Jun. 26 at 12:00 PM
$ANRO Alto Neuroscience identifies biomarker, reports ALTO-203 pharmacodynamic results
Alto Neuroscience announced the identification of a patient selection biomarker and pharmacodynamic results from its exploratory Phase 2 proof-of-concept trial of ALTO-203 in major depressive disorder patients with elevated levels of anhedonia. ALTO-203 is a novel, oral, histamine H3 inverse agonist, designed to modulate circuits underlying cognition, wakefulness, and alertness. The profile exhibited by ALTO-203 in the exploratory POC trial demonstrated clear effects on objective measures of attention and wakefulness, with observed improvements linked to changes in the EEG theta/beta ratio-a biomarker indexing cortical arousal and attentional control.
These findings replicate results from the Phase 1 study in healthy volunteers, where ALTO-203 treatment led to improvements in sustained attention and reductions in the EEG theta/beta ratio. Baseline EEG theta/beta ratio predicted attentional benefits of ALTO-203 in both the Phase 1 study and Phase 2 POC trial. Patients reported significant improvements from baseline on BL-VAS for alertness & mood at the 5-hour timepoint post dosing with ALTO-203. A higher-than-expected placebo response was observed on the Bond & Lader measurements - no significant separation between ALTO-203 and placebo was observed.
The theta/beta ratio, a neurophysiological marker linked to attentional control, was confirmed as a key pharmacodynamic readout. The effects of ALTO-203 on reducing theta/beta ratio were significant compared to placebo. This marker was previously shown to be significantly reduced by ALTO-203 in the completed Phase 1 study in healthy subjects, as well as in preclinical studies. ALTO-203 treatment led to significant improvements in sustained attention, aligning with reductions in the EEG theta/beta ratio. Improvement in attention was greatest in patients with high baseline theta/beta ratios.
The observed improvements in attention and corresponding changes in EEG theta/beta ratio replicated significant findings from the Phase 1 study. Objective sleep measures from wearable devices supported the wake-promoting effects of ALTO-203, and the increased wakefulness exhibited by ALTO-203 was significant for both doses. ALTO-203 displayed predictable accumulation over multiple doses with no adverse pharmacokinetic signals. ALTO-203 was well tolerated, with insomnia as the most frequent adverse event, consistent with its wake-promoting profile.
Patients taking 25microgram of ALTO-203 exhibited a mean improvement of 2 points at week 3 and 0.9 points at week 4 compared to placebo. The differences were not observed in the 75microgram dose group. MADRS improvements were evaluated during the 28-day multi-dose period, which was not powered to detect significance. Alto plans to report additional results from this exploratory study at a future medical meeting and expects to determine the next development steps for ALTO-203 following the complete analysis of the data set.
