a new source of hope and peace of mind for people whose treatments have failed them, and I feel incredibly lucky to have been able to participate in the clinical trial program.”

TaiMed and Theratechnologies partnered on the development of Trogarzo™ so patients who can benefit from the treatment have access to it. For patients who need assistance accessing Trogarzo™ or who face challenges affording medicines, Theratechnologies has a team of patient care coordinators available to help. Patients can get assistance and expert support by contacting THERA patient support™ at 1-833-23-THERA (84372).

“In Phase 3 ibalizumab trials, we saw marked improvements in patients’ health who not only were heavily treatment-experienced and had limited remaining treatment options, but in cases they also had extremely high viral loads and significantly impaired immune systems,” said Edwin DeJesus, M.D., Medical Director for the Orlando Immunology Center. “As an investigator for ibalizumab clinical trials over nearly 10 years, it was remarkable and inspiring to see the dramatic effect ibalizumab had on such vulnerable patients. As a clinician, I am excited that we will now have another option with a different mechanism of action for our heavily pretreated patients who are struggling to keep their viral load below detection because their HIV is resistant to multiple drugs.”

Clinical Trial Findings

Clinical studies show that Trogarzo™, in combination with other ARTs, significantly reduces viral load and increases CD4+ (T-cell) count among patients with multidrug resistant HIV-1.

The Phase 3 trial showed:1

  • Trogarzo™ significantly reduced viral load within seven days after the first dose of functional monotherapy and maintained the treatment response when combined with an optimized background regimen that included at least one other active ART for up to 24 weeks of treatment, while being safe and well tolerated.
  • More than 80% of patients achieved the study’s primary endpoint – at least a 0.5 log10 (or 70%) viral load reduction from baseline seven days after receiving a 2,000 mg loading dose of Trogarzo™ and no adjustment to the failing background regimen.
  • The average viral load reduction after 24 weeks was 1.6 log10 with 43% of patients achieving undetectable viral loads.

Patients experienced a clinically-significant mean increase in CD4+ T-cells of 44 cells/mm3, and increases varied based on T-cell count at baseline. Rebuilding the immune system by increasing T-cell count is particularly important as people with multidrug resistant HIV-1 often have the most advanced form of HIV.1

The most common drug-related adverse reactions (incidence ≥ 5%) were diarrhea (8%), dizziness (8%), nausea (5%) and rash (5%). No drug-drug interactions were reported with other ARTs or medications, and no cross-resistance with other ARTs were observed.1

About Trogarzo™ (ibalizumab-uiyk) Injection

Trogarzo™ is a humanized monoclonal antibody for the treatment of multidrug resistant HIV-1 infection. Trogarzo™ binds primarily to the second extracellular domain of the CD4+ T receptor, away from major histocompatibility complex II molecule binding sites. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function.

IMPORTANT SAFETY INFORMATION

Trogarzo™ is a prescription HIV medicine that is used with other antiretroviral medicines to treat human immunodeficiency virus-1 (HIV-1) infections in adults.

Trogarzo™ blocks HIV from infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body.

Before you receive Trogarzo™, tell your healthcare provider if you:

  • are pregnant or plan to become pregnant. It is not known if Trogarzo™ may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Trogarzo™ passes into breast milk.

Tell your healthcare provider about all the medicines you take, including all prescription and over-the-counter medicines, vitamins, and herbal supplements.

Trogarzo™ can cause serious side effects, including:

Changes in your immune system (Immune Reconstitution Inflammatory Syndrome) can happen when you start taking HIV-1 medicines.  Your immune system might get stronger and begin to fight infections that have been hidden in your body for a long time.  Tell your health care provider right away if you start having new symptoms after starting your HIV-1 medicine.

The most common side effects of Trogarzo™ include:

  • Diarrhea
  • Dizziness
  • Nausea
  • Rash

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Trogarzo™. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.  You may also report side effects to at 1-833-23THERA (1-833-238-4372).

 

About Theratechnologies

Theratechnologies (TSX: TH) is a specialty pharmaceutical company addressing unmet medical needs to promote healthy living and an improved quality of life among HIV patients. Further information about Theratechnologies is available on the Company’s website at www.theratech.com and on SEDAR at www.sedar.com.

/////Trogarzo, ibalizumab-uiyk, fda 2018, Fast TrackPriority Review, Breakthrough Therapy designations,  Orphan Drug designation

FDA approves new treatment Erleada (apalutamide) for a certain type of prostate cancer using novel clinical trial endpoint


FDA approves new treatment Erleada (apalutamide) for a certain type of prostate cancer using novel clinical trial endpoint

The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer. Continue reading.

February 14, 2018

Release

The U.S. Food and Drug Administration today approved Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.

“The FDA evaluates a variety of methods that measure a drug’s effect, called endpoints, in the approval of oncology drugs. This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public.”

According to the National Cancer Institute (NCI) at the National Institutes of Health, prostate cancer is the second most common form of cancer in men in the U.S.. The NCI estimates approximately 161,360 men were diagnosed with prostate cancer in 2017, and 26,730 were expected to die of the disease. Approximately 10 to 20 percent of prostate cancer cases are castration-resistant, and up to 16 percent of these patients show no evidence that the cancer has spread at the time of the castration-resistant diagnosis.

Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.

The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or with surgery to lower the amount of testosterone in their body (surgical castration). The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.

Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).

Severe side effects of Erleada include falls, fractures and seizures.

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The sponsor for Erleada is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, certain information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.

The FDA granted the approval of Erleada to Janssen Pharmaceutical Companies.

//////////////fda 2018, Erleada, apalutamide, Priority Review, Janssen

FDA approves new treatment for certain digestive tract cancers Lutathera (lutetium Lu 177 dotatate)


Image result for lutetium Lu 177 dotatate

lutetium Lu 177 dotatate

FDA approves new treatment for certain digestive tract cancers

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs. Continue reading.\

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm?utm_campaign=01262018_PR_FDA%20approves%20new%20treatment%20for%20digestive%20cancers&utm_medium=email&utm_source=Eloqua

January 26, 2018

Release

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs.

“GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment.”

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia).

Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

 

MORE FROM PUBLIC DOMAIN……………..

WATCH THIS SPACE FOR SYNTHESIS COMING

Dotatate lutenium Lu-177.png

Dotatate lutenium Lu-177; 437608-50-9; DTXSID20195927

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium(3+)

Image result for lutetium Lu 177 dotatate

 

Lutetium-177

Lutetium 1777

Lutetium-177 has been quite a late addition as an isotope of significance to the nuclear medicine yet it is making big strides especially as a therapeutic radiopharmaceutical for neuroendocrine tumours in the form of 177Lu-DOTA-TATE on regular basis as described by Das & Pillai (2013). 

 
Lutetium-177 a lanthanide is an f block element that has a half-life of 6.7 days and decays mainly by beta emission to Hf-177, is accompanied by two gamma ray emissions. These radionuclide properties are very similar to those of I-131 which has long served as a therapeutic radionuclide, it was therefore not surprising that Lu-177 also emerged as a highly valuable radionuclide for similar applications,
 
There are several other upcoming applications especially for bone pain palliatiion. As a result of its convenient production logistics Lu-177 as discussed by Pillai et al (2003) is fast emerging a radionuclide of choice in radionuclide therapy (RNT).
 
Lu-177 can be prepared in a nuclear reactor by one of the two reactions given below :
176Lu(n,gamma)177Lu or
 
176Yb(n,gamma)177Yb –beta–> 177Lu
 
The former reaction has a high thermal neutron capture cross section and is presently the method adopted at our reactors in spite of the  formation of long lived Lu-177m whose yield is very much low and is considered insignificant to cause any great concern.
Lutetium-177 Impact 
Recently there has been a rush of several research reviews and articles where Lu-177 holds the centre stage, for example, Banerjee et al (2015) have reviewed the chemistry and applications of Lu-177; Dash et al (2015) reviewed its production and available options; Knapp & Pillai (2015) highlighted its usefulness in cancer treatment and chronic diseases and Pillai and Knapp (2015) have discussed the evolving role of Lu-177 in nuclear medicine with this ready availability of Lu-177. Peptide receptor radionuclide therapy is one of the upcoming field of investigation where Lu-177 holds much promise among few other radionuclides. Indeed Lutetium-177 has covered a good distance especially for Therapeutic and as a palliative radiopharmaceutical.
 
Chemistry
Das et al (2014) have described the preparation of Lu-177 EDTMP kit.
Parus et al (2015) have discussed chemistry of bifunctional chelating agents for binding Lu-177.
Gupta et al (2014) have compiled methods of labelleing antibdoies with radioiodine and radiometals. 
 
Applications
Limouris (2012) has reviewed applications in neuroendocrine tumors with focus on Liver metastasis. Das and Banerjee (2015) described the potential theranostic applications with Lu-177.
Anderson et al (1960) were among the first to use Lutetium (as chloride and citrate) in a clinical trial which were not so successful and did not encourage much promise. Keeling et al (1988) published their results with in vitro uptake of Lutetium hydroxylapatite particles. Lu-EDTMP as bone palliating agent by Ando et al (1998) soon followed,  However the greatest impact was seen with the advent of a somatostatin analogue Lu-DOTATATE for targetting neuroendocrine tumors reported by Kwekkeboom et al (2001) and reviewed recently by Bodei et al (2013).
PRRNT  – IAEA (2013) has brought out a human health series booklet on the subject with emphasis on neuroendocrine tumors.
177Lu Labelled Peptides in NET Kam et al (2012).
177Lu- DOTATATE – PRRNT – Bakker et al (2006)
177Lu-EDTMP – Bone Pain Palliation –  Bahrami-Samani et al (2012)
177Lu-EDTMP – Pharmacokinetics, dosimetry and Therapeutic efficacy – Chakraborty S et al (2015)
177Lu-Hydroxylapatite – Radiosynovectomy – Kamalleshwaran et al. (2014) Shinto et al. (2015)
117Lu- Radioimmunotherapy – Kameshwaran et al (2015) 
177Lu – Pretargeted Radioimmunotherapy (PRIT) Frost et al (2015).
 
More specific applications and additional information about the highly valuable therapeutic isotope would soon be added.
 
References and Notes
Anderson J, Farmer FT, Haggith JW, Hill M. (1960). The treatment of myelomatosis with Lutetium. Br J Radiol. 33:374-378.
Ando A, Ando L, Tonami N, Kinuya S, Kazuma K, Kataiwa A, Nakagawa M, Fujita N. (1998). 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 19: 587-591.
Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. (2012). Production, Quality Control and Pharmacokinetic Studies of 177Lu-EDTMP for Human Bone Pain Palliation Therapy Trials. Iran J Pharm Res. 11:137-44.
Bakker WH, Breeman WAP, Kwekkeboom DJ, De Jong LC, Krenning EP. ((2006) Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q J Nucl Med Mol Imaging 50: 265-271.

Banerjee S, Pillai MR, Knapp FF (2015). Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry, Radiochemistry, and Practical Applications. Chem Rev. 115: 2934-2974.
 
Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ. (2013).The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013 40:800-16.
 
Chakraborty S, Balogh L, Das T, Polyák A, Andócs G, Máthé D, Király R, Thuróczy J, Chaudhari PR, Jánoki GA, Jánoki G, Banerjee S, Pillai MR (2015). Evaluation of 177Lu-EDTMP in dogs with spontaneous tumor involving bone: Pharmacokinetics, dosimetry and therapeutic efficacy. Curr Radiopharm (ahead of Pub)
Das T, Banerjee S. (2015). Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr Radiopharm. (ahead of print).
Das T , Sarma HD, Shinto A, Kamaleshwaran KK, Banerjee S. (2014). Formulation, Preclinical Evaluation, and Preliminary Clinical Investigation of an In-House Freeze-Dried EDTMP Kit Suitable for the Preparation of Lu-177-EDTMP. Cancer Biotherap Radiopharm. 29: (ahead of publication).
Das T, Pillai M.R.A. (2013).Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol. 40: 23-32.
 
Dash A, Pillai MR, Knapp FF Jr. (2015). Production of 177Lu for targeted radionuclide therapy : Available options. Nucl Med Mol Imaging. 49: 85-107. 

Frost SH, Frayo SL, Miller BW, Orozco JJ, Booth GC, Hylarides MD, Lin Y, Green DJ, Gopal AK, Pagel JM, Bäck TA, Fisher DR, Press OW. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One. 2015 Mar 18;10(3):e0120561.
 
Gupta S, Batra S, Jain M (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol. 2014;1141:147-57. 
IAEA (2013). Peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumors. IAEA Human Health Series No. 20., IAEA, Vienna. 
 
Kam BLR, Teunissen JJM, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ. (2012). Lutetium-labelled peptides for therapy of neuroendocrine tumours.  Eur J Nucl Med Mol Imaging 39 (Suppl 1):S103–S112.
 
Kamaleshwaran KK, Rajamani V, Thirumalaisamy SG, Chakraborty S, Kalarikal R, Mohanan V, Shinto AS.(2014). 

Kameshwaran M, Pandey U, Dhakan C, Pathak K, Gota V, Vimalnath KV, Dash A, Samuel G. (2015) .Synthesis and Preclinical Evaluation of (177)Lu-CHX-A”-DTPA-Rituximab as a Radioimmunotherapeutic Agent for Non-Hodgkin’s Lymphoma. Cancer Biother Radiopharm. 2015 Aug;30(6):240-6

Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JL, de Jong M, Krenning EP.. (2001). [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients.Eur J Nucl Med.  28: 1319-1325.

Parus JL, Pawlak D, Mikolajczak R, Duatti A. (2015) Chemistry and bifunctional chelating agents for binding 177Lu Curr Radiopharm (Ahead of Pub)
 
Limouris G. (2012) Neuroendocrine tumors: a focus on liver metastatic lesions. Front Oncol. 2:20 (Ahead of Pub) PMC article
Pillai MR, (Russ) Knapp FF. (2015). Evolving Important Role of Lutetium-177 for Therapeutic Nuclear Medicine Curr Radiopharm (ahead of print).
Pillai MR, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N. (2003). Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot. 59: 109-118.
 
Shinto AS, Kamaleshwaran KK, Vyshakh K, Thirumalaisamy SG, Karthik S, Nagaprabhu VN, Vimalnath KV, Das T, Chakraborty S, Banerjee S. (2015)  Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra‑Articular Administration of 177Lu‑Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience. World J Nucl Med. 14: (ahead of print).
 
Videos
DOTA-TATE
DOTATATE.svg
Names
Other names

DOTA-(Tyr3)-octreotate
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C65H90N14O19S2
Molar mass 1,435.63 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DOTA-TATEDOTATATE or DOTA-octreotate is a substance which, when bound to various radionuclides, has been tested for the treatment and diagnosis of certain types of cancer, mainly neuroendocrine tumours.

Chemistry and mechanism of action

DOTA-TATE is an amide of the acid DOTA (top left in the image), which acts as a chelator for a radionuclide, and (Tyr3)-octreotate, a derivative of octreotide. The latter binds to somatostatin receptors, which are found on the cell surfaces of a number of neuroendocrine tumours, and thus directs the radioactivity into the tumour.

Usage examples

Gallium (68Ga) DOTA-TATE (GaTate[1]) is used for tumour diagnosis in positron emission tomography (PET).[2] DOTA-TATE PET/CT has a much higher sensitivitycompared to In-111 octreotide imaging.[1]

Lutetium (177Lu) DOTA-TATE[3] has been tested for the treatment of tumors such as carcinoid and endocrine pancreatic tumor. It is also known as Lutathera.[4]

Patients are typically treated with an intravenous infusion of 7.5 GBq of lutetium-177 octreotate. After about four to six hours, the exposure rate of the patient has fallen to less than 25 microsieverts per hour at one metre and the patients can be discharged from hospital.

A course of therapy consists of four infusions at three monthly intervals.[5]

Availability

Lu177 octreotate therapy is currently available under research protocols in five different medical centers in North America: Los Angeles (CA), Quebec City, (Qc), Birmingham, AL, Edmonton, (Ab), London, (On) as Houston (Tx) on clinical trial.[6] Medical centers in Europe also offer this treatment. For instance: Cerrahpasa Hospital in TurkeyUppsala Centre of Excellence in Neuroendocrine Tumors in Sweden and Erasmus University in the Netherlands.[7] In Israel, treatment is available at Hadassah Ein Kerem Medical Center. In Australia, treatment is available at St George Hospital and Royal North Shore Hospital, Sydney;[8] the Royal Brisbane and Women’s Hospital in Brisbane [9], the Peter MacCallum Cancer Centre [1] and at the Department of Nuclear Medicine at Fremantle Hospital in Western Australia.[10] In Aarhus universitet hospital in Denmark. In the coming years such therapy will also become commercially available in Latvia, Riga – “Clinic of nuclear medicine”.

See also

  • DOTATOC or edotreotide, a similar compound

References

  1. Jump up to:a b c Hofman, M. S.; Kong, G.; Neels, O. C.; Eu, P.; Hong, E.; Hicks, R. J. (2012). “High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours”. Journal of Medical Imaging and Radiation Oncology56 (1): 40–47. doi:10.1111/j.1754-9485.2011.02327.xPMID 22339744.
  2. Jump up^ Breeman, W. A. P.; De Blois, E.; Sze Chan, H.; Konijnenberg, M.; Kwekkeboom, D. J.; Krenning, E. P. (2011). “68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives”. Seminars in Nuclear Medicine41 (4): 314–321. doi:10.1053/j.semnuclmed.2011.02.001PMID 21624565.
  3. Jump up^ Bodei, L.; Cremonesi, M.; Grana, C. M.; Fazio, N.; Iodice, S.; Baio, S. M.; Bartolomei, M.; Lombardo, D.; Ferrari, M. E.; Sansovini, M.; Chinol, M.; Paganelli, G. (2011). “Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study”. European Journal of Nuclear Medicine and Molecular Imaging38(12): 2125–2135. doi:10.1007/s00259-011-1902-1PMID 21892623.
  4. Jump up^ Radiolabeled Peptide Offers PFS Benefit in Midgut NET
  5. Jump up^ Claringbold, P. G.; Brayshaw, P. A.; Price, R. A.; Turner, J. H. (2010). “Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours”. European Journal of Nuclear Medicine and Molecular Imaging38 (2): 302–311. doi:10.1007/s00259-010-1631-xPMID 21052661.
  6. Jump up^ Clinical trial number NCT01237457 for “177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms” at ClinicalTrials.gov
  7. Jump up^ “PRRT Behandelcentrum Rotterdam”PRRT Behandelcentrum RotterdamErasmus Universiteit.
  8. Jump up^ http://www.swslhd.nsw.gov.au/liverpool/pet/PET.html
  9. Jump up^ https://agitg.org.au/control-nets-study-set-to-commence
  10. Jump up^ Turner, J. H. (2012). “Outpatient therapeutic nuclear oncology”. Annals of Nuclear Medicine26 (4): 289–97. doi:10.1007/s12149-011-0566-zPMID 22222779.

//////////////Lutathera, lutetium Lu 177 dotatate, fda 2018, PRIORITY REVIEW, ORPHAN DRUG

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(C(C)O)C(=O)O)O.[Lu+3]

ELAGOLIX


Elagolix.svgChemSpider 2D Image | Elagolix | C32H30F5N3O5Elagolix.png

ELAGOLIX

  • Molecular FormulaC32H30F5N3O5
  • Average mass631.590 Da
NBI56418, ABT 620
UNII:5B2546MB5Z
4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid
834153-87-6 FREE ACID
SODIUM SALT  832720-36-2
Acide 4-({(1R)-2-[5-(2-fluoro-3-méthoxyphényl)-3-[2-fluoro-6-(trifluorométhyl)benzyl]-4-méthyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phényléthyl}amino)butanoïque
Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-

GNRH antagonist, Endometriosis

Endometriosis PREREGISTERED

Phase III Uterine leiomyoma

WO2001055119A2,

Inventors Yun-Fei ZhuChen ChenFabio C. TucciZhiqiang GuoTimothy D. GrossMartin RowbottomR. Scott Struthers,
Applicant Neurocrine Biosciences, Inc.

WO 2005007165 PDT PATENT

Image result for Neurocrine Biosciences, Inc.

Inventors Zhiqiang GuoYongsheng ChenDongpei WuChen ChenWarren WadeWesley J. DwightCharles Q. HuangFabio C. Tucci
Applicant Neurocrine Biosciences, Inc.
  • Originator Icahn School of Medicine at Mount Sinai
  • Developer AbbVie; Neurocrine Biosciences
  • Class Antineoplastics; Fluorinated hydrocarbons; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Highest Development Phases
  • Preregistration Endometriosis
  • Phase III Uterine leiomyoma
  • Discontinued Benign prostatic hyperplasia; Prostate cancer
  • Most Recent Events
  • 23 Nov 2017 AbbVie plans a phase III trial for Endometriosis (Monotherapy, Combination therapy) in USA in November 2017 (NCT03343067)
  • 01 Nov 2017 Updated efficacy and adverse events data from two phase III extension trials in Endometriosis released by AbbVie
  • 27 Oct 2017 Elagolix receives priority review status for Endometriosis in USA

 

SYN

Elagolix is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.

Image result for Neurocrine Biosciences, Inc.

In 2010, elagolix sodium was licensed to Abbott by Neurocrine Biosciences for worldwide development and commercialization for the treatment of endometriosis. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie.

AbbVie , following its spin-out from Abbott in January 2013, under license from Neurocrine , is developing elagolix, the lead from a series of non-peptide gonadotropin-releasing hormone antagonists, for treating hormone-dependent diseases, primarily endometriosis and uterine fibroids.

Elagolix sodium is an oral gonadotropin releasing hormone (GnRH) antagonist in development at Neurocrine Biosciences and Abbvie (previously Abbott). In 2017, Abbvie submitted a New Drug Application (NDA) in the U.S. for the management of endometriosis with associated pain. The candidate is being evaluated in phase III trials for the treatment of uterine fibroids.

Elagolix (INNUSAN) (former developmental code names NBI-56418ABT-620) is a highly potent, selective, orally-active, short-duration, non-peptide antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (KD = 54 pM) which is under development for clinical use by Neurocrine Biosciences and AbbVie.[2][3] As of 2017, it is in pre-registration for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.[1][4] The drug was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia, but development for these indications was ultimately not pursued.[4] Elagolix is the first of a new class of GnRH inhibitors that have been denoted as “second-generation”, due to their non-peptide nature and oral bioavailability.[1]

Because of the relatively short elimination half-life of elagolix, the actions of gonadotropin-releasing hormone (GnRH) are not fully blocked throughout the day.[1][5] For this reason, gonadotropin and sex hormone levels are only partially suppressed, and the degree of suppression can be dose-dependently adjusted as desired.[1][5] In addition, if elagolix is discontinued, its effects are rapidly reversible.[1][5] Due to the suppression of estrogen levels by elagolix being incomplete, effects on bone mineral density are minimal, which is in contrast to first-generation GnRH inhibitors.[6][7] Moreover, the incidence and severity of menopausal side effects such as hot flashes are also reduced relative to first-generation GnRH inhibitors.[1][5]

Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl] -4-methyl-2,6-dioxopyrimidin- 1 -yl] -1 -phenylethyl] amino] butanoate as below.

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-IH.

The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

The US patent number 7056927 B2 discloses a process for preparation of elagolix sodium salt in Example -1 as given in below scheme -I.

Scheme -I

The US patent number 8765948 B2 describes a process for preparation of elagolix sodium in example- 1 and 4 as given below scheme-II:

(1c) (1e) (4a)

Scheme-II

Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (le) as mentioned below scheme-Ill.

Scheme -III

PATENT

WO2001055119A2 * Jan 25, 2001 Aug 2, 2001 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

PATENT

WO 2005007165

https://encrypted.google.com/patents/WO2005007165A1?cl=en

EXAMPLE 1

3-[2(R)-{HYD OXYCARBONYLPROPYL-AMINθ} -2-PHENYLETHYL]-5-(2-FLUORO-3- METHOXYPHENYL)-l-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL- PYRIMIDINE-2,4(lH,3H)-DIONE

Figure imgf000027_0001

Step IA: Preparation of 2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of TΗF was added 1 M BΗ3:TΗF slowly at 60 °C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (C\) m/z 194.0 (MH+).

Step IB: Preparation of N-|2-fluoro-6-(trifluoromethyl)benzyl|urea lb To 2-fluoro-6-(trifluoromethyl)benzylamine la (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HC1 (cone, 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave lb as a white solid (46.2 g, 0J96 mmol). MS (CI) m/z 237.0 (MH+).

Step 1C: Preparation of l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2.4(lH.3H)-dione lc Nal (43.9 g, 293 mmol) was added to N-[2-fluoro-6- (trifluoromethyl)benzyl]urea lb (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give lc as a white solid (48.5 g, 16 mmol). 1H ΝMR (CDC13) δ 2.15 (s, 3Η), 5.37 (s, 2H), 5.60 (s, 1H), 7.23-7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).

Step ID: Preparation of 5-bromo-l -[2-fluoro-6-(trifluoromethyl)benzyl|-6- methylpyrimidine-2.4(lH.3H)-dione Id Bromine (16.5 mL, 0.32 mmol) was added to l-[2-fluoro-6-

(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(lHJH)-dione lc (48.5 g, 0J6 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. ΝaΗCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of Id (0J56 mol) total. Η NMR (CDC13) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+). 5-Bromo-l-[2, 6-difluorobenzyl]-6-methylpyrimidine-2,4(lHJH)-dione ld.l was made using the same procedure.

Step IE: Preparation of 5-bromo-l -r2-fluoro-6-(trifluoromethyl)benzyll-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyll-pyrimidine-2.4(lHJH)-dione le To 5-bromo- 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- 2,4(lHJH)-dione Id (15 g, 39.4 mmol) in 225 mL of TΗF were added N-t-Boc-D- phenylglycinol (11.7 g, 49.2 mmol) and triphenylphosphine (15.5 g, 59J mmol), followed by addition of di-tert-butyl azodicarboxylate (13.6 g, 59J mmol). The resulting yellow solution was stirred overnight. The volatiles were evaporated and the residue was purified by silica gel with 3:7 EtOAc Ηexane to give le as a white solid (23.6 g, 39.4 mmol). MS (CI) m/z 500.0 (MΗ+-Boc).

Step IF: Preparation of 3-[2(R)-amino-2-phenylethyll-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyll-6-methyl-pyrimidine- 2.4(lH.3H)-dione If To 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)- tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione le (15 g, 25 mmol) in 30 mL/90 mL of Η2O/dioxane in a pressure tube were added 2-fluoro-3- methoxyphenylboronic acid (4.25 g, 25 mmol) and sodium carbonate (15.75 g, 150 mmol). N2 gas was bubbled through for 10 min.

Tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol) was added, the tube was sealed and the resulting mixture was heated with stirring at 90 °C overnight. After cooling to ambient temperature, the precipitate was removed by filtration. The volatiles were removed by evaporation and the residue was partitioned between EtOAc/sat. NaHCO3. The organic solvent was evaporated and the residue was chromatographed with 2:3 EtOAc/Hexane to give 13.4 g (20.8 mmol, 83 %) yellow solid. This yellow solid (6.9 g, 10.7 mmol) was dissolved in 20 mL/20 mL CH2C12/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave If as a yellow oil (4.3 g, 7.9 mmol, 74%). Η NMR (CDC13) δ 2.03 (s, 3H), 3.72-4.59 (m, 6H), 5.32-5.61 (m, 2H), 6.74-7.56 (m, 11H); MS (CI) m/z 546.0 (MH+). 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2,6- difluorobenzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione lf.l was made using the same procedure described in this example.

Step 1G: Preparation of 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyll-5-

(2-fluoro-3 -methoxyphenyl)- 1 -[2-fluoro-6-(trifluoromethyl)benzyl|-6-methyl- pyrimidine-2,4(lHJH)-dione lg To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione If (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4- bromobutyrate (4 mL, 28.2 mmol) and Ηunig’s base (1.6 mL, 9.4 mmol). After reflux at 95 °C overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10: 1 EtOAc/Ηexane/Et3N to give lg as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).

Step 1H: Preparation of 3-[2(R)- {hydroxycarbonylpropyl-amino} -2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l- 2-fluoro-6-(trifluoromethyl)benzyl1-6-methyl- pyrimidine-2,4(lHJH)-dione 1-1 Compound 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione lg (2.6 g, 4.0 mmol) was dissolved in 30 mL/30 mL of TΗF/water. Solid NaOΗ (1.6 g, 40 mmol) was added and the resulting mixture was heated at 50 °C overnight. The mixture was cooled to ambient temperature and the volatiles were evaporated. Citric acid was added to the aqueous solution until pΗ = 3. Extraction with EtOAc followed by evaporation of solvent gave 1.96 g of a white gel. The gel was passed through a Dowex MSC-1 macroporous strong cation-exchange column to convert to sodium salt. Lyopholization gave white solid 1-1 as the sodium salt (1.58 g, 2.47 mmol). Η NMR (CD3OD) δ 1.69-1.77 (m, 2H), 2.09 (s, 3H), 2.09-2.19 (t, J = 7.35 Hz, 2H), 2.49-2.53 (t, J = 735 H, 2H), 3.88 (s, 3H), 4.15-4.32 (m, 3H), 5.36-5.52 (m, 2H), 6.60-7.63 (m, 1 IH); HPLC-MS (CI) m/z 632.2 (MH+), tR = 26.45, (method 5)

PATENT

WO 2017221144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017221144&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the preparation of elagolix sodium and its polymorph forms and intermediates is claimed. Represents first filing from Dr. Reddy’s Laboratories Limited and the inventors on this API.

n a seventh aspect, the present invention provides a process for preparation of compound of formula (VII)

(VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like,

comprising;

a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above

b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula

(VII)

(VI) (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

The seventh aspect of the present invention is depicted below scheme-IV.

Scheme-IV

The eighth aspect of the present invention is depicted below scheme-IV.

R=alkyl

Scheme-IV

Example 11: Preparation of ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (Ilia; R is ethyl)

R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with IN HC1 (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). ¾ NMR (400 MHz, DMSO-d6): δ 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH )

Example 12: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l-phenylethyl) amino)butanoate (III; R is ethyl)

Ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5 °C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). ¾ NMR (400 MHz, CDC13): δ 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH )

Example 13: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl)

Ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l -phenyl ethyl) amino)butanoate (III; R is ethyl) (1.0 g), 5-bromo-l-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); l NMR (DMSO-d6) δ 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+

Example 14: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl)

Ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethylacetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethylacetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.

Example 15: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VII; R is ethyl)

Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoro methyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5 °C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5 °C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). ‘H NMR (400 MHz, DMSO-d6): δ 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH )

PAPER

Discovery of sodium R-(+)-4-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl-)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-1-phenylethamino)butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2008, 51(23): 7478

Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Department of Medicinal Chemistry, Department of Endocrinology, and Department of Preclinical Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130
J. Med. Chem.200851 (23), pp 7478–7485
DOI: 10.1021/jm8006454

* To whom correspondence should be addressed. Phone: 1-858-617-7600. Fax: 1-858-617-7925. E-mail: cchen@neurocrine.comsstruthers@neurocrine.com., †

Department of Medicinal Chemistry., ‡ Department of Endocrinology., § Department of Preclinical Development.

Abstract

Abstract Image

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

NA SALT

(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric Acid Sodium Salt

sodium salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100% (220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 4.24 (m, 3H), 5.40 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H). MS: 632 (M − Na + 2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.

PATENT

CN 105218389

PATENT

WO2014143669A1

“Elagolix” refers to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2- fluoro-6 rifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l- phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof. Elagolix is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Elagolix produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Elagolix and a pharmaceutically acceptable salt thereof are described in WO 2005/007165, the contents of which are herein incorporated by reference.

References

  1. Jump up to:a b c d e f g Ezzati, Mohammad; Carr, Bruce R (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Women’s Health11(1): 19–28. doi:10.2217/whe.14.68ISSN 1745-5057.
  2. Jump up^ Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M, Chen Y, Tucci FC, Rowbottom M, Pontillo J, Zhu YF, Wade W, Saunders J, Bozigian H, Struthers RS (2008). “Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem51 (23): 7478–85. doi:10.1021/jm8006454PMID 19006286.
  3. Jump up^ Thomas L. Lemke; David A. Williams (24 January 2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1411–. ISBN 978-1-60913-345-0.
  4. Jump up to:a b AdisInsight: Elagolix.
  5. Jump up to:a b c d Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513Freely accessiblePMID 19033369.
  6. Jump up^ Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study”. Reprod Sci21 (3): 363–71. doi:10.1177/1933719113497292PMID 23885105.
  7. Jump up^ Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density”Reprod Sci21 (11): 1341–51. doi:10.1177/1933719114549848PMC 4212335Freely accessiblePMID 25249568.

External links

Citing Patent Filing date Publication date Applicant Title
WO2014143669A1 Mar 14, 2014 Sep 18, 2014 AbbVie Inc . Compositions for use in treating heavy menstrual bleeding and uterine fibroids
EP2881391A1 Dec 5, 2013 Jun 10, 2015 Bayer Pharma Aktiengesellschaft Spiroindoline carbocycle derivatives and pharmaceutical compositions thereof
US8084614 Apr 4, 2008 Dec 27, 2011 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588 Apr 4, 2008 Sep 11, 2012 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738 Nov 10, 2011 Jul 9, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8507536 Aug 10, 2012 Aug 13, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8952161 Jun 5, 2013 Feb 10, 2015 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9034850 Nov 19, 2010 May 19, 2015 Sk Chemicals Co., Ltd. Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same
US9422310 Jan 8, 2015 Aug 23, 2016 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Patent ID

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2014-09-25
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2010-02-05
2010-07-29
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2009-09-03
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2006-06-08
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Elagolix
Elagolix.svg
Clinical data
Synonyms NBI-56418; ABT-620
Routes of
administration
By mouth
Drug class GnRH analogueGnRH antagonistantigonadotropin
Pharmacokinetic data
Biological half-life 2.4–6.3 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H30F5N3O5
Molar mass 631.590 g/mol
3D model (JSmol)

///////////////ELAGOLIX, NBI 56418, UNII:5B2546MB5Z, ABT 620, priority review status, PHASE 3, AbbVie, Neurocrine Biosciences, Endometriosis

CC1=C(C(=O)N(C(=O)N1CC2=C(C=CC=C2F)C(F)(F)F)CC(C3=CC=CC=C3)NCCCC(=O)O)C4=C(C(=CC=C4)OC)F

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome


FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

December 12, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

//////////////Nucala, mepolizumab, fda 2017, gsk,  Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Hemlibra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves new treatment for certain advanced or metastatic breast cancers


FDA approves new treatment for certain advanced or metastatic breast cancers

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized). Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm

Abemaciclib.svg

(abemaciclib)

September 28, 2017

Release

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized).

“Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Verzenio works by blocking certain molecules (known as cyclin-dependent kinases 4 and 6), involved in promoting the growth of cancer cells. There are two other drugs in this class that are approved for certain patients with breast cancer, palbociclib approved in February 2015 and ribociclib approved in March 2017.

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The safety and efficacy of Verzenio in combination with fulvestrant were studied in a randomized trial of 669 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and who had not received chemotherapy once the cancer had metastasized. The study measured the length of time tumors did not grow after treatment (progression-free survival). The median progression-free survival for patients taking Verzenio with fulvestrant was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant.

The safety and efficacy of Verzenio as a stand-alone treatment were studied in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. The study measured the percent of patients whose tumors completely or partially shrank after treatment (objective response rate). In the study, 19.7 percent of patients taking Verzenio experienced complete or partial shrinkage of their tumors for a median 8.6 months.

Common side effects of Verzenio include diarrhea, low levels of certain white blood cells (neutropenia and leukopenia), nausea, abdominal pain, infections, fatigue, low levels of red blood cells (anemia), decreased appetite, vomiting and headache.

Serious side effects of Verzenio include diarrhea, neutropenia, elevated liver blood tests and blood clots (deep venous thrombosis/pulmonary embolism). Women who are pregnant should not take Verzenio because it may cause harm to a developing fetus.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted the approval of Verzenio to Eli Lilly and Company.

//////////Verzenio, abemaciclib, fda 2017, metastatic breast cancers, Eli Lilly ,  Priority Review,  Breakthrough Therapy designations, antibodies

FDA approval brings first gene therapy to the United States


Image result for FDA approval brings first gene therapy to the United States
08/30/2017
The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases

The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.

The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.

Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

/////////////Kymriah, Novartis Pharmaceuticals Corp, Actemra, Genentech Inc., gene therapy, fda 2017

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