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Denosumab ?
Monoclonal antibody
Source Human
Target RANK ligand
Identifiers
CAS number 615258-40-7
ATC code M05BX04
PubChem  ?
Chemical data
Formula C 6404H9912N1724O2004S50  
Mol. mass 144.7 kDa
Pharmacokinetic data
Bioavailability N/A
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

Denosumab formerly known as AMG 162, proposed trade name Prolia is a fully-human monoclonal antibody which is being studied in the treatment of osteoporosis, treatment-induced bone loss, bone metastases, rheumatoid arthritis, multiple myeloma and giant cell tumor of bone.[1][2]

Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab therefore mimicks the endogenous effects of osteoprotegerin.

Contents

Effectiveness

Amgen has reported on two clinical trials designed and funded by the company:[3]

  • In a phase 3 clinical trial ('FREEDOM') involving 7,808 women, aged 60 to 90, there were significant improvements in the subset of women with more severe disease at the beginning of the study (two or more prevalent vertebral fractures and/or one or more prevalent vertebral fractures with moderate or severe deformity). Researchers reported a 35% risk reduction with denosumab compared with placebo (17% vs. 49%), with new vertebral fractures in this subset of only 31% for those taking denosumab, versus 71% receiving the placebo.[4][5]
  • The second phase 3 clinical trial involved 1,468 prostate cancer patients receiving hormone-deprivation therapy, who were randomised to receive either denosumab or a placebo every 6 months over a 36 month period. All patients also received supplemental calcium and vitamin D. Of those taking the placebo, 3.9% experienced bone fractures during the 36 months, compared with 1.5% of those who received denosumab.[6]

Regulatory approval

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United States

The antibody is being developed by the company Amgen.[7] The U.S. Food and Drug Administration (FDA) delayed approval of denosumab in October 2009 because they needed more information.[8]

On 13 August 2009, the company issued a press release regarding the meeting that day with the Advisory Committee for Reproductive Health Drugs (ACRHD) of the (FDA), to review the potential uses of Prolia. The press release said:

After reviewing safety and efficacy data from 30 clinical studies involving more than 12,000 patients, the Committee recommended approval of Prolia for the treatment of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer. The Committee recommended against approval of Prolia to treat or prevent bone loss in women with breast cancer undergoing hormone ablation until additional data are available. The Committee also recommended against approval of Prolia to prevent bone loss in low-risk patients in all three populations. Finally, the panel recommended that Prolia have a Risk Evaluation and Mitigation Strategy (REMS), which could include a medication guide and a healthcare provider communications plan.[9]

If approved, denosumab will be the first biologic therapy – a drug made from biological, rather than chemical, processes – that will be sold to primary care physicians, aside from vaccines.[10]

Europe

The Committee for Medicinal Products for Human Use (CHMP) issued a Positive Opinion for denosumab on 17 December 2009.[11][12] In most cases, a CHMP Positive Opinion leads to drug approval within a few months.

Sales and pricing

In mid-September 2009, The Wall Street Journal reported that Amgen was building a primary care sales force, in expectation of regulatory approval of denosumab by the FDA in mid-October. The focus of the company's efforts will be on primary care physicians in the U.S.[10]

In September 2009, the firm Sanford Bernstein projected that annual worldwide sales of the drug would reach $5 billion in the year 2015.[13] It projected 2010 sales of over $650 million, mostly from use as a twice-yearly injectable for osteoporosis treatment in post-menopausal women over 50.[14]

Amgen has not said how much the drug will cost, but analysts expect it to be at least $2,000 a year, and potentially much higher.[3]

References

  1. ^ McClung MR, Lewiecki EM, Cohen SB, et al. (February 2006). "Denosumab in postmenopausal women with low bone mineral density". The New England journal of medicine 354 (8): 821–31. doi:10.1056/NEJMoa044459. PMID 16495394. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=16495394&promo=ONFLNS19.  
  2. ^ Ellis GK, Bone HG, Chlebowski R, et al. (August 2008). "Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer". Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26 (30): 4875–82. doi:10.1200/JCO.2008.16.3832. PMID 18725648. http://www.jco.org/cgi/pmidlookup?view=long&pmid=18725648.  
  3. ^ a b Thomas H. Maugh II (August 12, 2009). "New osteoporosis drug shown to reduce spinal fractures". Los Angeles Times. http://www.latimes.com/features/health/la-sci-bone-drug12-2009aug12,0,1313143.story.  
  4. ^ Donald A. Bergman (September 16, 2009). "Denosumab: Fracture risk reduced in high-risk subset in FREEDOM". Endocrine Today. http://www.endocrinetoday.com/view.aspx?rid=43797.  
  5. ^ Cummings, S. R.; Martin, J. S.; McClung, M. R.; Siris, E. S.; Eastell, R.; Reid, I. R.; Delmas, P.; Zoog, H. B. et al. (2009). "Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis". New England Journal of Medicine 361: 756. doi:10.1056/NEJMoa0809493. http://content.nejm.org/cgi/content/abstract/361/8/756.  
  6. ^ John Otrompke (September 15, 2009). "Experimental Drug Reduces Fractures Related to Prostate Cancer Treatment: Presented at ASBMR". Doctor's Guide. http://www.docguide.com/news/content.nsf/news/852576140048867A85257632006F9B70.  
  7. ^ Denosumab from Amgen.
  8. ^ Pollack, Andrew (19 October 2009). "F.D.A. Says No to an Amgen Bone Drug". New York Times. http://www.nytimes.com/2009/10/20/business/20amgen.html?_r=1&ref=business.  
  9. ^ "Amgen Issues Statement on Outcomes of Advisory Committee for Reproductive Health Drugs (ACRHD) Meeting". PRNewswire/FirstCall. August 13, 2009. http://www.urotoday.com/3401/browse_categories/prostate_cancer/amgen_issues_statement_on_outcomes_of_advisory_committee_for_reproductive_health_drugs_acrhd_meeting08192009.html.  
  10. ^ a b Thomas Gryta (September 17, 2009). "Amgen Hiring Mobile Reps In Building Bone Drug Sales Force". Wall Street Journal. http://online.wsj.com/article/BT-CO-20090917-712405.html.  
  11. ^ "Summary of Positive Opinion for Prolia". European Medicines Agency. 17 December 2009. http://www.ema.europa.eu/pdfs/human/opinion/Prolia_77616809en.pdf. Retrieved 7 January 2010.  
  12. ^ "Amgen Receives CHMP Positive Opinion for Prolia(TM) (Denosumab) in the European Union". Amgen. 18 December 2010. http://www.amgen.com/media/media_pr_detail.jsp?year=2009&releaseID=1367560. Retrieved 7 January 2010.  
  13. ^ Jacob Goldstein (August 14, 2009). "Analysts React to FDA Panel: 'It Wasn’t a Perfect Day for Amgen'". The Wall Street Journal. http://blogs.wsj.com/health/2009/08/14/analysts-react-to-fda-panel-it-wasnt-a-perfect-day-for-amgen/.  
  14. ^ Dimitra Defotis (September 7, 2009). "At Amgen, a Prescription for Success". Barrons. http://online.barrons.com/article/SB125211286339588089.html.  

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