Clementia unveils results from phase 2 trial of palovarotene to treat FOP patients

FOP is an extremely rare, serious disease in which an accumulation of heterotopic ossification (HO, extraskeletal bone) in muscle and soft tissue progressively restricts movement by locking joints leading to loss of function, physical disability, and risk of early death.

Several positive trends were detected in this 40-subject placebo-controlled trial, including palovarotene-related reductions in the proportion of subjects who developed new HO, reductions in volume of new HO, reductions in patient-reported pain associated with flare-ups, and reductions in the time to resolution of FOP-related flare-ups though none reached statistical significance.

Palovarotene was well-tolerated, with all subjects completing the 12-week trial and enrolling into the open-label extension trial.

Principal investigator, Frederick Kaplan, MD, the Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the Division of Molecular Orthopaedic Medicine in the Perelman School of Medicine at the University of Pennsylvania said: “The results of this landmark clinical trial are encouraging and closely mirror what was observed in previously reported animal studies with palovarotene.

“This study has considerably enhanced our knowledge of FOP and is a significant step forward for the entire FOP community.”

The 12-week Phase 2 trial randomized subjects to three dose groups: 10 mg palovarotene for 2 weeks followed by 5 mg for 4 weeks (10/5), 5 mg for 2 weeks followed by 2.5 mg for 4 weeks (5/2.5), or placebo. Treatment was initiated within 7 days of the onset of a flare-up with evaluations made at baseline, at the end of treatment (6 weeks), and after a 6-week observation period (12 weeks).

Subjects on placebo were at 2.6 times greater risk of forming HO than those on palovarotene 10/5 mg treatment, while those on either palovarotene regimen with new HO formed less HO than those on placebo. Subjects on the 10/5 regimen reported a greater improvement in pain associated with flare-ups and a reduction in the duration of overall flare-up symptoms.

Though a dose-related increase in the incidence of mucocutaneous adverse events was observed, no subject required a reduction in dose due to tolerability issues nor was discontinued from the trial.

Full results of the Phase 2 trial are expected to be published next year. Clementia continues to gather important additional data in the Phase 2 extension trial and in the ongoing observational Natural History Study. Data from these studies will inform the design of a Phase 3 registration trial, which is expected to start in 2017.

Clementia CMO Donna Grogan, MD said: “That patients were able to tolerate palovarotene with no discontinuations for safety reasons at a 10-mg dose encouraged us to implement a higher dose in the Phase 2 open-label extension and to extend the number of days dosed.”

The extension trial has also introduced a chronic daily dose based on new research conducted by scientists at Penn and The Children’s Hospital of Philadelphia (CHOP) and findings from the completed Phase 2 trial.

Many years of laboratory research paved the way for this clinical trial. A leading investigator, Maurizio Pacifici, PhD, director of Orthopedic Research at CHOP, and his collaborators first showed that palovarotene produces powerful biological effects in transgenic mouse models of human FOP and inhibits HO markedly.

Pacifici said: “Those results have provided the basis and rationale for testing palovarotene to prevent HO in FOP patients in this trial.”

Clementia CEO Clarissa Desjardins said: “We would like to thank the patients, their families, the investigators, and their research teams.

“Developing a potential treatment for FOP is our passion and our goal, and we will continue to press forward as rapidly and rigorously as possible to deliver a much needed potential therapy for all FOP patients.”