As Amgen gets ready for a review of denosumab by advisors to the US Food and Drug Administration, agency staff have taken a fairly cautious stance over the risk/benefit profile of the eagerly-anticipated osteoporosis therapy.

In a memo posted on the FDA’s website, staffers noted, ahead of a Reproductive Health Drugs Advisory Committee meeting on Thursday, that a number of safety issues associated with denosumab exposure have been identified in trials. Amgen is seeking approval for the drug to treat or prevent osteoporosis in postmenopausal women and bone loss caused by hormone therapy in patients with breast or prostate cancer.

These safety concerns include serious infection, the development of new malignancies, and “the potential for tumour progression in patients with cancer”. The FDA memo also points to findings that suggest suppression of bone remodelling which may lead to complications such as “delayed fracture healing, osteonecrosis of the jaw or atypical fracture with long-term use”, as well as dermatologic adverse events.

The memo gos on to say that “of particular concern, in light of these safety issues, is whether the risk/benefit balance for the osteoporosis prevention indication, both for patients with and without cancer, supports approval”. The staffers add that if denosumab were to be approved, they would want to know whether a risk evaluation and mitigation strategy would be needed to ensure that its benefits outweigh its risks.

Amgen said that the overall safety and efficacy of denosumab “offer a meaningful alternative to existing therapies". The FDA memo acknowledged that the drug is effective at increasing bone mineral density and reducing the risk of fractures and its dosing schedule of twice-yearly injections should help the application as well.

The comments did not seem to trouble analysts too much and Joel Sendek at Lazard Capital Markets issued a note saying that Amgen should be able to address the concerns to the panellists’ satisfaction. He wrote that “based on the briefing documents, which did not reveal any new safety or efficacy concerns, we anticipate that the advisory panel will likely vote for denosumab approval”.

Other analysts are a bit concerned as to whether the panel will recommend a tough REMS which could affect take-up of the drug, which Amgen plans to market as Prolia in osteoporosis and in bone loss associated with hormone therapy for breast and prostate cancer, if it is approved. A final decision is due by October 19.

If given the green light, denosumab, a human monoclonal antibody that targets RANK ligand, a regulator of osteoclasts (the cells that break down bone), will compete against the likes of Novartis’ Reclast/Zometa (zoledronic acid) and Merck & Co’s Fosamax (alendronate), which is now available generically.