Safety event delays US market approval of romosozumab

In a active comparator study, the humanised anti-sclerostin-antibody orginally developed by Celltech met the primary and key secondary endpoints. At the primary analysis, treatment with romosozumab (AMG-785) for 12 months followed by bisphosphonate treatment with alendronate significantly reduced the incidence of new vertebral fractures through 24 months, clinical fractures (primary endpoints) and non-vertebral fractures (key secondary endpoint) in postmenopausal women with osteoporosis at high risk for fracture, vs alendronate monotherapy.

However, Amgen and UCB, which acquired Celltech in 2004, observed a new relevant safety signal. 2.5% of patients treated with romosozumab showed serious cardiovascular adverse events versus 1.9% on alendronate at 12 months. “The newly observed cardiovascular safety signal will have to be assessed as part of the overall benefit to risk profile for Evenity,” said Sean Harper, R&D executive VP at Amgen. Overall adverse events and serious adverse events were generally similar between the treatment groups throughout the study and the first 12 months of romosozumab therapy.

Romosozumab is an investigational antibody targeting sclerostin, which inhibits bone formation through WNT signalling and thus promotes bone formation and reduces bone resorption simultaneously, increases bone mineral density and reduces the risk of fracture. In this study, women received subcutaneous injection of romosozumab monthly for 12 months followed by oral alendronate weekly for at least 12 months. At 24 months, women in the romosozumab arm experienced a 50% reduction in the relative risk of a new vertebral (spine) fracture compared to patients receiving alendronate. They also experienced a 27% reduction in the relative risk of clinical fracture (non-vertebral fracture and clinical vertebral fracture) at the primary analysis. Additionally, non-vertebral fractures were statistically significantly reduced by 19% in the romosozumab arm, including a nominally significant reduction in hip fractures.

No imbalance in cardiovascular serious adverse events was previously seen in the 7,180-patient placebo-controlled FRAME study subject to submission to the US FDA, Health Canada and Japanese PMDA for market authorisation. As Amgen has agreed with the FDA, to include the ARCH data in the regulatory review prior to marketing authorization, the company does not expect approval of romosozumab in the US in 2017.