The FDA has placed two trials of palovarotene on partial clinical hold eight months after Ipsen gained the drug in its $1 billion (€900 million) takeover of Clementia Pharmaceuticals. FDA staff took the action in response to cases of early growth plate closure in children on the retinoic acid receptor gamma agonist.
Ipsen is developing palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP), a rare bone disease. At the time of the Clementia takeover, Ipsen CEO David Meek called the asset “largely derisked,” reflecting a belief that phase 2 data generated on the episodic use of the drug will support FDA approval in that indication next year.
However, Ipsen now faces risks associated with palovarotene. The prospects of the chronic use of the therapy in children with FOP have been thrown into doubt by reports of patients experiencing early growth plate closure while taking the drug.
The FDA took the cases seriously enough to place the pediatric portions of two trials on hold. All the growth plate closure serious adverse events occurred in the phase 3 trial Ipsen is running to assess the chronic treatment of FOP, which entails daily dosing for 24 months. However, the FDA thinks kids in a phase 2 multiple osteochondromas (MO) trial may also be at risk. That is bad news for Ipsen.
"Assuming Ipsen is unable to assuage concerns, removing the MO indication and restricting chronic FOP treatment to older patients could cut our peak sales to $270m, from $1.85bn," analysts at Jefferies wrote in a note to investors.
Ipsen’s MO phase 2 is giving daily doses of palovarotene for 24 months, although some of the patients in that trial are receiving a lower dose than the one used in the FOP study. As the MO trial is only enrolling kids, it is stopping completely. Ipsen will keep dosing FOP patients aged 14 years and older in the other study.
The FDA put the studies on hold to give it time to review additional details about the adverse events. Ipsen expects to receive additional requests for information from the FDA within the next 30 days.
The outcome of the FDA’s deliberations could impact the commercial prospects of palovarotene. A review of French health databases found 22% of FOP patients are aged 10 years and under. A further 25% are 11 to 20 years old, suggesting the under-14 subgroup affected by the clinical hold represents a significant minority of the overall patient population. Worse still, the entire MO population is pediatric.
Ipsen estimates palovarotene can generate peak annual sales of $400 million in chronic and flare-up FOP indications, plus “significant upside” from approval in MO.
Work to secure the first of those sales is continuing. Ipsen recently delayed the planned filing for approval of palovarotene in flare-up FOP from the back half of 2019 to the first quarter of next year “as a result of the processing of additional supportive data.” The drugmaker is continuing to work toward that target despite the clinical hold.
Shares in Ipsen fell more than 20% in early trading in Paris.