Romosozumab, ロモソズマブ (遺伝子組換え)

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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 Medicine. 375: 1532–1543. doi:10.1056/NEJMoa1607948. PMID 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

Monoclonals for bone, musculoskeletal, circulatory, and neurologic systems
Bone (“-os-“, “-s(o)-“)
Human (“-osu-“)
Humanized (“-sozu-“)
Musculoskeletal (“-mul-“)
Human (“-mulu-“)
Circulatory (“-c(i[r])-“)
Human (“-ciru-“)
Mouse (“-ciro-“)
Chimeric (“-cixi-“)
Humanized (“-cizu-“)
Neurologic (“-ne(u)(r)-“)
Human (“-neru-“)
Humanized (“-nezu-“/”-neuzu-“)
Angiogenesis inhibitor (“-anibi-“)
Humanized (“-anibizu-“)
Growth factor (“-gr(o)-“)
Human (“-gru-“)
Humanized (“-grozu-“)
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