Osteochondroma

Despite the setback, Ipsen said it will continue to seek regulatory approvals in other countries and regions. While Ipsen’s troubled rare disease candidate was given a second chance by the FDA, the regulator’s European equivalents haven’t been as sympathetic. The European Commission has ruled not to grant marketing authorization for palovarotene to treat an ultra-rare bone growth disorder called fibrodysplasia ossificans progressiva (FOP), Ipsen revealed this morning. The decision won’t have come as complete surprise, following a negative opinion by the Committee for Medicinal Products for Human Use back in May. Despite the regulatory setback, Ipsen said it will continue to seek regulatory approvals in other countries and regions. It may still succeed in the U.S., where the FDA initially rejected the biotech’s application. That decision came two months after the agency delayed an advisory panel meeting to discuss palovarotene and requested additional data. But when Ipsen sent over the information, the FDA scheduled a decision date of Aug. 16 for the resubmitted approval application. The extra data included additional analyses spanning a range of trials, including MOVE, the first phase 3 study on people with FOP. Ipsen tried a similar approach in Europe, where it requested that the European Medicines Agency (EMA) reexamine the recommendation of its committee in January not to authorize palovarotene. At the time, the biotech said it would call for the decision to be reviewed. While that attempt clearly didn’t prove as effective, it at least seems that the European Commission’s decision was priced in by investors. Ipsen’s stock remaining unmoved around the 111 euro mark in Thursday morning trading on the Paris stock exchange. “We believe that our clinical data provide evidence supporting the effect of palovarotene on the reduction of new, abnormal bone formation, known as heterotopic ossification, which characterizes the disease,” Ipsen’s head of R&D Howard Mayer, M.D., said in the release. “We are therefore disappointed that the European Commission decided not to approve this treatment for patients with FOP in Europe.” The FDA and EMA rejections were only the latest obstacles in what has been a difficult journey for palovarotene since Ipsen acquired the asset in a $1.31 billion purchase of Clementia Pharmaceuticals in 2019. The drug would go on to receive a four-month partial clinical hold on a study in pediatric populations with FOP and multiple osteochondromas after evidence of cases of early growth plate closure. Dosing in a phase 3 FOP trial that included adults was also paused after early evidence suggested the trial would not meet its primary endpoint. Ipsen’s persistence can be explained by the fact that there remain no FDA-approved drugs for FOP. BioCryst axed development of a FOP candidate in November, leaving Ipsen and Regeneron as the two major players left in the space. Should the FDA’s decision go Ipsen’s way in August, it will still be ahead of Regeneron, which is expected to submit its approval application next year.

The FDA and EMA rejections were only the latest obstacles in what has been an uphill journey for palovarotene. Despite an FDA rejection only three months ago, the saga of Ipsen’s rare disease candidate isn’t over yet—and there’s a chance it could still have a happy ending. The biotech ended 2022 on a downer, with the FDA rejecting an application for palovarotene to treat an ultra-rare bone growth disorder called fibrodysplasia ossificans progressiva (FOP). The decision came two months after the agency delayed an advisory panel meeting to discuss palovarotene and requested additional data. Now that Ipsen has sent over this information, the FDA has scheduled a decision date of August 16 for the resubmitted approval application. The extra data includes additional analyses spanning a range of trials, including MOVE, the first phase 3 study on people with FOP, Ipsen said in a release yesterday afternoon. An interim analysis of the 107-participant MOVE study in December showed a 60% reduction in new abnormal bone formation heterotopic ossification volume in participants treated with palovarotene, compared to those on standard of care. Not content with taking on just the FDA again, Ipsen has also requested that the European Medicines Agency re-examine the recommendation of its committee in January not to authorize palovarotene. At the time, the biotech said it would call for the decision to be reviewed. The FDA and EMA rejections were only the latest obstacles in what has been an uphill journey for palovarotene since Ipsen acquired the drug in a $1.31 billion purchase of Clementia Pharmaceuticals in 2019. David Meek, Ipsen’s CEO at the time, called the med “largely derisked,” but subsequent developments suggest that verdict was a tad optimistic. The drug would go on to receive a four-month partial clinical hold on a study in pediatric populations with FOP and multiple osteochondromas after evidence of cases of early growth plate closure. Dosing in a phase 3 FOP trial that included adults was also paused after early evidence suggested the trial would not meet its primary endpoint. The company pulled its first new drug application in August 2021 to add more data, and the FDA accepted the resubmitted file in June 2022. While Ipsen hashed out its approval package in the U.S., the drug was approved in Canada in January. Ipsen’s persistence can be explained by the fact that there remain no FDA-approved drugs for FOP. BioCryst axed development of a FOP candidate in November, leaving Ipsen and Regeneron as the two major players left in the space. Should the FDA’s decision go Ipsen’s way in August, it will still be ahead of Regeneron, which is expected to submit its approval application next year.

The FDA's rejection of palovarotene comes months after the agency postponed an advisory meeting to discuss the med. Ipsen’s “largely derisked” rare disease candidate was evidently still too risky for regulators, with the FDA rejecting the company’s new drug application for palovarotene. The decision by regulators, announced by the company late Friday night, comes two months after the FDA delayed an advisory panel meeting to discuss palovarotene and the agency's request for additional data. Ipsen said the complete response letter is related to that previous request, and it intends to respond by the first quarter of 2023, triggering a new six-month review cycle. The company also said the FDA has not yet rescheduled the advisory meeting.  Ipsen has not specified what kind of data regulators have been asking for, saying only that it’s not a request for additional efficacy or safety data beyond existing studies. A spokesperson for the company declined to comment when asked which data it's working to provide. Such secrecy naturally leaves open a plethora of possibilities regarding the data request, including the drug's development and manufacturing. Palovarotene is being developed as a treatment for fibrodysplasia ossificans progressiva (FOP), an ultra-rare bone growth disorder marked by the development of bones in parts of the body where they shouldn’t be.  The news marks the latest and greatest setback for palovarotene, which has faced a persistent uphill climb since Ipsen acquired the drug in its $1.31 billion purchase of Clementia Pharmaceuticals in 2019. Then-Ipsen CEO David Meek called the med “largely derisked,” evidently jinxing its future development path, which has been treacherous ever since.  Before 2019 concluded, palovarotene was slapped with a clinical hold in studies evaluating the med in pediatric populations with FOP and multiple osteochondromas after evidence of cases of early growth plate closure. The company ultimately diverted all efforts toward FOP, with the hold lifted four months later. But before that happened, the company paused dosing in a phase 3 FOP trial that included adults after early evidence suggested the trial would not meet its primary endpoint.  But that did not deter Ipsen from haggling with U.S. regulators about its therapeutic potential, particularly for a population that had no options. The company pulled its first NDA application in August 2021 to add more data, and the FDA accepted its resubmitted file in June 2022. While the company hashed out its approval package in the U.S., the drug was approved in Canada in January.  Buoying Ipsen’s prospects, as bleak as they seem, has been the market potential should the company expand on its green light in Canada. Competitor BioCryst axed development of its FOP candidate in November, leaving Ipsen and Regeneron as the two major players in the space. Should Ipsen meet its first-quarter timeline for answering the FDA’s questions, it would still be on pace for a definitive answer from the FDA before Regeneron is expected to submit an approval application for its candidate in 2024. Editor's note: This story was updated to include a response from an Ipsen spokesperson.