– Identified and prospectively replicated an EEG-based biomarker for placebo response in MDD –

– New data strengthen the mechanistic link between ALTO-300 and the EEG biomarker being used for patient selection; biomarker signature induced by activating 5-HT2C or depleting dopamine directly –

– Preclinical ALTO-101 rescue study underscores the therapeutic potential of this novel PDE4 inhibitor, and validates EEG theta response as a robust translational biomarker for CIAS –

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 Society of Biological Psychiatry (SOBP) Annual Meeting, in Toronto, Canada, held April 24-26, 2025.

“The biological and clinical insights we presented at SOBP support our precision psychiatry pipeline and mark important advancements for the field,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “To address the longstanding challenge of high placebo response in neuropsychiatric clinical development, we have successfully identified and prospectively replicated an EEG biomarker that captures placebo response patterns in patients with major depressive disorder. We believe this biomarker has the potential to reduce noise and improve the detection of true therapeutic effect.”

Dr. Etkin continued, “We enhanced our understanding of the mechanistic link between ALTO-300 and the machine-learning derived, EEG biomarker used to identify patients who are more likely to respond to treatment. We showed that increasing 5-HT2C activity or directly depleting dopamine—both the opposite mechanistic effect of ALTO-300—resulted in greater EEG irregularity, consistent with a biomarker positive profile. Additionally, in a preclinical rescue study we demonstrated that ALTO-101 increased theta response, demonstrating its robustness as a translational biomarker for cognitive impairment associated with schizophrenia and potential pro-cognitive drug effect. We look forward to leveraging these findings to drive meaningful innovation in psychiatry and enhance clinical outcomes for patients.”

Summary of Data Presentations Across Clinical Programs

EEG-based biomarker for placebo response in MDD

  • Background and Rationale: High placebo response is a major challenge in clinical trials for patients with major depressive disorder (MDD), yet no validated biomarker exists for reliably identifying high placebo responders.
    • A shared predictor across diverse established antidepressant treatments was hypothesized to approximate a placebo response.
    • Prospective replication was conducted in two randomized trials, including placebo and active arms.
    • Within the two randomized trials, the ability to increase drug-placebo effect size was evaluated by incorporating placebo response predictions as sample weights.
  • Key Takeaways:
    • An EEG-based biomarker capable of predicting non-specific treatment response across multiple interventions and independent datasets​ was developed and validated. The placebo biomarker yielded significant predictions for the open-label ALTO-100 and sertraline treatment response, both analyzed prospectively.
    • Additional prospective analyses in two randomized-controlled MDD studies were conducted to further validate the previously identified EEG-based placebo biomarker (ALTO-100 Phase 2b trial and the EMBARC sertraline trial) on both placebo response and drug-placebo differences.
      • In the ALTO-100 placebo arm, the biomarker significantly predicted MADRS score change across all weeks with correlation ranging from 0.29 to 0.19 (p=0.001 to p=0.029; Cohen’s d=0.49 to d=0.41) at weeks 2 and 6 respectively. In the EMBARC placebo arm, the biomarker significantly predicted HAMD score change, with a partial correlation ranging from 0.24 to 0.31 (p=0.009 to p=0.001) at weeks 6 and 8 respectively.
      • Drug-placebo treatment effect sizes were enhanced across diverse drug mechanisms when accounting for individual differences in predicted placebo response, as demonstrated by both the Phase 2b trial of ALTO-100 and EMBARC trial of sertraline.
    • This biomarker has the potential to enable more precise identification of high placebo responders in MDD trials, reduce trial variability, and enhance detection of treatment effects.
  • Intellectual Property:
    • Alto has patent protection covering the use of EEG biomarkers to predict placebo response.

ALTO-300

  • Background and Rationale: ALTO-300 is an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist. ALTO-300 has been shown to enhance dopaminergic and noradrenergic input to the frontal cortex and rescue anhedonia-like behavioral deficits. Greater gamma sample entropy (SE), or EEG irregularity, was previously shown to predict antidepressant response to ALTO-300 in MDD.
    • Increasing 5-HT2C activity or directly depleting dopamine (both the opposite mechanism of ALTO-300) was hypothesized to increase gamma SE and create a more biomarker positive EEG pattern.
  • Key Takeaways:
    • Administered two different 5-HT2C agonists (R0-0175 and YM348) in independent preclinical studies and revealed a dose-related increase in SE. 5-HT2C agonism also led to an anhedonic phenotype as demonstrated by a sucrose preference test.
    • In a double-blind, placebo-controlled, cross-over study, healthy participants consumed a nutritionally balanced amino acid mixture (placebo) and a mixture deficient in the dopamine precursors tyrosine and phenylalanine (APTD) in a counterbalanced order. SE was significantly larger in the APTD condition compared to the placebo condition (p<0.01, Cohen’s d=0.94), indicating that dopamine depletion drives a biomarker positive EEG pattern.
    • The ALTO-300 biomarker signal likely reflects increased neural noise due to elevated 5-HT2C tone and reduced dopaminergic activity. The mechanism of action of ALTO-300 involves an increase in dopamine in part through 5-HT2C antagonism. These findings therefore provide a direct link between ALTO-300 and the EEG biomarker used to identify MDD patients who are more likely to be responders to treatment.

ALTO-101

  • Background and Rationale: Cognitive Impairment Associated with Schizophrenia (CIAS) remains a high unmet need, with no approved treatments specifically targeting these deficits. Theta EEG response, measured by inter-trial coherence (ITC), is reproducibly disrupted in patients with schizophrenia and was previously identified as a promising marker for CIAS. Theta response strongly correlated with cognitive deficits in patients in multiple datasets.
    • N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a key role in CIAS pathophysiology. A rodent model was used to evaluate the effects of ALTO-101 on theta response following administration of MK-801, an NMDAR antagonist.
  • Key Takeaways:
    • Administration of MK-801 reduced theta response, modeling neural and behavioral abnormalities in schizophrenia.
    • Administration of ALTO-101 led to a dose-dependent rescue of the theta response abnormality induced by MK-801 and was statistically significant at the highest dose of 0.1 mg/kg (p<0.001).
    • Results are consistent with the completed Phase 1 trial in healthy volunteers, where ALTO-101 demonstrated robust, dose-dependent effects on theta response and cognitive test performance. The effects on these two measures were also correlated. Taken together, results validate theta response as a robust translational biomarker and underscore the potential cognitive benefits of ALTO-101 for patients with CIAS.

ALTO-203

  • Background and rationale: ALTO-203 is a novel, differentiated histamine H3 inverse agonist shown to increase dopamine release in the nucleus accumbens in rodents. This is a property not shared by pitolisant, the only FDA approved H3R inverse agonist, indicated for the treatment of excessive daytime sleepiness in narcolepsy.
    • A dopamine-related anhedonic state can be induced in rats through dopamine depletion with α-methyl-p-tyrosine (AMPT). Rescue of this sucrose preference deficit was evaluated to further investigate the behavioral effect of ALTO-203 on accumbens dopamine. Rats received ALTO-203, pitolisant, or vehicle co-administered with AMPT. Sucrose preference was assessed at baseline, five hours, and 20 hours post-treatment.
  • Key Takeaways: ALTO-203 (0.1 mg/kg) effectively reversed anhedonia-like behavior induced by dopamine depletion and demonstrated a significantly higher sucrose preference at five hours versus vehicle co-administered with AMPT (p=0.014). Pitolisant showed no significant effect at any dose. These findings underscore the distinct behavioral effects of ALTO-203, which may be driven by enhancing the function and control of dopamine in the reward system.

The following posters presented at SOBP 2025 are available under “Publications” in the platform section of Alto’s website:

  • An EEG Biomarker for Predicting Placebo Response in Major Depressive Disorder: Development and Validation Across Open-Label and Double-Blind Trials
    • Poster First Author: Chao Wang, Ph.D.
  • Prospective Replication and Application of an EEG-Based Placebo Response Prediction Biomarker in Randomized Controlled Trials in Depression
    • Poster First Author: Akshay S. Ravindran, Ph.D.
  • Gamma Band EEG Sample Entropy, a Patient Selection Biomarker for ALTO-300, is Increased by Acute Dopamine Precursor Depletion in Humans
    • Poster First Author: Guhan Sundar
  • Gamma Band EEG Sample Entropy, a Patient Selection Biomarker for ALTO-300, is Increased by 5-HT2C Agonists in Mice
    • Poster First Author: Yueqi Guo, Ph.D.
  • Translational Utility of ERP and Time-Frequency Features: Effects of the NMDA Antagonist MK-801 in Rats
    • Poster First Author: Guhan Sundar
  • ALTO-203, a Novel Histamine H3 Inverse Agonist, Increases Sucrose Preference in Dopamine-Depleted Rats
    • Poster First Author: Li Shen, Ph.D.

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 bipolar depression, major depressive disorder, 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 about the potential benefits, activity, and effectiveness of its product candidates, biomarkers, and Precision Psychiatry Platform (“Platform”); and Alto’s expectations with regard to the design and results of its clinical trials. 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 Annual Report on Form 10-K for the fiscal year ended December 31, 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

Alto routinely uses its investor relations website to post presentations to investors and other important information, including information that may be material. Accordingly, Alto encourages investors and others interested in Alto to review the information it makes public on its investor relations website.

Investor Contact: Nick Smith investors@altoneuroscience.com

Media Contact: Mari Purpura media@altoneuroscience.com

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