Assistant Managing Editor

As the dust settled following Thursday's messy panel vote, Amgen Inc.'s much-touted bone drug looked a bit worse for wear.

Despite winning favor in the critical $1-billion-plus postmenopausal osteoporosis (PMO) indication, denosumab got knocked around on safety issues, causing some analysts to rethink the drug's overall sales potential. While most believe the RANK ligand inhibitor will score a first-pass approval in postmenopausal osteoporosis, hopefully by the Oct. 19 PDUFA date, the product's uptake in the market likely will hinge on the severity of a risk evaluation and mitigation strategy, almost certain to be required after the Reproductive Health Drugs Advisory Committee voted 12 to 1 in favor of a REMS. (See BioWorld Today, Aug. 14, 2009.)

A worst-case scenario, a black-box warning similar to the label for Eli Lilly and Co.'s parathyroid hormone drug Forteo (teriparatide), would not come as a surprise to Leerink Swann analyst Joshua Schimmer. "We did not walk away from the discussion feeling warm and fuzzy regarding Dmab's PMO commercial prospects," he wrote in a research note.

The panel's split decision also sided with denosumab's use for bone loss associated with hormone ablation therapy in prostate cancer but came down against the drug for use in early stage breast cancer patients and as a preventative therapy in all three indications, including PMO. Advisors cited adverse reactions including tumor metastases and endocarditis, also raising concerns that long-term use of the drug could cause atypical fracture or osteonecrosis of the jaw.

The PMO prevention market and cancer treatment-induced bone loss markets are comparatively small - Deutsche Bank estimates put those markets at about $325 million total vs. $1 billion for PMO treatment opportunity - but the bigger question is whether those safety issues could hamper Amgen's plan to seek expanded approval of the drug in late-stage cancer patients with bone metastases, a market that potentially could exceed $2 billion.

So far, the data have been positive - particularly in breast cancer, in which denosumab beat current standard Zometa (zoledronic acid) - but denosumab was administered at a higher rate in that indication, given monthly, instead of twice-yearly, and at double the dose used in the PMO trials. Any risk of cancer or infection does "not bode well for denosumab use" for the bone metastases market, wrote Lazard analyst Joel Sendek.

But analyst Bret Holley, of Oppenheimer & Co., was more optimistic. If full efficacy and safety data confirm top-line results to date, the advisory panel likely would have a favorable opinion, he wrote in a research note.

It also might help that a denosumab application for cancer metastases is expected to go before the FDA's Oncologic Drugs Advisory Committee, rather than the reproductive health panel, which Leerink's Schimmer called "sloppy," and "disorganized and poorly run."

Analyst Michael Aberman, of Credit Suisse, echoed that comment, writing in a research note that the panel was "highly disappointing, in our opinion, primarily because of what we believe to be dubious comments made by the panelists."

And, so far, the bone metastases trials are going well. Data from the second Phase III trial testing denosumab in bone metastases in multiple myeloma or solid tumors (excluding breast and prostate cancers) were not quite as impressive as those from the first trial in breast cancer patients, but the drug still met its primary endpoint of noninferiority compared to Novartis AG's Zometa. (See BioWorld Today, July 9, 2009, and Aug. 5, 2009.)

Next year, Amgen expects to release results from two Phase III prostate cancer trials, one of which is testing denosumab's ability to reduce skeletal-related events in patients with bone metastases while the other is evaluating the drug in delaying bone metastases in earlier-stage patients. Pending positive data from the final two studies, the Thousand Oaks, Calif.-based firm expects to file for approval in the larger cancer indication next year.

Deutsche Bank analyst Mark Schoenebaum projects denosumab's SRE market potential as high as $2.1 billion in peak sales.

And approval for bone loss prevention still could be in the cards. Oppenheimer's Holley said there was clear evidence that denosumab did not promote prostate cancer progression and called the panel's decision "puzzling." He wrote that additional data likely will show that concern to be "overblown."

If denosumab wins FDA approval in all indications, peak sales could range between $4 billion and $5 billion, which would go a long way to help offset declining sales from Amgen's troubled erythropoiesis-stimulating agent franchise.

Amgen also is working to expand the label for EGFR drug Vectibix (panitumumab), which is approved in colorectal cancer, with ongoing Phase III studies in head and neck cancer and additional colorectal cancer indications. But sales growth of that drug is limited at best, and most investors are pinning their hopes on denosumab to be the firm's next blockbuster.

Denosumab also is under review in Europe, where, as of last month, it is partnered with GlaxoSmithKline plc. Under that deal, London-based GSK gained rights to the monoclonal antibody for PMO in Europe, Australia, New Zealand and Mexico, in exchange for up to $120 million in up-front and near-term milestone payments. (See BioWorld Today, July 28, 2009.)

Shares of Amgen (NASDAQ:AMGN) closed at $60.85 Friday, down 1 cent.

Published  August 17, 2009