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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 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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Tralokinumab

July 2, 2021 2:28 am / Leave a comment

(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGW ISANNGDTNY
GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS SSSWARWFFD LWGRGTLVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
EGNVFSCSVM HEALHNHYTQ KSLSLSLGK
(Light chain)
SYVLTQPPSV SVAPGKTARI TCGGNIIGSK LVHWYQQKPG QAPVLVIYDD GDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DTGSDPVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)

Tralokinumab

トラロキヌマブ (遺伝子組換え)

Formula	C6374H9822N1698O2014S44
CAS	1044515-88-9
Mol weight	143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,^[1] and is designed for the treatment of asthma and other inflammatory diseases.^[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354^[3] and taken through pre-clinical and early clinical development.^[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.^[5]^[6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists^[7] using protein optimization based on Ribosome Display.^[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.^[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.^[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.^[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.^[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.^[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.^[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.^[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.^[14]

The applicant for this medicinal product is LEO Pharma A/S.

References

^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery. 9 (9): 703–18. doi:10.1038/nrd2805. PMID 20811382. S2CID 23769909.
^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America. 103 (20): 7619–24. Bibcode:2006PNAS..103.7619T. doi:10.1073/pnas.0602341103. PMC 1458619. PMID 16684878.
^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”. British Journal of Pharmacology. 166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.x. PMC 3415647. PMID 21895629.
^ “Pipeline”. MedImmune. Retrieved 11 June 2013.
^ “Studies found for CAT-354”. ClinicalTrials.gov. Retrieved 11 June 2013.
^ Jump up to:^a ^b Human Antibody Molecules for Il-13, retrieved 2015-07-26
^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”. Proceedings of the National Academy of Sciences of the United States of America. 98 (1): 75–80. Bibcode:2001PNAS…98…75J. doi:10.1073/pnas.98.1.75. PMC 14547. PMID 11134506.
^ Jump up to:^a ^b “Tralokinumab”. Adis Insight. Springer Nature Switzerland AG.
^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at ClinicalTrials.gov
^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”. The Journal of Allergy and Clinical Immunology. 143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029. PMID 29906525.
^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis”. leo-pharma.com. AstraZeneca. 1 July 2016.
^ “Adtralza: Pending EC decision”. European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.

Monoclonal antibody
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y.
Type	Whole antibody
Source	Human
Target	IL-13
Clinical data
ATC code	D11AH07 (WHO)
Identifiers
CAS Number	1044515-88-9
ChemSpider	none
UNII	GK1LYB375A
KEGG	D09979
Chemical and physical data
Formula	C₆₃₇₄H₉₈₂₂N₁₆₉₈O₂₀₁₄S₄₄
Molar mass	143875.20 g·mol⁻¹
(what is this?) (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,

NEW DRUG APPROVALS

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Imdevimab

June 1, 2021 3:24 am / Leave a comment

(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS NYAMYWVRQA PGKGLEWVAV ISYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRTED TAVYYCASGS DYGDYLLVYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
QSALTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVSKRPSGV
SNRFSGSKSG NTASLTISGL QSEDEADYYC NSLTSISTWV FGGGTKLTVL GQPKAAPSVT
LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK AGVETTTPSK QSNNKYAASS
YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS
(Disulfide bridge: H22-H96, H147-H203, H223-L215, H229-H’229, H264-H324-H370-H428, H’22-H’96, H’147-H’203, H’223-L’215, H’264-H’324, H’370-H’428, L22-L90, L138-L197, L’22-L’90, L’138-L’197)

Imdevimab

イムデビマブ;

Immunoglobulin G1, anti-(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10987 γ1-chain), disulfide with human monoclonal REGN10987 λ-chain, dimer

Formula	C6396H9882N1694O2018S42
CAS	2415933-40-1
Mol weight	144141.7693

Monoclonal antibody
Treatment and prophylaxis of SARS-CoV-2 infection

ANTIVIRAL

SARS-CoV-2 spike glycoprotein

REGN 10987
RG 6412

Fact Sheet – US Food and Drug Administration

https://www.fda.gov › media › download
PDFBenefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab.

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

Trials

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

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

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

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

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

Authorization

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

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

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

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

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

Deployment

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

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

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

References

^ Jump up to:^a ^b ^c “REGEN-COV- casirivimab and imdevimab kit”. DailyMed. Retrieved 18 March 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”. U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020. This article incorporates text from this source, which is in the public domain.
^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”. Reuters. Retrieved 14 September 2020.
^ “Regeneron’s COVID-19 Response Efforts”. Regeneron Pharmaceuticals. Retrieved 14 September 2020.
^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”. BBC News Online. Retrieved 14 September2020.
^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”. ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”. Science. 369 (6506): 1014–1018. Bibcode:2020Sci…369.1014B. doi:10.1126/science.abd0831. PMC 7299283. PMID 32540904.
^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”. Recovery Trial. Retrieved 14 September 2020.
^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”. streetinsider.com. Archived from the original on 2021-04-12. Retrieved 2021-04-12.
^ Jump up to:^a ^b ^c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
^ “Casirivimab and Imdevimab”. Regeneron Pharmaceuticals. Retrieved 19 March 2021.
^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”. http://www.cipla.com. Retrieved 2021-05-06.
^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”. The Daily Gazette.
^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”. BioProcess International.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ “Roche and Regeneron link up on a coronavirus antibody cocktail”. CNBC. 19 August 2020. Retrieved 14 September 2020.
^ Jump up to:^a ^b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”. The New York Times. ISSN 0362-4331. Retrieved 2 October 2020.
^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”. http://www.precisionvaccinations.com. Archived from the original on 3 October 2020.

External links

“Casirivimab”. Drug Information Portal. U.S. National Library of Medicine.
“Imdevimab”. Drug Information Portal. U.S. National Library of Medicine.
“Casirivimab and Imdevimab EUA Letter of Authorization” (PDF). U.S. Food and Drug Administration (FDA).
“Frequently Asked Questions on the Emergency Use Authorization of Casirivimab + Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).

Combination of
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG.
Casirivimab	Monoclonal antibody against spike protein of SARS-CoV-2
Imdevimab	Monoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade names	REGEN-COV
Other names	REGN-COV2
AHFS/Drugs.com	Monograph
License data	US DailyMed: Casirivimab
Routes of administration	Intravenous
ATC code	None
Legal status
Legal status	US: Unapproved (Emergency Use Authorization)^[1]^[2]
Identifiers
DrugBank	DB15691
KEGG	D11938 D11939

////////Imdevimab, ANTI VIRAL, PEPTIDE, CORONA VIRUS, COVID19, APPROVALS 2020, FDA 2020, イムデビマブ, REGN 10987, RG 6412,

NEW DRUG APPROVALS

one time

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Casirivimab

May 31, 2021 3:22 am / Leave a comment

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

Casirivimab

カシリビマブ;

Immunoglobulin G1, anti-(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10933 γ1-chain), disulfide with human monoclonal REGN10933 κ-chain, dimer

Formula	C6454H9976N1704O2024S44
CAS	2415933-42-3
Mol weight	145233.3296

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

SARS-CoV-2 spike glycoprotein

Protein Sequence
Sequence Length: 1328, 450, 450, 214, 214

REGN 10933
RG 6413

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

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

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

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

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

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

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

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

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

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

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

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

The EUA was issued to Regeneron Pharmaceuticals Inc.

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

Related Information

Trials

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

Authorization

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

Deployment

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

References

^ Jump up to:^a ^b ^c “REGEN-COV- casirivimab and imdevimab kit”. DailyMed. Retrieved 18 March 2021.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”. U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020. This article incorporates text from this source, which is in the public domain.
^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”. Reuters. Retrieved 14 September 2020.
^ “Regeneron’s COVID-19 Response Efforts”. Regeneron Pharmaceuticals. Retrieved 14 September 2020.
^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”. BBC News Online. Retrieved 14 September2020.
^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”. ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”. Science. 369 (6506): 1014–1018. Bibcode:2020Sci…369.1014B. doi:10.1126/science.abd0831. PMC 7299283. PMID 32540904.
^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”. Recovery Trial. Retrieved 14 September 2020.
^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”. streetinsider.com. Archived from the original on 2021-04-12. Retrieved 2021-04-12.
^ Jump up to:^a ^b ^c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
^ “Casirivimab and Imdevimab”. Regeneron Pharmaceuticals. Retrieved 19 March 2021.
^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”. http://www.cipla.com. Retrieved 2021-05-06.
^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”. The Daily Gazette.
^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”. BioProcess International.
^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
^ “Roche and Regeneron link up on a coronavirus antibody cocktail”. CNBC. 19 August 2020. Retrieved 14 September 2020.
^ Jump up to:^a ^b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”. The New York Times. ISSN 0362-4331. Retrieved 2 October 2020.
^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”. http://www.precisionvaccinations.com. Archived from the original on 3 October 2020.

External links

“Casirivimab”. Drug Information Portal. U.S. National Library of Medicine.
“Imdevimab”. Drug Information Portal. U.S. National Library of Medicine.
“Casirivimab and Imdevimab EUA Letter of Authorization” (PDF). U.S. Food and Drug Administration (FDA).
“Frequently Asked Questions on the Emergency Use Authorization of Casirivimab + Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).

Combination of
REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB: 6VSB, 6XDG.
Casirivimab	Monoclonal antibody against spike protein of SARS-CoV-2
Imdevimab	Monoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade names	REGEN-COV
Other names	REGN-COV2
AHFS/Drugs.com	Monograph
License data	US DailyMed: Casirivimab
Routes of administration	Intravenous
ATC code	None
Legal status
Legal status	US: Unapproved (Emergency Use Authorization)^[1]^[2]
Identifiers
DrugBank	DB15691
KEGG	D11938

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

NEW DRUG APPROVALS

ONE TIME

$10.00

Dostarlimab

May 12, 2021 3:42 am / Leave a comment

(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK

>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-(programmed cell death protein 1 (PDCD1)) (humanized clone ABT1 γ4-chain), disulfide with humanized clone ABT1 κ-chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

GSK-4057190
GSK4057190
TSR 042
TSR-042
WBP-285
ANB 011

Formula	C6420H9832N1680O2014S44
CAS	2022215-59-2
Mol weight	144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

NEW DRUG APPROVALS

ONE TIME

$10.00

Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.^[1]^[2]^[3]^[4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.^[1]^[2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.^[1]^[2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.^[1]^[2]

Dostarlimab was approved for medical use in the United States in April 2021.^[1]^[2]^[5]

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Jemperli	Injection	50 mg/1mL	Intravenous	GlaxoSmithKline LLC	2021-04-22	Not applicable

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.^[1]^[2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having durations ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.^[1]^[2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.^[1]^[2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.^[6]^[7]^[8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.^[6]^[9]^[10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.^[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.^[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).^[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.^[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.^[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.^[13]

References[

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”. U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Jemperli- dostarlimab injection”. DailyMed. Retrieved 28 April 2021.
^ Statement On A Nonproprietary Name Adopted By The USAN Council – Dostarlimab, American Medical Association.
^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information. 32 (2).
^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
^ Jump up to:^a ^b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”. Tesaro (Press release). Retrieved 1 January 2020.
^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”. Targeted Oncology. Retrieved 1 January 2020.
^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”. Drugs.com. Retrieved 29 April 2020.
^ “FDA Approves New Immunotherapy for Endometrial Cancer”. Medscape. Retrieved 23 April 2021.
^ Jump up to:^a ^b “Jemperli: Pending EC decision”. European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

“Dostarlimab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov

Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	PCDP1
Clinical data
Trade names	Jemperli
Other names	TSR-042, WBP-285, dostarlimab-gxly
License data	US DailyMed: Dostarlimab
Routes of administration	Intravenous
Drug class	Antineoplastic
ATC code	L01XC40 (WHO)
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
CAS Number	2022215-59-2
PubChem SID	384585344
DrugBank	DB15627
UNII	P0GVQ9A4S5
KEGG	D11366
Chemical and physical data
Formula	C₆₄₂₀H₉₈₃₂N₁₆₉₀O₂₀₁₄S₄₄
Molar mass	144325.73 g·mol⁻¹

/////////Dostarlimab, PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

Evinacumab

February 26, 2021 9:34 am / 1 Comment on Evinacumab

(Heavy chain)
EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA ISGDGGSTYY
ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL RNTIFGVVIP DAFDIWGQGT
MVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF
LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE
QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS
QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK
SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK ASSLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H140-L214, H153-H209, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’140-L’214, H’153-H’209, H’267-H’327, H’373-H’431, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Evinacumab

エビナクマブ (遺伝子組換え)

Immunoglobulin G4, anti-(human protein ANGPTL3 (angiopoietin-like 3)) (human monoclonal REGN1500 heavy chain), disulfide with human monoclonal REGN1500 light chain, dimer

Formula	C6480H9992N1716O2042S46
CAS	1446419-85-7
Mol weight	146081.9345

Protein Sequence

Sequence Length: 1334, 453, 453, 214, 214multichain; modified (modifications unspecified)

FDA APPROVED, 2021/2/11, EVKEEZA

Antihyperlipidemic, Anti-angiopietin like 3

Monoclonal antibody
Treatment of dyslipidemia

REGN 1500
REGN-1500
REGN1500

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence:

Sequence Modifications

Type	Location	Description
bridge	Cys-22 – Cys-96	disulfide bridge
bridge	Cys-140 – Cys-214”	disulfide bridge
bridge	Cys-153 – Cys-209	disulfide bridge
bridge	Cys-232 – Cys-232′	disulfide bridge
bridge	Cys-235 – Cys-235′	disulfide bridge
bridge	Cys-267 – Cys-327	disulfide bridge
bridge	Cys-373 – Cys-431	disulfide bridge
bridge	Cys-22′ – Cys-96′	disulfide bridge
bridge	Cys-140′ – Cys-214”’	disulfide bridge
bridge	Cys-153′ – Cys-209′	disulfide bridge
bridge	Cys-267′ – Cys-327′	disulfide bridge
bridge	Cys-373′ – Cys-431′	disulfide bridge
bridge	Cys-23” – Cys-88”	disulfide bridge
bridge	Cys-134” – Cys-194”	disulfide bridge
bridge	Cys-23”’ – Cys-88”’	disulfide bridge
bridge	Cys-134”’ – Cys-194”’	disulfide bridge

PATENTS

WO 2017024062

US 20170305999

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).^[1]^[2]

Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions – including involvement in the regulation of lipid metabolism – which have made them desirable therapeutic targets in recent years.² Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.³

In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name “Evkeeza”.⁸ Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.

Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.^[2]

Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3).^[2] ANGPTL3 slows the function of certain enzymes that break down fats in the body.^[2] Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol.^[2] Evinacumab was approved for medical use in the United States in February 2021.^[2]^[3]

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Evkeeza	Injection, solution, concentrate	150 mg/1mL	Intravenous	Regeneron Pharmaceuticals, Inc.	2021-02-11	Not applicable
Evkeeza	Injection, solution, concentrate	150 mg/1mL	Intravenous	Regeneron Pharmaceuticals, Inc.	2021-02-11	Not applicable

History

The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH).^[2] In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo.^[2] Participants were taking other lipid-lowering therapies as well.^[2]

The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24.^[2] At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.^[2]

The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drug, breakthrough therapy, and priority review designations.^[2] The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc.^[2]

References

^ Jump up to:^a ^b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA approves add-on therapy for patients with genetic form of severely”. U.S. Food and Drug Administration (FDA). 11 February 2021. Retrieved 12 February 2021. This article incorporates text from this source, which is in the public domain.
^ “FDA Approves First-in-class Evkeeza (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol” (Press release). Regeneron Pharmaceuticals. 11 February 2021. Retrieved 12 February 2021 – via PR Newswire.

External links

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

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Angiopoietin-like 3 (ANGPTL3)
Clinical data
Trade names	Evkeeza
Other names	REGN1500, evinacumab-dgnb
License data	US DailyMed: Evinacumab
Routes of administration	Intravenous
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]^[2]
Identifiers
CAS Number	1446419-85-7
DrugBank	DB15354
ChemSpider	none
UNII	T8B2ORP1DW
KEGG	D11753
Chemical and physical data
Formula	C₆₄₈₀H₉₉₉₂N₁₇₁₆O₂₀₄₂S₄₆
Molar mass	146083.95 g·mol⁻¹

//////////////

#Evinacumab, #Peptide, #APPROVALS 2021, #FDA 2021, #Monoclonal antibody, #dyslipidemia, #エビナクマブ (遺伝子組換え) , #REGN 1500, #REGN-1500, #REGN1500, #Anthony melvin crasto, #world drug tracker. # new drug approvals, #pharma

GLUCAGON

January 6, 2021 2:32 am / Leave a comment

glucagon

EMA……Ogluo (glucagon), a hybrid medicine for the treatment of severe hypoglycaemia in diabetes mellitus. Hybrid applications rely in part on the results of pre-clinical tests and clinical trials of an already authorised reference product and in part on new data.

On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Ogluo, intended for the treatment of severe hypoglycaemia in diabetes mellitus. The applicant for this medicinal product is Xeris Pharmaceuticals Ireland Limited.

Ogluo will be available as 0.5 and 1 mg solution for injection. The active substance of Ogluo is glucagon, a pancreatic hormone (ATC code: H04AA01); glucagon increases blood glucose concentration by stimulating glycogen breakdown and release of glucose from the liver.

The benefits with Ogluo are its ability to restore blood glucose levels in hypoglycaemic subjects. The most common side effects are nausea and vomiting.

Ogluo is a hybrid medicine¹ of GlucaGen/GlucaGen Hypokit; GlucaGen has been authorised in the EU since October 1962. Ogluo contains the same active substance as GlucaGen but is available as a ready-to-use formulation intended for subcutaneous injection.

The full indication is:

Ogluo is indicated for the treatment of severe hypoglycaemia in adults, adolescents, and children aged 2 years and over with diabetes mellitus.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

¹ Hybrid applications rely in part on the results of pre-clinical tests and clinical trials for a reference product and in part on new data.

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body.^[3] It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose.^[4] It is produced from proglucagon, encoded by the GCG gene.

The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver to engage in glycogenolysis: converting stored glycogen into glucose, which is released into the bloodstream.^[5] High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.^[6] Glucagon belongs to the secretin family of hormones.

Function

Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.^[7] Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.^[8]

Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.

Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).^[9]

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.^[10]

Mechanism of action

Metabolic regulation of glycogen by glucagon.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gɑ separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates phosphorylase kinase.^[11] Phosphorylated phosphorylase kinase phosphorylates phosphorylase. Phosphorylated phosphorylase clips glucose units from glycogen as glucose 1-phosphate. Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate.^[12] The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose 2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)^[13] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.^[14]

Physiology

Production

A microscopic image stained for glucagon

The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Production, which is otherwise freerunning, is suppressed/regulated by amylin, a peptide hormone co-secreted with insulin from the pancreatic β cells.^[15] As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.

In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.^[16]

Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.^[17]

Regulation

Secretion of glucagon is stimulated by:

Hypoglycemia
Epinephrine (via β2, α2,^[18] and α1^[19] adrenergic receptors)
Arginine
Alanine (often from muscle-derived pyruvate/glutamate transamination (see alanine transaminase reaction).
Acetylcholine^[20]
Cholecystokinin
Gastric inhibitory polypeptide

Secretion of glucagon is inhibited by:

Somatostatin
Amylin ^[21]
Insulin (via GABA)^[22]
PPARγ/retinoid X receptor heterodimer.^[23]
Increased free fatty acids and keto acids into the blood.^[24]
Increased urea production
Glucagon-like peptide-1

Structure

Glucagon is a 29-amino acid polypeptide. Its primary structure in humans is: NH₂–His–Ser–Gln–Gly–Thr–Phe–Thr–Ser–Asp–Tyr–Ser–Lys–Tyr–Leu–Asp–Ser–Arg–Arg–Ala–Gln–Asp–Phe–Val–Gln–Trp–Leu–Met–Asn–Thr–COOH.

The polypeptide has a molecular mass of 3485 daltons.^[25] Glucagon is a peptide (nonsteroid) hormone.

Glucagon is generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. In intestinal L cells, proglucagon is cleaved to the alternate products glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth).^[26]

Pathology

Abnormally elevated levels of glucagon may be caused by pancreatic tumors, such as glucagonoma, symptoms of which include necrolytic migratory erythema,^[27] reduced amino acids, and hyperglycemia. It may occur alone or in the context of multiple endocrine neoplasia type 1^[28]

Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis.^[29] It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.^{[citation needed]}

The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.

History

In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.^[30] The amino acid sequence of glucagon was described in the late 1950s.^[31] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.^{[citation needed]}

Etymology

Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist.^[32]

References

^ Jump up to:^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115263 – Ensembl, May 2017
^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Voet D, Voet JG (2011). Biochemistry (4th ed.). New York: Wiley.
^ Reece J, Campbell N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 978-0-8053-6624-2.
^ Orsay J (2014). Biology 1: Molecules. Examkrackers Inc. p. 77. ISBN 978-1-893858-70-1.
^ Jones BJ, Tan T, Bloom SR (March 2012). “Minireview: Glucagon in stress and energy homeostasis”. Endocrinology. 153 (3): 1049–54. doi:10.1210/en.2011-1979. PMC 3281544. PMID 22294753.
^ Voet D, Voet JG (2011). Biochemistry (4th ed.). New York: Wiley.
^ HABEGGER, K. M., HEPPNER, K. M., GEARY, N., BARTNESS, T. J., DIMARCHI, R. & TSCHÖP, M. H. (2010). “The metabolic actions of glucagon revisited”. Nature Reviews. Endocrinology. 6 (12): 689–697. doi:10.1038/nrendo.2010.187. PMC 3563428. PMID 20957001.
^ Liljenquist JE, Bomboy JD, Lewis SB, Sinclair-Smith BC, Felts PW, Lacy WW, Crofford OB, Liddle GW (January 1974). “Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men”. The Journal of Clinical Investigation. 53 (1): 190–7. doi:10.1172/JCI107537. PMC 301453. PMID 4808635.
^ Leinen RL, Giannini AJ (1983). “Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish”. Society for Neuroscience Abstracts. 9: 604.
^ Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A (July 2019). “Glucose controls glucagon secretion by directly modulating cAMP in alpha cells”. Diabetologia. 62 (7): 1212–1224. doi:10.1007/s00125-019-4857-6. PMC 6560012. PMID 30953108.
^ Hue L, Rider MH (July 1987). “Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues”. The Biochemical Journal. 245 (2): 313–24. doi:10.1042/bj2450313. PMC 1148124. PMID 2822019.
^ Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ (1984). “The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism”. Current Topics in Cellular Regulation. 23: 57–86. doi:10.1016/b978-0-12-152823-2.50006-4. ISBN 9780121528232. PMID 6327193.
^ Feliú JE, Hue L, Hers HG (August 1976). “Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes”. Proceedings of the National Academy of Sciences of the United States of America. 73 (8): 2762–6. Bibcode:1976PNAS…73.2762F. doi:10.1073/pnas.73.8.2762. PMC 430732. PMID 183209.
^ Zhang, Xiao-Xi (2016). “Neuroendocrine Hormone Amylin in Diabetes”. World J Diabetes. 7 (9): 189–197. doi:10.4239/wjd.v7.i9.189. PMC 4856891. PMID 27162583.
^ Unger RH, Cherrington AD (January 2012). “Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover”. The Journal of Clinical Investigation. 122(1): 4–12. doi:10.1172/JCI60016. PMC 3248306. PMID 22214853.
^ Holst JJ, Holland W, Gromada J, Lee Y, Unger RH, Yan H, Sloop KW, Kieffer TJ, Damond N, Herrera PL (April 2017). “Insulin and Glucagon: Partners for Life”. Endocrinology. 158(4): 696–701. doi:10.1210/en.2016-1748. PMC 6061217. PMID 28323959.
^ Layden BT, Durai V, Lowe WL (2010). “G-Protein-Coupled Receptors, Pancreatic Islets, and Diabetes”. Nature Education. 3 (9): 13.
^ Skoglund G, Lundquist I, Ahrén B (November 1987). “Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse”. European Journal of Pharmacology. 143 (1): 83–8. doi:10.1016/0014-2999(87)90737-0. PMID 2891547.
^ Honey RN, Weir GC (October 1980). “Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas”. Endocrinology. 107 (4): 1065–8. doi:10.1210/endo-107-4-1065. PMID 6105951.
^ Zhang, Xiao-Xi (2016). “Neuroendocrine Hormone Amylin in Diabetes”. World J Diabetes. 7 (9): 189–197. doi:10.4239/wjd.v7.i9.189. PMC 4856891. PMID 27162583.
^ Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q (January 2006). “Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system”. Cell Metabolism. 3 (1): 47–58. doi:10.1016/j.cmet.2005.11.015. PMID 16399504.
^ Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W (February 2008). “A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription”. Molecular Pharmacology. 73 (2): 509–17. doi:10.1124/mol.107.035568. PMID 17962386. S2CID 10108970.
^ Johnson LR (2003). Essential Medical Physiology. Academic Press. pp. 643–. ISBN 978-0-12-387584-6.
^ Unger RH, Orci L (June 1981). “Glucagon and the A cell: physiology and pathophysiology (first two parts)”. The New England Journal of Medicine. 304 (25): 1518–24. doi:10.1056/NEJM198106183042504. PMID 7015132.
^ Orskov C, Holst JJ, Poulsen SS, Kirkegaard P (November 1987). “Pancreatic and intestinal processing of proglucagon in man”. Diabetologia. 30 (11): 874–81. doi:10.1007/BF00274797 (inactive 2020-10-11). PMID 3446554.
^ John AM, Schwartz RA (December 2016). “Glucagonoma syndrome: a review and update on treatment”. Journal of the European Academy of Dermatology and Venereology. 30 (12): 2016–2022. doi:10.1111/jdv.13752. PMID 27422767. S2CID 1228654.
^ Oberg K (December 2010). “Pancreatic endocrine tumors”. Seminars in Oncology. 37 (6): 594–618. doi:10.1053/j.seminoncol.2010.10.014. PMID 21167379.
^ Fasanmade OA, Odeniyi IA, Ogbera AO (June 2008). “Diabetic ketoacidosis: diagnosis and management”. African Journal of Medicine and Medical Sciences. 37 (2): 99–105. PMID 18939392.
^ Kimball C, Murlin J (1923). “Aqueous extracts of pancreas III. Some precipitation reactions of insulin”. J. Biol. Chem. 58 (1): 337–348.
^ Bromer W, Winn L, Behrens O (1957). “The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence”. J. Am. Chem. Soc. 79 (11): 2807–2810. doi:10.1021/ja01568a038.
^ “History of glucagon – Metabolism, insulin and other hormones – Diapedia, The Living Textbook of Diabetes”. http://www.diapedia.org. Archived from the original on 2017-03-27. Retrieved 2017-03-26.

External links

PDBe-KB provides an overview of all the structure information available in the PDB for Human Glucagon

GCG

Available structuresPDBHuman UniProt search: PDBe RCSB showList of PDB id codes
Identifiers
Aliases	GCG, GLP1, glucagon, GRPP, GLP-1, GLP2
External IDs	OMIM: 138030 HomoloGene: 136497 GeneCards: GCG
hideGene location (Human)Chr.Chromosome 2 (human)^[1]Band2q24.2Start162,142,882 bp^[1]End162,152,404 bp^[1]
hide RNA expression pattern More reference expression data
show Gene ontology
Orthologs
Species	Human	Mouse
Entrez	2641	n/a
Ensembl	ENSG00000115263	n/a
UniProt	P01275	n/a
RefSeq (mRNA)	NM_002054	n/a
RefSeq (protein)	NP_002045	n/a
Location (UCSC)	Chr 2: 162.14 – 162.15 Mb	n/a
PubMed search	^[2]	n/a
Wikidata
View/Edit Human

///////////GLUCAGON, DIABETES, PEPTIDE, HORMONE

Naxitamab

December 26, 2020 2:48 am / Leave a comment

(Heavy chain)
QVQLVESGPG VVQPGRSLRI SCAVSGFSVT NYGVHWVRQP PGKGLEWLGV IWAGGITNYN
SAFMSRLTIS KDNSKNTVYL QMNSLRAEDT AMYYCASRGG HYGYALDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(Light chain)
EIVMTQTPAT LSVSAGERVT ITCKASQSVS NDVTWYQQKP GQAPRLLIYS ASNRYSGVPA
RFSGSGYGTE FTFTISSVQS EDFAVYFCQQ DYSSFGQGTK LEIKRTVAAP SVFIFPPSDE
QLKSGTASVV CLLNNFYPRE AKVQWKVDNA LQSGNSQESV TEQDSKDSTY SLSSTLTLSK
ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C
(Disulfide bridge: H22-H95, H146-H202, H222-L211, H228-H’228, H231-H’231, H263-H323, H369-H427, H’22-H’95, H’146-H’202, H’222-L’211, H’263-H’323, H’369-H’427, L23-L88, L131-L191, L’23-L’88, L’131-L’191)

Naxitamab

ナキシタマブ;

Antineoplastic, Anti-GD2 antibody

Formula	C6414H9910N1718O1996S44
CAS	1879925-92-4
Mol weight	144434.4882

FDA APPROVED 2020/11/25, Danyelza

FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-naxitamab-high-risk-neuroblastoma-bone-or-bone-marrow

On November 25, 2020, the Food and Drug Administration granted accelerated approval to naxitamab (DANYELZA, Y-mAbs Therapeutics, Inc.) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for pediatric patients one year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.

Efficacy was evaluated in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm, open-label trials: Study 201 (NCT 03363373) and Study 12-230 (NCT 01757626). Patients with progressive disease following their most recent therapy were excluded. Patients received 3 mg/kg naxitamab administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m²/day on days -4 to 0 and at 500 µg/m²/day on days 1 to 5. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to non-target bony lesions or soft tissue disease in Study 12-230.

The main efficacy outcome measures were confirmed overall response rate (ORR) per the revised International Neuroblastoma Response Criteria (INRC) and duration of response (DOR). Among 22 patients treated in the multicenter Study 201, the ORR was 45% (95% CI: 24%, 68%) and 30% of responders had a DOR greater or equal to 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR greater or equal to 6 months. For both trials, responses were observed in either the bone, bone marrow or both.

The prescribing information contains a Boxed Warning stating that naxitamab can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). To mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.

The most common adverse reactions (incidence ≥25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.

The recommended naxitamab dose is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle, administered after dilution as an intravenous infusion in combination with GM-CSF, subcutaneously at 250 µg/m²/day on days -4 to 0 and at 500 µg/m²/day on days 1 to 5. Treatment cycles are repeated every 4 to 8 weeks.

View full prescribing information for DANYELZA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761171lbl.pdf

This review used the Real-Time Oncology Review (RTOR) pilot program and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

This application was granted priority review, breakthrough therapy, and orphan drug designation. A priority review voucher was issued for this rare pediatric disease product application. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

////////////Naxitamab, priority review, breakthrough therapy, orphan drug, FDA 2020, 2020 APPROVALS, Danyelza, MONOCLONAL ANTIBODY, PEPTIDE, ナキシタマブ,

Setmelanotide

December 14, 2020 3:34 am / 1 Comment on Setmelanotide

ChemSpider 2D Image | Setmelanotide | C49H68N18O9S2

Setmelanotide

Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2

Molecular FormulaC₄₉H₆₈N₁₈O₉S₂
Average mass1117.309 Da
N-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide (2->8)-disulfide

1,2-Dithia-5,8,11,14,17,20-hexaazacyclotricosane-4-carboxamide, 22-[[(2S)-2-(acetylamino)-5-[(diaminomethylene)amino]-1-oxopentyl]amino]-10-[3-[(diaminomethylene)amino]propyl]-16-(1H-imidazol-5-ylmeth yl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-13-(phenylmethyl)-, (4R,7S,10S,13R,16S,19R,22R)- [ACD/Index Name]10011920014-72-8[RN]Imcivree [Trade name]N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-Ltryptophyl- L-cysteinamide, cyclic (2-8)-disulfideN7T15V1FUYRM-493, BIM-22493UNII-N7T15V1FUYсетмеланотид [Russian] [INN]سيتميلانوتيد [Arabic] [INN]司美诺肽 [Chinese] [INN](4R,7S,10S,13R,16S,19R,22R)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide

FDA 11/25/2020, Imcivree, To treat obesity and the control of hunger associated with pro-opiomelanocortin deficiency, a rare disorder that causes severe obesity that begins at an early age
Drug Trials Snapshot, 10MG/ML, SOLUTION;SUBCUTANEOUS, Orphan

Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE™ (setmelanotide) as First-ever Therapy for Chronic Weight Management in Patients with Obesity Due to POMC, PCSK1 or LEPR Deficiency Nasdaq:RYTM

DESCRIPTION

IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist. Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide α-MSH (alpha-melanocyte stimulating hormone).

The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-Lhistidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide acetate. Its molecular formula is C₄₉H₆₈N₁₈O₉S₂ (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base).

The chemical structure of setmelanotide is:

IMCIVREE (setmelanotide) Structrual Formula Illustration

IMCIVREE injection is a sterile clear to slightly opalescent, colorless to slightly yellow solution. Each 1 mL of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3phosphoethanolamine sodium salt, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 11 mg mannitol, 5 mg phenol, 10 mg benzyl alcohol, 1 mg edetate disodium dihydrate, and Water for Injection. The pH of IMCIVREE is 5 to 6.

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor. Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects. Setmelanotide increases resting energy expenditure in both obese animals and humans. Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).

Setmelanotide, sold under the brand name Imcivree, is a medication for the treatment of obesity.^[1]

The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others.^[1] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment.^[1] Depression and suicidal ideation have also occurred with setmelanotide.^[1]

SYN

WO 2011060355

Medical uses

Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.^[1] Setmelanotide is the first FDA-approved treatment for these genetic conditions.^[1]

Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.^[1]

Setmelanotide binds to and activates MC₄ receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects.^[2] In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans.^[3] Importantly, unlike certain other MC₄ receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in heart rate or blood pressure.^[4]

Setmelanotide has been reported to possess the following activity profile (cAMP, EC₅₀): MC₄ (0.27 nM) > MC₃ (5.3 nM) ≈ MC₁ (5.8 nM) > MC₅ (1600 nM) ≟ MC₂ (>1000 nM).^[5] (19.6-fold selectivity for MC₄ over MC₃, the second target of highest activity.)

History

Setmelanotide was evaluated in two one-year studies.^[1] The first study enrolled participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older.^[1] The effectiveness of setmelanotide was determined by the number of participants who lost more than ten percent of their body weight after a year of treatment.^[1]

The effectiveness of setmelanotide was assessed in 21 participants, ten in the first study and eleven in the second.^[1] In the first study, 80 percent of participants with POMC or PCSK1 deficiency lost ten percent or more of their body weight.^[1] In the second study, 46 percent of participants with LEPR deficiency lost ten percent or more of their body weight.^[1]

The study also assessed the maximal (greatest) hunger in sixteen participants over the previous 24 hours using an eleven-point scale in participants twelve years and older.^[1] In both studies, some, but not all, of participants’ weekly average maximal hunger scores decreased substantially from their scores at the beginning of the study.^[1] The degree of change was highly variable among participants.^[1]

The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review.^[1] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.^[1]

Research

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC₄ receptor.^[6]^[4] Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes.^[6] In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC₄ receptor deficiency and associated symptoms such as excessive appetite and obesity.^[7] As of December 2014, the drug is in phase II clinical trials for obesity and PWS.^[6]^[8]^[9]^{[needs update]} So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.^[10]

PATENT

WO 2007008704

WO 2011060355

WO 2011060352

US 20120225816

PAPER

Journal of Medicinal Chemistry, 61(8), 3674-3684; 2018

PATENT

https://patents.google.com/patent/US9314509

Synthesis of Example 1i.e., Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂

The title peptide having the above structure was assembled using Fmoc chemistry on an Apex peptide synthesizer (Aapptec; Louisville, Ky., USA). 220 mg of 0.91 mmol/g (0.20 mmoles) Rink Amide MBHA resin (Polymer Laboratories; Amherst, Mass., USA) was placed in a reaction well and pre-swollen in 3.0 mL of DMF prior to synthesis. For cycle 1, the resin was treated with two 3-mL portions of 25% piperidine in DMF for 5 and 10 minutes respectively, followed by 4 washes of 3-mL DMF—each wash consisting of adding 3 mL of solvent, mixing for 1 minute, and emptying for 1 minute. Amino acids stocks were prepared in NMP as 0.45M solutions containing 0.45M HOBT. HBTU was prepared as a 0.45M solution in NMP and DIPEA was prepared as a 2.73M solution in NMP. To the resin, 2 mL of the first amino acid (0 9 mmoles, Fmoc-Cys(Trt)-OH) (Novabiochem; San Diego, Calif., USA) was added along with 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA. After one hour of constant mixing, the coupling reagents were drained from the resin and the coupling step was repeated. Following amino acid acylation, the resin was washed with two 3-mL aliquots of DMF for 1 minute. The process of assembling the peptide (deblock/wash/acylate/wash) was repeated for cycles 2-9 identical to that as described for cycle 1. The following amino acids were used: cycle 2) Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); cycle 3) Fmoc-Arg(Pbf)-OH (Novabiochem); cycle 4) Fmoc-DPhe-OH (Genzyme); cycle 5) Fmoc-His(Trt)-OH (Novabiochem); cycle 6) Fmoc-D-Ala-OH (Genzyme); cycle 7) Fmoc-Cys(Trt)-OH, (Novabiochem); and cycle 8) Fmoc-Arg(Pbf)-OH (Genzyme). The N-terminal Fmoc was removed with 25% piperidine in DMF as described above, followed by four 3-mL DMF washes for 1 minute. Acetylation of the N-terminus was performed by adding 0.5 mL of 3M DIPEA in NMP to the resin along with 1.45 mL of 0.45M acetic anhydride in NMP. The resin was mixed for 30 minutes and acetylation was repeated. The resin was washed with 3 mL of DMF for a total of 5 times followed with 5 washes with 5 mL of DCM each.

To cleave and deprotect the peptide, 5mL of the following reagent was added to the resin: 2% TIS/5% water/5% (w/v) DTT/88% TFA. The solution was allowed to mix for 3.5 hours. The filtrate was collected into 40 mL of cold anhydrous ethyl ether. The precipitate was pelleted for 10 minutes at 3500 rpm in a refrigerated centrifuge. The ether was decanted and the peptide was re-suspended in fresh ether. The ether workup was performed three times. Following the last ether wash, the peptide was allowed to air dry to remove residual ether.

The peptide was dissolved in 10% acetonitrile and analyzed by mass spectrometry and reverse-phase HPLC employing a 30×4.6 cm C18 column (Vydac; Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile (0.1% TFA) over 30 minutes. This analysis identified a product with ˜53% purity. Mass analysis employing electrospray ionization identified a main product containing a mass of 1118.4 corresponding to the desired linear product. The crude product (˜100 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid. To this solution, 0.5M iodine/methanol was added dropwise with vigorous stirring until a pale yellow color was achieved. The solution was vigorously stirred for another 10 minutes. Excess iodine was then quenched by adding 1.0M sodium thiosulfate under continuous mixing until the mixture was rendered colorless. The peptide was re-examined by mass spectrometry analysis and HPLC. Mass spectrometry analysis identified a main species with a mass of 1116.4 which indicated successful oxidation to form the cyclic peptide. The peptide solution was purified on a preparative HPLC equipped with a C18 column using a similar elution gradient. The purified product was re-analyzed by HPLC for purity (>95%) and mass spectrometry (1116.9 which is in agreement with the expected mass of 1117.3) and subsequently lyophilized. Following lyophilization, 28 mg of purified product was obtained representing a 24% yield.

The other exemplified peptides were synthesized substantially according to the procedure described for the above-described synthetic process. Physical data for select exemplified peptides are given in Table 1.

TABLE 1 Example Mol. Wt. Mol. Wt. Purity Number (calculated) (ES-MS) (HPLC) 1 1117.3 1116.9 95.1% 2 1117.3 1116.8 99.2% 3 1280.5 1280.6 98.0% 5 1216.37 1216.20 99.9%

Preparation of Pamoate Salt of Example 1

The acetate salt of Example 1 (200 mg, 0.18 mmole) was dissolved in 10 mL of water. Sodium pamoate (155 mg, 0.36 mmole) was dissolved in 10 mL of water. The two solutions were combined and mixed well. The precipitates were collected by centrifugation at 3000 rpm for 20 minutes, washed for three times with water, and dried by lyophilization.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r “FDA approves first treatment for weight management for people with certain rare genetic conditions”. U.S. Food and Drug Administration (FDA) (Press release). 27 November 2020. Retrieved 27 November 2020. This article incorporates text from this source, which is in the public domain.
^ Kim GW, Lin JE, Blomain ES, Waldman SA (January 2014). “Antiobesity pharmacotherapy: new drugs and emerging targets”. Clinical Pharmacology and Therapeutics. 95 (1): 53–66. doi:10.1038/clpt.2013.204. PMC 4054704. PMID 24105257.
^ Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. (April 2015). “RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals”. The Journal of Clinical Endocrinology and Metabolism. 100 (4): 1639–45. doi:10.1210/jc.2014-4024. PMC 4399297. PMID 25675384.
^ Jump up to:^a ^b Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. (February 2013). “Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques”. Diabetes. 62 (2): 490–7. doi:10.2337/db12-0598. PMC 3554387. PMID 23048186.
^ Muniyappa R, Chen K, Brychta R, Abel B, Mullins K, Staker P, et al. (June 2014). “A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of a Melanocortin Receptor 4 (MC4R) Agonist, RM-493, on Resting Energy Expenditure (REE) in Obese Subjects” (PDF). Endocrine Reviews. Rhythm Pharmaceuticals. 35 (3). Retrieved 2015-05-21.
^ Jump up to:^a ^b ^c Lee EC, Carpino PA (2015). “Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)”. Pharmaceutical Patent Analyst. 4 (2): 95–107. doi:10.4155/ppa.15.1. PMID 25853469.
^ “Obesity and Diabetes Caused by Genetic Deficiencies in the MC4 Pathway”. Rhythm Pharmaceuticals. Retrieved 2015-05-21.
^ Jackson VM, Price DA, Carpino PA (August 2014). “Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies”. Expert Opinion on Investigational Drugs. 23 (8): 1055–66. doi:10.1517/13543784.2014.918952. PMID 25000213. S2CID 23198484.
^ “RM-493: A First-in-Class, Phase 2-Ready MC4 Agonist: A New Drug Class for the Treatment of Obesity and Diabetes”. Rhythm Pharmaceuticals. Archived from the original on 2015-06-14. Retrieved 2015-05-21.
^ Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, et al. (March 2019). “A multidisciplinary approach to the clinical management of Prader-Willi syndrome”. Molecular Genetics & Genomic Medicine. 7 (3): e514. doi:10.1002/mgg3.514. PMC 6418440. PMID 30697974.

ADDITIONAL INFORMATION

The peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It is being researched by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II clinical trials for obesity and PWS.

L-Cysteinamide, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-, cyclic (2->8)-disulfide
Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2

REFERENCES

1: Lee EC, Carpino PA. Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014). Pharm Pat Anal. 2015;4(2):95-107. doi: 10.4155/ppa.15.1. PubMed PMID: 25853469.

2: Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, Zhao X, Ring M, Psota TL, Cone RD, Panaro BL, Gottesdiener KM, Van der Ploeg LH, Reitman ML, Skarulis MC. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45. doi: 10.1210/jc.2014-4024. Epub 2015 Feb 12. PubMed PMID: 25675384; PubMed Central PMCID: PMC4399297.

3: Clemmensen C, Finan B, Fischer K, Tom RZ, Legutko B, Sehrer L, Heine D, Grassl N, Meyer CW, Henderson B, Hofmann SM, Tschöp MH, Van der Ploeg LH, Müller TD. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med. 2015 Feb 4;7(3):288-98. doi: 10.15252/emmm.201404508. PubMed PMID: 25652173; PubMed Central PMCID: PMC4364946.

4: Jackson VM, Price DA, Carpino PA. Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies. Expert Opin Investig Drugs. 2014 Aug;23(8):1055-66. doi: 10.1517/13543784.2014.918952. Epub 2014 Jul 7. Review. PubMed PMID: 25000213.

5: Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013 Feb;62(2):490-7. doi: 10.2337/db12-0598. Epub 2012 Oct 9. PubMed PMID: 23048186; PubMed Central PMCID: PMC3554387.

6: Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900. doi: 10.1016/j.peptides.2009.07.012. Epub 2009 Jul 29. PubMed PMID: 19646498; PubMed Central PMCID: PMC2755620.

External links

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

Clinical data

Trade names	Imcivree
Other names	RM-493; BIM-22493; IRC-022493; N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide
ATC code	None
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name [show]
CAS Number	920014-72-8
PubChem CID	11993702
ChemSpider	10166169
UNII	N7T15V1FUY
KEGG	D11927
Chemical and physical data
Formula	C₄₉H₆₈N₁₈O₉S₂
Molar mass	1117.32 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide]C[C@@H]1C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N)Cc2c[nH]c3c2cccc3)CCCN=C(N)N)Cc4ccccc4)Cc5cnc[nH]5
InChI [hide]InChI=1S/C49H68N18O9S2/c1-26-41(70)63-37(20-30-22-55-25-59-30)46(75)64-35(18-28-10-4-3-5-11-28)44(73)62-34(15-9-17-57-49(53)54)43(72)65-36(19-29-21-58-32-13-7-6-12-31(29)32)45(74)66-38(40(50)69)23-77-78-24-39(47(76)60-26)67-42(71)33(61-27(2)68)14-8-16-56-48(51)52/h3-7,10-13,21-22,25-26,33-39,58H,8-9,14-20,23-24H2,1-2H3,(H2,50,69)(H,55,59)(H,60,76)(H,61,68)(H,62,73)(H,63,70)(H,64,75)(H,65,72)(H,66,74)(H,67,71)(H4,51,52,56)(H4,53,54,57)/t26-,33+,34+,35-,36+,37+,38+,39+/m1/s1Key:HDHDTKMUACZDAA-PHNIDTBTSA-N

///////////Setmelanotide, FDA 2020, 2020 APPROVALS, Imcivree, Orphan, PEPTIDE, ANTIOBESITY, UNII-N7T15V1FUY, сетмеланотид , سيتميلانوتيد , 司美诺肽 , BIM 22493, RM 493

CC1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)N1)NC(=O)C(CCCN=C(N)N)NC(=O)C)C(=O)N)CC2=CNC3=CC=CC=C32)CCCN=C(N)N)CC4=CC=CC=C4)CC5=CN=CN5

Isatuximab

December 13, 2020 5:10 am / Leave a comment

(A chain)
QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY
AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(B chain)
QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGT IYPGDGDTGY
AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD YYGSNSLDYW GQGTSVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(C chain)
DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD
RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(D chain)
DIVMTQSHLS MSTSLGDPVS ITCKASQDVS TVVAWYQQKP GQSPRRLIYS ASYRYIGVPD
RFTGSGAGTD FTFTISSVQA EDLAVYYCQQ HYSPPYTFGG GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: A22-A96, A147-A203, A223-C214, A229-B229, A232-B232, A264-A324, A370-A428, B22-B96, B147-B203, B223-D214, B264-B324, B370-B428, C23-C88, C134-C194, D23-D88, D134-D194)

Isatuximab

イサツキシマブ (遺伝子組換え)

APPROVED USFDA 2020/3/2, Sarclisa

EU APPROVED 2020/5/30

JAPAN APPROVED 2020/6/29

CAS 1461640-62-9

Antineoplastic, Anti-CD38 antibody
Disease	Multiple myeloma

SARCLISA (sanof-aventis U.S. LLC)

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.^[4]^[3]

The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion reactions, pneumonia (infection of the lungs), upper respiratory tract infection (such as nose and throat infections), diarrhoea and bronchitis (inflammation of the airways in the lungs).^[3]

Isatuximab is an anti-CD38 mAb intended to treat relapsed or refractory multiple myeloma.^[5] It entered in Phase II trials for multiple myeloma^[6] and T-cell leukemia in 2015.^[7]

Medical uses

In the United States it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.^[8]^[9]^[10]

In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI) and have demonstrated disease progression on the last therapy.^[3]

History

It was granted orphan drug designation for multiple myeloma by the European Medicines Agency (EMA) in April 2014, and by the U.S. Food and Drug Administration (FDA) in December 2016.^[3]^[11]

Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM). The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.^[12]

Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.^[13]

A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with an estimated completion date of 2021.^{[medical citation needed]}

Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant (IMROZ trial). The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines (IKEMA). There is currently^[when?] no treatment for MM, however promising improvements have been made and the study is still ongoing.^[14]^[15]

In March 2020, it was approved for medical use in the United States.^[8]^[9]^[10]

The U.S. Food and Drug Administration (FDA) approved isatuximab-irfc in March 2020, based on evidence from a clinical trial (NCT02990338) of 307 subjects with previously treated multiple myeloma.^[10] The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.^[10]

The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma.^[10] Subjects were randomly assigned to receive either isatuximab-irfc (in combination with pomalidomide and low-dose dexamethasone) or active comparator (pomalidomide and low-dose dexamethasone).^[10] Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity.^[10] Both subjects and health care providers knew which treatment was given.^[10] The trial measured the time patients lived without the cancer growing (progression-free survival or PFS).^[10]

It was approved for medical use in the European Union in May 2020.^[3]

Structure and reactivity

The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking.^[16] Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.^[17]

Reactions

Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly.^[18] Isatuximab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab.^[19] The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.^{[medical citation needed]}

The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species.^[20]

Available forms

Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL (20 mg/mL) solution in single-dose vial or 500 mg/25 mL (20 mg/mL) solution in single-dose vial.^[4]

Mechanism of action

Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment.^[21] CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.^[22]

Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells (as well as other tumor cells). This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). Isatuximab-irfc is able to stimulate natural killer (NK) cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells.^[4] Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope.^[23] According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model.^[4]

Metabolism and toxicity

Metabolism

Isatuximab-irfc is likely to be metabolized through catabolic pathways into smaller peptides. When isatuximab is at a constant state it is expected that the ≥99% elimination will occur approximately two months after the last dose was administered. The clearance percentage diminished when the dosages were increased over time, as well as when multiple doses were administered. However, the elimination of isatuximab-irfc did not differ when applied as a single agent or as a combination therapy.^[4]

Toxicity

A dose-limiting toxicity (DLT) has characterized been characterized as the development of any of the following: grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia or grade 4 thrombocytopenia lasting more than 5 days; grade ≥ 2 allergic reactions or hypersensitivity (i.e., infusion reactions); or any other toxicity considered to be dose-limiting by the investigators or sponsor. Grade ≤ 2 infusion reactions were excluded from the DLT definition, because, with suitable care, patients that suffered a grade 2 infusion reaction prior to completion of the infusion were able to finalize isatuximab administration.^[23]

There is no recommended reduced dose of isatuximab-irfc. In the eventuality of hematological toxicity it may be necessary to delay administration so that the blood count may be recovered.^[4] Although there is no counteracting agent for isatuximab, clinical experience with overdoses is seemingly nonexistent as well. Overdose symptoms will probably be in line with the side effects attached to isatuximab. Therefore, infusion reactions, gastrointestinal disturbances and an elevated risk of infections may occur. It is necessary to carefully monitor the patient in case of an overdose and to employ clinically indicated symptomatic and supportive procedures.^[21]

No studies have been conducted with isatuximab concerning carcinogenicity, genotoxicity or fertility.^[4]

Pregnancy

When given to pregnant women isatuximab-irfc can cause fetal injury, due to the mechanism of action. It can precipitate depletion of immune cells as well as decreased bone density in the fetus. Pregnant women are therefore notified of the potential risks to a fetus, and women that are able to reproduce are advised to use effective contraceptives during treatment and at least five months subsequent to the last dose of isatuximab-irfc.

Furthermore, it is not recommended to combine isatuximab-irfc with pomalidomide in women that are carrying a child, because pomalidomide may cause birth defects and death of the unborn child.^[4]

Indications

Isatuximab is indicated as a CD38-directed cytolytic antibody. By inhibiting the enzymatic activity of CD38.

The binding of isatuximab to CD38 on multiple myeloma (MM) cells leads to a trigger to several mechanisms leading to direct apoptosis of target cancer cells. The triggered pathways are the caspase-dependent apoptotic and the lysosome-mediated cell death pathway in MM cells.^[24]

It is used in a combination with dexamethasone and pomalidomide. The drug is thus to treat patients with multiple myeloma. Restrictions for the use of isatuximab is that the patients have to be adults who have at least received two previous treatments with lenalidomide and a proteasome inhibitor.^[4]

Isatuximab is currently^[when?] also being tested in a Phase II trial as a monotherapy against refractory/recurrent systemic light-chain amyloidosis.^[24]

Efficacy and side effects

Efficacy

A Phase III study of patients with refractory and relapsed MM, who were resistant to lenalidomide and a proteasome inhibitor, and could not have received daratumumab, another anti-CD38 monoclonal antibody was published in 2019 (ICARIA-MM). The addition of isatuximab to pomalidomide and dexamethasone improved progression free survival to 11.5 months compared to 6.5 months, with an overall response rate of 63%.^[25]

Side effects

Adverse reactions to isatuximab-irfc may include neutropenia, infusion-related reactions and/or secondary primary malignancies.^[4] Of these three the most commonly occurring ones are the infusion-related reactions.^[24] Examples of the most frequent symptoms of infusion-related reactions are dyspnea, cough, chills, and nausea, while the severest signs and symptoms included hypertension and dyspnea.^[4]

Effects on animals

The activity of isatuximab has been researched in mouse tumor models. It has been proven that isatuximab leads to antitumor activity in MM cells. Furthermore, the combination of isatuximab and pomalidomide will lead to an extra enhanced antitumor activity in MM cells. Thus, pomalidomide in vivo and in vitro leads to an increase of the activity of isatuximab.^[24]

Animal studies in reproduction toxicity have not yet been carried out. So, the risks of birth defects and miscarriage risks are unknown.^[4]

Names

Isatuximab is the United States Adopted Name (USAN).^[26]

It was developed by ImmunoGen and Sanofi-Aventis with the development name SAR-650984.

References

^ Jump up to:^a ^b “Sarclisa Australian prescription medicine decision summary”. Therapeutic Goods Administration (TGA). 14 May 2020. Retrieved 16 August 2020.
^ “Isatuximab (Sarclisa) Use During Pregnancy”. Drugs.com. 25 March 2020. Retrieved 25 June 2020.
^ Jump up to:^a ^b ^c ^d ^e ^f “Sarclisa EPAR”. European Medicines Agency (EMA). 24 March 2020. Retrieved 25 June 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l “Sarclisa- isatuximab injection, solution, concentrate”. DailyMed. 2 March 2020. Retrieved 26 March 2020.
^ ImmunoGen, Inc. Announces Data Presentations at Upcoming 57th ASH Annual Meeting and Exposition
^ Martin T (2015). “A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma”. Blood. 126 (23): 509. doi:10.1182/blood.V126.23.509.509.
^ “Safety and Efficacy of Isatuximab in Lymphoblastic Leukemia”. ClinicalTrials.gov. Retrieved 4 March 2020.
^ Jump up to:^a ^b “FDA approves isatuximab-irfc for multiple myeloma”. U.S. Food and Drug Administration (FDA). 2 March 2020. Retrieved 2 March 2020. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b “FDA Approves New Therapy for Patients with Previously Treated Multiple Myeloma”. U.S. Food and Drug Administration (FDA) (Press release). 2 March 2020. Retrieved 4 March 2020. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Drug Trials Snapshots: Sarclisa”. U.S. Food and Drug Administration(FDA). 2 March 2020. Retrieved 25 March 2020. This article incorporates text from this source, which is in the public domain.
^ “Isatuximab Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 4 March 2020.
^ Mikhael J, Richardson P, Usmani SZ, Raje N, Bensinger W, Karanes C, et al. (July 2019). “A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma”. Blood. 134 (2): 123–133. doi:10.1182/blood-2019-02-895193. PMC 6659612. PMID 30862646.
^ Martin T (7 December 2015). “A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma”. ASH.
^ Orlowski RZ, Goldschmidt H, Cavo M, Martin TG, Paux G, Oprea C, Facon T (20 May 2018). “Phase III (IMROZ) study design: Isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM)”. Journal of Clinical Oncology. 36 (15_suppl): TPS8055. doi:10.1200/JCO.2018.36.15_suppl.TPS8055.
^ Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, Martin T (January 2020). “Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design”. Future Oncology. 16 (2): 4347–4358. doi:10.2217/fon-2019-0431. PMID 31833394.
^ Rajan AM, Kumar S (July 2016). “New investigational drugs with single-agent activity in multiple myeloma”. Blood Cancer Journal. 6 (7): e451. doi:10.1038/bcj.2016.53. PMC 5030378. PMID 27471867.
^ Martin T, Baz R, Benson DM, Lendvai N, Wolf J, Munster P, et al. (June 2017). “A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma”. Blood. 129 (25): 3294–3303. doi:10.1182/blood-2016-09-740787. PMC 5482100. PMID 28483761.
^ Martin TG, Corzo K, Chiron M (2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
^ Dhillon S (2020). “Isatuximab: First Approval”. Drugs. 80 (9): 905–912. doi:10.1007/s40265-020-01311-1. PMID 32347476. S2CID 216597315.
^ Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
^ Jump up to:^a ^b “Isatuximab”. Drugbank. 20 May 2019.
^ Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F (28 November 2018). “CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma”. Frontiers in Immunology. 9: 2722. doi:10.3389/fimmu.2018.02722. PMC 6279879. PMID 30546360.
^ Jump up to:^a ^b Martin T, Strickland S, Glenn M, Charpentier E, Guillemin H, Hsu K, Mikhael J (March 2019). “Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma”. Blood Cancer Journal. 9 (4): 41. doi:10.1038/s41408-019-0198-4. PMC 6440961. PMID 30926770.
^ Jump up to:^a ^b ^c ^d Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). “Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab”. Cells. 8 (12): 1522. doi:10.3390/cells8121522. PMC 6953105. PMID 31779273.
^ Attal, Michel; Richardson, Paul G; Rajkumar, S Vincent; San-Miguel, Jesus; Beksac, Meral; Spicka, Ivan; Leleu, Xavier; Schjesvold, Fredrik; Moreau, Philippe; Dimopoulos, Meletios A; Huang, Jeffrey Shang-Yi (2019). “Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study”. The Lancet. 394 (10214): 2096–2107. doi:10.1016/s0140-6736(19)32556-5. ISSN 0140-6736. PMID 31735560. S2CID 208049235.
^ Statement On A Nonproprietary Name Adopted By The USAN Council – Isatuximab, American Medical Association

External links

“Isatuximab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02990338 for “Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients (ICARIA-MM)” at ClinicalTrials.gov

Monoclonal antibody
Isatuximab (pale blue) binding CD38 (purple). PDB: 4CMH
Type	Whole antibody
Source	Chimeric (mouse/human)
Target	CD38
Clinical data
Trade names	Sarclisa
Other names	SAR-650984, isatuximab-irfc
AHFS/Drugs.com	Monograph
MedlinePlus	a620023
License data	US DailyMed: Sarclisa
Pregnancy category	AU: C^[1]US: N (Not classified yet)^[2]
Routes of administration	Intravenous
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	AU: S4 (Prescription only) ^[1]US: ℞-onlyEU: Rx-only ^[3]
Identifiers
CAS Number	1461640-62-9
DrugBank	DB14811
ChemSpider	none
UNII	R30772KCU0
KEGG	D11050
Chemical and physical data
Formula	C₆₄₅₆H₉₉₃₂N₁₇₀₀O₂₀₂₆S₄₄
Molar mass	145190.99 g·mol⁻¹

////////Isatuximab, Sarclisa, 2020APPROVALS, JAPAN 2020, US 2020, EU 2020, PEPTIDE, SANOFI , イサツキシマブ (遺伝子組換え) ,

Bulevirtide acetate

September 26, 2020 2:24 am / Leave a comment

Bulevirtide acetate

(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.

molecular formula C248H355N65O72,

molecular mass is 5398.9 g/mol

ブレビルチド酢酸塩;

APROVED 2020/7/31, EU, Hepcludex

MYR GmbH

Antiviral, Entry inhibitor
Disease	Hepatitis delta virus infection

Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol

Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.

Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.

The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.

https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdf

Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.

HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.

HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.

Hepcludex contains the active substance bulevirtide.

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).^[2]

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.^[2]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.^[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.^[2]

Bulevirtide was approved for medical use in the European Union in July 2020.^[2]

Medical uses

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.^[2]^[3]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.^[4]

The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1^[5]^[6] that can also dock to NTCP, blocking the virus’s entry mechanism.^[7]

The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.^[7]

References

^ Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews. 21 (3): 126–134. doi:10.24875/AIDSRev.19000080. PMID 31532397.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Hepcludex EPAR”. European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Summary of opinion: Hepcludex” (PDF). European Medicines Agency. 28 May 2020.
^ Francisco, Estela Miranda (29 May 2020). “Hepcludex”. European Medicines Agency. Retrieved 6 August 2020.
^ Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology. 58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008. PMID 23246506.
^ Abbas Z, Abbas M (August 2015). “Management of hepatitis delta: Need for novel therapeutic options”. World Journal of Gastroenterology. 21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461. PMC 4548107. PMID 26327754.
^ Jump up to:^a ^b Spreitzer H (14 September 2015). “Neue Wirkstoffe – Myrcludex B”. Österreichische Apothekerzeitung (in German) (19/2015): 12.

External links

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

Bulevirtide
Clinical data
Trade names	Hepcludex
Other names	MyrB, Myrcludex-B^[1]
License data	EU EMA: by INN
Routes of administration	Subcutaneous injection
ATC code	None
Legal status
Legal status	EU: Rx-only ^[2]
Identifiers
CAS Number	2012558-47-1
DrugBank	DB15248
UNII	WKM56H3TLB
KEGG	D11877
ChEMBL	ChEMBL4297711

/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS

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Fact Sheet – US Food and Drug Administration

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Protein Sequence

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Protein Sequence

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Function

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