– $11.7 million award will be used to advance ALTO-100, a first-in-class small molecule, in a 200-patient placebo-controlled, double-blind, randomized Phase 2b study in bipolar depression –

– Alto will leverage the same cognitive biomarker being used in the ongoing Phase 2b MDD, which was previously identified and replicated in MDD and PTSD patients –

– This study represents the first precision psychiatry trial in bipolar depression, an indication identified by Wellcome Trust as an area of high unmet need in mental health with under-representation across drug development efforts –

Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO), a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced that the Company has been awarded $11.7 million by the Wellcome Trust to advance the clinical development of lead candidate ALTO-100 through a Phase 2b study in patients with bipolar depression characterized by a cognitive biomarker. The Company has initiated this study and expects to report topline data in 2026.

“Bipolar depression is among the most challenging psychiatric conditions, yet the only available treatments are antipsychotics, which carry limited efficacy and substantial side effects,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “Bipolar depression is associated with memory, cognitive, and neuroplasticity abnormalities at similar or greater rates than seen in major depression. Given the pro-neuroplasticity mechanism of ALTO-100, we have an opportunity to address an important subset of patients displaying a similar neurobiological profile. We are grateful to Wellcome for their commitment to addressing this devastating condition and eagerness to accelerate our late-stage clinical program as we work to develop the first precision treatment for bipolar disorder.”

Dr. Lynsey Bilsland, Head of Mental Health Translation at Wellcome, added, “We are committed to funding research and innovation to advance early intervention in mental health, helping create a world where people do not feel held back from the lives they wish to lead. We’re encouraged by Alto’s precision psychiatry drug candidate, which has the potential to have a significant impact on patients affected by bipolar depression and other mental health conditions. To make meaningful and effective progress, we must support these opportunities that promote targeted treatment approaches for patients, particularly in an industry that has relied on trial-and-error for too long.”

ALTO-100, a first-in-class, oral small molecule believed to work through enhancing neural plasticity, is currently in Phase 2b development for the treatment of major depressive disorder (MDD), with topline results expected in October 2024. Previously, Alto reported positive results from a Phase 2a study of ALTO-100 in MDD and post-traumatic stress disorder (PTSD), in which favorable safety and tolerability were established, and patients with a memory-based cognitive biomarker signature exhibited greater response to the drug candidate.

The Company is leveraging the same memory biomarker and study design being employed in the ongoing Phase 2b study of ALTO-100 in MDD. The randomized, double-blind, placebo-controlled study is expected to enroll approximately 200 adults with bipolar depression. Patients will be evaluated over a six-week treatment period. The primary endpoint is the change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), consistent with the endpoint in the ongoing Phase 2b MDD study, and the commonly used endpoint in registrational studies in bipolar depression.

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, PTSD, schizophrenia, and other mental health conditions. For more information, visit www.altoneuroscience.com or follow Alto on X.

About Wellcome

Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health.

About ALTO-100

ALTO-100 is a novel oral small molecule that has shown evidence of a pro-neurogenesis/neuroplasticity mechanism of action and first-in-class therapeutic potential. ALTO-100 is being developed for major depressive disorder (MDD) and bipolar depression, disease states characterized by cognitive impairment with no currently available treatments targeting these symptoms. In Phase 2a clinical trials, ALTO-100 demonstrated favorable safety and tolerability, and significantly greater treatment response in patients with an objectively defined cognitive biomarker.

About the ALTO-100 Cognitive Biomarker

Alto leverages its Precision Psychiatry Platform™ to identify brain-based biomarkers as predictors of response to medication. The predictive biomarker identified, and prospectively replicated, for ALTO-100 is a test of verbal memory, or the ability to recall lists of unrelated words. Verbal memory is a direct measure of hippocampal neuroplasticity; therefore, selecting patients based on poor performance on this test provides a clear biological link between the proposed pro-plasticity mechanism of ALTO-100 and this characteristic of responsive patients. The test used to compute the biomarker score is Alto’s digital adaptation of a well validated instrument that has been used in clinical practice for assessing memory for more than 80 years and is highly test-retest reliable. The web-based memory test is self-administered and can be completed by the patient in less than 20 minutes in any setting, including at home. This convenient, reliable, and efficient test enables high-quality data collection at a broad clinical scale.

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 “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “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, progress, and results of Alto’s Phase 2b study of Alto-100 in patients with bipolar depression, and the number of subjects to be enrolled in the study. 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 design, initiation, progress, and completion of Alto’s Phase 2b study of Alto-100 in patients with bipolar depression; the risk that Alto may not achieve the targeted enrollment in the study or that enrollment may take longer than expected; the availability and timing of results from the study; 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 March 31, 2023 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.

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