PROSPECTIVE REPLICATION OF AN EEG BIOMARKER FOR PREDICTING CHANGES IN ATTENTION IN ALTO-203, AN H3 INVERSE AGONIST

Background

Psychiatric disorders are heterogeneous, leading to drugs developed in broad populations showing no or minimal benefit over placebo. Predictive biomarkers may enhance treatment effects by targeting subpopulations for a given drug and reducing trial and error prescribing. ALTO-203 is an H3 inverse agonist that releases dopamine, norepinephrine, acetylcholine, and histamine, suggesting a pro-wakeful, pro-cognitive profile that may be beneficial for Major Depressive Disorder (MDD) and other disorders. A prior Phase 1 trial in healthy volunteers showed acute benefits on subjective positive emotion and alertness, along with improved attention and reduced theta/beta ratio (TBR), a neurophysiological index of cortical arousal and attentional control. Moreover, subjects with higher TBRs at baseline showed greater changes in attention with ALTO-203 than subjects with lower TBRs, suggesting that ALTO-203 may be better at improving attention in those with higher TBRs ratios. A subsequent study was conducted with a goal of replicating the Phase 1 findings in MDD participants.

Methods

69 participants with MDD and anhedonia (defined as a Snaith Hamilton Pleasure Scale [SHAPS] > 28) were enrolled in a Phase 2 proof-of-concept (POC) trial of ALTO-203 (NCT06391593). Participants underwent a single-dose period, in which they received two single-doses of ALTO-203 (25µg and 75µg) and placebo in a three-way crossover design with an at least 10-day washout period. The primary outcome was an acute change in positive emotion assessed by the Bond-Lader Visual Analog Scale (BL-VAS). Participants underwent cognitive assessments, electroencephalography (EEG), and sleep and activity monitoring using a wearable device. Following the single-dose period, participants received daily administration of ALTO-203 (25µg or 75µg QD) or placebo over 28 days to evaluate extended safety, tolerability and pharmacokinetics. Our analysis set includes 52 participants that passed blinded prospective central review and completed the single-dose period. Mixedeffects models evaluated the efficacy of ALTO-203 versus placebo; subgroup analyses of subjects with higher TBRs were also tested. Statistical significance was evaluated with twosided p-values with no correction for multiple comparisons.

Results

There was no significant difference between ALTO-203 and placebo on the BLVAS as there was a higher than expected placebo response (p > 0.407). Compared to placebo, ALTO-203 improved attention (25µg p < 0.05; 75µg p = 0.06) and decreased TBRs (25µg p < 0.05). Improvement in attention with ALTO-203 was greatest among participants with high baseline TBRs (25µg: p < 0.01; 75µg: p < 0.05 vs. placebo). Increased wakefulness (reduced minutes asleep) supported the wake-promoting effects of ALTO-203 (25µg: p < 0.05; 75µg: p < 0.001 vs. placebo). ALTO-203 displayed predictable accumulation over multiple doses and was well tolerated, with insomnia as the most frequent adverse event.

Conclusions

These data replicate prior findings that ALTO-203, a novel H3 inverse agonist, improves sustained attention and cortical arousal, and that individuals with higher TBRs are more likely to realize the greatest benefit in sustained attention. These data suggest that ALTO-203 may be best suited for disorders with hypersomnolence or excessive daytime sleepiness, along with deficits in attention. The cross-over design of the study allowed an efficient assessment of ALTO-203 in patients. 4:15 p.m. - 6:15 p.m. Workshops