Alto Neuroscience Shares Phase 2 Results for ALTO-101 and Refocuses Pipeline Strategy
Alto Neuroscience, Inc., a clinical-stage biopharmaceutical company dedicated to developing precision medicines for neuropsychiatric disorders, has released topline findings from its Phase 2 proof-of-concept (POC) study evaluating ALTO-101. Alongside these results, the company also provided an update on its broader development pipeline, highlighting a strategic shift toward its lead program, ALTO-207.
While the study did not meet its primary endpoints, the data revealed encouraging directional signals in certain neurophysiological measures. At the same time, Alto emphasized its continued financial strength, clinical momentum, and commitment to advancing innovative therapies for patients with unmet mental health needs.
Phase 2 Study Overview and Objectives
The Phase 2 POC clinical trial was designed to evaluate the safety, tolerability, and efficacy of ALTO-101 in patients with cognitive impairment associated with schizophrenia (CIAS). Cognitive impairment remains one of the most challenging aspects of schizophrenia to treat, with limited effective therapies currently available.
The study utilized electroencephalography (EEG) biomarkers alongside cognitive assessments to measure treatment effects. EEG-based endpoints, such as theta inter-trial coherence (theta-ITC), are increasingly recognized as objective markers linked to cognitive processing and neural synchronization.
Despite a well-structured design and rigorous methodology, ALTO-101 did not achieve statistical significance compared to placebo on either the primary EEG endpoints or cognitive measures.
Key Findings: Mixed Results with Encouraging Signals
Although the primary endpoints were not met, the study generated several noteworthy findings that may inform future research and development.
Across the overall study population, ALTO-101 demonstrated directional improvements in multiple EEG parameters. One of the most notable observations was a near-statistically significant improvement in theta-ITC, with a p-value of 0.052 and an effect size (Cohen’s d) of 0.34 in a sample size of 83 participants. Theta-ITC is a biomarker associated with cognitive function, particularly in attention and information processing.
Further analysis revealed more promising results within a pre-specified subgroup of patients with greater baseline cognitive impairment. In this subgroup (n=59), ALTO-101 achieved nominal statistical significance on theta-ITC compared to placebo, with a stronger effect size (d=0.44) and a p-value of 0.03.
Additionally, improvements in EEG measures—including theta-ITC—were observed to increase over time, particularly between Day 5 and Day 10 of treatment. This temporal trend suggests that a longer duration of therapy might yield more pronounced effects, an insight that could guide future study designs.
Safety and Tolerability Profile
One of the more encouraging aspects of the trial was ALTO-101’s favorable tolerability profile.
Historically, drugs in the phosphodiesterase-4 (PDE4) inhibitor class have been limited by side effects such as nausea and vomiting. However, in this study, rates of these adverse events were comparable between the ALTO-101 and placebo groups. This finding indicates that ALTO-101’s pharmacokinetic profile may help overcome a key barrier that has hindered broader adoption of PDE4 inhibitors.
That said, the study did observe a high incidence of application site skin reactions across both treatment and placebo arms. While these reactions were not unique to the active drug, they remain an important consideration for formulation and delivery optimization.
Strategic Shift: Prioritizing ALTO-207
Based on the overall findings, Alto Neuroscience has decided not to independently advance ALTO-101 for the treatment of CIAS. Instead, the company will redirect its internal resources toward its most advanced and strategically important program, ALTO-207.
ALTO-207 is being developed as a treatment for patients with treatment-resistant depression (TRD), a population with significant unmet clinical needs. The program represents a novel approach, combining two pharmacological agents—pramipexole and ondansetron—into a single fixed-dose therapy.
Pramipexole acts as a dopamine D3/D2 receptor agonist, while ondansetron is a 5-HT3 receptor antagonist. Together, the combination is designed to enable rapid titration to higher, more effective doses of pramipexole by mitigating the dose-limiting side effects of nausea and vomiting.
Upcoming Phase 2b Trial for ALTO-207
Alto confirmed that ALTO-207 remains on track to enter a Phase 2b clinical trial in the first half of 2026. This randomized, double-blind, placebo-controlled study will evaluate the therapy as an adjunctive treatment in approximately 178 adults with treatment-resistant depression.
Participants in the trial will have experienced between two and five prior treatment failures, making this a particularly difficult-to-treat population. The study aims to further validate ALTO-207’s efficacy and safety profile while supporting its progression toward late-stage development.
The program is supported by strong prior evidence, including results from the PAX-D study conducted by the University of Oxford and published in The Lancet Psychiatry. In that study, pramipexole demonstrated a large effect size (Cohen’s d = 0.87) compared to placebo at 12 weeks—substantially exceeding the effect sizes typically observed with currently approved TRD treatments.
In addition, Alto’s own Phase 2a trial of ALTO-207 successfully met both primary and secondary endpoints. Following a productive meeting with the U.S. Food and Drug Administration in 2025, the company is now positioned to advance the program into Phase 3 and potentially toward a New Drug Application (NDA).
Development of a Modified-Release ALTO-101 Formulation
While ALTO-101 will not be advanced internally for CIAS, Alto continues to see potential in the asset through an improved formulation strategy.
The company has developed a modified-release, once-daily oral version of ALTO-101 that has demonstrated improved pharmacokinetic and tolerability characteristics compared to the original immediate-release formulation. This advancement could expand the drug’s potential applications across multiple therapeutic areas beyond schizophrenia-related cognitive impairment.
Alto has indicated that it plans to explore strategic partnering opportunities to further develop and commercialize this formulation. The modified-release version is also supported by a pending patent application, which could enhance its long-term value proposition.
Leadership Perspective and Future Outlook
Commenting on the results, Alto Neuroscience’s founder and CEO, Amit Etkin, M.D., Ph.D., acknowledged the disappointment of not achieving the desired outcomes with ALTO-101, while emphasizing the exploratory nature of the program.
He highlighted the company’s continued focus on ALTO-207, describing it as one of the most compelling and well-validated mechanisms currently in development within psychiatry. He also expressed optimism about the potential of the modified-release ALTO-101 formulation and the opportunity to unlock value through partnerships.
From a broader perspective, Alto underscored its strong financial position, with approximately $275 million in cash, as well as its diversified clinical pipeline. This foundation is expected to support ongoing development efforts and upcoming clinical milestones.
Alto Neuroscience’s latest update reflects both the challenges and opportunities inherent in neuropsychiatric drug development. While the Phase 2 study of ALTO-101 did not meet its primary endpoints, the presence of encouraging biomarker signals and a favorable safety profile provide valuable insights for future research.
More importantly, the company’s decision to prioritize ALTO-207 underscores a disciplined and strategic approach to pipeline management. With a promising mechanism, strong clinical backing, and a Phase 2b trial on the horizon, ALTO-207 now stands at the forefront of Alto’s development efforts.
At the same time, ongoing work on a modified-release formulation of ALTO-101 and plans for potential partnerships demonstrate Alto’s commitment to maximizing the value of its assets while maintaining focus on its highest-impact opportunities.
As the company moves forward, upcoming clinical data and strategic collaborations will be key factors shaping its trajectory in the evolving landscape of precision psychiatry.
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.
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