Ipsen withdraws palovarotene NDA from US FDA

Paris, August 14, 2021:

Ipsen announced, following very recent discussions with the US Food and Drug Administration (FDA), withdrawal of the New Drug Application (NDA) for palovarotene. This follows ongoing dialogue with the FDA following the acceptance of the NDA for Priority Review which was announced on 28 May 2021.

During the review and ongoing dialogue between Ipsen and the FDA, it was recognized that additional analyses and evaluation of data collected from Ipsen’s phase III MOVE and FOP programme would be required to progress and complete the review process. It was agreed between Ipsen and the FDA that it would not be possible to complete this within the current NDA review cycle. As a result, Ipsen has therefore confirmed their withdrawal of the NDA for palovarotene. After recent discussion with FDA, Ipsen plans to resubmit to the FDA upon completion of the additional data analyses.

Dr. Howard Mayer, executive vice president and head of research and development, Ipsen, said “We remain committed to the FOP community through our clinical programs for Ipsen’s two investigational therapies palovarotene and IPN60130. We recognize the urgency from this community to bring a much-needed treatment option to people living with FOP around the world. Unfortunately, as there is no regulatory mechanism to “pause” the current ongoing review process, we have taken the decision to withdraw the NDA for palovarotene to undertake the additional analyses and evaluation needed, with plans to resubmit the data for palovarotene as soon as possible.”

Palovarotene is an oral, investigational, selective RAR? agonist for the prevention of heterotropic ossification (new bone formation) as a potential treatment for people living with fibrodysplasia ossificans progressiva (FOP). The target regulatory action date assigned by the FDA under a Priority Review status for palovarotene was 30 November 2021.

FOP is an ultra-rare genetic disorder with an estimated prevalence of 1.36 per million individuals globally; however, the number of confirmed cases varies by country. It is characterized by new bone formation outside of the normal skeletal system, like in soft connective tissues, a process known as heterotopic ossification (HO), which can be preceded by painful soft-tissue swelling or “flare-ups”. Flare-up episodes are common and are a substantial contributor to the formation of new HO, however HO can form in the absence of a flare-up. HO, once formed, is irreversible and leads to loss of mobility and shortened life expectancy.

The phase III MOVE (NCT03312634) trial is an ongoing open-label, single-arm trial evaluating the efficacy and safety of a chronic/flare-up dosing regimen of palovarotene, which comprises a 5mg daily dose that is increased at the start of a flare-up to 20mg for four weeks, followed by 10mg for eight weeks. At the end of the flare-up dosing period, the dose returns to the chronic 5mg daily dose. All dosing is weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at screening). The trial is being conducted in Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, the United Kingdom, and the United States.4 There are two ongoing phase II (PVO-1A-202 [NCT02279095] and PVO-1A-204 [NCT02979769]) extension trials: 1) Study 202, an open-label extension of Study 201, the initial Phase II randomized, double-blind, multi-center trial; and 2) Study 204, an open-label trial to evaluate the safety and efficacy of different palovarotene dosing regimens in patients with FOP in France.

In December 2019, a partial clinical hold was applied to participants under the age of 14 years participating in the phase II (PVO-1A-202/204 and PVO-2A-201) and phase III (PVO-1A-301) studies at all clinical sites globally. This was due to reports of premature physeal closure (PPC). A decision to pause dosing of palovarotene in all remaining participants in the global phase III MOVE trial (PVO-1A-301), as well as the ongoing phase II (PVO-1A-202/204) extension studies in FOP was made by Ipsen on January 24, 2020, based on results of a futility analysis as part of the pre-specified interim analysis (Bayesian compound Poisson analysis with square root transformation of the new HO volume data).

Palovarotene is an oral investigational, selective retinoic-acid receptor gamma (RAR?) agonist being developed as a potential treatment for people living with the debilitating ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). Palovarotene, which received rare pediatric disease and breakthrough therapy designations from the FDA for the potential treatment of FOP, was acquired by Ipsen through the acquisition of Clementia Pharmaceuticals in April 2019. The palovarotene NDA was accepted by the US FDA for Priority Review on 28 May 2021.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by bone that forms outside the normal skeleton, in muscles, tendons, or soft tissue. FOP has an estimated prevalence of 1.36 per million individuals globally; however, the number of confirmed cases varies by country.

Ipsen is a global, mid-sized biopharmaceutical company focused on transformative medicines in oncology, rare disease and neuroscience; it also has a well-established consumer healthcare business.

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