Ipsen Halts Palovarotene Development for Multiple Osteochondromas Following $1.3B Clementia Acquisition

Author:Ten Yuan

On March 26, Ipsen announced the termination of clinical trials of palovarotene for patients with multiple osteochondromas (MO), while simultaneously restarting clinical trials of palovarotene for patients aged 14 years and older with fibrodysplasia ossificans progressiva (FOP).

Palovarotene is a novel retinoic acid receptor gamma (RARγ) agonist developed by Clementia Pharmaceuticals, intended for the treatment of ultra-rare bone disorders including fibrodysplasia ossificans progressiva (FOP) and myositis ossificans (MO), as well as other conditions such as dry eye disease. It has been granted orphan drug designation, Fast Track designation, and Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of FOP and MO. In February 2019, Ipsen acquired Clementia Pharmaceuticals for $1.31 billion, thereby adding palovarotene to its portfolio.

In late 2019, Ipsen submitted a safety report to the FDA regarding palovarotene for the treatment of pediatric patients with fibrodysplasia ossificans progressiva (FOP), noting premature closure of growth plates in patients receiving palovarotene. Upon receipt of the report, the FDA issued a partial clinical hold on palovarotene clinical trials for FOP, requiring Ipsen to investigate the adverse event-related data and respond within 30 days. Although similar adverse events were not observed in clinical studies of palovarotene for myositis ossificans (MO), the FDA also imposed a partial clinical hold on MO-related clinical trials as a precautionary measure. Given that the upper age limit for enrolled patients in the palovarotene MO studies was 14 years, the FDA required that treatment be discontinued for already-enrolled patients and that enrollment of new patients be halted until further notice.

On December 6, 2019, Ipsen announced that, following discussions with the U.S. Food and Drug Administration (FDA), it had decided to partially suspend clinical studies of palovarotene in pediatric patients under 14 years of age. This suspension primarily involved the Phase II studies PVO-1A-202/204 and PVO-2A-201, as well as the Phase III study PVO-1A-301, with all clinical centers worldwide ceasing enrollment of pediatric patients under 14 years of age. The FDA agreed to allow Ipsen to continue conducting clinical trials of palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP) and myositis ossificans (MO) in patients aged 14 years and older.

However, studies conducted in FOP patients aged 14 years and older also encountered setbacks. On January 24, 2020, Ipsen announced the suspension of patient dosing in the Phase III PVO-1A-301 study and the Phase II PVO-1A-202/204 extension study, as interim futility analysis results from the Independent Data Monitoring Committee (IDMC), conducted per the original plan, indicated that the Phase III PVO-1A-301 study might fail to meet its primary endpoint. Nevertheless, the IDMC identified some positive efficacy signals during a post hoc analysis of this Phase III study and therefore did not recommend terminating the PVO-1A-301 study. The IDMC also noted that the pre-specified analytical model likely influenced the final conclusions regarding efficacy evaluation. Consequently, Ipsen decided to suspend dosing and conduct a comprehensive analysis of the full dataset, while also engaging in further discussions with regulatory authorities regarding these findings to determine the next steps in the development program for palovarotene in the treatment of FOP.

Following the IDMC’s recommendations, Ipsen amended the protocol for the Phase III PVO-1A-301 study and incorporated a new data analysis model. The resumption of clinical studies of palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP) has also been approved by numerous regulatory authorities worldwide, including the UK MHRA, the French ANSM, the Swedish MPA, and the Argentine ANMAT. However, the FDA’s clinical hold on palovarotene studies in FOP and myositis ossificans (MO) patients under 14 years of age remains in effect. Ipsen is currently responding to inquiries from the FDA and other regulatory agencies, seeking to clarify its development plan for palovarotene in FOP patients under 14 years of age.

In explaining the termination of the clinical study of palovarotene in patients with MO, Ipsen pointed out that when the FDA issued a partial clinical hold, the number of enrolled patients was insufficient to conduct an interim analysis. It had become virtually impossible to complete patient enrollment and dosing according to the original plan and obtain complete data to support the submission of a New Drug Application (NDA). Furthermore, there was insufficient sample size to evaluate the benefit-risk profile of palovarotene in patients with MO.

Jefferies analysts had previously predicted that peak sales of palovarotene for the MO indication could reach $1.5 billion; the FDA’s clinical hold and the current situation have undoubtedly significantly weakened this expectation.