FDA Agrees to Give Ipsen’s Rare Disease Drug Another Look As Palovarotene Saga Rumbles On

Although Ipsen’s Palovarotene was rejected by the FDA just three months ago, the rare disease candidate’s story is not yet over. The fibrodysplasia ossificans progressiva (FOP) candidate may still get FDA approval.

Ipsen’s unrelenting mission to bring Palovarotene to the forefront of the FOP fight

Ipsen has undoubtedly had an ultra-busy calendar in recent years. After spending the better half of 2018 relocating its North American headquarters to Kendall Square near MIT in Cambridge, Massachusetts, the French R&D drug company has continued to make major inroads, especially in the field of rare diseases.

Palovarotene is Ipsen’s investigational drug candidate geared towards treating FOP, an extremely rare genetic disorder. The oral, selective retinoic-acid receptor gamma (RARγ) agonist is designed to prevent the formation of heterotopic ossification (HO), which is the growth of new bone outside the skeletal system.

Ipsen initially filed a New Drug Application (NDA) for Palovarotene with the U.S. Food and Drug Administration (FDA) in mid-2022, and it was granted priority review status. Unfortunately, the FDA issued a complete response letter (CRL) at the close of the year, essentially failing to approve Palovarotene for FOP treatment.

The CRL decision followed a couple of months after the FDA asked for more data from Ipsen and postponed a crucial advisory panel meeting to discuss the FOP candidate.

Interestingly, Health Canada has already green-lighted Sohonos, becoming the world’s first regulatory body to authorize palovarotene capsules for both FOP and HO. The Canadian approval of Sohonos for both chronic use and flare-ups in FOP patients demonstrates its efficacy in treating this specific population. That’s why Ipsen has been unrelenting on its mission to get approval — or at least a second chance— from the FDA.

Ipsen’s prayers might be answered soon, as the FDA has agreed to take a second look at the FOP treatment candidate. Following Ipsen’s submission of supplementary information, the regulatory agency has set a decision date of August 16 for the revised approval application.

Positive findings from phase 3 trials

Ipsen disclosed in a recent press release that the additional data comprises further analyses across various trials, including the initial phase 3 study on individuals with fibrodysplasia ossificans progressiva (FOP), known as MOVE.

In December, an interim assessment of the MOVE study involving 107 participants revealed that individuals treated with palovarotene experienced a 60% decrease in the volume of heterotopic ossification, which is the abnormal growth of bone, compared to those who received standard of care.

One-of-its-kind FOP treatment

If palovarotene gets the green light, it will mark a groundbreaking achievement as the first resort for the estimated 400 individuals in the U.S. grappling with FOP. Bone disease is a remarkably rare and degenerative condition that significantly impacts the quality of life and curtails life expectancy.

The FDA has granted the drug Breakthrough Therapy and Orphan Drug designations, paving the way for it to be accessible to those in need. Only a few new investigational drugs, including Sanofi/Regeneron’s Libtayo®, have attracted the same limelight.

In addition to challenging the FDA, Ipsen has taken further steps to request the European Medicines Agency (EMA) to reconsider its committee’s decision earlier this year, which denied authorization for the use of palovarotene. Ipsen had previously announced that it would pursue a review of the committee’s ruling and is now following through with its commitment.

Double dose of rejection for palovarotene

The EMA and FDA rejections are just the tip of the iceberg in a series of obstacles that palovarotene has faced since the French pharma company obtained the FOP candidate through the 2019 purchase of Clementia Pharmaceuticals for $1.31 billion.

Although Ipsen’s CEO, David Meek, described the medication as “largely de-risked” at the time of the acquisition, subsequent events have shown that this assessment may have been too optimistic.

The drug was subjected to a partial clinical hold lasting 4 months during a study targeting pediatric populations with FOP and multiple osteochondromas after the investigators detected cases of early growth plate closure. To cap it off, dosing for the phase 3 FOP trial, which featured adult participants, was also paused after the trial showed telltale signs that it would not achieve its primary endpoint.

Ipsen withdrew its initial application for an NDA in August 2021 due to insufficient data. Subsequently, the company resubmitted the file, which the FDA accepted in June 2022. While the French drugmaker worked on finalizing its approval package in the United States, the drug gained approval in Canada in January.

Ipsen’s unwavering efforts can be attributed to the lack of viable drugs approved by the FDA for FOP treatment. Another major player in the FOP space, BioCryst, abandoned the development of a candidate for the rare disease in November.

Howard Mayer, VP of R&D at Ipsen, was quoted as saying, “Currently, people living with FOP in the United States have no approved treatment option to slow the progression of the disease, and this remains our reason for being steadfast in our pursuit of bringing this potential treatment option for FOP.”

Ipsen and Regeneron essentially remain alone to battle it out for the entire FOP market. If the FDA approves Ipsen’s candidate in August, the company will still have a massive advantage over Regeneron, which is projected to file its approval application next year.

Recapping palovarotene’s journey towards FDA approval

Palovarotene is a selective retinoic-acid receptor gamma agonist currently under investigation as a potential treatment for FOP, an ultra-rare genetic disorder that causes debilitating effects. The FDA has granted palovarotene Breakthrough Therapy Designations for the treatment of FOP.

Ipsen obtained palovarotene through its acquisition of Clementia Pharmaceuticals in April 2019. On May 28, 2021, the FDA initially accepted the palovarotene New Drug Application (NDA) for Priority Review, but Ipsen withdrew the NDA on August 13, 2021. However, the FDA has now accepted the resubmission of the palovarotene NDA for Priority Review in the U.S.