8-K: Alto Neuroscience Unveils Positive Phase 2 Biomarker and Pharmacodynamic Results for ALTO-203 in Major Depressive Disorder

Alto Neuroscience, Inc. announced positive pharmacodynamic results and the identification of a patient selection biomarker from its exploratory Phase 2 proof-of-concept trial of ALTO-203 for major depressive disorder.

Summary

• Alto Neuroscience reported positive pharmacodynamic results and identified a patient selection biomarker (EEG theta/beta ratio) from its exploratory Phase 2 proof-of-concept (POC) trial of ALTO-203 in major depressive disorder (MDD) patients with elevated anhedonia.
• ALTO-203, a novel oral histamine H3 inverse agonist, demonstrated clear effects on objective measures of attention and wakefulness, linked to changes in the EEG theta/beta ratio, a biomarker indexing cortical arousal and attentional control.
• These findings replicated results from a prior Phase 1 study in healthy volunteers, where ALTO-203 treatment also led to improvements in sustained attention and reductions in the EEG theta/beta ratio.
• Baseline EEG theta/beta ratio successfully predicted attentional benefits of ALTO-203 in both the Phase 1 study and the Phase 2 POC trial.
• The exploratory Phase 2 POC trial enrolled 69 patients and was conducted in two sequential, double-blind, placebo-controlled periods (single-dose and multi-dose).
• The trial was designed to characterize pharmacodynamic, pharmacokinetic, safety, and tolerability profiles and was not powered to detect statistical significance on traditional depression outcome scales (e.g., MADRS).
• ALTO-203 significantly reduced the theta/beta ratio compared to placebo (25g: p<0.05).
• Significant improvements in sustained attention were observed (25g: p<0.05; 75g: p=0.06 vs. placebo), with the greatest improvement in patients with high baseline theta/beta ratios (25g: p<0.01; 75g: p<0.05 vs. placebo).
• Objective sleep measures from wearable devices supported significant wake-promoting effects for both doses (25g: p<0.05; 75g: p<0.001 vs. placebo).
• ALTO-203 was well tolerated, with insomnia as the most frequent adverse event, consistent with its wake-promoting profile, and displayed predictable accumulation over multiple doses with no adverse pharmacokinetic signals.
• Patients taking 25g of ALTO-203 exhibited a mean improvement of 2 points at week 3 and 0.9 points at week 4 on MADRS compared to placebo, though the trial was not powered for significance on this endpoint and differences were not observed in the 75g dose group.

Sentiment

Score: 7

Explanation: The identification of a robust, replicated biomarker and positive pharmacodynamic effects are significant advancements for Alto's precision psychiatry platform and ALTO-203's development. The consistency with Phase 1 data adds confidence. However, the exploratory nature of the trial and the fact it was not powered for traditional clinical efficacy endpoints (like MADRS) temper the overall enthusiasm, as further, larger trials are still needed to confirm clinical benefit.

Positives

• Identification of a robust patient selection biomarker, EEG high-theta/beta ratio, for ALTO-203, which is an FDA-cleared measure for use alongside clinical evaluation in ADHD diagnosis.
• Positive pharmacodynamic results demonstrating target engagement and response prediction for ALTO-203 by the theta/beta ratio.
• Replication of Phase 1 study findings regarding improvements in attention and corresponding reductions in EEG theta/beta ratio, enhancing confidence in the drug's mechanism.
• ALTO-203 showed significant effects on reducing theta/beta ratio compared to placebo (25g: p<0.05).
• Significant improvements in sustained attention were observed (25g: p<0.05; 75g: p=0.06 vs. placebo), particularly in patients with high baseline theta/beta ratios (25g: p<0.01; 75g: p<0.05 vs. placebo).
• Objective sleep measures from wearable devices supported significant wake-promoting effects (25g: p<0.05; 75g: p<0.001 vs. placebo).
• ALTO-203 was well tolerated with predictable pharmacokinetics and no adverse pharmacokinetic signals.

Negatives

• The exploratory Phase 2 POC trial was not powered to detect statistical significance on traditional depression outcome scales (e.g., MADRS), limiting definitive conclusions on clinical efficacy for depression.
• A higher-than-expected placebo response was observed on the Bond & Lader Visual Analog Scale (BL-VAS) for subjective alertness & mood, resulting in no significant separation between ALTO-203 and placebo on this measure.
• While MADRS improvements were noted for the 25g dose, these differences were not observed in the 75g dose group, and the trial was not powered for statistical significance on this endpoint.

Risks

• Uncertainties inherent in the initiation, progress, and completion of clinical trials, which could cause actual results to differ materially from forward-looking statements.
• The exploratory nature of the Phase 2 trial means that further, larger, and adequately powered clinical trials will be required to confirm the efficacy and safety of ALTO-203 on traditional clinical endpoints for major depressive disorder.

Future Outlook

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. The company aims to leverage objective biomarkers to enable targeted neuropsychiatric drug development, believing their Precision Psychiatry Platform has the potential to enable data-driven indication selection and trial design early in development, accelerating the path to more effective, personalized treatment. ALTO-203 is seen as having clear potential to be a meaningful treatment across various neuropsychiatric conditions where sleep and attention are significantly impaired.

Management Comments

• Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience: "We aim to leverage objective biomarkers to enable targeted neuropsychiatric drug development so that patients can get better, faster."
• Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience: "In this exploratory trial, we identified a robust biomarker for ALTO-203, EEG high-theta/beta ratio, which is a well-validated measure of abnormal cortical arousal and poor attentional control. Notably, this biomarker is FDA-cleared for use alongside clinical evaluation in the diagnosis of ADHD, reinforcing its clinical relevance."
• Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience: "These positive results replicate findings from an ALTO-203 Phase 1 study and enhance our understanding of the patient subtypes most likely to benefit from the drug, further strengthening the foundation of our precision psychiatry approach."
• Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience: "We believe our platform has the potential to enable data-driven indication selection and trial design early in development—accelerating the path to more effective, personalized treatment."
• Adam Savitz, M.D., Ph.D., Chief Medical Officer of Alto Neuroscience: "We are encouraged by the positive pharmacodynamic activity observed in the study, which aligns with the proposed mechanism of ALTO-203."
• Adam Savitz, M.D., Ph.D., Chief Medical Officer of Alto Neuroscience: "The wake-promoting and pro-cognitive effects demonstrated, suggest clear potential for ALTO-203 to be a meaningful treatment across various neuropsychiatric conditions in which sleep and attention are significantly impaired."

Industry Context

The announcement by Alto Neuroscience aligns with the broader industry trend towards precision medicine in neuropsychiatry, moving beyond traditional trial-and-error approaches. The identification and validation of a specific biomarker (EEG theta/beta ratio) for patient selection and response prediction for ALTO-203 represents a significant step in developing targeted therapies for complex conditions like major depressive disorder. This approach aims to improve treatment efficacy and reduce development costs by focusing on patient subtypes most likely to respond, a critical need in a field historically challenged by high failure rates and heterogeneous patient populations. The use of an FDA-cleared biomarker, even if for a different indication (ADHD), adds credibility to Alto's platform and its potential clinical utility.

Comparison to Industry Standards

• The document does not provide specific comparisons to other companies' clinical trial results or projects. The focus is on Alto's internal data, particularly the replication of its own Phase 1 study findings for ALTO-203.

Stakeholder Impact

• Shareholders: The positive biomarker and pharmacodynamic data could increase investor confidence in Alto's precision psychiatry platform and ALTO-203's potential, potentially leading to increased share price. However, the exploratory nature and lack of statistical significance on traditional endpoints might temper long-term enthusiasm until further trials.
• Patients: The identification of a specific biomarker could lead to more targeted and effective treatments for MDD patients with particular neurobiological profiles, potentially improving treatment outcomes and reducing the current trial-and-error approach to prescribing.
• Employees: Positive trial results can boost morale and validate the company's research and development efforts, reinforcing the strategic direction of the company.

Next Steps

• Alto plans to report additional results from this exploratory study at a future medical meeting.
• Alto expects to determine the next development steps for ALTO-203 following the complete analysis of the data set.

Key Dates

Recommendation

Keywords

Alto Neuroscience, ALTO-203, Phase 2 trial, Major Depressive Disorder, MDD, Anhedonia, Biomarker, EEG, Theta/Beta Ratio, Pharmacodynamics, Neuropsychiatric, Clinical Trial, Biopharmaceutical, Precision Psychiatry, Attention, Wakefulness, Histamine H3 inverse agonist