To the Editor,

Following its approval in Canada in 2022, the US Food and Drug Administration (FDA) approved palovarotene (Sohonos, Ipsen, Paris, France) as a treatment option for fibrodysplasia ossificans progressiva (FOP) on August 16, 2023. This drug is now approved for use in children aged 8 years and older in females, 10 years and older in males, and adults, marking a major landmark in the management of FOP [1]. This ultra-rare genetic disorder has long needed a targeted treatment option, and the approval of palovarotene brings promising prospects for patients who have been suffering from the debilitating effects of this condition. However, the European Medicines Agency (EMA) has denied marketing authorization for Sohonos, citing insufficient data and a lack of evidence supporting its efficacy as the primary reasons [2].

FOP is an extremely rare, autosomal dominant disease caused by an active genetic point mutation within a bone morphogenetic protein (BMP) in type I receptor, which is the ACVR1R206H gene. This results in atypical new bone growth, also known as heterotrophic calcification (HO), in soft tissue such as muscles, tendons, and ligaments, leading to severe issues in mobility. Sporadic episodes of painful soft tissue swelling (flare-ups) are seen in this condition that leads to the formation of heterotopic bone. These flare-up episodes are caused by altered immune responsiveness and viral infections [3] and are often precipitated by soft tissue injuries such as falls, IV injections, and muscle stretching. Therefore, it significantly impacts the quality of life among these patients and shorten their life span [4]. Since these flare-ups are accompanied by inflammation causing swelling and pain, conventional therapies such as steroids and nonsteroidal anti-inflammatory drugs are currently employed. Unfortunately, these treatments have yielded poor results, further emphasizing the need for a novel therapy.

Palovarotene is a retinoic acid receptor γ (RARγ) agonist that inhibits BMP signaling by binding to RAR γ; hence, suppressing these pathways hinders chondrogenesis and, eventually, HO [5, 6]. Preclinical studies have demonstrated the efficacy of palovarotene in mitigating heterotopic ossification in mouse models of FOP [7]. However, it is also essential to acknowledge the concerns regarding the toxic effects of palovarotene on the skeletons of juvenile mice. These concerns must be balanced with the overall benefits and progress made in the treatment of FOP [8]. It is essential to note that the respective study does not challenge the veracity of the outcomes or the rigor with which the experiments were performed. These findings highlighted the necessity for greater research and investigation to fully comprehend any additional possible risks and side effects of palovarotene.

Several human trials have assessed the effectiveness and safety of palovarotene. The safety of palovarotene was assessed in a double-blind, randomized, crossover, single-dose phase I trial in Japan with both local and international healthy participants. The results showed that palovarotene was well tolerated and metabolized identically in both Japanese and non-Japanese individuals, indicating its potential for global effectiveness and applicability [9]. Two trials studied the efficacy of palovarotene in patients with FOP. The phase 2 trial showed positive results in favor of palovarotene, demonstrating relatively better primary endpoint results compared to the placebo, and it was well-tolerated. However, the difference between the palovarotene group and the placebo group was not statistically significant, indicating partial efficacy of the drug in preventing HO [10]. In another trial named the MOVE trial, a multicenter, phase 3 trial, there was evidence of palovarotene effectively reducing new HO in FOP [11]. Trials studying the long-term effects of palovarotene in patients with FOP are currently underway [12].

Palovarotene was well tolerated among patients in these trials; however, an elevated risk of premature physeal closure (PPC) was observed in skeletally immature patients in the MOVE trial, and as a result, younger patients should be actively monitored under FDA requirements. Some notable side effects of this drug class include mucocutaneous reactions, embryo-fetal toxicity (thus contraindicated in pregnancy), PPC, metabolic bone disorders, psychiatric disorders, and night blindness, which may be dose dependent. Drug interactions to look out for include CYP3A4 inhibitors and inducers, its additive effects with vitamin A, and avoiding using it with tetracyclines as increased benign intracranial hypertension was observed [13]. Although the renal/hepatic insufficiency data is inadequate, contraindication for its use in patients with severe hepatic impairment could be expected due to its hepatic clearance and retinoic acid receptor activation.

In conclusion, the recent approval of palovarotene for FOP in Canada and the USA represents a significant advancement for the treatment of this debilitating condition. This breakthrough drug, targeting heterotopic ossification, provides sanguineness for patients suffering from this rare genetic disorder. While acknowledging potential concerns, the overall encouraging positive results from clinical trials highlight its potency and efficacy. This approval, along with various targeted therapies currently under study such as gene therapy and garetosmab, underscores a crucial step forward in managing FOP and improving the quality of life for affected individuals [14, 15].