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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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BQ-788


BQ-788.svg

ChemSpider 2D Image | BQ-788 | C34H50N5NaO7

Image result for bq-788

Image result for bq-788

BQ-788

  • Molecular FormulaC34H50N5NaO7
  • Average mass663.780 Da

SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022

FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm

CAS 156161-89-6 [RN]
CAS 173326-37-9 FREE ACID
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle
BQ 788 sodium salt
BQ788
D-Norleucine, N-(((2R,6S)-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-((cis-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-[[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, sodium salt (1:1)
MFCD00797882
N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt
 
Sodium N-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ-788 is a selective ETB antagonist.[1]

presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.

Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,

SYN

By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005

CONTD…………

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo00130a028

N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:

HPLC £r = 16.4 (gradient A, > 99%);

NMR (400 MHz, DMSO-d6) ó 0.80 (s, 9H), 0.74-0.85 (m, 3H), 1.00 (d, 3H), 1.02 (d, 3H), 1.10-1.25 (m, 6H), 1.30-1.55 (m, 6H), 1.60-1.75 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H), 3.78 (m, 1H), 3.95 (s, 3H), 4.08 (m, 1H), 4.13 (m, 1H), 4.29 (m, 1H), 4.50 (m, 1H), 5.98 (d, 1H), 7.22 (t, 1H), 7.32 (t, 1H), 7.50 (s, 1H), 7.58 (br d, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.15 (br d, 1H) ESMS m/z 640.6 (M).

PATENT

WO-2019140324

Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019140324&tab=PCTDESCRIPTION&_cid=P22-JYJK98-13819-1

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0196978105001415

Image result for bq-788

PAPER

By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6

Journal of medicinal chemistry (1996), 39(12), 2313-30.

References

  1. ^ Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews20 (1): 53–66. PMID 12070534.
BQ-788
BQ-788.svg
Names
Systematic IUPAC name

Sodium N-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C34H50N5NaO7
Molar mass 663.792 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////BQ-788, BQ 788, BQ788, ETBR antagonist, cancers,  brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma, squamous cell carcinoma, PEPTIDE

CCCC[C@H](C(=O)O)NC(=O)[C@@H](Cc1cn(c2c1cccc2)C(=O)OC)NC(=O)[C@H](CC(C)(C)C)NC(=O)N3[C@@H](CCC[C@@H]3C)C

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Caplacizumab-yhdp, カプラシズマブ


FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ  , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

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

The FDA granted the approval of Cablivi to Ablynx.

 EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
FORMULA
C1213H1891N357O380S10
CAS
915810-67-2
MOL WEIGHT
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. [6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).39Peyvandi FScully MKremer Hovinga JACataland SKnöbl PWu HArtoni AWestwood JPMansouri Taleghani MJilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):51122; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref][PubMed][Web of Science ®][Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

///////////////caplacizumab, Cablivi,  Ablynx, Priority Review, Orphan Drug designation,  fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Elapegademase, エラペグアデマーゼ (遺伝子組換え)


AQTPAFNKPK VELHVHLDGA IKPETILYYG RKRGIALPAD TPEELQNIIG MDKPLSLPEF
LAKFDYYMPA IAGSREAVKR IAYEFVEMKA KDGVVYVEVR YSPHLLANSK VEPIPWNQAE
GDLTPDEVVS LVNQGLQEGE RDFGVKVRSI LCCMRHQPSW SSEVVELCKK YREQTVVAID
LAGDETIEGS SLFPGHVKAY AEAVKSGVHR TVHAGEVGSA NVVKEAVDTL KTERLGHGYH
TLEDTTLYNR LRQENMHFEV CPWSSYLTGA WKPDTEHPVV RFKNDQVNYS LNTDDPLIFK
STLDTDYQMT KNEMGFTEEE FKRLNINAAK SSFLPEDEKK ELLDLLYKAY GMPSPA

str1

>>Elapegademase<<<
AQTPAFNKPKVELHVHLDGAIKPETILYYGRKRGIALPADTPEELQNIIGMDKPLSLPEF
LAKFDYYMPAIAGSREAVKRIAYEFVEMKAKDGVVYVEVRYSPHLLANSKVEPIPWNQAE
GDLTPDEVVSLVNQGLQEGERDFGVKVRSILCCMRHQPSWSSEVVELCKKYREQTVVAID
LAGDETIEGSSLFPGHVKAYAEAVKSGVHRTVHAGEVGSANVVKEAVDTLKTERLGHGYH
TLEDTTLYNRLRQENMHFEVCPWSSYLTGAWKPDTEHPVVRFKNDQVNYSLNTDDPLIFK
STLDTDYQMTKNEMGFTEEEFKRLNINAAKSSFLPEDEKKELLDLLYKAYGMPSPA

ChemSpider 2D Image | ELAPEGADEMASE | C10H20N2O5

Elapegademase, エラペグアデマーゼ (遺伝子組換え)

EZN-2279

Protein chemical formula C1797H2795N477O544S12

Protein average weight 115000.0 Da

Peptide

APPROVED, FDA, Revcovi, 2018/10/5

CAS: 1709806-75-6

Elapegademase-lvlr, Poly(oxy-1,2-ethanediyl), alpha-carboxy-omega-methoxy-, amide with adenosine deaminase (synthetic)

L-Lysine, N6-[(2-methoxyethoxy)carbonyl]-
N6-[(2-Methoxyethoxy)carbonyl]-L-lysine

EZN-2279; PEG-rADA; Pegademase recombinant – Leadiant Biosciences; Pegylated recombinant adenosine deaminase; Polyethylene glycol recombinant adenosine deaminase; STM-279, UNII: 9R3D3Y0UHS

  • Originator Sigma-Tau Pharmaceuticals
  • Developer Leadiant Biosciences; Teijin Pharma
  • Class Antivirals; Polyethylene glycols
  • Mechanism of Action Adenosine deaminase stimulants
  • Orphan Drug Status Yes – Immunodeficiency disorders; Adenosine deaminase deficiency
  • Registered Adenosine deaminase deficiency; Immunodeficiency disorders
  • 05 Oct 2018 Registered for Adenosine deaminase deficiency (In adults, In children) in USA (IM)
  • 05 Oct 2018 Registered for Immunodeficiency disorders (In adults, In children) in USA (IM)
  • 04 Oct 2018 Elapegademase receives priority review status for Immunodeficiency disorders and Adenosine deaminase deficiency in USA

検索キーワード:Elapegademase (Genetical Recombination)
検索件数:1


エラペグアデマーゼ(遺伝子組換え)
Elapegademase (Genetical Recombination)

[1709806-75-6]

Elapegademase is a PEGylated recombinant adenosine deaminase. It can be defined molecularly as a genetically modified bovine adenosine deaminase with a modification in cysteine 74 for serine and with about 13 methoxy polyethylene glycol chains bound via carbonyl group in alanine and lysine residues.[4] Elapegademase is generated in E. coli, developed by Leadiant Biosciences and FDA approved on October 5, 2018.[15]

Indication

Elapegademase is approved for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.[1] This condition was previously treated by the use of pegamedase bovine as part of an enzyme replacement therapy.[2]

ADA-SCID is a genetically inherited disorder that is very rare and characterized by a deficiency in the adenosine deaminase enzyme. The patients suffering from this disease often present a compromised immune system. This condition is characterized by very low levels of white blood cells and immunoglobulin levels which results in severe and recurring infections.[3]

Pharmacodynamics

In clinical trials, elapegademase was shown to increase adenosine deaminase activity while reducing the concentrations of toxic metabolites which are the hallmark of ADA-SCID. As well, it was shown to improve the total lymphocyte count.[6]

Mechanism of action

The ADA-SCID is caused by the presence of mutations in the ADA gene which is responsible for the synthesis of adenosine deaminase. This enzyme is found throughout the body but it is mainly active in lymphocytes. The normal function of adenosine deaminase is to eliminate deoxyadenosine, created when DNA is degraded, by converting it into deoxyinosine. This degradation process is very important as deoxyadenosine is cytotoxic, especially for lymphocytes. Immature lymphocytes are particularly vulnerable as deoxyadenosine kills them before maturation making them unable to produce their immune function.[3]

Therefore, based on the causes of ADA-SCID, elapegademase works by supplementing the levels of adenosine deaminase. Being a recombinant and an E. coli-produced molecule, the use of this drug eliminates the need to source the enzyme from animals, as it was used previously.[1]

Absorption

Elapegademase is administered intramuscularly and the reported Tmax, Cmax and AUC are approximately 60 hours, 240 mmol.h/L and 33000 hr.mmol/L as reported during a week.[Label]

Volume of distribution

This pharmacokinetic property has not been fully studied.

Protein binding

This pharmacokinetic property is not significant as the main effect is in the blood cells.

Metabolism

Metabolism studies have not been performed but it is thought to be degraded by proteases to small peptides and individual amino acids.

Route of elimination

This pharmacokinetic property has not been fully studied.

Half life

This pharmacokinetic property has not been fully studied.

Clearance

This pharmacokinetic property has not been fully studied.

Toxicity

As elapegademase is a therapeutic protein, there is a potential risk of immunogenicity.

There are no studies related to overdose but the highest weekly prescribed dose in clinical trials was 0.4 mg/kg. In nonclinical studies, a dosage of 1.8 fold of the clinical dose produced a slight increase in the activated partial thromboplastin time.[Label]

FDA label. Download (145 KB)

General References

  1. Rare DR [Link]
  2. Globe News Wire [Link]
  3. NIH [Link]
  4. NIHS reports [File]
  5. WHO Drug Information 2017 [File]
  6. Revcovi information [File]

/////////////Elapegademase, Peptide, エラペグアデマーゼ (遺伝子組換え) , EZN-2279, Elapegademase-lvlr, Orphan Drug, STM 279, FDA 2018

COCCOC(=O)NCCCC[C@H](N)C(=O)O

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

 

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ANTHONY MELVIN CRASTO

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

 

Calaspargase pegol, カラスパルガーゼペゴル


LPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG EQVVNIGSQD
MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD LTVKCDKPVV MVGAMRPSTS
MSADGPFNLY NAVVTAADKA SANRGVLVVM NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG
YIHNGKIDYQ RTPARKHTSD TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV
SAGVGNGNLY KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ
KARVLLQLAL TQTKDPQQIQ QIFNQY
(tetramer; disulfide bridge 77-105, 77′-105′, 77”-105”, 77”’-105”’)

Image result for Calaspargase pegol

str3

Calaspargase pegol

Molecular Formula, C1516-H2423-N415-O492-S8 (peptide monomer), Molecular Weight, 10261.2163

APPROVED, Asparlas, FDA 2018/12/20

CAS 941577-06-6

UNII T9FVH03HMZ

カラスパルガーゼペゴル;

(27-Alanine,64-aspartic acid,252-threonine,263-asparagine)-L-asparaginase 2 (EC 3.5.1.1, L-asparagineamidohydrolase II) Escherichia coli (strain K12) tetramer alpha4, carbamates with alpha-carboxy-omega-methoxypoly(oxyethylene)

Asparaginase (Escherichia coli isoenzyme II), conjugate with alpha-(((2,5-dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)

List Acronyms
Peptide
  • Calaspargase pegol
  • calaspargase pegol-mknl
  • EZN-2285
  • Used to treat acute lymphoblastic leukemia., Antineoplastic
  • BAX-2303
    SC-PEG E. Coli L-asparaginase
    SHP-663

Calaspargase pegol-mknl (trade name Asparlas) is a drug for the treatment of acute lymphoblastic leukemia (ALL). It is approved by the Food and Drug Administration for use in the United States as a component of a multi-agent chemotherapeutic regimen for ALL in pediatric and young adult patients aged 1 month to 21 years.[1]

Calaspargase pegol was first approved in 2018 in the U.S. as part of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.

In 2008, orphan drug designation was assigned in the E.U.

Calaspargase pegol is an engineered protein consisting of the E. coli-derived enzyme L-asparaginase II conjugated with succinimidyl carbonate monomethoxypolyethylene glycol (pegol).[2] The L-asparaginase portion hydrolyzes L-asparagine to L-aspartic acid depriving the tumor cell of the L-asparagine it needs for survival.[2] The conjugation with the pegol group increases the half-life of the drug making it longer acting.

Asparaginase is an important agent used to treat acute lymphoblastic leukemia (ALL) [1]. Asparagine is incorporated into most proteins, and the synthesis of proteins is stopped when asparagine is absent, which inhibits RNA and DNA synthesis, resulting in a halt in cellular proliferation. This forms the basis of asparaginase treatment in ALL [1][2][6].

Calaspargase pegol, also known as asparlas, is an asparagine specific enzyme which is indicated as a part of a multi-agent chemotherapy regimen for the treatment of ALL [3]. The asparagine specific enzyme is derived from Escherichia coli, as a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker to create a stable molecule which increases the half-life and decreases the dosing frequency [Label][1].

Calaspargase pegol, by Shire pharmaceuticals, was approved by the FDA on December 20, 2018 for acute lymphoblastic anemia (ALL) [3].

Indication

This drug is is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years [Label].

The pharmacokinetics of calaspargase pegol were examined when given in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL [3]. The FDA approval of this drug was based on the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when administering calaspargase, 2500 U/m2 intravenously, at 3-week intervals.

Associated Conditions

Pharmacodynamics

The effect of this drug is believed to occur by selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase are less capable of producing L-asparagine, and therefore rely on exogenous L-asparagine for survival [Label]. When asparagine is depleted, tumor cells cannot proliferate [6].

During remission induction, one dose of SC-PEG (2500 IU/m2) results in a sustained therapeutic serum asparaginase activity (SAA) without excessive toxicity or marked differences in the proportion of patients with low end-induction minimum residual disease (MRD) [5].

Pharmacodynamic (PD) response was studied through measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations with an LC-MS/MS assay (liquid chromatography–mass spectrometry). Asparagine concentration in plasma was sustained below the assay limit of quantification for more than 18 days after one dose of calaspargase pegol, 2,500 U/m2, during the induction phase of treatment. Average cerebrospinal asparagine concentrations decreased from a pretreatment concentration of 0.8 μg/mL (N=10) to 0.2 μg/mL on Day 4 (N=37) and stayed decreased at 0.2 μg/mL (N=35) 25 days after the administration of one of 2,500 U/m2 in the induction phase [Label].

Mechanism of action

L-asparaginase (the main component of this drug) is an enzyme that catalyzes the conversion of the amino acid L-asparagine into both aspartic acid and ammonia [Label][2]. This process depletes malignant cells of their required asparagine. The depletion of asparagine then blocks protein synthesis and tumor cell proliferation, especially in the G1 phase of the cell cycle. As a result, tumor cell death occurs. Asparagine is important in protein synthesis in acute lymphoblastic leukemia (ALL) cells which, unlike normal cells, cannot produce this amino acid due to lack of the enzyme asparagine synthase [2][Label].

Pegylation decreases enzyme antigenicity and increases its half-life. Succinimidyl carbamate (SC) is used as a PEG linker to facilitate attachment to asparaginase and enhances the stability of the formulation [4][1]. SC-PEG urethane linkages formed with lysine groups are more hydrolytically stable [2].

Toxicity

Pancreatitis, hepatotoxicity, hemorrhage, and thrombosis have been observed with calaspargase pegol use [Label].

Pancreatitis: Discontinue this drug in patients with pancreatitis, and monitor blood glucose.

Hepatotoxicity: Hepatic function should be tested regularly, and trough levels of this drug should be measured during the recovery phase of the drug cycle [Label].

Hemorrhage or Thrombosis: Discontinue this drug in serious or life-threatening hemorrhage or thrombosis. In cases of hemorrhage, identify the cause of hemorrhage and treat appropriately. Administer anticoagulant therapy as indicated in thrombotic events [Label].

A note on hypersensitivity:

Observe the patient for 1 hour after administration of calaspargase pegol for possible hypersensitivity [Label]. In cases of previous hypersensitivity to this drug, discontinue this drug immediately.

Lactation: Advise women not to breastfeed while taking this drug [Label].

Pregnancy: There are no available data on the use of calaspargase pegol in pregnant women to confirm a risk of drug-associated major birth defects and miscarriage. Published literature studies in pregnant animals suggest asparagine depletion can cause harm to the animal offspring. It is therefore advisable to inform women of childbearing age of this risk. The background risk of major birth defects and miscarriage for humans is unknown at this time [Label].

Pregnancy testing should occur before initiating treatment. Advise females of reproductive potential to avoid becoming pregnant while taking this drug. Females should use effective contraceptive methods, including a barrier methods, during treatment and for at least 3 months after the last dose. There is a risk for an interaction between calaspargase pegol and oral contraceptives. The concurrent use of this drug with oral contraceptives should be avoided. Other non-oral contraceptive methods should be used in women of childbearing potential [Label].

References
  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]

References

  1. ^ “FDA approves longer-acting calaspargase pegol-mknl for ALL” (Press release). Food and Drug Administration. December 20, 2018.
  2. Jump up to:a b “Calaspargase pegol-mknl”NCI Drug Dictionary. National Cancer Institute.

FDA label, Download(300 KB)

General References

  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Asparlas Approval History [Link]
  4. NCI: Calaspargase Pegol [Link]
  5. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]
  6. Medsafe NZ: Erwinaze inj [File]
Calaspargase pegol-mknl
Clinical data
Trade names Asparlas
Synonyms EZN-2285
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////////Calaspargase pegol, Peptide, FDA 2018, EZN-2285, カラスパルガーゼペゴル  , BAX-2303, SC-PEG E. Coli L-asparaginase , SHP-663, orphan drug

CC(C)C[C@@H](C(=O)O)NC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC.COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)NCCCC[C@@H](C(=O)O)N

Tagraxofusp タグラクソフスプ


MGADDVVDSS KSFVMENFSS YHGTKPGYVD SIQKGIQKPK SGTQGNYDDD WKGFYSTDNK
YDAAGYSVDN ENPLSGKAGG VVKVTYPGLT KVLALKVDNA ETIKKELGLS LTEPLMEQVG
TEEFIKRFGD GASRVVLSLP FAEGSSSVEY INNWEQAKAL SVELEINFET RGKRGQDAMY
EYMAQACAGN RVRRSVGSSL SCINLDWDVI RDKTKTKIES LKEHGPIKNK MSESPNKTVS
EEKAKQYLEE FHQTALEHPE LSELKTVTGT NPVFAGANYA AWAVNVAQVI DSETADNLEK
TTAALSILPG IGSVMGIADG AVHHNTEEIV AQSIALSSLM VAQAIPLVGE LVDIGFAAYN
FVESIINLFQ VVHNSYNRPA YSPGHKTRPH MAPMTQTTSL KTSWVNCSNM IDEIITHLKQ
PPLPLLDFNN LNGEDQDILM ENNLRRPNLE AFNRAVKSLQ NASAIESILK NLLPCLPLAT
AAPTRHPIHI KDGDWNEFRR KLTFYLKTLE NAQAQQTTLS LAIF
(disulfide bridge: 187-202, 407-475)

Image result for Tagraxofusp US FDA APPROVAL

methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,https://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf

Tagraxofusp

タグラクソフスプ

CAS: 2055491-00-2
C2553H4026N692O798S16, 57694.4811

FDA 2018/12/21, Elzonris APPROVED

Antineoplastic, Immunotoxin, Peptide

DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401

UNII8ZHS5657EH

Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)

FDA approves first treatment for rare blood disease

>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF

December 21, 2018

Release

The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.

“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.

The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

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

The FDA granted the approval of Elzonris to Stemline Therapeutics.

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.[4] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[67] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.[3] This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status.[2] Tagraxofusp has been designed as an orphan drug in EU since November 2015.[7]

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.[2]

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.[1] A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.[6]

Associated Conditions

PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.[6] One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.[5]

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.[2]

Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).[5] To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.[4,6]

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.[6]

Absorption

The reported Cmax in clinical trials was of around 23 ng/ml.[6] After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.[Label]

Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.[Label]

Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.[6]

MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.[6]

ClearanceThe clearance of tagraxofusp was reported to fit a mono-exponential model.[6] The reported clearance rate is reported to be of 7.1 L/h.[Label]

ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.[Label]

  1. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
  2. FDA news [Link]
  3. FDA approvals [Link]
  4. Oncology nursing news [Link]
  5. Stemline therapeutics news [Link]
  6. Blood journal [Link]
  7. NHS reports [Link]

FDA label, Download (455 KB)

/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ  , Stemline Therapeutics, Breakthrough Therapy,  Priority Review designation,  Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 ,  Molecule 129 ,  Molecule-129 ,  SL-401, 

Caplacizumab, カプラシズマブ Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder


Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

1 http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
Formula
C1213H1891N357O380S10
CAS
915810-67-2
Mol weight
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

References

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

/////////////eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Lanadelumab, ラナデルマブ


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSG IYSSGGITVY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAYRR IGVPRRDEFD IWGQGTMVTV
SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL
GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR
EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS
RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIS SWLAWYQQKP GKAPKLLIYK ASTLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNTYWTFGQG TKVEIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; dishulfide bridge: H22-H96, H149-H205, H225-L213, H231-H’231, H234-H’234, H266-H326, H372-H430, H’22-H’96, H’149-H’205, H’225-L’213, H’266-H’326, H’372-H’430, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Lanadelumab

DX 2930

Fda approved 2018/8/23, Takhzyro

Formula
C6468H10016N1728O2012S48
Cas
1426055-14-2
Mol weight
145714.225

Peptide, Monoclonal antibody
Prevention of angioedema in patients with hereditary angioedema

Immunomodulator, Plasma kallikrein inhibitor

breakthrough therapyUNII: 2372V1TKXK

Image result for Lanadelumab

Image result for Lanadelumab

Lanadelumab (INN) (alternative identifier DX-2930[1]) is a human monoclonal antibody (class IgG1 kappa)[2] that targets plasma kallikrein (pKal)[1] in order to promote prevention of angioedema in patients with hereditary angioedema.[3][4] In phase 1 clinical trialsLanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedeman and decrease the number of patients experiencing attacks of angioedema.[1][5][6][7] As of 2017 ongoing trials for Lanadelumab include two phase 3 studies focused on investigating the utility of Lanadelumab in preventing of acute angioedema attacks in hereditary angioedema patients[8][9]

Image result for Lanadelumab

This drug was produced by Dyax Corp and currently under development by Shire.[10] Lanadelumab has been designated by the U.S. Food and Drug Administration (FDA) as a breakthrough therapy.[11]

Image result for Lanadelumab

References

  1. Jump up to:a b c Banerji, Aleena; Busse, Paula; Shennak, Mustafa; Lumry, William; Davis-Lorton, Mark; Wedner, Henry J.; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A. (2017-02-23). “Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis”. The New England Journal of Medicine376 (8): 717–728. doi:10.1056/NEJMoa1605767ISSN 1533-4406PMID 28225674.
  2. Jump up^ Kenniston, Jon A.; Faucette, Ryan R.; Martik, Diana; Comeau, Stephen R.; Lindberg, Allison P.; Kopacz, Kris J.; Conley, Gregory P.; Chen, Jie; Viswanathan, Malini (2014-08-22). “Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody”The Journal of Biological Chemistry289 (34): 23596. doi:10.1074/jbc.M114.569061PMC 4156074Freely accessiblePMID 24970892.
  3. Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – LanadelumabAmerican Medical Association.
  4. Jump up^ World Health Organization (2015). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114”(PDF). WHO Drug Information29 (4).
  5. Jump up^ Chyung, Yung; Vince, Bradley; Iarrobino, Ryan; Sexton, Dan; Kenniston, Jon; Faucette, Ryan; TenHoor, Chris; Stolz, Leslie E.; Stevens, Chris (2014-10-01). “A phase 1 study investigating DX-2930 in healthy subjects”. Annals of Allergy, Asthma & Immunology113 (4): 460–466.e2. doi:10.1016/j.anai.2014.05.028ISSN 1534-4436PMID 24980392.
  6. Jump up^ “A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  7. Jump up^ “Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  8. Jump up^ “Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  9. Jump up^ “Long-term Safety and Efficacy Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  10. Jump up^ “Lanadelumab – AdisInsight”adisinsight.springer.com. Retrieved 2017-03-24.
  11. Jump up^ “Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema”http://www.businesswire.com. Retrieved 2017-03-24.
Lanadelumab
Monoclonal antibody
Type Whole antibody
Source Human
Target kallikrein
Clinical data
Synonyms DX-2930
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
Chemical and physical data
Formula C6468H10016N1728O2012S47
Molar mass 145.7 kDa

///////////Lanadelumab, Peptide, Monoclonal antibody, FDA 2018, ラナデルマブ ,Immunomodulator, Plasma kallikrein inhibitor, DX 2930,  breakthrough therapy, Takhzyro

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

Burosumab-twza, ブロスマブ


> Burosumab Heavy Chain Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHYMHWVRQAPGQGLEWMGIINPISGSTSN
AQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDIVDAFDFWGQGTMVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
> Burosumab Light Chain Sequence
AIQLTQSPSSLSASVGDRVTITCRASQGISSALVWYQQKPGKAPKLLIYDASSLESGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNDYFTFGPGTKVDIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

ALSO

(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NHYMHWVRQA PGQGLEWMGI INPISGSTSN
AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARDI VDAFDFWGQG TMVTVSSAST
KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY
SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV
FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK
NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG
NVFSCSVMHE ALHNHYTQKS LSLSPGK
(Light chain)
AIQLTQSPSS LSASVGDRVT ITCRASQGIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ FNDYFTFGPG TKVDIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; disulfide bridge:H22-H96, H144-H200, H220-L213, H220-H’226, H229-H’229, H261-H321, H367-H425, H’22-H’96, H’144-H’200, H’220-L’213, H’261-H’321, H’367-H’425, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Burosumab-twza, KRN 23

ブロスマブ

CAS1610833-03-8

UNII G9WJT6RD29

Protein chemical formulaC6388H9904N1700O2006S46

Protein average weight144100.0 Da

Protein Based Therapies
Monoclonal antibody (mAb)

breakthrough therapy and orphan drug designations

Approval Status:Approved April 2018

Specific Treatments:X-linked hypophosphatemia

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody.

This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons [4].

Burosumab (INN, trade name Crysvita) known as KRN23 is a human monoclonal antibody designed for the treatment of X-linked hypophosphatemia.[1][2][3] Burosumab was approved by the FDA for its intended purpose, in patients aged 1 year and older, on 17 April 2018.[4] The FDA approval fell under both the breakthrough therapy and orphan drug designations.[4]

This drug was developed by Ultragenyx and is in a collaborative license agreement with Kyowa Hakko Kirin.[5]

Burosumab (KRN23) is an entirely human monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23) and has been successfully tested in clinical trials in children with X-linked hypophosphatemic rickets [1].

The U.S. Food and Drug Administration approved Crysvita (burosumab) in April 2018. This is the first drug approved to treat adults and children ages 1 year and older with X-linked hypophosphatemia (XLH), which is a rare, inherited form of rickets. X-linked hypophosphatemia causes low circulating levels of phosphorus in the blood. It causes impaired bone growth and development in children and adolescents and issues with bone mineralization throughout a patient’s life [3].

XLH is a serious disease which affects about 3,000 children and 12,000 adults in the United States. Most children with XLH suffer from bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with this condition suffer from persistent, unrelenting discomfort and complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss [3]

Crysvita is specifically indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.

Crysvita is supplied as a subcutaneous injection. The recommended starting dose for pediatrics is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. After initiation of treatment with Crysvita, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule per the drug label. The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.  After initiation of treatment with Crysvita, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose. See drug label for specific dose adjustments.

Mechanism of Action

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody. X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.

REFERENCES

1 file:///H:/761068Orig1s000ChemR.pdf

REF

  • Kutilek S: Burosumab: A new drug to treat hypophosphatemic rickets. Sudan J Paediatr. 2017;17(2):71-73. doi: 10.24911/SJP.2017.2.11. [PubMed:29545670]
  • Kinoshita Y, Fukumoto S: X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. Endocr Rev. 2018 Jan 26. pii: 4825438. doi: 10.1210/er.2017-00220. [PubMed:29381780]
  • FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia [Link]
  • Crysvita Drug Label [Link]
  • Burosumab for a rare bone disease [Link]
  • DRUG: Burosumab [Link]
  • NHS document [Link]
  • Burosumab for XLH [Link]
Burosumab
Monoclonal antibody
Type Whole antibody
Source Human
Target FGF 23
Clinical data
Trade names Crysvita
Synonyms KRN23
ATC code
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6388H9904N1700O2006S46
Molar mass 144.1 kDa

References

//////////////Burosumab-twza, Crysvita  FDA 2018, BLA 761068, Protein Based Therapies, Monoclonal antibody, mAb, KRN 23,  breakthrough therapyorphan drug designations, Peptide, ブロスマブ

Efmoroctocog alfa, エフモロクトコグアルファ;


(Heavy chain)
ATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL FVEFTDHLFN
IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA VGVSYWKASE GAEYDDQTSQ
REKEDDKVFP GGSHTYVWQV LKENGPMASD PLCLTYSYLS HVDLVKDLNS GLIGALLVCR
EGSLAKEKTQ TLHKFILLFA VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR
SLPGLIGCHR KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL
MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL TDSEMDVVRF
DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL APDDRSYKSQ YLNNGPQRIG
RKYKKVRFMA YTDETFKTRE AIQHESGILG PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI
TDVRPLYSRR LPKGVKHLKD FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME
RDLASGLIGP LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG
VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS VFFSGYTFKH
KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR GMTALLKVSS CDKNTGDYYE
DSYEDISAYL LSKNNAIEPR SFSQNPPVLK RHQREITRTT LQSDQEEIDY DDTISVEMKK
EDFDIYDEDE NQSPRSFQKK TRHYFIAAVE RLWDYGMSSS PHVLRNRAQS GSVPQFKKVV
FQEFTDGSFT QPLYRGELNE HLGLLGPYIR AEVEDNIMVT FRNQASRPYS FYSSLISYEE
DQRQGAEPRK NFVKPNETKT YFWKVQHHMA PTKDEFDCKA WAYFSDVDLE KDVHSGLIGP
LLVCHTNTLN PAHGRQVTVQ EFALFFTIFD ETKSWYFTEN MERNCRAPCN IQMEDPTFKE
NYRFHAINGY IMDTLPGLVM AQDQRIRWYL LSMGSNENIH SIHFSGHVFT VRKKEEYKMA
LYNLYPGVFE TVEMLPSKAG IWRVECLIGE HLHAGMSTLF LVYSNKCQTP LGMASGHIRD
FQITASGQYG QWAPKLARLH YSGSINAWST KEPFSWIKVD LLAPMIIHGI KTQGARQKFS
SLYISQFIIM YSLDGKKWQT YRGNSTGTLM VFFGNVDSSG IKHNIFNPPI IARYIRLHPT
HYSIRSTLRM ELMGCDLNSC SMPLGMESKA ISDAQITASS YFTNMFATWS PSKARLHLQG
RSNAWRPQVN NPKEWLQVDF QKTMKVTGVT TQGVKSLLTS MYVKEFLISS SQDGHQWTLF
FQNGKVKVFQ GNQDSFTPVV NSLDPPLLTR YLRIHPQSWV HQIALRMEVL GCEAQDLYDK
THTCPPCPAP ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV
EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ
PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG
SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPG
(Lignt chain)
DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK
GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS
DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG
(disulfide bridges: H153-H179, H248-H329, H528-H554, H630-H711, H938-H964, H1005-H1009, H1127-H1275, H1280-H1432, H1444-L6, H1447-L9, H1479-H1539, H1585-H1643, L41-L101, L147-L205)

Efmoroctocog alfa

Protein chemical formulaC9736H14863N2591O2855S78

Protein average weight220000.0 Da (Apparent, B-domain deleted)

Peptide

CAS: 1270012-79-7

エフモロクトコグアルファ;

2015/11/19 ema APPROVED elocta

Image result for Efmoroctocog alfa

Image result for Efmoroctocog alfa

Efmoroctocog alfa is a fully recombinant factor VIII-Fc fusion protein (rFVIIIFc) with an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products such as Moroctocog alfa[1]. It is an antihemorrhagic agent used in replacement therapy for patients with haemophilia A (congenital factor VIII deficiency). It is suitable for all age groups. Haemophilia A is a rare bleeding disorder associated with a slow clotting process caused by the deficiency of factor VIII. Patients with this disorder are more susceptible to recurrent bleeding episodes and excessive bleeding following minor traumatic injuries or surgical procedures [1]. Prophylactic treatment may dramatically improve the management of severe haemophilia A in the future by reducing joint bleeding and other hemorrhages that cause chronic pain and disability to patients [12]. Prophylaxis has also shown to reduce the formation of neutralizing anti-FVIII antibodies, or inhibitors [2].

Factor VIII is a blood coagulant factor involved in the intrinsic pathway to form fibrin, or a blood clot. Efmoroctocog alfa is a first commercially available rFVIII-Fc fusion protein (rFVIIIFc) where the conjugated molecule of rFVIII to polyethylene glycol is covalently fused to the dimeric Fc domain of human immunoglobulin G1, a long-lived plasma protein [FDA Label]. The B domain of factor VIII is deleted. In animal models of haemophilia, efmoroctocog alfa demonstrated an approximately two-fold longer t½ than commercially available rFVIII products [1].

Other drug products with similar structure and function to Efmoroctocog alfa include Moroctocog alfa, which is produced by recombinant DNA technology and is identical in sequence to endogenously produced Factor VIII, but does not contain the B-domain, which has no known biological function, and Antihemophilic factor human, which is purified endogenous Factor VIII from human pooled blood and contains both A- and B-subunits.

It is commonly marketed as Elocta or Eloctate for intravenous injection. To date, no confirmed inhibitory autoantibodies were seen in previously treated patients included in clinical studies and treatment-emergent adverse events were generally consistent with those expected in the patient populations being studied [1]. The extended half-life of efmoroctocog alfa provides several clinical benefits for patients, including reduced frequency of injections required and improved adherence to prophylaxis [1].

Haemophilia A is an inherited sex-linked disorder of blood coagulation in which affected males (very rarely females) do not produce functional coagulation FVIII in sufficient quantities to achieve satisfactory haemostasis. The incidence of congenital haemophilia A is approximately 1 in 10,000 births. Disease severity is classified according to the level of FVIII activity (% of normal) as mild (>5% to <40%), moderate (1% to 5%) or severe (<1%). This deficiency in FVIII predisposes patients with haemophilia A to recurrent bleeding episodes in joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Without adequate treatment these repeated haemarthroses and haematomas lead to long-term sequelae with severe disability. Other less frequent, but more severe bleeding sites, are the central nervous system, the urinary or gastrointestinal tract, eyes and the retro-peritoneum. Patients with haemophilia A are at high risk of developing major and life-threatening bleeds after surgical procedures, even after minor procedures such as tooth extraction. The development of cryoprecipitate and subsequently FVIII concentrates, obtained by fractionation of human plasma, provided replacement FVIII and greatly improved clinical management and life expectancy of patients with haemophilia A. Current treatment approaches focus on either prophylactic or on demand factor replacement therapy with plasma-derived FVIII or recombinant FVIII products. In the short term, prophylaxis can prevent spontaneous bleeding and in the long term, prophylaxis can prevent bleeding into joints that will eventually lead to debilitating arthropathy. Prophylaxis with FVIII concentrates is currently the preferred treatment regimen for patients with severe haemophilia A, especially in very young patients. The majority of patients receiving prophylaxis are treated 3-times weekly or every other day at a dose of 25–40 international units (IU)/kg (or 15–25 IU/kg in an intermediate dose regimen), although an escalating dose regimen is also used. However, on-demand treatment is still the predominant replacement approach in many countries. The most serious complication in the treatment of haemophilia A is the development of neutralising antibodies (inhibitors) against FVIII, rendering the patient resistant to replacement therapy and thereby increasing the risk of unmanageable bleeding, particularly arthropathy, and disability.

ELOCTA (efmoroctocog alfa) is a recombinant human coagulation factor VIII Fc fusion protein (rFVIIIFc) consisting of B-domain deleted FVIII covalently attached to the Fc domain of human immunoglobulin G1 (IgG1) thus aiming at prolongation of plasma half-life. It has been developed as a long-acting version of recombinant FVIII (rFVIII) for the control and prevention of bleeding episodes, routine prophylaxis, and perioperative management (surgical prophylaxis) in individuals with hemophilia A. ELOCTA is formulated as powder for intravenous administration in a single-use vial. Each single-use vial contains nominally 250, 500, 750, 1000, 1500, 2000, or 3000 International Units (IU) of rFVIIIFc for reconstitution with a solvent (Sterile Water for Injections), which is provided in a pre-filled syringe. In 2013, national scientific advice was sought from the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA), Swedish Medicinal Products Agency, and German Paul-Ehrlich-Institute. No substantial deviations from the advices provided could be identified. On 2 April 2014, the Paediatric Committee (PDCO) of the European Medicines Agency adopted a favourable opinion on the modification of an agreed paediatric investigation plan (PIP) (P/0077/2014) and a partially completed compliance procedure was finalised on 16-18 July 2014 (EMEA-C1-001114-PIP01-10-MO2). Completed studies, Study 997HA301 and Study 8HA02PED, and the initiation of Study 8HA01EXT are considered compliant with EMA Decision P/0077/2014.

The active substance of ELOCTA, efmoroctocog alfa, is a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc) comprising B-domain deleted (BDD) human FVIII covalently linked to the Fc domain of human immunoglobulin G1(IgG1). It has been developed as a long-acting version of recombinant FVIII (rFVIII). ELOCTA is formulated as a sterile, non-pyrogenic, preservative-free, lyophilized, white to off-white powder to cake for intravenous administration in a single-use vial. Each single-use vial contains nominally 250, 500, 750, 1000, 1500, 2000, or 3000 International Units (IU) of rFVIIIFc for reconstitution with liquid diluent (Sterile Water for Injection), which is provided in a pre-filled syringe. The finished medicinal product consists of a package containing a rFVIIIFc drug product vial, a pre-filled diluent (SWFI) syringe and medical devices (a plunger rod, a vial adapter (used as a transfer device during reconstitution), an infusion set, alcohol swabs, plasters and gauze pad for intravenous administration).

Structure The active substance of Elocta, efmoroctocog alfa, is a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc) comprised of a single molecule of B-domain deleted human Factor VIII (BDD FVIII) fused to the dimeric Fc region of human IgG1 with no intervening linker sequence.

The rFVIIIFc protein has a molecular weight of approximately 220 kDa. rFVIIIFc is synthesized as 2 polypeptide chains, one chain consisting of BDD FVIII fused to the N-terminal of human IgG1 Fc domain the other chain consisting of the same Fc region alone. The two subunits of rFVIIIFc, FVIIIFc single chain and Fc single chain, are associated through disulfide bonds in the hinge region of Fc as well as through extensive noncovalent interactions between the Fc fragments.

Characterisation rFVIIIFc was extensively characterised by physicochemical methods in accordance with guideline ICH Q6B. The structural characterisation and the physicochemical properties confirmed the expected properties for a recombinant FVIIIFc product. In general, the characterization performed was considered appropriate for this complex fusion molecule. The panel of tests was comprehensive and covered most of its structural and functional attributes. The comparability between representative batches from development and commercial manufacture (including process validation batches) as well as with rFVIIIFc reference materials was demonstrated. The biological activity was analysed by the FVIII one stage clotting assay (activated partial thromboplastin time (aPTT)), the FVIII chromogenic assay and the FcRn binding assay. Additional in vitro functional tests were performed comprising the binding to von Willebrand factor and the generation of Factor Xa. Since it is anticipated that the potency of modified products measured by the one stage clotting assay (aPTT) may be dependent on the choice of the aPTT reagent, the ISTH recommends for all new FVIII products to perform a study including assay variations (different aPTT reagents) for FVIII testing when using the coagulation assay. Respective studies were provided by the Applicant in Module 5 (no significant dependence on the aPTT reagent was observed). REF 3

AUSTRALIA REF 4

Submission details Type of submission: New biological entity Decision: Approved Date of decision: 18 June 2014 Active ingredient: Efmoroctocog alfa (rhu2)3

Product name: Eloctate Sponsor’s name and address: Biogen Idec Australia Pty Ltd Suite 1, Level 5 123 Epping Rd North Ryde, NSW 2113 Dose form: Powder for injection and diluent Strengths: 250 international units (IU), 500 IU, 750 IU, 1000 IU, 1500 IU, 2000 IU and 3000 IU Containers: Type I glass vial (powder) and pre-filled syringe (diluent) Pack size: Single Approved therapeutic use: Eloctate is a long-acting antihaemophilic factor (recombinant) indicated in adults and children ( ≥ 12 years) with haemophilia A (congenital factor VIII deficiency) for: · control and prevention of bleeding episodes · routine prophylaxis to prevent or reduce the frequency of bleeding episodes · perioperative management (surgical prophylaxis) Eloctate does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s disease. Route of administration: Intravenous (IV) infusion Dosage: Refer to the Product Information (PI; Attachment 1) ARTG numbers: 210521 (250 IU), 210519 (500 IU), 210523 (750 IU), 210525 (1000 IU), 210522 (1500 IU), 210524 (2000 IU), 210520 (3000 IU). 2 recombinant human 3 The ingredient name at the time of submission and registration was Efraloctocog alfa, The name was subsequently changed on 20 February 2015 to harmonise to the International Non-proprietary Name (INN) Efmoroctocog alfa. The AusPAR document has been amended by replacing the previous name efraloctocog alfa with approved INN efmoroctocog alfa.

  1. Frampton JE: Efmoroctocog Alfa: A Review in Haemophilia A. Drugs. 2016 Sep;76(13):1281-1291. doi: 10.1007/s40265-016-0622-z. [PubMed:27487799]
  2. Tiede A: Half-life extended factor VIII for the treatment of hemophilia A. J Thromb Haemost. 2015 Jun;13 Suppl 1:S176-9. doi: 10.1111/jth.12929. [PubMed:26149020]
  3. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003964/WC500198644.pdf
  4. https://www.tga.gov.au/sites/default/files/auspar-efmoroctocog-alfa-rhu-150317.pdf
  5. http://www.who.int/medicines/publications/druginformation/innlists/RL73_pre.pdf

///////////Efmoroctocog alfa, Peptide, ema 2015

Abaloparatide, абалопаратид , أبالوباراتيد , 巴罗旁肽 ,


Chemical structure for Abaloparatide

Abaloparatide

BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

абалопаратид [Russian] [INN]
أبالوباراتيد [Arabic] [INN]
巴罗旁肽 [Chinese] [INN]
str1

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

  1. C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide

Biologic Depiction

Abaloparatide biologic depiction
IUPAC Condensed

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

Sequence

AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA

HELM

PEPTIDE1{A.V.S.E.H.Q.L.L.H.D.K.G.K.S.I.Q.D.L.R.R.R.E.L.L.E.K.L.L.[Aib].K.L.H.T.A.[am]}$$$$

IUPAC

(N-(L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysyl-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl)-2-aminoisobutyryl)-L-lysyl-L-leucyl-L-histidyl-L-threonyl-L-alaninamide

Tymlos

FDA 4/28/2017

To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot

2D chemical structure of 247062-33-5

Image result for AbaloparatideImage result for Abaloparatide

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

Abaloparatide (brand name Tymlos; formerly BA058) is a parathyroid hormone-related protein (PTHrP) analog drug used to treat osteoporosis. Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[1] A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis.[2] This single study found a decrease in fractures.[3] In 28 April 2017, it was approved by Food and drug administration (FDA) to treat postmenopausal osteoporosis.

Image result for Abaloparatide

Therapeutics

Medical use

Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]

Dosage

The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]

Warnings and Precautions

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient’s lifetime.[4][6]

Image result for Abaloparatide

Side Effects

The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[4]

Pharmacology

Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[7] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[8][9]

History

Preclinical studies

Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[4]

Clinical Trials

Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[13] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[14]

In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[2] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[3]

Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study – ACTIVExtend study (2012-2016).[15] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[16]

A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[17]

In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[1]

Commercialization

As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. Abaloparatide is the only drug currently marketed by Radius Health. RDUS reported that sales for abaloparatide were $3.5million for the third quarter of 2017.[17] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[18] The net loss most likely reflects the substantial expenses associated with the preparation and launching of abaloparatide into the US market in May 2017.

In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[19]

Regulatory Information

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[20] which was validated in December, 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[17]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[21] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[22] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]

Intellectual Property

Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[23] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

As previously mentioned, Teijin Limited was granted use of Radius Health intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

  1. A peptide of the formula:

    [Glu22, 25, Leu23, 2831, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
    [Glu22, 25, Leu23, 28, 3031, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25,29, Leu23, 28, 30, 31, Lys26]hpTHrP(1-34)NH2; [Glu22, 25, 29, Leu23, 28, 31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, 23, 28, 31, His14, Cha15, Glu22, 25, Lys26, 30, Aib29]hPTHrP (1-34)NH2; [Cha22, Leu23, 28, 31, Glu25, 29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7, 1115]hPTHrP(1-34)NH2; [Cha7, 8, 15]hPTHrP(1-34)NH2; [Glu22, Leu23, 28, Aib25, 29, Lys26]hpTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, 30]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Aib26, 29, Lys30] hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.

PATENT

SEE……http://www.google.com.ar/patents/US8148333?cl=en

PATENT

SEE…………http://www.google.im/patents/US20090227498?cl=pt

EP5026436A Title not available
US3773919 Oct 8, 1970 Nov 20, 1973 Du Pont Polylactide-drug mixtures
US4767628 Jun 29, 1987 Aug 30, 1988 Imperial Chemical Industries Plc Polylactone and acid stable polypeptide
WO1994001460A1* Jul 13, 1993 Jan 20, 1994 Syntex Inc Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis
WO1994015587A2 Jan 5, 1994 Jul 21, 1994 Steven A Jackson Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
WO1997002834A1* Jul 3, 1996 Jan 30, 1997 Biomeasure Inc Analogs of parathyroid hormone
WO1997002834A1* 3 Jul 1996 30 Jan 1997 Biomeasure Inc Analogs of parathyroid hormone
WO2008063279A2* 3 Oct 2007 29 May 2008 Radius Health Inc A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof
US5695955 * 23 May 1995 9 Dec 1997 Syntex (U.S.A.) Inc. Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder
US20030166836 * 6 Nov 2002 4 Sep 2003 Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation Analogs of parathyroid hormone
US20050282749 * 14 Jan 2005 22 Dec 2005 Henriksen Dennis B Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity
Tymlos abaloparatide 4/28/2017 To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot
Abaloparatide
Clinical data
Trade names Tymlos
Synonyms BA058, BIM-44058
Routes of
administration
Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C174H299N56O49
Molar mass 3,959.65 g·mol−1
3D model (JSmol)

/////////FDA 2017, Abaloparatide, TYMLOS, RADIUS HEALTH, PEPTIDE, BA058, BIM 44058; 247062-33-5, абалопаратид أبالوباراتيد 巴罗旁肽 

CCC(C)C(C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C)(C)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC1=CN=CN1)C(=O)NC(C(C)O)C(=O)NC(C)C(=O)N)NC(=O)C(CO)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(CC2=CN=CN2)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCC(=O)N)NC(=O)C(CC3=CN=CN3)NC(=O)C(CCC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(C)N

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