Alto Neuroscience Highlights Peer-Reviewed Publication of PAX-D Study in The Lancet Psychiatry Demonstrating Robust Clinical Effects of Pramipexole for Patients with Treatment-Resistant Depression

–  Compelling PAX-D results guided Alto's acquisition of ALTO-207, designed to induce rapid antidepressant effects while mitigating dose-limiting adverse events of pramipexole –

–  Alto plans to collaborate with National Health Service, PAX-D clinical sites for the planned Phase 2b trial of ALTO-207, designed to be a potentially pivotal study; trial expected to initiate by mid-2026 –

Alto Neuroscience, Inc. ("Alto") (NYSE:ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today highlighted The Lancet Psychiatry publication of data from the PAX-D study evaluating pramipexole in patients with treatment-resistant depression (TRD). The study was conducted by the University of Oxford and was funded by the UK government's National Institute for Health and Care Research. Results showed pramipexole augmentation of antidepressant treatment, at a target dose of 2.5mg, demonstrated a large (Cohen's d=0.87) reduction in symptoms relative to placebo at 12 weeks, but was associated with a high rate of adverse effects. The link to the online publication can be found here. The PAX-D study results guided Alto's acquisition of ALTO-207, a fixed-dose combination of pramipexole and the antiemetic, ondansetron.

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"Publication in an esteemed peer-reviewed journal like The Lancet Psychiatry underscores the significance of these findings and therapeutic potential of ALTO-207 to address a critical gap in TRD," said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. "ALTO-207 is designed to consistently achieve rapid antidepressant effect through faster titration, while mitigating the dose-limiting nausea and vomiting experienced with pramipexole alone. As we prepare to initiate our potentially pivotal, Phase 2b trial by mid-2026, we look forward to drawing on our proprietary insights on dopamine biomarkers in depression and partnering with the National Health Service network, including PAX-D sites to expand our clinical footprint and maximize the likelihood of success."

The PAX-D sites are supported by the National Institute for Health and Care Research (NIHR) Mental Health Translational Research Collaboration (MH-TRC) mission.

Michael Browning, DPhil, MB.BS, MRCP, MRCPsych, Professor of Computational Psychiatry, University of Oxford, and lead study author added, "As a physician, I am encouraged by the robust and durable clinical effects seen for pramipexole in patients with TRD. While pramipexole may offer greater antidepressant effects than other available TRD treatments, the slow titration aimed at mitigating dose-limiting AEs is likely to hinder adoption. These results make it clear that optimizing tolerability to overcome current barriers may lead to a paradigm shift in treatment."

Professor Browning presented results from The Lancet Psychiatry publication during Alto's recent investor conference call to discuss the acquisition of ALTO-207. A replay of the webcast is accessible on the Company's website here.

About ALTO-207

ALTO-207 (formerly known as CTC-501) is a fixed-dose combination of pramipexole, a dopamine D3-preferring D3/D2 agonist, approved for the treatment of Parkinson's disease with demonstrated antidepressant effect, and ondansetron, an antiemetic, selective 5-HT3 receptor antagonist. As a fixed-dose combination, ALTO-207 is designed to enable rapid titration and higher dosing by mitigating the dose-limiting adverse events typically experienced with pramipexole. ALTO-207 is being developed to address the significant unmet need for patients with TRD.

Chase Therapeutics Corporation, prior to asset acquisition by Alto, completed a randomized, placebo-controlled Phase 2a clinical trial evaluating CTC-501 in 32 patients with depression. CTC-501 met primary and secondary endpoints demonstrating significantly greater improvements on MADRS compared to placebo. Patients randomized to receive CTC-501 reached a mean dose of 4.1mg per day. CTC-501 was well tolerated in the maintenance period of the study with an adverse event rate similar to placebo.

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, treatment resistant depression (TRD), and 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, progress, and results of the planned ALTO-207 study, Alto's expectations about the potential benefits, activity, effectiveness and safety of its product candidates 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 the planned ALTO-207 study and clinical development of ALTO-207; the risk that Alto may not achieve targeted enrollment in the ALTO-207 study or that enrollment may take longer than expected; the availability and timing of results from the ALTO-207 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, 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.

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