Romosozumab Receives FDA Approval for Postmenopausal Osteoporosis
Drug/Device: Romosozumab - Drug
Sponsor: Amgen Inc.
Committee: Bone, Reproductive, and Urologic Drugs Advisory Committee
Indications: Treatment of osteoporosis in postmenopausal women at high risk of fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy
Question 1：Is the overall benefit/risk profile of romosozumab acceptable to support approval?
Vote Results: Yes 18 No 1 Abstain 0
FDA Documents:
Romosozumab Background :
Applicant submitted application for new drug romosozumab with three studies. FDA agreed that the applicant has established the effectiveness of romosozumab for the treatment of postmenopausal osteoporosis. A placebo-controlled fracture trial 20070337 in women with postmenopausal osteoporosis was to support approval of the biologics license application (BLA). All three trials demonstrated effectiveness of romosozumab on their primary efficacy endpoints compared to control arms. However, there was a higher incidence of positively adjudicated cardiovascular serious adverse events (MACE) during the year of romosozumab therapy in studies 20110142 and 20110174.
Unique Challenges:
Study design:
In this application, three pivotal phase 3 clinical trials were submitted to support FDA approval. These studies differed by patient populations and control treatments . The study 20070337 was a placebo-controlled fracture trial in women with postmenopausal osteoporosis. The trial 20110142 was an alendronate-controlled fracture trial in postmenopausal women with osteoporosis; and trial 20110174 was a placebo-controlled bone mineral density (BMD) study in men with osteoporosis.
Statistical Analysis:
FDA performed a fixed-effect network meta-analysis to investigate increased MACE associated with romosozumab for the core 12-month double blind trial period. This approach was also used to indirectly estimate the effect of alendronate vs placebo. The result of meta-analysis showed increased but not statistically significant difference in risk of MACE between the trial arms (HR 1.38 [0.96 – 1.99]) and insignificantly decreased risk associated with alendronate vs placebo (HR 0.55 [0.27-1.44]).
Efficacy:
All three trials were able to demonstrate effectiveness of romosozumab on their primary efficacy endpoints. However, the FDA expressed concerns over applicability of the findings to the U.S. population as there were very few U.S. participants in trials 20070337 (1.8%) and 20110142 (1.4%). The applicant was able to demonstrate the applicability by 1) indicating a consistent change in BMD across all geographical areas, and 2) demonstrating a lack of treatment-by-region interaction through statistical analysis.
Safety:
There is a concern over increased cardiovascular (CV) risk in both trials 20110142 and 20110174. The number of CV events in trial 20110174 was too few to draw definitive conclusions. Therefore trials 20070337 and 20110142 were compared. Given that the placebo-controlled trial 20070337 had not shown an increase in CV risk, whether romosozumab confers CV risk is still unclear. Furthermore, it may be biologically plausible that the control treatment in trial 20110142, alendronate, is cardioprotective. The applicant also attempted to decipher whether baseline CV risk differed between the two trials but due to trial design, was unable to conclude adequately. Due to the cardiovascular safety signal, the applicant narrowed indication to “treatment of osteoporosis in postmenopausal women at high risk of fracture”. The applicant also proposed a “boxed warning” as well as a “warning and precaution for CV risk”. The committee stressed the necessity of post-marketing follow-up.
Risk:
An increase in MACE among postmenopausal women with osteoporosis was observed in study though the mechanism of romosozumab on MACE is unknown.
Risk/Benefit Analysis:
Due to a tremendous amount of morbidity and mortality associated with osteoporotic bone fracture, there is clearly an unmet need for prevention of the condition. With proven effectiveness of romosozumab together with proposed safety issues addressed through Box warning and precaution of CV risk, FDA advisory committee voted 18 against 1 in favor of approval of romosozumab.