Ipsen's Palovarotene Receives Priority Review in US and Europe as First Potential Therapy for Fibrodysplasia Ossificans Progressiva (FOP)

May 29, 2021 /BioonBIOON/ -- French pharmaceutical company Ipsen (ipsRecently announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for palovarotene and granted it Priority Review. The drug is indicated for the treatment ofFibrodysplasia Ossificans Progressiva (FOP, also known as "Stone Man Syndrome”). The FDA will issue a review decision by November 30, 2021. In addition toFDA, the European Medicines Agency (EMA) and Swissmedic have also accepted the marketing authorization application (MAA) for palovarotene and granted it priority review.

If approved,Palovarotene will become the world's first drug for the treatment of fibrodysplasia ossificans progressiva (FOP).palovarotene is an oral, selective,Retinoic acid receptor γ (RARγ) agonist, for the prevention of heterotopic ossification (new bone formation). Previously,FDAPalovarotene has been granted Rare Pediatric Disease Designation (RPDD) and Breakthrough Therapy Designation (BTD) for the treatment of FOP. Ipsen acquired palovarotene through its acquisition of Clementia Pharmaceuticals in April 2019.

Skeletal and Clinical Manifestations in a Male Patient with FOP (Image sourced from literature: DOI:10.1056/NEJM199608223350804)

FOP is a very rare autosomal dominantGeneticsThe disease has an estimated prevalence of 1.36 per million people. However, the number of confirmed cases varies by country. FOP is characterized by the formation of new bone outside the normal skeletal system, such as in soft connective tissues (muscles, tendons). This process, known as heterotopic ossification (HO), may be accompanied by painful soft tissue swelling or “flare-ups”.

Flare-ups are common and represent a significant factor in the formation of new HO; however, HO can also develop in the absence of flare-ups. Once formed, HO is irreversible and results in mobility impairment and reduced life expectancy. FOP is a relentless, devastating disease,Many patients are confined to wheelchairs or immobilized in a fixed posture, resulting in a significantly shortened life expectancy.。Currently, there is no effective treatment for FOP.

Molecular structure of palovarotene (Image source: focusbio.com.au)

FOP is caused by mutations in the ALK2/ACVR1 (activin receptor type IA/activin-like kinase 2, MIM102576) gene., mutated ACVR1 leads to constitutive activation of bone morphogenetic protein (BMP) type I receptor signaling, thereby inducing heterotopic ossification in patients.

ipsDr. Howard Mayer, Executive Vice President and Head of Research and Development, stated: "Due to the lack of approved treatments for this progressive and debilitating disease, the medical needs of the FOP community remain unmet."This year marks the 15th anniversary of the discovery of the ALK2/ACVR1 gene mutation responsible for FOP, and palovarotene is the world's first drug with the potential to treat this disease."Our team at Ipsen is currently working closely with regulatory authorities to bring this potential treatment to patients with FOP worldwide. We would like to thank all FOP patients, their families, caregivers, and healthcare teams who participated in the palovarotene clinical program."

Palovarotene Mechanism of Action (Click image to enlarge. Image source: mosmedpreparaty.ru)

The palovarotene NDA is primarily based on data from the ongoing MOVE trial (NCT03312634), which is the first global, multicenter Phase 3 trial conducted in FOP. MOVE is an open-label, single-arm trial evaluating the efficacy and safety of the palovarotene chronic/flare dosing regimen in reducing new annualized HO in patients with FOP.

Post hoc analysis of the trial's primary endpoint showed that,Compared with untreated subjects in the natural history study (n=98; 23,318 mm³), subjects treated with palovarotene (n=97; 8,821 mm³) demonstrated a 62% reduction in mean annual new HO volume.(Predicted by the nominal weighted linear mixed effects [wLME] model, -11611 mm³, p=0.0292). Overall, 29.3% of subjects reported at least one adverse event (AE), including premature physeal closure (PPC) or physeal disorders in 27.1% of subjects who were skeletally immature at baseline. As of the data cutoff date, the most common treatment-related adverse events included skin and subcutaneous tissue disorders (97%), gastrointestinal disorders (77.8%), and infections (74.7%). (Bioon.com)