Palovarotene ‘potential’ therapeutic option for rare, disabling bone disease
Palovarotene reduced new heterotopic ossification volume in children and adults with fibrodysplasia ossificans progressiva, according to data from a phase 3 trial.
Fibrodysplasia ossificans progressiva is a rare and severely disabling genetic disease characterized by extraskeletal bone formation in muscle and soft tissue.
“There are currently no approved treatments for the reduction or prevention of heterotopic bone formation in fibrodysplasia ossificans progressiva,” Robert Pignolo, MD, PhD, chair of the division of geriatric medicine and gerontology, department of internal medicine, Mayo Clinic, told Healio. “The findings from the MOVE trial show that palovarotene can reduce new heterotopic ossification volume in patients with fibrodysplasia ossificans progressiva, representing the potential for an important therapeutic option in this disease area.”
Pignolo presented the findings at the American Society for Bone and Mineral Research virtual meeting.
Palovarotene (Clementia/Ipsen) was previously found to reduce new heterotopic ossification in animal models and people with fibrodysplasia ossificans progressiva during a phase 2 trial. Pignolo and colleagues enrolled people with fibrodysplasia ossificans progressiva aged 4 years and older in MOVE, an ongoing, 48-month, single-arm, open-label phase 3 trial. The participants came from 15 sites globally; all had fibrodysplasia ossificans progressiva caused by a documented ACVR1 mutation.
Participants received a chronic daily regimen of 5 mg palovarotene for up to 48 months. An episodic regimen of palovarotene was given to any individuals who had a flare-up. The episodic dose was 20 mg a day for 4 weeks, followed by 10 mg per day for 8 weeks or until the flare-up was resolved. Data from the MOVE study was compared with data from untreated people with fibrodysplasia ossificans progressiva enrolled in a longitudinal 36-month national history study.
Pignolo presented efficacy analysis at an 18-month follow-up, with data from 97 MOVE trial participants (mean age, 15 years; 52.6% male) compared with data of 98 people from the national history study (mean age, 18 years, 55.1% male). In post hoc Bayesian analyses of nontransformed data, MOVE trial participants had a mean annualized new heterotopic ossification volume reduction of 62% when compared with nontreated participants.
“There’s a much larger variability in annualized heterotopic ossification in the natural history subjects group compared to MOVE,” Pignolo said in discussing individual new heterotopic ossification volume data during the presentation. “The other thing to notice is that there are far more individuals that participated in the MOVE trial that had a negative annualized new heterotopic ossification.”
As of Feb. 28, all MOVE participants reported at least one treatment-emergent adverse event, with 32.3% of the events categorized as mild, 45.5% as moderate and 22.2% as severe.
Premature physeal closure or epiphyseal disorder was reported in 27.1% of participants who were skeletally immature at baseline.
“Noting the identified risk of premature physeal closure in children, caution should be taken in pediatric patients with open growth plates,” Pignolo said during the presentation.
Pignolo added that, other than premature physeal closure, the safety data are generally consistent with the known adverse event profile of retinoids.
“The MOVE trial provides an important insight into long-awaited treatment strategies and demonstrates that the oral therapy palovarotene can reduce new heterotopic ossification volume, signifying a potentially disease-modifying therapy in fibrodysplasia ossificans progressiva, especially in older children and adults.” Pignolo said. “The International Clinical Council on Fibrodysplasia Ossificans Progressiva clinical guidelines will also be updated in 2021 and will certainly take into account published results from clinical studies in fibrodysplasia ossificans progressiva.”
Pignolo added that more research is needed to explore the variability and characteristics of fibrodysplasia ossificans progressiva and look at whether reducing heterotopic ossification could slow the progression of disability.
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Pignolo RJ, et al. Palovarotene (PVO) for Fibrodysplasia Ossificans Progressiva (FOP): Data from the Phase III MOVE Trial. Presented at: American Society for Bone and Mineral Research Annual Meeting; Sept. 11-15, 2020 (virtual meeting).
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