Reduction of New Heterotopic Ossification (HO) in the Open‐Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP)

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS.

Administration of a selective retinoic acid receptor-γ agonist improves neuromuscular strength in a rodent model of volumetric muscle loss

“…A generally favorable safety profile has been observed with treatment strategies similar to those used here, with daily, 5 mg doses being well tolerated for greater than a year, and 20 mg doses routinely administered in response to disease flare ups [37,44,46] Side effects are consistent with general retinoid use with the most reported being mucocutaneous effects of the skin, eye, and gut. Adverse effects on skeletal growth in younger populations are being actively monitored, however, and future risk-benefit assessments will likely be needed in these populations [31,37]. Of note, the level of functional recovery observed here is similar to that achieved with the tissue engineering-based strategy of minced muscle graft repair [7,25].…”

“…The results presented here are highly encouraging as they suggest that pharmacological activation of RARs may be a facile and promising method to improve functional recovery and repair of severe skeletal muscle injuries. RARγ agonist treatment benefits have previously demonstrated the ability to translate from preclinical models to patient use with phase 3 clinical investigation of fibrodysplasia ossificans progressive (NCT03312634) and phase 2 investigation of multiple osteochondromas (NCT03442985) currently ongoing [37]. A generally favorable safety profile has been observed with treatment strategies similar to those used here, with daily, 5 mg doses being well tolerated for greater than a year, and 20 mg doses routinely administered in response to disease flare ups [37,44,46] Side effects are consistent with general retinoid use with the most reported being mucocutaneous effects of the skin, eye, and gut.…”

“…RARγ agonist treatment benefits have previously demonstrated the ability to translate from preclinical models to patient use with phase 3 clinical investigation of fibrodysplasia ossificans progressive (NCT03312634) and phase 2 investigation of multiple osteochondromas (NCT03442985) currently ongoing [37]. A generally favorable safety profile has been observed with treatment strategies similar to those used here, with daily, 5 mg doses being well tolerated for greater than a year, and 20 mg doses routinely administered in response to disease flare ups [37,44,46] Side effects are consistent with general retinoid use with the most reported being mucocutaneous effects of the skin, eye, and gut. Adverse effects on skeletal growth in younger populations are being actively monitored, however, and future risk-benefit assessments will likely be needed in these populations [31,37].…”

Retinoic acid signaling suppresses chondrocyte identity during cartilage development and regeneration

“…A major side effect of PVO in mice and adolescent patients is accelerated closure of the growth plates (Inubushi et al, 2018; Pignolo et al, 2023). We find that this effect of PVO on growth plates is conserved in zebrafish.…”

“…Despite the success of PVO in suppressing exostoses, severe side effects in adolescents remain a concern. For example, a phase 3 clinical trial of PVO in adolescents was recently halted due to accelerated closure of growth plates (Pignolo et al, 2023). The role of RA signaling in growth plate biology has remained elusive (Koyama et al, 1999; Yoshida, 1999).…”