Efficacy and safety of garetosmab, an activin A-blocking antibody, in fibrodysplasia ossificans progressiva (OPTIMA): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder resulting in progressive heterotopic ossification of ligaments, tendons, and muscles, leading to disability and early mortality. FOP is caused by heterozygous gain-of-function mutations in the activin receptor type 1A, allowing this receptor to be aberrantly activated by activin A (ActA), which normally inhibits this receptor, thus driving heterotopic bone formation. In preclinical models and an earlier phase 2 trial (LUMINA-1) in FOP, an antibody blocking ActA (garetosmab) prevented heterotopic ossification. We aimed to evaluate the efficacy and safety of garetosmab in adults living with FOP. METHODS OPTIMA is a randomised, double-blind, placebo-controlled, phase 3 trial conducted at 18 study sites across 16 countries and regions. Participants aged 18 years or older with FOP were randomly assigned (1:1:1) to monthly intravenous placebo, garetosmab 3 mg/kg, or garetosmab 10 mg/kg. Randomisation was stratified by baseline Cumulative Analogue Joint Involvement Scale score and previous participation in the LUMINA-1 study. The primary efficacy and safety endpoints were total number of new heterotopic bone lesions at week 56 and treatment-emergent adverse events of special interest (AESIs) through week 56, analysed in all randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT05394116); the trial is active (completed primary endpoint) but not recruiting participants. FINDINGS Between Nov 21, 2022, and July 4, 2024, 63 participants were enrolled and randomly assigned (placebo, n=21; garetosmab 3 mg/kg, n=19; garetosmab 10 mg/kg, n=23). The mean age was 26·6 years (SD 6·8); 38 (60%) participants were female and 25 (40%) male. 62 participants completed 56 weeks of treatment; one participant in the placebo group discontinued at 53 weeks. The total number of new heterotopic bone lesions was significantly lower with garetosmab: there were 19 lesions with placebo versus one lesion with garetosmab 3 mg/kg (rate ratio vs placebo: 0·06 [95% CI 0·00-0·73]; p=0·027) and two lesions with garetosmab 10 mg/kg (rate ratio vs placebo: 0·10 [0·01-0·76]; p=0·026). Treatment-emergent AESIs occurred in one (5%) of 21 participants receiving placebo, zero of 19 receiving garetosmab 3 mg/kg, and four (17%) of 23 receiving garetosmab 10 mg/kg; all were considered treatment-related. No deaths occurred. INTERPRETATION Garetosmab substantially reduced the number of new heterotopic bone lesions, providing robust evidence of its potential to be an efficacious and generally well tolerated disease-modifying therapy for FOP.