Ipsen's Rare Disease Drug Palovarotene Rejected by European Commission Following FDA Setbacks

On July 20, Ipsen announced that the European Commission (EC) did not approve the marketing application of palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP). This is the second rejection decision received by palovarotene from a regulatory agency after being rejected by the FDA. Ipsen stated that it will continue to advance the work of submitting the marketing application of palovarotene to other regulatory agencies. Currently, this product is only approved for marketing in Canada.

EC's move was not surprising. In January this year, the Committee for Medicinal Products for Human Use (CHMP) had decided not to recommend the approval of palovariclib for marketing based on the results of the Phase III MOVE study.

The MOVE study is a multi-center, open-label, single-arm clinical trial that enrolled 107 patients. It aims to evaluate the efficacy and safety of palovaricin as a chronic or flare-up treatment regimen for reducing the volume of new heterotopic ossification (HO) in patients with FOP. Patients in the chronic treatment group will receive palovaricin 5mg once daily for 24 months, while those in the flare-up treatment group will first receive palovaricin 20mg once daily for 4 weeks, followed by palovaricin 10mg once daily for 8 weeks. The primary endpoint of the study is the change in the volume of new HO.

Post-hoc analysis showed that, compared with untreated patients (23318mm³) in the natural history study (n=97), the annualized new HO volume in patients treated with palovaritinib (n=98) was reduced by 62% (nominal weighted linear mixed-effects [wLME] model estimate –11611mm³, P=0.0292). Overall, 29.3% of patients reported at least one serious adverse event (SAE), including premature physeal closure (PPC) or physeal disorders occurring in 27.1% of patients with immature skeletons at baseline. The most common treatment-related adverse events (TRAEs) included skin and subcutaneous tissue disorders (97%), gastrointestinal disorders (77.8%), and infections (74.7%).

Ipsen was not satisfied with the CHMP's opinion and requested the CHMP to re-evaluate the safety and efficacy of Palovarotene. In May this year, the CHMP still decided not to recommend approval. The path to market for Palovarotene in Europe has reached a dead end.

The journey of Palovarotene to the U.S. market has also been fraught with obstacles. As early as May 2021, Ipsen submitted a marketing application for Palovarotene to the FDA, but voluntarily withdrew the application three months later, citing the need for additional analysis and evaluation of the data.

In June 2022, Ipsen submitted a new drug application for Palovarotene in the U.S. However, four months later, the FDA announced a delay of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting and requested additional clinical trial data from Ipsen for Palovarotene. Two months after that, the FDA again asked Ipsen to provide more clinical trial data, unrelated to efficacy and safety this time. Ipsen had no choice but to postpone the launch plan for Palovarotene. Looking back further, the setbacks encountered by Palovarotene were numerous (see: ).

However, perhaps as the saying goes "God helps those who help themselves," in March this year, the FDA re-accepted the marketing application for Palovaricin. In June, EMDAC voted 10 to 4 in favor of Palovaricin's efficacy at the meeting and voted 11 to 3 that the benefits of using Palovaricin to treat FOP outweigh the risks. The FDA’s final decision will be announced on August 16.

FOP is an extremely rare genetic disorder with a prevalence of approximately 1.36 per million people. It is characterized by the formation of new bone in areas outside the normal skeletal system, such as soft connective tissues—a process known as heterotopic ossification (HO). This can 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. Once HO occurs, it is irreversible and can lead to restricted mobility and reduced life expectancy.

Palovarotene is an orally available, selective retinoic acid receptor γ (RARγ) agonist developed by Clementia, a subsidiary of Roche. It inhibits the abnormal activation of downstream pathways by acting on bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2 (ACVR1/ALK2 mutation is the pathogenic mechanism of FOP), thereby exerting its effect in inhibiting heterotopic ossification (HO). In April 2019, Ipsen acquired Clementia for $1.31 billion, obtaining global rights to palovarotene.

Palovarotene is currently the only FOP therapy under application for marketing. Besides, the fastest progressing therapy is Regeneron's anti-activin A monoclonal antibody garetosmab, which is currently in Phase III clinical trials.

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