Romosozumab Benefits Sustained After Transition to Denosumab

Nancy A. Melville

September 19, 2014

HOUSTON – The investigational antisclerostin antibody romosozumab (Amgen/UCB Pharma) appears to promote substantial increases in bone-mineral density (BMD) following 2 years of treatment, according to new phase 2 clinical-trial results. Moreover, the improvements are sustained for a third year when patients are transitioned to the antiresorptive drug denosumab (Prolia, Amgen).

"We found romosozumab leads to substantial and continued BMD increases over 2 years through an increase in bone formation and a simultaneous reduction in bone resorption," said study investigator Michael McClung, MD, director of the Oregon Osteoporosis Center, in Portland.

However, he commented, "Discontinuation of romosozumab after 2 years of treatment, meanwhile, resulted in decreases of BMD toward baseline levels and the return of bone-formation marker P1NP to pretreatment levels."

Sclerostin is an important inhibitor of osteoblast-mediated bone formation, and an earlier phase 2 study of romosozumab (N Engl J Med. 2014;370:412-420), as reported by Medscape Medical News, showed rapid and marked increases in markers of bone formation, along with sustained decreases in markers of bone resorption after treatment for 12 months in postmenopausal women with low BMD.

The best currently available osteoporosis drugs either provide bone remodeling or prevent resorption. Therefore, the possibility that a single drug might work through both mechanisms has some researchers referring to romosozumab as a potential breakthrough therapy, providing that the early safety and efficacy results are replicated in longer-term studies.

In the updated results from the phase 2 trial, presented here at the American Society for Bone and Mineral Research (ASBMR) 2014 Annual Meeting, Dr. McClung reported on 2-year treatment data, followed by a 1-year extension phase in which patients were randomized to either subcutaneous denosumab 60 mg every 6 months or placebo.

A total of 419 postmenopausal women with low BMD enrolled in the trial. In the first 2 years of the study, the women received 1 of 5 romosozumab regimens (70, 140, or 210 mg once monthly or 140 mg or 210 mg every 3 months) or placebo.

The rapid and significant increases in lumbar-spine and total-hip BMD seen in the romosozumab group in the first year were sustained through the second year, with the largest gains seen with the 210-mg once-monthly group, which showed an improvement of 15.7% in lumbar-spine BMD and 6.0% increase in total-hip BMD.

The researchers also saw decreases in the bone-resorption biomarker CTX. They also detected increases in bone-formation biomarker P1NP; however, those increases were transitory, returning to near-baseline levels within 6 to 12 months.

In women who switched to denosumab for the third year of the trial, BMD continued to increase at a rate similar to that seen the second year on romosozumab. By contrast, BMD returned to pretreatment levels in women who were switched to placebo for the third year.

Women receiving denosumab further showed a rapid stimulation of the bone-formation marker P1NP and decreased CTX, a marker of bone resorption.

There were no differences between the treatment groups of romosozumab or denosumab and placebo in terms of side effects, with the exception of injection-site reactions, which were reported as mild.

"The transition to denosumab after 2 years of romosozumab resulted in continued increases in important skeletal sites," Dr. McClung said. "The effects of BMD are augmented by the follow-on therapy with a potent antiremodeling drug like denosumab."

The drug is currently being evaluated in 2 large phase 3 trials as a 1-year treatment followed by antiremodeling therapy.

Endocrinologist Erik Fink Eriksen, MD, of Oslo University Hospital in Norway, commented that the results show romosozumab's potential value as another tool to tackle osteoporosis.

"The romosozumab study underscores the potency of this drug," he told Medscape Medical News. "The findings further show that denosumab is effective as a follow-up therapy in a sequential pattern [following romosozumab treatment].

"This combination seems to be a very effective option for the future treatment of osteoporosis."

The study was supported by Amgen and UCB Pharma. Dr. McClung has received research grants from Amgen and Regeneron and served on speaker's bureaus for Amgen and Vivus. Dr. Eriksen has consulted for Novartis, Amgen, Lilly, and Merck in the past but currently is in academic medicine and holds no stock in any drug company.

American Society for Bone and Mineral Research 2014 Annual Meeting; September 14, 2014; Houston, Texas. Abstract 1152.

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