– Data generated from Alto’s precision psychiatry platform and clinical-stage product candidates highlighted across three poster presentations and a panel discussion –

– New preclinical data from a reverse translation study demonstrates the link between the mechanism of ALTO-300 and the EEG biomarker used for patient selection –

– An interim analysis will be conducted for the ongoing Phase 2b trial of ALTO-300 as an adjunctive treatment in MDD; results from the interim analysis are expected in the first quarter of 2025, followed by topline data from the complete study sample in the first half of 2025 –

Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced multiple presentations at the 63^rd annual meeting of the American College of Neuropsychopharmacology (ACNP), in Phoenix, Arizona, held December 8-11, 2024.

“At this year’s ACNP meeting, we highlighted the continued progress across our pipeline and precision psychiatry platform,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “Notably, we shared exciting new mechanistic findings that support the ALTO-300 biomarker. Extensive literature suggests that dopaminergic activity stabilizes neural signaling and ALTO-300, which blocks the 5-HT2C serotonin receptor, has been shown to increase dopamine release. As demonstrated by new data, the ALTO-300 biomarker is a measure of reduced neural signal stability and can be generated by activating the 5-HT2C receptor. These insights enhance our understanding of the patient phenotype we are studying in our ongoing Phase 2b study and provide clear mechanistic relevance to our machine-learning derived biomarker. We believe the reverse translation of this biomarker underscores the promise of our precision medicine approach and brings us closer to developing more effective, targeted treatments through a deeper understanding of neurobiological processes in defined patient subtypes. This is enhanced by the scalability of our EEG biomarker, which is calculated based on signal from a single electrode.”

The details of each presentation are as follows:

Presentation Title: Neural and Molecular Mechanistic Correlates of an EEG Biomarker Predictive of the Antidepressant Response to ALTO-300 in Patients with Major Depression

Presentation Highlights:

• Background: ALTO-300, an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist, is an approved antidepressant medication in Europe and Australia. Along with a range of synergistic neurobiological effects, ALTO-300 has been shown to enhance dopaminergic and noradrenergic input to the frontal cortex and rescue anhedonia-like behavioral deficits. Response to ALTO-300 is predicted by greater levels of sample entropy, a measure of resting-state EEG (rsEEG) irregularity.
• Human connectivity analysis: Greater sample entropy is associated with decreased neural connectivity. Across multiple independent datasets (N=784), biomarker positive patients demonstrated reduced medial prefrontal neural connectivity, a brain region frequently implicated in MDD.
• Reverse-translation preclinical study: In mice (N=13), administration of a 5-HT2C agonist (R0-0175) led to a dose-related increase in sample entropy, consistent with a biomarker positive phenotype. These results tie the human-discovered EEG biomarker to ALTO-300’s molecular mechanism of action, as a 5-HT2C antagonist.
• Key Takeaway: The ALTO-300 biomarker is characterized by reduced medial prefrontal neural connectivity, providing functional evidence of the consequence of more irregular neural signal, which may reflect an increase in 5-HT2C activity in patients. This biomarker, which was previously identified and prospectively replicated, is being used to select patients for the ongoing Phase 2b study of ALTO-300 as an adjunctive treatment in patients with MDD (NCT05922878).

Presentation Title: Validation of Assessments for Reward Processing for Use in a Phase 2 Study of a Novel Histamine H3 Inverse Agonist, ALTO-203, in Major Depression

Presentation Highlights:

• Background: Established tests of reward processing tend to be lengthy and poorly tolerated. Two novel computerized cognitive tests for different aspects of reward processing and motivation were developed, validated and examined in relationship to anhedonia.
  • Effort Tapping is a paradigm where participants can earn +10 (low reward) or +100 points (high reward) based on rate of finger tapping. Anhedonia was hypothesized to relate to the ability to mobilize effort and achieve greater reward.
  • The Probabilistic Instrumental Learning Task (PILT) is an adaptation of a classic, two-choice learning test, which measures the ability to learn arbitrary stimulus-reward probabilistic associations. Anhedonia was hypothesized to be associated with a lower learning rate and increased decision noise, as dopamine release has been shown to be a driver of learning in similar paradigms.
• Results: Compared to established tests of reward processing, Effort Tapping and PILT showed strong test-retest reliability, are shorter and better tolerated, and display stronger evidence of construct and external validity through association with anhedonia and motivation, than established reward tasks. Associations were furthermore replicated across two large studies.
• Key Takeaway: These novel tasks may be used to more effectively characterize pharmacodynamic effects of ALTO-203 in the ongoing Phase 2 proof-of-concept trial in patients with MDD and anhedonia (NCT06391593).

Presentation Title: Prevalence and Correlates of Cognitive Impairment in Depression: Findings from the Texas Resilience Against Depression Study

Presentation Highlights:

• Background: Cognitive impairment (CI) in MDD is associated with worse clinical and functional outcomes in depression.
• Results: Across participants (N=391), 51% met the criteria for CI, a highly stable phenotype similarly evident across age groups and different levels of premorbid cognitive function. Individuals with CI and depression are no more depressed or anxious than non-CI depressed, but are more likely to report impairments in activities, worse quality of life, and greater anhedonia and suicidality.
• Key Takeaway: Findings from the Texas Resilience Against Depression study (T-RAD; NCT02919280) underscore the high unmet need for patients with MDD who experience CI, comprising approximately 50% of the overall MDD population.

During ACNP, Dr. Etkin participated in a panel discussion, titled Neuroimaging in Psychiatry: Toward Mechanistic Insights and Clinical Utility to discuss advances and the implementation of neuroimaging tools for psychiatric treatment development, both in industry and academia.

Today, the Company also announced that it plans to conduct an interim analysis for the ongoing Phase 2b trial of ALTO-300. Following the completion of the ALTO-100 Phase 2b trial in MDD, the Company conducted a thorough review of patients included in its ongoing trials. Based on learnings from this review, the Company expects the planned interim analysis to be used to inform the final sample size needed to achieve adequate powering of the ALTO-300 Phase 2b trial. The Company expects to conduct and report the outcome from the interim analysis in the first quarter of 2025.

About Alto Neuroscience

Alto Neuroscience is a clinical-stage biopharmaceutical company with a mission to redefine psychiatry by leveraging neurobiology to develop personalized and highly effective treatment options. Alto’s Precision Psychiatry Platform™ measures brain biomarkers by analyzing EEG activity, neurocognitive assessments, wearable data, and other factors to better identify which patients are more likely to respond to Alto product candidates. Alto’s clinical-stage pipeline includes novel drug candidates in depression, schizophrenia, and other mental health conditions. For more information, visit www.altoneuroscience.com or follow Alto on X.

Forward-Looking Statements

This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “expects,” “plans,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding Alto’s expectations for the timing and results of Alto’s Phase 2b study of ALTO-300. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including uncertainties inherent in the initiation, progress and completion of clinical trials and other important factors, any of which could cause Alto’s actual results to differ from those contained in the forward-looking statements, which are described in greater detail in the section titled “Risk Factors” in Alto’s Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2024 filed with the Securities and Exchange Commission (“SEC”) as well as in other filings Alto may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Alto expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as required by law.

Availability of Information on Alto’s Website

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