MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.

Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.

Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.

But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.

Romosozumab is a first-in-class monoclonal antibody directed against sclerostin, a glycoprotein that prevents mesenchymal cells from becoming osteoblasts. By inhibiting sclerostin, romosozumab promotes osteoblast production. The result is increased bone mineral density and bone formation coupled with decreased bone resorption, providing physicians with a promising new avenue for rapidly building strong bone.

FRAME randomized 7,180 postmenopausal women with osteoporosis to monthly injections of romosozumab 210 mg or placebo for 12 months; after that, patients who had been taking placebo switched to denosumab. Dr. Geusens presented only the first year’s placebo-controlled portion. The full FRAME study was published in the New England Journal of Medicine last September (doi: 10.1056/NEJMoa1607948).

At baseline, the women had a mean bone mineral density T score of –2.7 at the lumbar spine, –2.4 at the total hip, and –2.7 at the femoral neck. Mean age was 71 years. About 20% of the women had a previous vertebral fracture, and 22% a previous nonvertebral fracture. The mean FRAX (fracture risk assessment tool) score was 13.4 in both groups.

After 12 months, a new vertebral fracture had occurred in 59 women taking placebo and 16 taking romosozumab (1.8% vs. 0.5%). This amounted to a 73% risk reduction, Dr. Geusens said. Although he did not present 24-month data, the published article cited the antibody’s sustained effect, with a 50% risk reduction evident after the 12-month comparison with denosumab.

The drug also exerted its benefit quickly, Dr. Geusens said. Most of the fractures in the active group occurred in the first 6 months of treatment, with only two additional fractures later.

Romosozumab also was associated with a 36% decrease in the risk of clinical fracture by 12 months (1.6% vs. 2.5% placebo). There was also a positive effect on nonvertebral fractures, which constituted more than 85% of the clinical fractures. Nonvertebral fractures occurred in 56 of those taking the antibody and 75 of those taking placebo (1.6% vs. 2.1%; hazard ratio [HR], .75).

By 12 months, bone mineral density had increased in the romosozumab group by 13% more than in the placebo group at the lumbar spine, by 7% more at the total hip, and by 6% more at the femoral neck.

Dr. Geusens did not address the adverse event profile during his talk. However, according to the published study, romosozumab was generally well tolerated. Serious hypersensitivity events occurred in seven romosozumab patients. Injection site reactions were mostly mild and occurred in 5% of the active group and 3% of the placebo group.

Two patients taking romosozumab experienced osteonecrosis of the jaw; both incidences occurred during the second 12 months and in conjunction with dental issues (tooth extraction and poorly fitted dentures). Anti-romosozumab antibodies developed in 18% and neutralizing antibodies in 0.7%.

Serious cardiovascular events occurred in about 1% of each treatment group, with 17 among those taking romosozumab and15 cardiovascular deaths among those taking placebo – not a significant difference.

UCB and Amgen were pleased with FRAME’s results and, last July, submitted a Biologics License Application to the FDA based on the positive data. A 2017 approval was anticipated, UCB spokesman Scott Fleming said in an interview. But in May, the primary safety analysis of another phase III study, ARCH, threw a monkey wrench in the works.

ARCH compared romosozumab to alendronate in 4,100 postmenopausal women with osteoporosis. ARCH met its primary and secondary endpoints, reducing the incidence of new vertebral fractures by 50%, clinical fractures by 27%, and nonvertebral fractures by 19%. But significantly more women taking the antibody experienced an adjudicated serious cardiovascular event (2.5% vs. 1.9% on alendronate).

On May 21, the companies said these new data would delay romosozumab’s progress toward approval, despite the fact that the submission was based on FRAMES’s positive safety and efficacy data.

Mr. Fleming confirmed this in an interview.

“Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result we do not expect approval of romosozumab in the U.S. to occur in 2017,” he said. “Patient safety is of utmost importance and whilst the cardiac imbalance observed in ARCH was not seen in FRAME, it is important and our responsibility to better understand this imbalance. Further analysis of the ARCH study data is ongoing and will be submitted to a future medical conference and for publication.”

Dr. Geusens refused to comment on the cardiovascular adverse events, saying he had not seen the ARCH data; nor did he explain the cardiovascular events that did occur in FRAME.

Romosozumab also is being reviewed in Canada and Japan; those processes are still underway. Mr. Fleming said the companies are preparing a European Medicines Agency application as well. “The preparation for the European regulatory submission will continue as planned – second half of 2017,” he said.

Dr. Geusens has received research support from Amgen and other pharmaceutical companies. He is a consultant for Amgen and a member of its speakers bureau.

msullivan@frontlinemedcom.com

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Romosozumab cuts new vertebral fracture risk by 73%, but safety data are concerning