The US FDA has now greenlit Palovarotene as a revolutionary treatment for fibrodysplasia ossificans progressiva disease (FOP) after its victorious approval in Canada in 2022. The approval now extends to children aged 8 years and older for females, 10 years and older for males, as well as adults, representing a suggestive in FOP management.

This therapy from the class of drugs known as ‘retinoids’ offers hope to patients suffering from the debilitating effects of FOP, a rare genetic disorder characterized by abnormal bone growth in soft tissues. However, the European Medicines Agency (EMA) has withheld marketing authorization for Palovarotene because of insufficient data and efficacy.

FOP is an extremely rare, autosomal dominant disease which causes sporadic attacks of painful soft tissue swelling (flare-ups) which significantly impacts the quality of life and shortens the life span of those affected. Conservative therapies (steroids, etc.) are used to relieve pain and inflammation linked with flare-ups. Unfortunately, these treatments had poor results, underscoring the necessity for a new treatment.

Palovarotene (retinoic acid receptor γ (RARγ) agonist), a hallmark of FOP therapy, has been evidenced by preclinical studies conducted on mouse models. However, concerns have surfaced regarding its impact on the skeletal development of juvenile mice which underscores the need for a thorough investigation, weighed against the strides made in FOP treatment.

What do the human trials reveal?

Human trials have shed light on both the efficacy and safety of Palovarotene. A phase I trial conducted in Japan demonstrated its favourable safety profile across diverse populations, indicating its potential for global applicability. Subsequent trials, including a phase 2 study, showcased promising results in reducing HO among FOP patients. Although not statistically significant, these findings hint at the drug's partial efficacy in preventing HO.

A multicenter phase 3 study (MOVE trial) further reinforced Palovarotene's effectiveness in curbing new instances of HO in FOP patients. As research proceeds, attention must be paid to potential risks (including premature epiphyseal closure [PPC]) despite its fair tolerability. Palovarotene is not without its share of side effects, ranging from mucocutaneous reactions to embryo-fetal toxicity, necessitating caution, especially in pregnant individuals. Additionally, vigilance is warranted concerning drug interactions and potential complications in patients with hepatic impairment.

To sum up…

The FDA's approval of Palovarotene offers renewed hope for patients with FOP and their families. While concerns about possible side effects continue, the overall optimistic results from clinical trials underscore the drug's potency and efficacy.