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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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Eptinezumab エプチネズマブ;


Fig. 4.7

Eptinezumab

エプチネズマブ;

(Heavy chain)
EVQLVESGGG LVQPGGSLRL SCAVSGIDLS GYYMNWVRQA PGKGLEWVGV IGINGATYYA
SWAKGRFTIS RDNSKTTVYL QMNSLRAEDT AVYFCARGDI WGQGTLVTVS SASTKGPSVF
PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV
TVPSSSLGTQ TYICNVNHKP SNTKVDARVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY ASTYRVVSVL
TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE EMTKNQVSLT
CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS
VMHEALHNHY TQKSLSLSPG K
(Light chain)
QVLTQSPSSL SASVGDRVTI NCQASQSVYH NTYLAWYQQK PGKVPKQLIY DASTLASGVP
SRFSGSGSGT DFTLTISSLQ PEDVATYYCL GSYDCTNGDC FVFGGGTKVE IKRTVAAPSV
FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL
SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC
(Disulfide bridge: H22-H95, H138-H194, H214-L219, H220-H’220, H223-H’223, H255-H315, H361-H419, H’22-H’95, H’138-H’194, H’214-L’219, H’255-H’315, H’361-H’419, L22-L89, L139-L199, L’22-L’89, L’139-L’199)

Formula
C6352H9838N1694O1992S46
cas
1644539-04-7
Mol weight
143281.2247

Antimigraine, Anti-calcitonin gene-related peptide (GCRP) antibody

Immunoglobulin G1, anti-(calcitonin gene-related peptide) (human-oryctolagus cuniculus monoclonal ALD403 heavy chain), disulfide with human-oryctolagus cuniculus monoclonal ALD403 kappa-chain, dimer

Approved 2020 fda

ALD403, UNII-8202AY8I7H

Humanized anti-calcitonin gene-related peptide (CGRP) IgG1 antibody for the treatment of migraine.

Eptinezumab, sold under the brand name Vyepti, is a medication for the preventive treatment of migraine in adults.[2] It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta.[3][4] It is administered by intravenous infusion every three months.[2]

Image result for Eptinezumab

Eeptinezumab-jjmr was approved for use in the United States in February 2020.[5]

Image result for Eptinezumab

References

  1. ^ “Alder BioPharmaceuticals Initiates PROMISE 2 Pivotal Trial of Eptinezumab for the Prevention of Migraine”. Alder Biopharmaceuticals. 28 November 2016.
  2. Jump up to:a b “Vyeptitm (eptinezumab-jjmr) injection, for intravenous use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 24 February2020.
  3. ^ Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. (November 2014). “Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial”. The Lancet. Neurology13 (11): 1100–1107. doi:10.1016/S1474-4422(14)70209-1PMID 25297013.
  4. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)WHO Drug Information. WHO. 31 (1). 2017.
  5. ^ “Vyepti: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 24 February 2020.

External links

Image result for Eptinezumab

Eptinezumab
Monoclonal antibody
Type Whole antibody
Source Humanized
Target CALCACALCB
Clinical data
Trade names Vyepti
Other names ALD403,[1] eeptinezumab-jjmr
License data
Routes of
administration
IV
Drug class Calcitonin gene-related peptide antagonist
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6352H9838N1694O1992S46
Molar mass 143283.20 g·mol−1

Biologics license application submitted for eptinezumab, an anti-CGRP antibody for migraine prevention

Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively.  In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.

Alder announced one-year results from the PROMISE 1 study in June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients.  In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018.  These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

If approved, eptinezumab would become the fourth antibody therapeutic for migraine prevention on the US market, following the approval of erenumab-aooe (Aimovig; Novartis), galcanezumab-gnlm (Emgality; Eli Lilly & Company) and fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals) in 2018.

//////////Eptinezumab, Monoclonal antibody, Peptide, エプチネズマブ  , fda 2020, approvals 2020

TERIPARATIDE, テリパラチド , терипаратид , تيريباراتيد , 特立帕肽 ,


Teriparatide structure.svg

ChemSpider 2D Image | Teriparatide | C181H291N55O51S2

Teriparatide recombinant human.png

Image result for teriparatide

Image result for teriparatide

TERIPARATIDE

テリパラチド;

терипаратид [Russian] [INN]
تيريباراتيد [Arabic] [INN]
特立帕肽 [Chinese] [INN]
  • PTH 1-34
  • LY 333334 / LY-333334 / LY333334 / ZT-034
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
Asn Phe-OH
  Type
Peptide
Formula
C181H291N55O51S2
CAS
52232-67-4
99294-94-7 (acetate)
Mol weight
4117.7151

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]hexanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid

SVG Image
SVG Image
IUPAC Condensed H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH
Sequence SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
PLN H-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-OH
HELM PEPTIDE1{S.V.S.E.I.Q.L.M.H.N.L.G.K.H.L.N.S.M.E.R.V.E.W.L.R.K.K.L.Q.D.V.H.N.F}$$$$
IUPAC L-seryl-L-valyl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparagyl-L-leucyl-glycyl-L-lysyl-L-histidyl-L-leucyl-L-asparagyl-L-seryl-L-methionyl-L-alpha-glutamyl-L-arginyl-L-valyl-L-alpha-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidyl-L-asparagyl-L-phenylalanine
L-Phenylalanine, L-seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-

Other Names

  • L-Seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-L-phenylalanine
  • (1-34)-Human parathormone
  • (1-34)-Human parathyroid hormone
  • 1-34-Human PTH
  • 1-34-Parathormone (human)
  • 11: PN: WO0039278 SEQID: 17 unclaimed protein
  • 14: PN: WO0181415 SEQID: 16 claimed protein
  • 15: PN: WO0123521 SEQID: 19 claimed protein
  • 1: PN: EP2905289 SEQID: 1 claimed protein
  • 1: PN: WO0198348 SEQID: 13 claimed protein
  • 1: PN: WO2011071480 SEQID: 14 claimed protein
  • 225: PN: US20090175821 SEQID: 272 claimed protein
  • 22: PN: US6110892 SEQID: 22 unclaimed protein
  • 2: PN: US20100261199 SEQID: 4 claimed protein
  • 31: PN: US20070099831 PAGE: 7 claimed protein
  • 32: PN: WO2008068487 SEQID: 32 claimed protein
  • 5: PN: WO2008033473 SEQID: 4 claimed protein
  • 692: PN: WO2004005342 PAGE: 46 claimed protein
  • 69: PN: US20050009742 PAGE: 20 claimed sequence
  • 7: PN: WO0031137 SEQID: 8 unclaimed protein
  • 7: PN: WO0040611 PAGE: 1 claimed protein
  • 93: PN: WO0069900 SEQID: 272 unclaimed protein
  • Forsteo
  • Forteo
  • HPTH-(1-34)
  • Human PTH(1-34)
  • Human parathormone(1-34)
  • Human parathyroid hormone-(1-34)
  • LY 333334
  • Osteotide
  • Parathar
  • Parathormone (human)
  • Teriparatide
  • ZT 034

Product Ingredients

INGREDIENT UNII CAS
Teriparatide acetate 9959P4V12N 99294-94-7

Teriparatide is a form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) agent[2] used in the treatment of some forms of osteoporosis.[3] It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone.

Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. A synthetic teriparatide from Teva Generics has been authorised for marketing in European territories[4]. Biosimilar product from Gedeon Richter plc has been authorised in Europe[5]. On October 4, 2019 the US FDA approved a recombinant teriparatide product, PF708, from Pfenex Inc. PF708 is the first FDA approved proposed therapeutic equivalent candidate to Forteo.

Teriparatide (recombinant human parathyroid hormone) is a potent anabolic agent used in the treatment of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.

Teriparatide is a recombinant form of parathyroid hormone. It is an effective anabolic (i.e., bone growing) agent used in the treatment of some forms of osteoporosis. It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone. Teriparatide is sold by Eli Lilly and Company under the brand name Forteo.

Indication

For the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. Also used to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Associated Conditions

Pharmacodynamics

Clinical trials indicate that teriparatide increases predominantly trabecular bone in the lumbar spine and femoral neck; it has less significant effects at cortical sites. The combination of teriparatide with antiresorptive agents is not more effective than teriparatide monotherapy. The most common adverse effects associated with teriparatide include injection-site pain, nausea, headaches, leg cramps, and dizziness. After a maximum of two years of teriparatide therapy, the drug should be discontinued and antiresorptive therapy begun to maintain bone mineral density.

Mechanism of action

Teriparatide is the portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34 of the complete molecule which contains amino acid sequence 1 to 84. Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. Daily injections of teriparatide stimulates new bone formation leading to increased bone mineral density.

Medical uses

Teriparatide has been FDA-approved since 2002.[6] It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[7] and reducing the risk of fragility fractures.[6][8] When studied, teriparatide only showed bone mineral density (BMD) improvement during the first 18 months of use. Teriparatide should only be used for a period of 2 years maximum. After 2 years, another agent such a bisphosphonate or denosumab should be used in cases of osteoporosis. [9]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[10]

Other

Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions.[11] It has been reported to have been successfully used to heal fracture nonunions.[12] Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery.[11] But an Italian football player, Francesco Totti, was given teriparatide after a tibia/fibula fracture, and he unexpectedly recovered in time for the 2006 World Cup.[11] It has been reported that Mark Mulder used it to recover from a hip fracture Oakland A’s for the 2003 MLB playoffs[13] and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl.[13]

Administration

Teriparatide is administered by injection once a day in the thigh or abdomen.

Contraindications

Teriparatide should not be prescribed for people who are at increased risks for osteosarcoma. This includes those with Paget’s Diseaseof bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior radiation therapy involving the skeleton. In the animal studies and in one human case report, it was found to potentially be associated with developing osteosarcoma in test subjects after over 2 years of use. [14]

Patients should not start teriparatide until any vitamin D deficiency is corrected. [15]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.[6] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[2] This may be because unlike humans, rat bones grow for their entire life.[2] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[15]After nine years on the market, there were only two cases of osteosarcoma reported.[7] This risk was considered by the FDA as “extremely rare” (1 in 100,000 people)[6] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[6]

Mechanism of action

Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores. However, intermittent exposure to PTH will activate osteoblasts more than osteoclasts. Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.[16][17][18]

Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.[19]

FDA approval

Teriparatide was approved by the Food and Drug Administration (FDA) on 26 November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Combined teriparatide and denosumab

Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture by increasing BMD. However, there is no evidence of fracture rate reduction in patients taking a teriparatide and denosumab combination. Moreover, the combination therapy group showed a significant decrease in their bone formation marker, indicating that denosumab, an antiresorptive agent, might actually counteract the effect of teriparatide, a bone formation anabolic agent, in bone formation. [20]

PATENT

KR 2011291

WO 2019077432

CN 109897099

CN 109879955

CN 109879954

CN 108373499

PATENT

WO-2020000555

Process for preparing teriparatide as parathyroid hormone receptor agonist, useful for treating osteoporosis in menopausal women. Appears to be the first filing from the assignee and the inventors on this compound, however, this invention was previously seen as a Chinese national filing published in 12/2013. Daiichi Sankyo , through its subsidiary  Asubio Pharma , was developing SUN-E-3001 , a nasally administered recombinant human parathyroid hormone, for the treatment of osteoporosis.

Teriparatide is a 1-34 fragment of human parathyroid hormone, which has the same biological activity as human parathyroid hormone. Hypogonadous osteoporosis and osteoporosis in menopausal women have great market prospects.

The peptide sequence is:
H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH.
Patent US6590081 uses a method of genetic recombination to obtain teriparatide. However, the genetic recombination method has problems such as complicated process, high cost and serious waste.
Patent CN201510005427 uses Wang resin or 2-Cl-CTC resin to synthesize teriparatide one by one from the C-terminus to the N-terminus, which belongs to the conventional solid-phase synthesis method. However, the reaction is incomplete when the method is coupled to the late stage, which makes purification of the final product difficult and the purity is not high.
Patent CN201310403743 is synthesized by one-by-one coupling method. Unlike patent CN201510005427, this patent ester-condenses the free hydroxyl of Ser at the 17-position with the carboxyl group of Asn at the 16-position, and then obtains teriparatide through O → N acyl transfer. Although this method can reduce the difficulty of coupling at subsequent sites by changing the spatial configuration of the target peptide, it still has the problem of many solid-phase coupling steps and difficult purification.

In patent CN201410262511, a pseudoproline dipeptide Fmoc-Asn (Trt) -Ser (ψ Me, Me Pro) -OH is used instead of the two amino acids at the original 16-17 positions for coupling one by one, and the final cleavage yields teriparatide. This method adopts the method of feeding pseudoproline dipeptide to avoid the generation of oxidative impurities, but it cannot avoid a variety of missing peptides due to the excessively long peptide chain. At the same time, the pseudoproline dipeptide is expensive and difficult to obtain.

Patent CN201511024053 uses multiple di- or tripeptide fragments to replace a single amino acid for coupling, and finally cleavages to obtain teriparatide. This method requires liquid phase synthesis to obtain 11 short peptide fragments, which are complicated in operation and low in production efficiency.
A method for preparing teriparatide includes:

[0016]
Step 1: Coupling 3-Fmoc-4-diaminobenzoic acid with a solid phase carrier, and then sequentially coupling Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc from the C-terminus to the N-terminus according to the peptide sequence -His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met -OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and PG- Ser (tBu) -OH, then benzimidazolone is closed by phenyl p-nitrochloroformate, and finally fragmented by salicylaldehyde and TFA to obtain fragment APG-Ser-Val-Ser-Glu-Ile-Gln-Leu- Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL;

[0017]
Step 2: Coupling Fmoc-Phe-OH with a solid support, and then coupling Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val in sequence from the C-terminus to the N-terminus according to the peptide sequence. -OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf ) -OH, Fmoc-Leu-OH, Fmoc-Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu)- OH, Fmoc-Met-OH and Fmoc-Ser (tBu) -OH, TFA cleavage to obtain fragment B Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-OH;

[0018]
Step 3: Coupling Fragment A and Fragment B, and then removing the protecting group of Ser at Fragment A to obtain a crude teriparatide peptide;

[0019]
Step 4: Purifying the teriparatide crude peptide to obtain teriparatide;

[0020]
Step 1 and Step 2 are not in order.

[0021]
Preferably, the solid phase carrier in step 1 is Rink Amide Resin or 2-Cl-CTC Resin.

[0022]
Preferably, the coupling agent in step 1 is HOBt / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0023]
Preferably, the PG of PG-Ser (tBu) -OH in step 1 is a Msz protecting group, a Teoc protecting group, or a Fmoc protecting group.

[0024]
Preferably, the cracking lysing agent in step 1 is a mixed solution of TFA and water.

[0025]
Preferably, the solid phase support in step 2 is Wang Resin.

[0026]
Preferably, the coupling agent in step 2 is HOBt / DIPCDI, HOBt / DMAP / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0027]
Preferably, the lysing lysing agent in step 2 is a mixed solution of TFA and TIS.

[0028]
Preferably, the specific operation of the coupling in step 3 is to dissolve in a pyridine / acetic acid buffer solution for 2-4 hours.

[0029]
Preferably, the specific operation of removing the protecting group of 1-Ser in the fragment A in step 3 is:

[0030]
When the PG of PG-Ser (tBu) -OH in the fragment A is the protecting group of Msz, the coupling of the fragment A and the fragment B is completed by adding TFA / ammonium iodide / dimethylsulfide to remove the protecting group Msz, and the ether precipitates;

[0031]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Teoc protecting group, the fragment A and the fragment B are coupled and tetrabutylammonium fluoride is added to remove the protecting group Teoc;

[0032]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Fmoc protecting group, the fragment A and the fragment B are coupled and diethylamine is added to remove the protecting group Fmoc.

[0033]
The method for preparing teriparatide in the present invention uses fragment condensation to prepare teriparatide. First synthesize the teriparatide peptide sequence 1-16 (fragment A) and the 17-34 peptide sequence (fragment B), and then couple the two fragments to obtain the crude teriparatide peptide. Riparide. The side chain of the fragment in the invention has no protecting group, has good solubility in water, does not have the problem of difficult coupling, simple operation, and high production efficiency. The obtained teriparatide product has high purity and is easy to purify. Experiments show that the crude peptide of teriparatide obtained by the present invention can obtain a purity of 80% and a total yield of 45%. After simple purification, the purity of spermeptide can reach 99.92%, and the single largest impurity is 0.05%. Compared with the prior art, the invention has the characteristics of high product quality, low cost, and suitability for industrial production.
Example 1: Synthesis of fragment one (Msz-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0097]
Weigh 20.0 g (10 mmol) of Rink Amide Resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 18.7 g (50 mmol) ) 3-Fmoc-4-diaminobenzoic acid and 8.1 g (60 mmol) of HOBt were dissolved in DMF, 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and added to a solid-phase reaction column, and reacted at room temperature for 2 hours. The solution was removed by DMF Wash 3 times. The 20% piperidine solution was used to remove the Fmoc protecting group (reaction time 5 + 7 minutes), and DMF was washed 6 times.

[0098]
According to the peptide sequence of fragment one, the above steps of amino acid coupling and removal of the Fmoc protecting group are repeated, using the coupling agent HOBt / DIPCDI or HOBt / PyBop / DIPEA or HATU / HOAt / DIPEA or HOAt / PyAop / DIPEA or HBTU / HOBt / DIPEA, coupled Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu- OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Msz-Ser (tBu) -OH.

[0099]
Weigh 10.1 g (50 mmol) of phenyl p-nitrochloroformate in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 12.9 g (100 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Separately weigh 10.6 g (100 mmol) of sodium carbonate and 100 ml of salicylaldehyde in a mixed solution of DCM / THF (1: 3), add to the peptide resin, react at room temperature overnight, filter, and concentrate the filtrate under reduced pressure to dryness. Finally, it was cleaved with TFA / H 2 O (95: 5) for 2 hours and precipitated with ether to obtain 19.2 g of fragment one.

[0100]
Example 2: Synthesis of fragment two (Teoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0101]
Weigh 16.7 g (10 mmol) of 2-Cl-CTC Resin with a substitution degree of 0.6 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 7.48 g (20 mmol) of 3-Fmoc-4-diaminobenzoic acid was dissolved in DMF, 5.2 g (40 mmol) of DIPEA was added under an ice bath, and the solid phase reaction column was added, and the reaction was performed at room temperature for 0 hours, and 6 ml of methanol was added to block the resin for 1 hour. The solution was removed and washed 6 times with DMF.

[0102]
Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH were sequentially coupled according to the peptide sequence of fragment two according to the method in Example 1. , F moc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Teoc-Ser (tBu) -OH.

[0103]
Weigh 6.1 g (30 mmol) of phenyl p-nitrochloroformate and dissolve it in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 7.7 g (60 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Another 6.4 g (60 mmol) of sodium carbonate and 60 ml of salicylaldehyde dissolved in a mixed solution of DCM / THF (1: 1) were added to the peptide resin, reacted at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to dryness. Finally, it was cleaved with TFA / H2O (95: 5) for 2 hours and precipitated with ether to obtain 10.5 g of fragment two.

[0104]
Example 3: Synthesis of fragment three (Fmoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0105]
Fmoc-Ser (tBu) -OH was used for serine at position 1. Other synthetic methods were the same as in Example 1.

[0106]
Example 4: Synthesis of fragment four (Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH)

[0107]
Weigh 62.5 g (50 mmol) of Wang Resin with a degree of substitution of 0.8 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 3 minutes, then weigh 19.37 g (50 mmol) of Fmoc-Phe- OH, 8.1 g (60 mmol) of HOBt and 6.1 g (5 mmol) of DMAP were dissolved in DMF. 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and the solid phase reaction column was added. The mixture was reacted at room temperature for 2 hours and washed with DMF 6 times. 79.1 g (1000 mmol) of pyridine and 102.1 g (1000 mmol) of acetic anhydride were added to seal the resin for 6 hours, washed with DMF 6 times, and the methanol was shrunk and dried to obtain 71.4 g of Fmoc-Phe-WangResin. .

[0108]
According to the method in Example 1, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val-OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf) -OH, Fmoc-Leu-OH, Fmoc- Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Met-OH and Fmoc-Ser ( tBu) -OH, the obtained peptide resin was cleaved with TFA / TIS (95: 5) for 2 hours, and the ether was precipitated to obtain 23.2 g of fragment four.

[0109]
Example 5: Synthesis of crude teriparatide

[0110]
19.2 g (10 mmol) of fragment 1 obtained in Example 1 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 2 hours, and concentrated under reduced pressure to Dry, add TFA / ammonium iodide / dimethylsulfide (90: 5: 5) to react for 30 minutes, and diethyl ether precipitates to obtain 37 g of teriparatide crude peptide, purity 80.10%, weight yield 90%. The purity test results are shown in Figure 2 and Table 1.

[0111]
Example 6: Synthesis of crude teriparatide

[0112]
21.9 g (10 mmol) of fragment 2 obtained in Example 2 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), and reacted at room temperature for 3 hours, and then 26.15 g was added. Tetrabutylammonium fluoride (100 mmol) was reacted overnight to obtain the teriparatide crude peptide solution for direct purification. The purity of the crude peptide was 67.97%. The purity test results are shown in Figure 3 and Table 1.

[0113]
Example 7: Synthesis of crude teriparatide

[0114]
21.5 g (10 mmol) of fragment 3 obtained in Example 3 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 4 hours, and concentrated under reduced pressure to Dry, add methanol to dissolve, then add 14.63 g of diethylamine (200 mmol), react at room temperature for 2 hours, and concentrate to dryness under reduced pressure to obtain 45 g of teriparatide crude peptide, purity 63.22%, weight yield 109%. The purity test results are shown in Figure 4 and Table 1.

[0115]
Example 8: Purification of crude teriparatide

[0116]
The crude teriparatide peptide obtained in Example 5 was purified by HPLC with a wavelength of 220 nm, a chromatographic column was a reversed-phase C18 column, a 0.1% TFA solution, and acetonitrile were used as mobile phases. The target fractions were collected, concentrated by rotary evaporation, and lyophilized. 18.5 g of teriparatide spermidine was obtained, with a purity of 99.92%, a single maximum impurity of 0.05%, and a total yield of 45%. The purity test results are shown in Figure 5 and Table 1.

[0117]
The crude teriparatide peptide obtained in Example 6 was purified under the same conditions as described above to obtain 14.8 g of teriparatide spermeptide with a purity of 99.76%, a single maximum impurity of 0.07%, and a total yield of 36%.

[0118]
The crude teriparatide peptide obtained in Example 7 was purified under the same conditions as described above to obtain 14.0 g of teriparatide spermeptide with a purity of 99.73%, a single maximum impurity of 0.06%, and a total yield of 34%.

References

  1. ^ http://www.minsa.gob.pa/sites/default/files/alertas/nota_seguridad_teriparatida.pdf
  2. Jump up to:a b c Riek AE and Towler DA (2011). “The pharmacological management of osteoporosis”Missouri Medicine108 (2): 118–23. PMC 3597219PMID 21568234.
  3. ^ Saag KG, Shane E, Boonen S, et al. (November 2007). “Teriparatide or alendronate in glucocorticoid-induced osteoporosis”. The New England Journal of Medicine357 (20): 2028–39. doi:10.1056/NEJMoa071408PMID 18003959.
  4. ^ BfArM (2017-05-08). “PUBLIC ASSESSMENT REPORT – Decentralised Procedure – Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection” (PDF).
  5. ^ “Summary of the European public assessment report (EPAR) for Terrosa”. Retrieved 2019-08-14.
  6. Jump up to:a b c d e Rizzoli, R.; Reginster, J. Y.; Boonen, S.; Bréart, G. R.; Diez-Perez, A.; Felsenberg, D.; Kaufman, J. M.; Kanis, J. A.; Cooper, C. (2011). “Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis”Calcified Tissue International89 (2): 91–104. doi:10.1007/s00223-011-9499-8PMC 3135835PMID 21637997.
  7. Jump up to:a b Kawai, M.; Mödder, U. I.; Khosla, S.; Rosen, C. J. (2011). “Emerging therapeutic opportunities for skeletal restoration”Nature Reviews Drug Discovery10 (2): 141–156. doi:10.1038/nrd3299PMC 3135105PMID 21283108.
  8. ^ Murad, M. H.; Drake, M. T.; Mullan, R. J.; Mauck, K. F.; Stuart, L. M.; Lane, M. A.; Abu Elnour, N. O.; Erwin, P. J.; Hazem, A.; Puhan, M. A.; Li, T.; Montori, V. M. (2012). “Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis”. Journal of Clinical Endocrinology & Metabolism97(6): 1871–1880. doi:10.1210/jc.2011-3060PMID 22466336.
  9. ^ O’Connor KM. Evaluation and Treatment of Osteoporosis. Med Clin N Am. 2016; 100:807-26
  10. ^ Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M (September 2018). “Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis”. Bone120: 1–8. doi:10.1016/j.bone.2018.09.020PMID 30268814.
  11. Jump up to:a b c Bruce Jancin (2011-12-12). “Accelerating Fracture Healing With Teriparatide”. Internal Medicine News Digital Network. Retrieved 2013-09-20.
  12. ^ Giannotti, S.; Bottai, V.; Dell’Osso, G.; Pini, E.; De Paola, G.; Bugelli, G.; Guido, G. (2013). “Current medical treatment strategies concerning fracture healing”Clinical Cases in Mineral and Bone Metabolism10 (2): 116–120. PMC 3796998PMID 24133528.
  13. Jump up to:a b William L. Carroll (2005). “Chapter 1: Defining the Issue”The Juice: The Real Story of Baseball’s Drug ProblemsISBN 1-56663-668-X. Retrieved 2013-09-23.
  14. ^ Harper KD, Krege JH, Marcus R, et al. Osteosarcoma and teriparatide? J Bone Miner Res 2007;22(2):334
  15. Jump up to:a b https://www.drugs.com/pro/forteo.html
  16. ^ Bauer, E; Aub, JC; Albright, F (1929). “Studies of calcium and phosphorus metabolism: V. Study of the bone trabeculae as a readily available reserve supply of calcium”J Exp Med49 (1): 145–162. doi:10.1084/jem.49.1.145PMC 2131520PMID 19869533.
  17. ^ Selye, H (1932). “On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol”. Endocrinology16 (5): 547–558. doi:10.1210/endo-16-5-547.
  18. ^ Dempster, D. W.; Cosman, F.; Parisien, M.; Shen, V.; Lindsay, R. (1993). “Anabolic actions of parathyroid hormone on bone”. Endocrine Reviews14 (6): 690–709. doi:10.1210/edrv-14-6-690PMID 8119233.
  19. ^ Fortéo: teriparatide (rDNA origin) injection Archived 2009-12-27 at the Wayback Machine
  20. ^ Tsai, Joy N; Uihlein, Alexander V; Lee, Hang; Kumbhani, Ruchit; Siwila-Sackman, Erica; McKay, Elizabeth A; Burnett-Bowie, Sherri-Ann M; Neer, Robert M; Leder, Benjamin Z (2013). “Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: The DATA study randomised trial”The Lancet382 (9886): 1694–1700. doi:10.1016/S0140-6736(13)60856-9PMC 4010689PMID 24517156.

External links

Teriparatide
Teriparatide structure.svg
Clinical data
Trade names Forteo/Forsteo, Teribone[1]
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • C
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Metabolism Hepatic (nonspecific proteolysis)
Elimination half-life Subcutaneous: 1 hour
Excretion Renal (metabolites)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ECHA InfoCard 100.168.733 Edit this at Wikidata
Chemical and physical data
Formula C181H291N55O51S2
Molar mass 4117.72 g/mol g·mol−1
3D model (JSmol)

FORTEO (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1- 34), and is also called rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids(the biologically active region) of the 84-amino acid human parathyroid hormone.

Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

FORTEO (teriparatide)Structural Formula Illustration

Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. FORTEO is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

REFERENCES

1: Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ. Teriparatide for osteoporosis: importance of the full course. Osteoporos Int. 2016 Feb 22. [Epub ahead of print] Review. PubMed PMID: 26902094.

2: Im GI, Lee SH. Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review. J Bone Metab. 2015 Nov;22(4):183-9. doi: 10.11005/jbm.2015.22.4.183. Epub 2015 Nov 30. Review. PubMed PMID: 26713309; PubMed Central PMCID: PMC4691592.

3: Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: What is the evidence? World J Orthop. 2015 Jul 18;6(6):457-61. doi: 10.5312/wjo.v6.i6.457. eCollection 2015 Jul 18. Review. PubMed PMID: 26191492; PubMed Central PMCID: PMC4501931.

4: Lecoultre J, Stoll D, Chevalley F, Lamy O. [Improvement of fracture healing with teriparatide: series of 22 cases and review of the literature]. Rev Med Suisse. 2015 Mar 18;11(466):663-7. Review. French. PubMed PMID: 25962228.

5: Sugiyama T, Torio T, Sato T, Matsumoto M, Kim YT, Oda H. Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality. Front Endocrinol (Lausanne). 2015 Jan 30;6:6. doi: 10.3389/fendo.2015.00006. eCollection 2015. Review. PubMed PMID: 25688232; PubMed Central PMCID: PMC4311704.

6: Wheeler AL, Tien PC, Grunfeld C, Schafer AL. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS. 2015 Jan 14;29(2):245-6. doi: 10.1097/QAD.0000000000000529. Review. PubMed PMID: 25532609; PubMed Central PMCID: PMC4438749.

7: Campbell EJ, Campbell GM, Hanley DA. The effect of parathyroid hormone and teriparatide on fracture healing. Expert Opin Biol Ther. 2015 Jan;15(1):119-29. doi: 10.1517/14712598.2015.977249. Epub 2014 Nov 3. Review. PubMed PMID: 25363308.

8: Yamamoto M, Sugimoto T. [Glucocorticoid and Bone. Beneficial effect of teriparatide on fracture risk as well as bone mineral density in patients with glucocorticoid-induced osteoporosis]. Clin Calcium. 2014 Sep;24(9):1379-85. doi: CliCa140913791385. Review. Japanese. PubMed PMID: 25177011.

9: Chen JF, Yang KH, Zhang ZL, Chang HC, Chen Y, Sowa H, Gürbüz S. A systematic review on the use of daily subcutaneous administration of teriparatide for treatment of patients with osteoporosis at high risk for fracture in Asia. Osteoporos Int. 2015 Jan;26(1):11-28. doi: 10.1007/s00198-014-2838-7. Epub 2014 Aug 20. Review. PubMed PMID: 25138261.

10: Eriksen EF, Keaveny TM, Gallagher ER, Krege JH. Literature review: The effects of teriparatide therapy at the hip in patients with osteoporosis. Bone. 2014 Oct;67:246-56. doi: 10.1016/j.bone.2014.07.014. Epub 2014 Jul 15. Review. PubMed PMID: 25053463.

11: Meier C, Lamy O, Krieg MA, Mellinghoff HU, Felder M, Ferrari S, Rizzoli R. The role of teriparatide in sequential and combination therapy of osteoporosis. Swiss Med Wkly. 2014 Jun 4;144:w13952. doi: 10.4414/smw.2014.13952. eCollection 2014. Review. PubMed PMID: 24896070.

12: Krege JH, Lane NE, Harris JM, Miller PD. PINP as a biological response marker during teriparatide treatment for osteoporosis. Osteoporos Int. 2014 Sep;25(9):2159-71. doi: 10.1007/s00198-014-2646-0. Epub 2014 Mar 6. Review. PubMed PMID: 24599274; PubMed Central PMCID: PMC4134485.

13: Nakano T. [Once-weekly teriparatide treatment on osteoporosis]. Clin Calcium. 2014 Jan;24(1):100-5. doi: CliCa1401100105. Review. Japanese. PubMed PMID: 24369286.

14: Yano S, Sugimoto T. [Daily subcutaneous injection of teriparatide : the progress and current issues]. Clin Calcium. 2014 Jan;24(1):35-43. doi: CliCa14013543. Review. Japanese. PubMed PMID: 24369278.

15: Lewiecki EM, Miller PD, Harris ST, Bauer DC, Davison KS, Dian L, Hanley DA, McClung MR, Yuen CK, Kendler DL. Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis. J Clin Densitom. 2014 Oct-Dec;17(4):490-5. doi: 10.1016/j.jocd.2013.09.018. Epub 2013 Oct 25. Review. PubMed PMID: 24206867.

16: Delivanis DA, Bhargava A, Luthra P. Subungual exostosis in an osteoporotic patient treated with teriparatide. Endocr Pract. 2013 Sep-Oct;19(5):e115-7. doi: 10.4158/EP13040.CR. Review. PubMed PMID: 23757619.

17: Borges JL, Freitas A, Bilezikian JP. Accelerated fracture healing with teriparatide. Arq Bras Endocrinol Metabol. 2013 Mar;57(2):153-6. Review. PubMed PMID: 23525295.

18: Thumbigere-Math V, Gopalakrishnan R, Michalowicz BS. Teriparatide therapy for bisphosphonate-related osteonecrosis of the jaw: a case report and narrative review. Northwest Dent. 2013 Jan-Feb;92(1):12-8. Review. PubMed PMID: 23516715.

19: Lamy O. [Bone anabolic treatment with Teriparatide]. Ther Umsch. 2012 Mar;69(3):187-91. doi: 10.1024/0040-5930/a000272. Review. German. PubMed PMID: 22403112.

20: Narváez J, Narváez JA, Gómez-Vaquero C, Nolla JM. Lack of response to teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw. Osteoporos Int. 2013 Feb;24(2):731-3. doi: 10.1007/s00198-012-1918-9. Epub 2012 Mar 8. Review. PubMed PMID: 22398853.

/////TERIPARATIDE, テリパラチド , терипаратид تيريباراتيد 特立帕肽 PTH 1-34, LY 333334,  LY-333334LY333334,  ZT-034, 52232-67-4, PEPTIDES

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

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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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

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

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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