Alto Neuroscience Initiates Phase 2b Trial of ALTO-207 in Treatment-Resistant Depression

— Phase 2b closely resembles PAX-D study design, which demonstrated an effect size for pramipexole more than two times larger than approved TRD therapies —

— Trial design and MADRS primary endpoint aligned with FDA standards in depression, potentially supporting a single Phase 3 registrational pathway —

— Prior Phase 2a demonstrated robust antidepressant effects of ALTO-207 and favorable tolerability —

— Topline data expected in 2H 2027 —

Alto Neuroscience, Inc. (NYSE:ANRO), a clinical-stage biopharmaceutical company focused on precision medicines for neuropsychiatric disorders, today announced the initiation of a Phase 2b randomized, placebo-controlled trial of ALTO-207 in treatment-resistant depression (TRD), a program designed to replicate the strongly positive PAX-D study results and support a streamlined path to registration. TRD is estimated to affect up to 7 million adults in the United States, representing patients who do not respond adequately to current antidepressant therapies.

"We are excited to be initiating this Phase 2b trial, which builds on one of the strongest efficacy signals observed in treatment-resistant depression," said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. "ALTO-207 is uniquely designed to build on the robust efficacy demonstrated with pramipexole while addressing the significant tolerability drawbacks that limit its use in clinical practice today. This study is designed like a registrational trial, and we believe it positions us to advance ALTO-207 efficiently."

The Phase 2b trial design is informed by the PAX-D study, a randomized, placebo-controlled trial published in The Lancet Psychiatry (July 2025), which demonstrated a Cohen's d effect size of 0.87 for pramipexole augmentation in TRD — substantially exceeding the effect sizes observed with currently approved therapies. ALTO-207, a fixed-dose combination of pramipexole and ondansetron, with a novel, modified-release formulation, is designed to mitigate pramipexole-associated nausea, thus enabling improved tolerability, more rapid titration, and higher dosing. The combination is further supported by results from a prior Phase 2a trial of ALTO-207, which demonstrated statistically significant improvement on MADRS (Cohen's d = 1.1) with a favorable tolerability profile at a higher mean dose of pramipexole.

"The results of the PAX-D trial, published in The Lancet Psychiatry, demonstrated the potential of pramipexole to reduce symptoms of depression, but also highlighted the side effect burden of this medication," said Michael Browning, Professor of Computational Psychiatry, University of Oxford, and Principal Investigator, PAX-D study. "An effect size of that magnitude in treatment-resistant depression is rare — and it carries an obligation to follow through. ALTO-207 is a thoughtful attempt to do exactly that: preserve the efficacy signal we observed while solving the tolerability challenges that have prevented pramipexole from becoming a standard-of-care option. Having NHS sites that participated in PAX-D contributing to the Alto Phase 2b trial gives this program a continuity that I believe will strengthen the science. I am genuinely excited to be involved and hopeful that this could translate into a real advancement for treatment resistant depression patients."

Phase 2b Trial Design

The Phase 2b trial will enroll approximately 178 adults with treatment-resistant depression who have experienced two to five prior treatment failures during their current episode of depression and remain on a stable background antidepressant.

Participants will be randomized 1:1 to receive ALTO-207 or placebo over an eight-week treatment period. ALTO-207 will be titrated up to a target dose of 3.2 mg pramipexole and 15 mg ondansetron per day.

The trial will be conducted at sites in the United States and United Kingdom, including National Health Service (NHS) sites that participated in the PAX-D study.

The primary endpoint is change from baseline in MADRS, consistent with FDA guidance for depression trials.

Topline data are expected in the second half of 2027.

About ALTO-207

ALTO-207 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 treatment resistant depression.

In a randomized, placebo-controlled Phase 2a clinical trial evaluating ALTO-207 in 32 patients with depression ALTO-207 met primary and secondary endpoints demonstrating significantly greater improvements on MADRS compared to placebo. Patients randomized to receive ALTO-207 reached a mean dose of 4.1mg per day. ALTO-207 was well tolerated in the maintenance period of the study with an adverse event rate similar to placebo.

About Treatment-Resistant Depression (TRD)

Treatment-resistant depression (TRD) is a serious form of major depressive disorder (MDD), typically defined as inadequate response to at least two prior antidepressant treatments of adequate dose and duration. Despite the availability of multiple therapies, approximately one-third of patients with MDD do not achieve sufficient symptom relief with standard treatments.

MDD affects approximately 21 million adults in the United States each year, suggesting that an estimated 6–7 million individuals may suffer from TRD. Patients with TRD often experience persistent, recurrent symptoms, increased risk of hospitalization and suicide, and significant impairment in daily functioning.

TRD represents a substantial unmet medical need and a disproportionate share of the overall economic burden of depression, driven by higher healthcare utilization, reduced productivity, and long-term disability. Current treatment approaches are frequently characterized by a trial-and-error process, delayed onset of action, substantial side effect burden, and limited rates of sustained response.

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, 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," "look forward," "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 about the potential benefits, activity, effectiveness, tolerability and safety of its product candidates and Precision Psychiatry Platform ("Platform"); statements regarding Alto's expectations for the design, timing, and results of its Phase 2b and planned Phase 3 trials of ALTO-207; Alto's expectations with regard to the general design and results of its research and development programs and clinical trials, including the timing of enrollment and the timing and availability of data from such trials; Alto's clinical development plans for its product candidates, including the timing or likelihood of approvals for its product candidates; Alto's business strategy, financial position, including anticipated cash runway, and the sufficiency of its financial resources to fund its operations through expected milestones; 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 development of Alto's product candidates; availability and timing of results from clinical trials; the risk that clinical trials may have unsatisfactory outcomes; the risk that Alto's projections regarding its financial position and expected cash runway are inaccurate or that its conduct of its business requires more cash than anticipated; 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, 2025 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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