– Despite its reported benefits for aspects of cognition, vortioxetine does not demonstrate greater clinical efficacy in major depressive disorder (MDD) patients with cognitive impairment–

– Findings further underscore the importance of developing ALTO-100 in depression characterized by poor cognition–

Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced a peer-review publication demonstrating baseline cognitive performance is not a moderator of response to standard-of-care antidepressants in patients with major depressive disorder (MDD). The analysis, titled “Baseline Cognition Is Not Associated With Depression Outcomes in Vortioxetine for Major Depressive Disorder: Findings From Placebo-Controlled Trials,” was published online in The Journal of Clinical Psychiatry.

Prior studies have shown that patients with depression, who are characterized by poor cognition, are generally more chronic, disabled, resistant to treatment and experience greater functional impairment. The current analysis suggests that, despite its reported benefits for aspects of cognition, the monoamine-based agent vortioxetine does not show greater benefit on depressive symptoms in MDD patients with cognitive impairment.

“These findings highlight the lack of effective treatment options for patients with MDD who experience cognitive impairment, comprising up to 50% of the overall MDD population,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “As there remains a high unmet need to develop effective treatment options, we are encouraged by the therapeutic potential of our lead program, ALTO-100, a first-in-class, oral small molecule, currently in development for this subgroup of MDD patients. Designed to enhance neural plasticity, ALTO-100’s differentiated mechanism is supported by a growing body of literature that suggests inhibition of hippocampal neurogenesis and a deficit in neuroplasticity leads to both impaired cognition and negative emotional biases in MDD. We are looking forward to reporting topline data from our Phase 2b MDD study in October 2024. We believe ALTO-100 could offer this underserved patient population a differentiated treatment option.”

In the publication, which was a reanalysis of individual-level data from 1,812 participants with MDD across four placebo-controlled trials, baseline cognition was measured by the Digit Symbol Substitution Test (DSST), the primary measure used to demonstrate vortioxetine’s procognitive effects in clinical studies. The DSST assesses processing speed and attention, as well as executive function, associative learning and working memory. Baseline DSST did not predict placebo-adjusted treatment effects of vortioxetine on depressive symptoms (pooled Cohen d = −0.02, 95% CI = −0.12 to 0.07). Analyses of additional cognitive measures similarly did not predict placebo-adjusted treatment effects on depression, including memory. Finally, analyses of trials with selective serotonin reuptake inhibitors (SSRIs)/serotonin and norepinephrine reuptake inhibitors (SNRIs) as active comparators also revealed no prediction of SSRI/SNRI adjusted treatment effects of vortioxetine on depression (i.e. a comparison between vortioxetine and other standard-of-care treatments).

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). In a Phase 2a clinical trial, ALTO-100 demonstrated favorable safety and tolerability, and significantly greater treatment response in patients with an objectively defined cognitive biomarker.

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 “believe,” “could,” “expects,” “look forward,” “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 with regard to the potential benefits, activity, effectiveness and safety of its product candidates and its ability to bring its product candidates to patients, Alto’s expectations for the timing and results of Alto’s Phase 2b study of ALTO-100, and other statements that are not historical fact. 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 clinical development of Alto’s product candidates; availability and timing of results from clinical trials; whether initial or interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; the risk that clinical trials may have unsatisfactory outcomes; 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 June 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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