FDA approved Amgen’s bone-strengthening drug denosumab Nov. 18 for its first oncology indication, prevention of skeletal-related events – bone fractures or bone pain requiring radiation treatment – in patients with bone metastases from solid tumors.

The new indication expands the monoclonal antibody’s label beyond its approval to treat osteoporosis in post-menopausal women, which FDA okayed in June (Also see "FDA Okays Amgen's Prolia, But With Hefty Post-Marketing Requirements In Tow" - Pink Sheet, 1 June, 2010.). Denosumab is marketed as Prolia for osteoporosis, but will be given at a higher dosage and greater frequency in the SRE-prevention setting, under a new brand name of Xgeva.

The sBLA for the SRE-prevention indication was filed in May, with FDA accepting the application for six-month priority review. With approval occurring on the user-fee date of Nov. 18, Amgen expressed some surprise that FDA was able to complete its review within that short time window. In an interview, Amgen VP-Global Development Ron Baynes, the therapeutic area head for hematology/oncology, noted that the filing totaled about 90 gigabytes, comprising more than 1.5 million case report forms and nearly half-a-million images.

Backing the filing was a program of three Phase III trials involving more than 5,700 patients that measured denosumab’s efficacy and safety compared to the current standard of care, Novartis’ bisphosphonate Zometa (zoledronic acid).

Tested in both advanced prostate cancer and advanced breast cancer which had involved metastases to bone, denosumab demonstrated superiority in preventing SREs. In a third trial, testing the two drugs head-to-head in a variety of solid tumors, including multiple myeloma, denosumab demonstrated non-inferiority but did not achieve statistical superiority.

FDA’s approval language clarifies that while denosumab was approved to prevent SREs in most solid tumors, it is not currently indicated for SRE prevention in multiple myeloma or in blood cancers.

Baynes had conceded the possibility of a split indication, noting that multiple myeloma patients made up only about 10% of the participants in the 244 study in solid tumors. “Myeloma has been one of the more challenging aspects, one where we just don’t have enough data right now,” he said. “We’re committed to doing additional trials in that disease.”

Sales progress has been slow for denosumab – a RANK ligand inhibitor – in the osteoporosis setting. At the end of the third quarter, Amgen announced total U.S. sales for the drug of $10 million for the year, below analyst expectations, and $3 million in ex-U.S. sales. The oncology indication is expected to be a major boon for the drug’s sales.

Low Sales Expected To Pick Up Dramatically

While ISI Group analyst Mark Schoenebaum predicts denosumab sales in oncology could hit the blockbuster mark by 2016, a Robert W. Baird & Co. projection envisions steady U.S. sales progress for the drug, starting at $172 million in 2011 and rising to $721 million by 2014.

Zometa, which is well established in the sizeable osteoporosis market as well, posted worldwide sales of $1.5 billion in 2009, according to Novartis.

Baynes explained that Amgen intends to target clinicians with a four-part rationale for why denosumab is a better supportive therapy in cancer than Zometa. In addition to superior efficacy, the company will stress that unlike Zometa, its drug requires no dose adjustment due to kidney complications, presents no flu-like syndrome, and is dosed with a simple subcutaneous injection. “Denosumab is not cleared by the kidney [and] there is no dose adjustment for kidney function,” he said. “In the clinical trials program, that was what was seen – essentially there was a quite significant number of dose adjustments and withholding for Zometa, but no dose adjustments for denosumab. That’s a big deal clinically.”

One area in which denosumab does not have an advantage over Zometa is in the incidence of adverse events, particularly osteonecrosis of the jaw. In an integrated analysis of the three Phase III trials, ONJ occurred infrequently, but in 1.8% of denosumab patients compared with 1.3% of those receiving Zometa. Hypocalcemia also occurred more frequently among denosumab users, 9.6% to 5.0% for Zometa.

Baynes stressed that incidence of ONJ was at the low end of what previously had been reported – rates of 2% to 12% – and that while denosumab had a slightly higher incidence it was “a small numeric imbalance but … not statistically significant.”

The Start Of Greater Expansions?

While the SRE indication is expected to be a powerful revenue generator, denosumab also is being studied for bone metastasis prevention in prostate cancer patients, an indication that market analysts say could be even more lucrative. In a July research note, JP Morgan analyst Geoffrey Meacham projected that opportunity as “easily a $1 billion indication at peak.”

Also pending is Amgen’s response to an October 2009 “complete response” letter for the indications of prevention of bone loss in patients undergoing hormone ablation therapy in breast and prostate cancer. An indication for prevention of post-menopausal osteoporosis was also rejected at that time; FDA requested a new clinical program for that claim.

Amgen is banking on denosumab to make up for flagging sales of its primary revenue producers, including Enbrel, Epogen/Aranesp, and Neulasta/Neupogen.

By Joseph Haas, Paul Bonanos

Amgen Obtains Broader Label For Denosumab With Oncology Indication

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