Palovarotene

Fibrodysplasia Ossificans Progressiva (FOP), with an estimated worldwide prevalence of one in 2 million individuals, is an exceptionally rare genetic disorder. FOP is caused by a gain-of-function mutation in the ACVR1/ALK2 gene which results in progressive heterotopic ossification, a process wherein connective tissues (e.g. skeletal muscle, ligaments, tendons) are replaced with bone. The ossification occurring as a result of FOP is insidious and cumulative and is provoked during flare-ups or in response to injury. Treatment options for patients with FOP are extremely limited, although there has been substantial recent interest in novel treatments for this disease.

Palovarotene is a selective agonist of retinoic acid receptor gamma (RARγ) belonging to a class of medications known as retinoids, similar in mechanism to drugs like tazarotene or trifarotene, which are derivatives of vitamin A. It first garnered interest as a potential treatment for emphysema but was eventually recognized as a potential novel therapy for patients with FOP. Agonists for retinoic acid receptors have been shown to inhibit chondrogenesis of heterotopic ossification in a transgenic mice model of FOP, with selective RARγ agonists (e.g. palovarotene) demonstrating the greatest efficacy.

Palovarotene was approved for use in Canada in January 2022 for the management of heterotopic ossification (HO) in patients with FOP, representing the first global approval for any FOP therapy. It has been granted rare pediatric disease and breakthrough therapy designations from the US FDA, although a previously submitted NDA was withdrawn in August 2021 pending the resubmission of additional data analyses. On August 16, 2023, palovarotene was also approved by the FDA for the management of HO associated with FOP.

Palovarotene is indicated in Canada to reduce the formation of heterotopic ossification in adults and children (≥8 years old for females and ≥10 years old for males) with Fibrodysplasia Ossificans Progressiva (FOP) by Health Canada and FDA.