Biohaven flunks Alzheimer's phase 2/3, touts failed subgroup as sign of efficacy

Biohaven on NYSE screens
Biohaven released news of the Alzheimer’s disease data on Martin Luther King Jr. Day, a federal holiday in the U.S. (Biohaven Pharma)

A phase 2/3 clinical trial of Biohaven Pharmaceutical’s troriluzole in Alzheimer’s disease has missed its co-primary endpoints. Biohaven, which slipped the news out on a federal holiday, is yet to quit on the program, though, pointing to a “nonsignificant numerical difference of a potential benefit” in a 97-subject subgroup to argue troriluzole may have a future in the indication.

Investigators randomized 350 patients with mild to moderate Alzheimer’s to take daily oral doses of the glutamate-targeting prodrug troriluzole or placebo for up to 48 weeks. Biohaven moved the drug into a phase 2/3 clinical trial in the belief it can improve outcomes by addressing the glutamatergic dysfunction implicated in Alzheimer’s. The top-line findings from the phase 2/3 are largely devoid of evidence to support the hypothesis.

The study missed its co-primary endpoints, which looked at the effect of 48 weeks of troriluzole on two assessments of cognition, namely ADAS-Cog 11 and CDR-Sum of boxes. Troriluzole also failed to beat placebo on the key secondary measure of hippocampal volume.

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Faced with a clean sweep of failures across key endpoints, Biohaven zeroed in on a subgroup analysis for evidence troriluzole may have a future in the indication. The subgroup analysis looked at the ADAS-cog scores and hippocampal volume of 97 patients with mild Alzheimer’s.

In the 48-subject troriluzole subgroup, investigators saw a mean deformation change from baseline hippocampal volume of minus 1.1%, as compared to a minus 1.6% change in the placebo. The p-value was 0.2. Biohaven said the subgroup analysis revealed “a nonsignificant numerical difference of a potential benefit” and a “potential biologic effect of troriluzole in patients with early stage disease.” 

Biohaven is continuing to analyze the data, including biomarker findings, before deciding whether to continue studying troriluzole in Alzheimer’s. Many other drugs have generated more robust evidence of efficacy in Alzheimer’s than a nonsignificant 97-subject subgroup analysis and gone on to fail later tests, suggesting the chances of troriluzole moving the needle in the indication are slim. 

However, there is recent precedent for Biohaven taking troriluzole forward after failing phase 2. Last year, a 12-week phase 2/3 trial of troriluzole in obsessive-compulsive disorder missed its primary endpoint, only for Biohaven to initiate a pivotal program on the strength of results at the eighth week of the failed study. Troriluzole has already failed a phase 3 generalized anxiety disorder clinical trial. 

Biohaven released news of the Alzheimer’s data on Martin Luther King Jr. Day, a federal holiday in the U.S. Stock markets were closed for the holiday, delaying the impact of the setback on Biohaven’s share price.