Amgen and its investors breathed a collective sigh of relief July 25 as top-line phase III results showed denosumab met all three endpoints in a pivotal trial for post menopausal osteoporosis - with no safety surprises.

Nonetheless, the biotech has a tremendous stake in the success of the monoclonal antibody, the brightest light in a dim development pipeline for a firm that has faced major financial setbacks with its erythropoiesis-stimulating agents, so until final data are released, likely in September, no one is resting easy.

Investors will still want to see how denosumab's effect on fractures compares to existing bisphosphonates, like Merck's Fosamax (alendronate), which is already available as a generic. During Amgen's second quarter earnings call July 28, management cautioned investors not to compare data from the trial to data from studies involving other osteoporosis therapies, leading some analysts to wonder if the data may not be significantly better than that for existing bisphosphonates.

However, CEO Kevin Sharer assured investors that with Aranesp sales declines leveling off and denosumab development on plan, Amgen will emerge as a stabilized growth engine moving into 2009 ( ¹ Also see "Amgen Seeks To Leave ESA Woes Behind In 2009" - Pink Sheet, 29 July, 2008. ).

Hinting at just how important denosumab is to Amgen, the biotech cancelled its R&D day, originally scheduled for June 6, according to sources, to await more promising denosumab findings and a new ESA label expected any day now.

With the positive signal from the FREEDOM trial, it's expected that Amgen will file a BLA for denosumab in the postmenopausal osteoporosis indication by year end, with FDA approval anticipated by third quarter 2009 at the latest.

FREEDOM, a randomized, placebo-controlled, study of 7,800 women with osteoporosis, compared twice-yearly denosumab injections to injections of placebo for three years. Those given the drug had a statistically significant decrease in the primary endpoint - incidence of new vertebral fractures - over the placebo group.

Amgen said the trial met its secondary endpoints as well - a significant reduction in incidence of new non-vertebral and hip fractures compared with placebo.

No specific numbers, percentages or p-values were released by the firm, which said it hopes to publish that information at the American Society of Bone and Mineral Research meeting Sept. 12-16 in Montreal.

The denosumab and placebo groups had "similar" incidence and types of both serious and adverse events, including serious infections and neoplasms, Amgen said. Most common adverse events across both treatment arms were arthralgia, back pain, hypertension and nasopharyngitis.

Serious infections, a safety signal in smaller trials of denosumab, may be an issue for an advisory panel. A 24-month trial of 332 women showed a higher number of patients in the denosumab-treated group had serious adverse event infections (² Also see "Amgen Denosumab Data Positive On Bone Mineral Density In Women" - Pink Sheet, 3 April, 2008.).

Denosumab is a fully human monoclonal antibody that specifically targets the RANK ligand, which regulates cells that break down bone. Amgen is studying it for several associated conditions, including rheumatoid arthritis, treatment-induced bone loss in addition to postmenopausal osteoporosis. In addition, the firm hopes the mAb can delay bone metastases and inhibit and treat bone destruction across many stages of cancer.

Wall Street analysts agree that denosumab has the opportunity to be a best-in-class first-line agent with the potential to generate as much as $2.4 billion worldwide by 2016, just in the postmenopausal osteoporosis indications.

"Data available ahead of this trial showed impressive improvements in bone mineral density, but raised questions on Dmab's effect on fractures," JPMorgan analyst Geoffrey Meacham wrote in a July 25 research note.

The positive news from FREEDOM removes that overhang. But even if denosumab follows a best-case scenario, it would add about $650 million to the firm's bottom line in 2009 and 2010. Meanwhile, Amgen could face revenue declines from Epogen , Neupogen and Neulasta after settling antitrust allegations with rival Johnson & Johnson, which accused Amgen of bundling the products with Aranesp.

Deutsche Bank Securities analyst Mark Schoenebaum presented a "conservative" denosumab market share model that projects, by 2016, that the drug would have a 10 percent share of the worldwide market for first-line treatment of postmenopausal osteoporosis and a 33 percent share in second line. Schoenebaum also projects a 10 percent share of the market for osteoporosis prevention.

All told, the postmenopausal osteoporosis indications could generate $2.4 billion by 2016. Schoenebaum projects another $1.6 billion for the drug in the other indications listed above.

-Pamela Taulbee (p.taulbee@elsevier.com)

[Editor's Note: The original version of this story included incorrect projections for denosumab worldwide market share. The figures here are corrected. We apologize for any inconvenience.]

Amgen’s Positive Denosumab Pivotal Trial Reduces Overhangs For Firm

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