Teva Pharmaceutical Industries said today it will halt a Phase III trial of fremanezumab (TEV-48125) for chronic cluster headaches, after concluding that the study is unlikely to meet its primary endpoint of a reduced number of headaches.

Teva said it is ending the chronic cluster headache trial (NCT02964338) after a prespecified futility analysis showed that fremanezumab was unlikely to meet the study’s primary endpoint of mean change from baseline in the monthly average number of cluster headache attacks during the 12-week treatment period.

The study, which has an estimated enrollment of 300 participants, is designed to assess the efficacy and safety of two dose regimens of fremanezumab—intravenous/subcutaneous and subcutaneous—compared with placebo. The trial had an estimated primary completion date of October 9 and a full completion date of November 6.

In addition, Teva said it was halting enrollment in its 68-week ENFORCE safety study (NCT03107052), an enrollment-by-invitation assessment of fremanezumab in chronic cluster headache patients.

“While we are disappointed with this outcome, we remain optimistic that fremanezumab could have clinical benefits in additional conditions, beyond migraine, where calcitonin gene-related peptide (CGRP) plays a contributory role in their pathophysiology,” Tushar Shah, M.D., Teva SVP, head of Global Specialty Clinical Development, said in a statement.

Chronic cluster headaches would have been an add-on indication for fremanezumab, which is under FDA review for prevention of migraines. After Teva submitted its Biologics License Application (BLA) for the drug to the FDA, the agency initially set a target date for a decision on Teva’s under the Prescription Drug User Fee Act (PDUFA) of June 16. Teva gained expedited review by acquiring a priority review voucher

Last month, however, Teva confirmed that the FDA pushed back fremanezumab’s PDUFA date to September 16. The delay followed manufacturing issues. In February, Teva disclosed that Celltrion, the manufacturer of the drug’s active pharmaceutical ingredient, received an FDA warning letter for its facility in Incheon, South Korea. Celltrion told Reuters in April it was working to address the undisclosed manufacturing issues raised by the agency.

Expecting Launch by Year’s End

“We are expecting now to see the preapproval inspection take place within the coming months, and this will have to go hand-in-hand with a reinspection of Celltrion, a warning letter reinspection,” Teva president and CEO Kåre Schultz told analysts on the company’s May 3 conference call following release of first-quarter results, according to a transcript by Seeking Alpha. “And of course, we have high confidence that both these inspections will be passed, and that means we will be able to get approval and launch before the end of 2018.”

Fremanezumab is also under review by the European Medicines Agency, with approval expected from the European Commission in the first half of next year.

Teva said today it will continue a Phase III trial assessing fremanezumab in episodic cluster headaches (NCT02945046). An estimated 300 patients are expected to be enrolled in the 13-week study, designed to compare the efficacy and safety of two dose regimens of fremanezumab versus placebo in adult patients for the prevention of ECH. The study’s estimated primary completion date is February 22, 2019.

Fremanezumab is a monoclonal antibody targeting the CGRP ligand, and is being developed as a quarterly or monthly injection for the preventive treatment of migraine in adults. Fremanezumab is also under study as a preventive treatment for several additional disorders, including cluster headache and post-traumatic headache disorder.

Fremanezumab is one of three migraine drugs in late-stage development that are designed to work by inhibiting the CGRP receptor, believed to play a causal role in migraine pathophysiology. On May 17, the FDA approved the first CGRP receptor inhibitor indicated for migraine prevention, Aimovig™ (erenumab), being marketed by Amgen and Novartis.

Later this year, the FDA is expected to decide on Eli Lilly’s migraine candidate galcanezumab, for which the company last month announced new positive Phase III results. Lilly said galcanezumab met its primary endpoint in a pivotal study of patients with episodic cluster headache, showing statistically significant differences in the reduction of weekly cluster headache attacks compared to placebo across the first three weeks of the two-month, double-blind treatment period.

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