Amgen’s recent announcement of phase III trial data showing that it’s monoclonal antibody, denosumab was superior to Novartis’ Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results.

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin.  It’s development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

RANK Ligand is a TNF famly member, a protein that is expressed on the sufrace of marrow, stromal cells and osteoblasts (the cells responsible for bone formation). When RANK-L binds with its receptor RANK it stimulates the activity of osteoclasts (cells responsible for bone resorption).  In the body, RANK-L production is naturally regulated by the protein Osteoprotegerin (OPG), which binds with RANK-L thereby preventing it from binding to its receptor, RANK.  When there is insufficient OPG, or too much RANK-L produced, excess bone loss occurs.   This occurs in post-menopausal women or in cancer related bone loss.

Denosumab acts by attaching itself to RANK-L, thereby inhibiting its action. Deprived of RANK-L, osteoclasts cannot form, function or survive.  The result is less bone destruction and bone loss.  Understanding the RANK Ligand pathway has been a breakthrough step in understanding bone biology.

Many cancer patients end up with bone metastases that not only causes pain, but also bone destruction.  Roodman, in a 2004 New England Journal article, proposed the “vicious cycle” hypothesis to explain this: Tumor cells produce parathyroid hormone-related peptide (PTHrP), which stimulates osteoblasts to produce RANK ligand leading to less production (downregulation) of osteoprotegerin (OPG), thereby stimulating osteoclasts to resorb more bone.  At the same time, production of PTHrP promotes tumor growth directly.  Therefore, it should come as no surprise that denosumab would be effective in cancer patients with bone mets and skeletal related events.

What does the future hold for denosumab?  In the postmenopausal osteoporosis market, a once or twice yearly injection is extremely attractive given its ease of use. Compliance is a real issue with bisphosphates such as alendronate or risedronate where a daily pill must be taken.  Many primary care physicians are not set-up to administer an infusion, which is what Novartis’ once a year osteoporosis treatment, Reclast requires.

However, despite impressive clinical data, Amgen does not yet have a home run.  It lacks a large sales force and infrastructure to sell to primary care physicians. Also with generic fosamax (alendronate) available, the cost/benefit trade off is going to be a key factor in uptake.  The cost of denosumab will need to be carefully considered for Amgen to enter this competitive market.  The FDA advisory board meets on August 13 to discuss Amgen’s BLA application and consider whether to recommend approval for the treatment and prevention of osteoporosis, and treatment of bone loss in patients undergoing hormone ablation for prostrate and breast cancer.  Given the positive data from the phase III pivotal studies, a positive recommendation is expected with approval by the FDA expected in October.

For cancer patients, denosumab could become the gold-standard for treatment of bone metastases given its superiority over Novartis’ Zometa.  For oncologists, the fact that denosumab only requires an injection while Zometa requires an infusion is less of an issue.  The key to success for oncology drugs is based solely on the data. If the positive results continue, Amgen are likely to take market share from Zometa once approval for the treatment of bone metastases is obtained in 2010 or 2011.

So, my take on this is that denosumab is a real winner for Amgen.  Whether it will capture the market for postmenopausal osteoporosis remains to be seen, but it is an exciting new drug that will benefit cancer patients.  Further data on denosumab can be expected from the September meeting of the American Society of Bone and Mineral Research (ASBMR) in Denver.

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