Garetosmab, an inhibitor of activin A, reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial

BackgroundFibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 (ACVR1), is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. MethodsLUMINA-1 (NCT03188666) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period_1), followed by an open-label period (Period_2). After Period_2, patients were allowed to stay on garetosmab in an open-label extension. For Period_1, primary endpoints were HO total lesion activity (HO-TLA) by 18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period_2 primary endpoint compared the number of new lesions in Period_2 versus Period_1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. FindingsPatients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P=0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18F-NaF PET, post-hoc P=0.009; 90% relative reduction by CT, post-hoc P=0.017); flare-ups were significantly reduced (P=0.0005). For placebo patients transitioning to garetosmab in Period_2, no patients developed new HO lesions (0% in Period_2 versus 40.9% in Period_1; P=0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period_2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. InterpretationGaretosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab. FundingRegeneron Pharmaceuticals, Inc.