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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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Romosozumab, ロモソズマブ (遺伝子組換え)


Image result for Romosozumab

Romosozumab

ロモソズマブ (遺伝子組換え)

AMG 785

Immunoglobulin G2, anti-(human sclerostin) (human-mouse monoclonal 785A070802 heavy chain), disulfide with human-mouse monoclonal 785A070802 κ-chain, dimer

  • Immunoglobulin G2, anti-(human sclerostin) (humanized monoclonal 785A070802 heavy chain), disulfide with humanized monoclonal 785A070802 κ-chain, dimer
Formula
C6452H9926N1714O2040S54
CAS
909395-70-6
Mol weight
145875.6186

Monoclonal antibody
Treatment of osteoporosis

Osteoporosis agent, Sclerostin activity inhibitor

JAPAN APPROVED 2019/1/8, Evenity

Romosozumab (AMG 785) is a humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis.[1]

Romosozumab was originally discovered by Chiroscience,[2] which was acquired by Celltech (now owned by UCB).[3] Celltech entered in a partnership with Amgen in 2002 for the product’s development.[4]

In 2016 results from 12 months of a clinical study were reported.[5]

Some results from the FRAME[6] and ARCH clinical studies were reported on in 2017.[7]

Japan’s Ministry of Health, Labor and Welfare has granted a marketing authorization for romosozumab (EVENITY) for the treatment of osteoporosis in patients at high risk of fracture. Developed by Amgen and UCB, romosozumab is a humanized IgG2 monoclonal antibody that targets sclerostin. The approval in Japan is based on results from the Phase 3 FRAME and BRIDGE studies, which included 7,180 postmenopausal women with osteoporosis and 245 men with osteoporosis, respectively.

A biologics license application (BLA) for romosozumab as a treatment of osteoporosis in postmenopausal women at high risk for fracture was submitted to the U.S. Food and Drug Administration (FDA) in July 2016, but additional safety and efficacy data was requested in the FDA’s complete response letter, as announced by Amgen and UCB in July 2017. In July 2018, Amgen and UCB announced that the BLA had been resubmitted. In addition to data from early-stage clinical studies, the original BLA included data from the Phase 3 FRAME study. The resubmitted BLA includes results from the more recent Phase 3 ARCH study, an alendronate-active comparator trial including 4,093 postmenopausal women with osteoporosis who experienced a fracture, and the Phase 3 BRIDGE study. The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee is scheduled to review data supporting the BLA for romosozumab at a meeting on January 16, 2019.

The European Medicines Agency is also currently reviewing a marketing application for romosozumab.

US 20170305999

Commercial production of cell culture-derived products (for example, protein-based products, such as monoclonal antibodies (mAbs)), requires optimization of cell culture parameters in order for the cells to produce enough product to meet clinical and commercial demands. However, when cell culture parameters are optimized for improving productivity of a protein product, it is also necessary to maintain desired quality specifications of the product such as glycosylation profile, aggregate levels, charge heterogeneity, and amino acid sequence integrity (Li, et al., 2010 , mAbs., 2(5):466-477).
      For instance, an increase of over 20% volumetric titer results in a significant improvement in large-scale monoclonal antibody production economics. Additionally, the ability to control the glycan forms of proteins produced in cell culture is important. Glycan species have been shown to significantly influence pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic proteins such as mAbs. Moreover, the ability to modulate the relative percentage of various glycan species can have drastic results over the behavior of a protein in vivo. For example, increased mannose-5-N-acetylglycosamine-2 (“Man5”) and other high-mannose glycan species have been shown to decrease mAb in vivo half-life (Liu, 2015 , J Pharm Sci., 104(6):1866-84; Goetze et al., 2011 , Glycobiology, 21(7):949-59; and Kanda et al. 2007 , Glycobiology, 17(1):104-18). On the other hand, glycosylated mAbs with mannose-3-N-acetylglycosamine-4 (“G0”) glycan species have been shown to impact antibody dependent cellular cytotoxicity (ADCC).
      Bioreactors have been successfully utilized for the cell-based production of therapeutic proteins using fed-batch, immobilized, perfusion and continuous modes. Strategies, such as the use of temperature, media formulation, including the addition of growth inhibitors, autocrine factors or cyclic mononucleotides, and hyperstimulation by osmolarity stress, have been used to enhance protein production by cells in culture. To the extent that they have worked at all, these approaches have shown only marginal success.
      As such, there is a particular need for improved compositions for use in cell culture for the production of medically or industrially useful products, such as antibodies. Ideally, such compositions and methods for utilizing the same would result in higher titers, modulated (e.g. decreased) high and low molecular weight species, as well as a more favorable glycosylation profile of the derived products in cell culture.
      Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.

References

  1. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Romosozumab” (PDF)American Medical Association.
  2. ^ Quested, Tony (June 7, 2015). “Cream of life science entrepreneurs’ first venture was selling doughnuts”Business Week. Cambridge, England: Q Communications. Retrieved December 24, 2018.
  3. ^ Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003 Dec 1;22(23):6267-76.
  4. ^ Celltech group Annual Report and Accounts 2002
  5. ^ Cosman; et al. (2016). “Romosozumab Treatment in Postmenopausal Women with Osteoporosis”. The New England Journal of Medicine375: 1532–1543. doi:10.1056/NEJMoa1607948PMID 27641143.
  6. ^ Efficacy and Safety of Romosozumab Treatment in Postmenopausal Women With Osteoporosis (FRAME)
  7. ^ Bone Loss Drug Effective, But is it Safe? Oct 2017
Romosozumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target Sclerostin
Clinical data
ATC code
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
KEGG
Chemical and physical data
Formula C6452H9926N1714O2040S54
Molar mass 145.9 kg/mol

///////////Romosozumab, ロモソズマブ (遺伝子組換え)  , JAPAN 2019, Monoclonal antibody, Osteoporosis, AMG 785

Romosozumab (AMG 785) shines in phase II for osteoporosis


Postmenopausal osteoporosis
Romosozumab is a humanized monoclonal antibody that inhibits the action of sclerostin. It is being developed in collaboration with UCB for the treatment of postmenopausal osteoporosis.

Romosozumab (AMG 785) is a humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis.[1]

Romosozumab was originally discovered by Celltech (now owned by UCB).[2] Celltech entered in a partnership with Amgen in 2002 for the product’s development.[3] As of January 2014, Phase 3 clinical trials are recruiting patients.[4]

  1.  “Statement On A Nonproprietary Name Adopted By The USAN Council: Romosozumab”American Medical Association.
  2.  Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003 Dec 1;22(23):6267-76.
  3.  Celltech group Annual Report and Accounts 2002
  4.  ClinicalTrials.gov: Romosozumab
Chemical data
Formula C6452H9926N1714O2040S54 
Mol. mass 145.9 kDa
Sclerostin / Source: Wikimedia Commons and JMROL

Sclerostin / Source: Wikimedia Commons and JMROL

Biloine Young • Thu, November 1st, 2012

Good news for postmenopausal women came from a report given by Michael R. McClung, M.D., at the annual meeting of the American Society for Bone and Mineral Research. McClung and colleagues have found an antibody that targets the Wnt signaling pathway and its osteocyte-regulating molecule sclerostin, which increases bone formation while decreasing bone resorption, according to Nancy Walsh, staff writer for MedPage Today.

Walsh reports that one year of treatment with the antibody romosozumab (formerly AMG 785) led to an 11.3% absolute increase in bone mineral density (BMD) in postmenopausal women with low BMD (body mass index). That compared with BMD increases of only 7% with teriparatide (Forteo), 4% with alendronate (Fosamax), and no change with a placebo. “The discovery of sclerostin as an osteocyte-mediated stimulator of osteoblast function and bone formation opened the door for considering the inhibition of this protein and regulator as a target for osteoporosis treatment,” McClung said.

To further explore the therapeutic potential of this antibody, the researchers conducted a Phase II study that enrolled 419 women whose lumbar spine, total hip, or femoral neck T-scores were between −2 and −3.5. The mean age of the participating women was 67. Researchers randomized participants to receive romosozumab in dosages of 70 mg, 140 mg, or 210 mg each month, 140 or 210 mg every three months, or a placebo.

The total hip increase in BMD with romosozumab was 4.1% at 12 months, which was approximately double that seen with alendronate and teriparatide. The researchers also saw changes in biomarkers of bone metabolism, McClung noted. The pattern seen with romosozumab, McClung said, was increases for serum P1NP, favoring bone formation, and decreases in serum CTX, suggesting a slowing of bone resorption after one week of treatment.

Adverse events were similar in the treatment groups. The most common was back or extremity pain. Serious adverse events occurred in 9.8% of the romosozumab groups and in 14% of the placebo group. The only treatment-related adverse events that occurred in the romosozumab groups were injection site reactions, but these were mild and did not lead to a discontinuation of treatment, said McClung.

jan 2014

Amgen/UCB osteoporosis drug shines in Phase II

Amgen and UCB have been boosted by promising mid-stage data for their investigational osteoporosis drug romosozumab.

A Phase II trial, the results from which have been published in the New England Journal of Medicine,showed that romosozumab demonstrated a significant increase in bone mineral density. Specifically, the trial demonstrated that, compared with placebo, treatment for 12 months with the anti-sclerostin biologic significantly increased BMD at the lumbar spine, total hip and femoral neck.

Amgen and UCB noted that significant increases were also observed in the first BMD assessment at three months and moreover, in exploratory analyses, increases observed at the lumbar spine and hip “were significantly greater than those observed with current treatments”, namely Merck & Co’s Fosamax (alendronate) and Eli Lilly’s Forteo (teriparatide).

Iris Loew-Friedrich, chief medical officer at UCB, noted that romosozumab is designed to stimulate bone formation, “which makes it different from most available treatments that reduce bone resorption”. She added that “we are encouraged by the emerging efficacy and safety profile, and look forward to further investigating its potential in the ongoing global Phase III clinical programme”. Final data from the latter, which will enroll up to 10,000 patients, are expected by the end of 2015.

Sean Harper, Amgen R&D chief, noted that broken bones due to osteoporosis are common “yet the seriousness of this health event remains underappreciated, with only two in ten women receiving follow-up testing or treatment after they have broken a bone”. He added that “with its bone-forming ability, romosozumab may result in new treatment strategies”.

If all goes well in Phase III, many observers believe romosozumab could be a blockbuster.

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