Alto Neuroscience Announces Initiation of Phase 2 Study of ALTO-203 in Patients with Major Depressive Disorder

Phase 2 study designed to evaluate the pharmacodynamic effects, pharmacokinetics, and tolerability of ALTO-203 in patients with major depressive disorder (MDD) and higher levels of anhedonia

ALTO-203 demonstrated a favorable tolerability profile across three Phase 1 clinical trials and produced a variety of emotional and brain effects that support its unique antidepressant potential

Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) today announced the initiation of its Phase 2 double-blind, single- and multiple-dose study to determine the pharmacodynamic effects of ALTO-203 in MDD patients as well as assess its safety, tolerability, and pharmacokinetics. To date, ALTO-203 has demonstrated positive emotional and cognitive effects in healthy participants after a single dose. The present study will evaluate these effects in patients with MDD to determine the potential of ALTO-203 as an antidepressant.

“This is the fifth Phase 2 study we have initiated across our pipeline, a milestone that marks significant progress in our efforts to redefine mental healthcare through our Precision Psychiatry Platform,” said Jessica Powell, chief development officer of Alto Neuroscience. “In a Phase 1 study, ALTO-203 demonstrated an acute increase in positive emotion relative to placebo and across several dosage levels. We look forward to completing this proof-of-concept study in patients as we believe this response may be an important attribute of an antidepressant to benefit patients with MDD and higher levels of anhedonia specifically.”

ALTO-203 is a novel small molecule histamine H3 receptor inverse agonist being developed for the treatment of patients with MDD and elevated anhedonia, or the lack of motivation or pleasure. This Phase 2 study consists of two sequential double-blind, placebo-controlled treatment periods and examines two doses of ALTO-203 and placebo given as monotherapy in patients with MDD.

The first period uses a randomized single-dose treatment design to evaluate patient pharmacodynamic responses to ALTO-203 compared to placebo. The powered primary outcome is measured by an acute change in positive emotion assessed by the alertness and mood components of the Bond-Lader Visual Analog Scale (BL-VAS), an established scale of subjective feelings also used in a prior Phase 1 study of ALTO-203. The second period uses a 28-day, multi-dose exposure design to assess the safety of ALTO-203 in patients with MDD. Exploratory, non-powered objectives for the multi-dose period will evaluate changes in measures of depression, anhedonia, and other clinical symptoms, along with cognition, EEG, and wearables.

Alto expects to enroll approximately 60 adult participants with MDD and evidence of anhedonia, and report topline data from this study in the first half of 2025. More information about this trial will be available at ClinicalTrials.gov.

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.

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 the ALTO-203 study, 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 initiation, progress and completion of the ALTO-203 study and clinical development of ALTO-203; the risk that Alto may not achieve the targeted enrollment in the ALTO-203 study or that enrollment may take longer than expected; the availability and timing of results from the ALTO-203 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 Annual Report on Form 10-K for the fiscal year ended December 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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