Rare Daily Staff

French specialty pharmaceutical Ipsen said it is pausing dosing patients in studies of palovarotene in patients with fibrodysplasia ossificans progressiva after results of a futility analysis reviewed by the Independent Data Monitoring Committee as part of an interim analysis that showed the therapy was unlikely to meet its primary efficacy endpoint.

Palovarotene was acquired by Ipsen through its acquisition in April 2019 of Clementia Pharmaceuticals for up to $1.3 billion.

Ipsen’s was studying palovarotene in a global phase 3 study designed to evaluate the efficacy and safety of palovarotene in patients with fibrodysplasia ossificans progressive (FOP), as well as in ongoing phase 2 extension studies.

The company said it will pause dosing patients in the trials and conduct further assessment of the complete data set and will discuss these findings with regulatory authorities to determine the path forward for the palovarotene program in FOP. Ipsen will collaborate with the patients and other stakeholders to define the next steps for the program.

Despite the results of the pre-specified interim analysis, signals of encouraging therapeutic activity were observed in preliminary post-hoc analyses of the phase 3 trial and shared with and acknowledged by the IDMC, which is recommending not discontinuing the study. In its recommendations, the IDMC noted highly disparate results that preclude a confident conclusion about futility.

The company noted that the protocol-pre-specified model may have negatively affected the efficacy analysis and shifted the statistical conclusion from significant therapeutic benefit to showing futility of the treatment. A U.S. Food and Drug Administration partial clinical hold announced in December for the pediatric population under the age of 14 for FOP and multiple osteochondromas (MO) remains in effect.

FOP is characterized by bone that forms outside the normal skeleton, in muscles, tendons, or soft tissue. In FOP, this bone growth progressively restricts movement by locking joints, leading to a cumulative loss of function, progressive disability, and increased risk of early death.

FOP is caused by a mutation in the ACVR1 gene, resulting in excess signaling in the bone morphogenetic pathway, a key pathway controlling bone growth and development, by way of both ligand-dependent and independent mechanisms. There are currently no approved treatments for the condition.

Palovarotene is a RARγ agonist that inhibits excess bone morphogenetic protein signaling, which is linked to the progression of FOP and MO.

“While the study has met pre-specified statistical futility, we are encouraged by the results observed in the preliminary post-hoc analyses and look forward to discussing these with regulators as quickly as possible to determine the next steps for the palovarotene program,” said Aymeric Le Chatelier, CEO at Ipsen.

Palovarotene has received Orphan Drug status for FOP and MO from the FDA and the European Medicines Agency. In addition, palovarotene has been granted Fast Track and Breakthrough Therapy designations for FOP from the FDA.

Photo: Aymeric Le Chatelier, CEO of Ipsen

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