Long term safety worries drive negative Xgeva vote

FDA experts’ verdict on a label expansion for Amgen’s Xgeva into prevention of bone metastases was decisive and expected. The 12-1 vote yesterday registered only slightly on Amgen’s share price, which closed down 2%, at $68.06.

With its current indication, prevention of skeletal related events in cancer patients with bone metastases, expected to generate blockbuster sales by 2014, the outlook for Xgeva far from fatally harmed. However, growth into a new setting has almost certainly been forestalled based on the risks of long-term use. Given that the antibody failed to extend overall survival and that its use in prevention could increase the chances patients could suffer from jawbone destruction, the FDA experts came down firmly on the risks outweighing the benefits.

Safety risks unknown

Xgeva is known generically as denosumab, and sold as Prolia it is also prescribed in osteoporosis. Its high cost - $1,650 a month – and place as a second-line medication for patients at a high risk of fracture means its growth will be limited in that indication - its 2016 forecast of $645m is a small share of the osteoporosis market, according to EvaluatePharma data.

Thus the cancer indications have always been the more promising ones. In 2010 it gained FDA approval in prevention of skeletal related events, such as fractures, in patients with bone metastases from solid tumours. That indication is forecast to bring in $1.61bn in 2016.

That the antibody managed to show any benefit at all, albeit it in disease progression, was somewhat of a surprise (Amgen data confirms Xgeva potential, December 14, 2010). However, its failure to show any survival benefit was a key question for the panel (Event - Survival the question in Xgeva bone metastases panel, January 17, 2012).

Given that many prostate cancer patients might have taken Xgeva for both prevention and treatment of bone metastases, the failure to calculate the risk of osteonecrosis of the jaw with this increased duration of treatment raised questions about whether its benefits outweighed its risks, FDA staff argued. The panel agreed, with the exception of a single vote, saying it had not demonstrated a favourable risk-benefit profile.

The damage to Amgen was negligible; many analysts did not forecast any sales and those who did will probably erase those figures after the advisory committee vote.

This ruling could impact some of Amgen’s other trials for the bone-building therapy. A 4,500 patient global phase III trial in prevention of bone metastases in breast cancer patients is underway, data is not due for four years, but observers will be looking closely at any interim looks at the trials.

Silver lining

However, there were some putting a postive shine on the panel result. Analysts from UBS noted that the vote may help maintain Xgeva's relatively good safety profile by averting the unexpectedly high rates of jawbone destruction asssociated with extended use in the prevention setting. Still, the UBS reduced its price target by $1 to $69 following the vote, and added that another $1 could come off should it also fail to get EU backing, now a very likely scenario.

Whilst Xgeva remains the most important growth driver for Amgen, the California group has so far been unable to widen its use. The decision by the panel will almost certainly be confirmed by the PDUFA action date of April 26, spelling the end to Xgeva's use in this setting.

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