The FDA has rejected Amgen’s application for approval of osteoporosis candidate romosozumab. Officials knocked back the filing after phase 3 data linked the sclerostin-targeting antibody to an increased risk of cardiovascular adverse events.
Amgen said it no longer expected to win FDA approval this year when it published the safety data in May. The FDA has now confirmed its rejection of romosozumab in a complete response letter to Amgen and its partner UCB. Amgen and UCB are now pooling their late-phase data and refiling in a bid to show romosozumab has a positive risk-benefit profile.
The original filing used data from the 7,180-person, placebo-controlled FRAME trial. That study was free from cardiovascular safety concerns but missed a key secondary endpoint. This miss on risk of nonvertebral fractures handed the advantage to Radius Health and its now-approved rival to romosozumab, Tymlos.
Amgen provided a further boost to Radius in May when it posted data from another phase 3 trial that used alendronate, also known as Merck’s Fosamax, as an active comparator. Romosozumab met its primary and key secondary endpoints in the 4,093-patient ARCH trial. But a higher rate of cardiovascular adverse events in the romosozumab arm tarnished the data and left Amgen looking down the barrel of a FDA rejection.
The FDA now wants Amgen to put together an application that pulls in data from ARCH, FRAME and a third, as-yet-unreported phase 3 trial dubbed BRIDGE. That third trial only enrolled 245 patients. And whereas ARCH and FRAME enrolled postmenopausal women, BRIDGE recruited men.
That difference in the inclusion/exclusion criteria rendered the BRIDGE efficacy data irrelevant for Amgen’s application for approval in postmenopausal women. But with the focus now shifting to the safety profile of romosozumab, all clinical data are relevant.
Having tested romosozumab in more than 13,000 patients and delivered a clean cardiovascular safety profile in the largest trial, Amgen potentially has the data to allay the FDA’s concerns. That gives it a shot at quickly resubmitting and winning approval in the next financial year. But the safety concerns could limit the label of romosozumab and in doing so dent its blockbuster ambitions.
“Ultimately based on a label that fits the right risk/benefit population and based on conversations with Amgen, we still think the drug could be a $500M+ franchise,” Jefferies analyst Michael Yee wrote in a note to investors.
The situation makes romosozumab part of an emerging clutch of Amgen drugs that have run into trouble—or look likely to do so—when trying to transition from promising clinical prospects to commercial successes. PCSK9 drug Repatha stumbled out of the blocks after winning approval. And CGRP migraine drug erenumab will have to fight off competition from a clutch of companies including Eli Lilly if it is to avoid a similar fate.