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Palovarotene for the treatment of patients with fibrodysplasia ossificans progressiva

Results from a phase 2 clinical trial investigating Palovarotene for the treatment of fibrodysplasia ossificans progressiva ( FOP ) were presented.
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 heterotopic ossification, reductions in volume of new heterotopic ossification, 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.

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 heterotopic ossification than those on Palovarotene 10/5 mg treatment, while those on either Palovarotene regimen with new heterotopic ossification formed less heterotopic ossification 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.

Fibrodysplasia ossificans progressiva is a rare, severely disabling congenital myopathy characterized by heterotopic ossification of muscle and soft tissues. Heterotopic ossification is bone that forms outside the normal skeleton and, in FOP, progressively restricts movement by locking joints leading to a cumulative loss of function, disability, and risk of early death.
Virtually all newborns with FOP have a hallmark toe malformation in which both big toes are shortened and bent inwards.
FOP is caused by a mutation in the ACVR1 gene resulting in increased activity of BMP type I receptor or ALK2 receptor involved in the bone morphogenetic ( BMP ) pathway, a key pathway controlling bone growth and development.
There are currently no approved treatments for fibrodysplasia ossificans progressive.

Palovarotene is a retinoic acid receptor gamma agonist ( RARgamma ) being investigated as a treatment for FOP. Preclinical studies in mouse models of FOP demonstrated that Palovarotene blocked both injury-induced and spontaneous heterotopic ossification, maintained mobility, and restored skeletal growth. ( Xagena )

Source: Clementia Pharmaceuticals, 2016