DUBLIN – To no one's great surprise, UCB SA and Amgen Inc. confirmed Monday that they had received a complete response letter from the FDA for their BLA for Evenity (romosozumab), which is in development for osteoporosis in postmenopausal women.

The drug's original PDUFA date was Tuesday. Its next one will be some time away. "We don't anticipate getting approval this year," Scott Fleming, spokesman at Brussels, Belgium-based UCB, told BioWorld.

The two partners had indicated the likelihood of such an outcome back in May, when unveiling data from the phase III Arch trial, which compared a regimen of romosozumab combined with alendronate with alendronate alone in about 4,100 patients. The study unearthed a potential cardiovascular safety signal not seen in a previous placebo-controlled study, called Frame, and it has prompted the FDA to take a deeper look. (See BioWorld Today, May 23, 2017.)

The original BLA, which they filed on July 19, 2016, and which the FDA accepted for review on Sept. 26, 2016, was primarily based on data from the Frame study, which recruited about 7,180 participants.

The two companies will release further details of the likely timelines involved in the resubmission process next week, when they report their respective half-yearly financial results. "It's not a full resubmission again," Fleming said.

Jefferies analyst Michael Yee attributed the differing safety signals to the play of chance. "Since neither of these studies are powered to show significant differences in CV [cardiovascular] events and preclinical and genetic data hasn't suggested anything target-related, it would seem to be just a numerical imbalance and bad luck," he wrote in a flash note. "If the two studies were pooled, [we would be] unlikely to see any major difference either."

According to Yee's analysis, the pooled data yield cardiovascular adverse event rates of 0.89 percent and 0.68 percent for the study and control groups, respectively.

However, another phase III study, Bridge, which recruited 245 men with osteoporosis, also demonstrated an imbalance between study and control arms in terms of cardiovascular signals – 4.9 percent (8/163) of subjects on romosozumab had a serious cardiovascular event, whereas 2.5 percent (1/81) of subjects in the control group did. The control arm registered more cardiovascular deaths (1/81; 1.2 percent than the study arm (1/163; 0.6 percent).

The FDA has also requested that the partners now include data from that trial, too. The data were unveiled last November and were already included in a Japanese regulatory filing submitted on Dec. 20, 2016, by Amgen Astellas Biopharma K.K, a joint venture between Amgen, of Thousand Oaks, Calif., and Tokyo-based Astellas Pharma Inc.

Filing plans for Europe remain unchanged. "The European submission was always planned for the end of this year or very early in 2018," Fleming said. "Preparation for that is continuing as planned."

Meanwhile, Amgen's existing bone health franchise, based on the RANK ligand inhibitor denosumab, continues to thrive. The company markets the drug under two different brands. Prolia, which is administered at 60 mg every six months, is licensed for women with osteoporosis, men with non-metastatic prostate cancer at high risk of fracture due to androgen deprivation therapy, and woman at high risk of fracture because of adjuvant aromatase inhibitor therapy for breast cancer. Xgeva is a higher-dose version of the same product and is administered at 120 mg every four weeks to prevent skeletal-related events in patients with bone metastases from solid tumors or to patients with unresectable giant cell tumor of the bone.

Between them, the two products amassed $827 million in first-quarter sales, with $425 million coming from Prolia and $402 million from Xgeva.

Denosumab is not a direct competitor to romosozumab, given their contrasting mechanisms of action. Denosumab combats the breakdown of bone by regulating the activity of osteoclasts, the cells that drive bone resorption. Romosozumab is a "bone builder" – it acts by inhibiting sclerostin, a signal protein thought to inhibit bone formation by down-regulating the Wnt signal pathway. The drug is being positioned as a complement to rather than a replacement for anti-resorption therapy.

Analysts have trimmed their original blockbuster forecasts, however, given the present uncertainty. "Approval still seems likely, although potentially in [a] narrower population," Jefferies analyst Peter Welford wrote in a flash note. Although he is currently forecasting $1.25 billion in worldwide peak sales, "greater understanding of Evenity's risk-benefit profile in due course could understandably have an impact on its commercial potential," he stated.

Nonetheless, Welford said he still sees a future for the drug. "We would highlight that despite the safety signal seen, Evenity has demonstrated efficacy in reducing both vertebral and the clinically relevant non-vertebral fractures, suggesting that there remains a role for this therapy for the treatment of [post-menopausal osteoporosis], albeit potentially in a narrower patient population than originally envisaged, in our view."