Alto Neuroscience’s phase 2 depression trial has missed its primary efficacy endpoint, as patients on the drug candidate fared no better on a measure of alertness and mood than their peers on placebo.
Still, the biotech pointed to other outcomes to make the case for the molecule.
The phase 2 trial enrolled 69 people with major depressive disorder and elevated levels of anhedonia, a reduced ability to feel pleasure. Sixty-three patients completed the first part of the study, which assessed the effect of single 25 µg or 75 µg doses of the histamine H3 receptor inverse agonist ALTO-203 on a measure of alertness and mood. Patients in the multi-dose part of the trial took ALTO-203 once a day for 28 days.
Alto reported significant improvements in alertness and mood five hours after a single dose of ALTO-203. The problem? Participants also improved on placebo. In a June 26 press release, Alto said the placebo response was higher than expected and there was no significant separation between ALTO-203 and the control.
The measure of alertness and mood was the primary endpoint in the single-dose part of the study. While the trial missed the endpoint, Alto reported significant changes in an EEG marker, the theta/beta ratio, that it has flagged as a way to identify people who might respond to treatment. The biotech said patients with more abnormal theta/beta ratios at baseline had the biggest improvements in attention.
Alto also linked ALTO-203 to increased wakefulness, as measured using wearables.
In the multi-dose part of the trial, the biotech reported a mean placebo-adjusted improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) of 2 points at week 3 and 0.9 points at week 4. Alto saw the improvement over placebo on the low dose of the drug candidate. The high dose performed no better than placebo.
The biotech expects to decide the next steps for ALTO-203 once it finishes the complete analysis of the dataset. At a Jefferies event earlier this month, Alto CEO Amit Etkin, M.D., Ph.D., discussed what the company was hoping to see in the results and how the insights would inform the next steps.
“What we're hoping for is some clear signal that helps you guide how to develop it,” Etkin said. “Obviously, statistical significance is an important cut point there, but also is that signal similar to what we've seen in healthy individuals? Does that signal help tell you what kind of clinical populations to develop it, be it in depression where it is now or anywhere else?”