Palovarotene impact on fibrodysplasia ossificans progressiva (FOP): data from month 48 of the phase III MOVE trial.

Palovarotene is approved in several countries for reducing heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare, severely debilitating, genetic disorder. Approval was based on interim phase III MOVE trial (NCT03312634) analyses at month 18 (IA3), the most complete dataset considering subsequent clinical holds for futility and study restart; however, long-term data remain limited. We report exploratory, post hoc analyses of once daily palovarotene over the 48-mo MOVE trial, including time on and off treatment. The primary efficacy outcome was annualized change in new HO volume, per low-dose whole-body CT. Safety was assessed throughout. Post-baseline HO volume measurements were available for 97 palovarotene-treated patients from MOVE and 101 untreated patients from a natural history study (NHS; NCT02322255). Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585). In patients who paused and stopped or paused and restarted palovarotene, mean annualized new HO volume appeared lower when patients received palovarotene compared with when they did not (significance not assessed). The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature. Adverse events were predominantly retinoid-associated mucocutaneous events. In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events. Computational analyses showed a significantly increased risk of radiographically-observed, asymptomatic new-onset vertebral deformities with palovarotene treatment. Overall, these exploratory analyses reaffirm the MOVE IA3 findings but should be interpreted with caution; potential efficacy must be weighed against the safety profile of palovarotene, particularly in growing patients. Clinical trial registration number: NCT03312634 (MOVE), NCT02322255 (NHS), and NCT02279095 (phase II OLE).