The D-Mab Men

Amgen's future lies in the hands of denosumab lead investigators Dr. Javier San Martin and Dr. Roger Dansey. Pharm Exec talked with them about the experience of developing what could be the industry's most promising new product
Oct 01, 2008

How D-Mab Works
All of a sudden, Amgen's future seems a whole lot brighter. The source of salvation? Denosumab, a Phase III monoclonal antibody that targets the RANK ligand pathway, which is responsible for regulating cells that destroy bones. Some analysts have called denosumab the most valuable late-stage compound in the industry's pipeline. And certainly, with Amgen testing the drug for the multi-billion dollar osteoporosis market as well as several oncology conditions, including breast and prostate cancer, excitement behind the biologic is mounting.

From Pathway to Product
With sales of Amgen's EPO drugs expected to slow, there's no time to waste, and the company is moving full-steam ahead. If successful—and the recent news that denosumab outperformed the osteo gold-standard Fosamax provides solid evidence—it could be the first personalized therapy for a primary care condition, and the first drug to target the RANK ligand pathway, discovered at Amgen.

Multiple indications for biopharmaceuticals is nothing new for the industry. But Amgen has bet big on denosumab by undertaking two enormous, nearly concurrent clinical trials for the drug. Its 8,000-patient oncology program is larger than the trials conducted for Avastin, Rituxan, Zometa, and Gleevec, and its osteoporosis study, with 10,000 patients, is Amgen's largest ever.

Steering the future for "d-mab"—and in essence, the company as a whole—are the program's two development heads, Dr. Javier San Martin, an Argentine native who cut his teeth designing osteoporosis and parathyroid hormone clinical trials for Lilly; and Dr. Roger Dansey, a physician from South Africa who brings a detail-oriented approach gleaned from his years as an associate professor and attending physician in a bone marrow transplant unit. Here, the men discuss the promise of denosumab, and their experience running these global clinical trials in tandem.

Osteoporosis and cancer seem like completely different conditions. What allows these two diseases to be treated with the same drug?

SAN MARTIN: The interesting feature for these two different indications is that the "bad guy" is the same: the osteoclast. The overfunction of osteoclasts is the key feature for both osteoporosis and cancer. Denosumab inhibits osteoclast formation, which has an effect on their function and survival.

With both conditions, the aim is to prevent clinical events related to bone failures. In osteoporosis, it's spine fractures and hip fractures. Osteoporosis is a chronic, progressive condition, and the goal is to increase overall bone strength to prevent those fractures from happening in the first place. We measure that improvement in bone strength by looking at bone density gains—and we have strong data there. On the oncology side, the failure happens where the bone metastasis makes the bone weaker in a particular place.

DANSEY: It's not without precedent. If you look at bisphosphonates, they play in both areas. There's the very potent intravenous bisphosphonate Zometa that dominates the cancer market versus the oral bisphosphonate market.

But we're fortunate. We have confidence in the specificity of the molecule and its ability to just do what it's supposed to do. The molecule for the RANK ligand pathway is well defined; the biological effects of blocking that pathway are well defined; we've got the molecule to block the pathway; and the molecule seems to only block this particular pathway.

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