Alto Neurosciences has stopped development of its schizophrenia treatment candidate ALTO-101 after the drug did not achieve its primary objective in a phase 2 clinical trial. The decision follows results from a mid-stage study evaluating the therapy’s effect on cognitive impairment associated with schizophrenia.
The trial enrolled 83 patients and compared 10 days of treatment with ALTO-101, a brain-penetrant phosphodiesterase-4 (PDE4) inhibitor administered through the skin, against a placebo. The main goal was to assess the therapy’s effect on cognition as measured by an electroencephalography (EEG) test of the brain’s activity. According to the company’s post-market disclosure, the therapy did not demonstrate a statistically significant improvement compared to placebo on this primary endpoint.
Despite the overall outcome, Alto reported directional changes in certain EEG measures. Among these was a near-significant effect on theta inter-trial coherence (theta-ITC), a biomarker associated with cognitive performance. In a pre-specified subgroup analysis involving 59 patients with greater cognitive impairment, the company stated that ALTO-101 exhibited nominally significant effects on theta-ITC compared with placebo.
The company also observed changes in EEG measures over time. “Further, certain EEG measures, including theta-ITC, showed improvements from Day 5 to Day 10 in the trial, suggesting a longer treatment period may elucidate greater effects,” Alto noted in its disclosure.
In terms of safety, Alto reported that rates of nausea and vomiting among patients receiving ALTO-101 were in line with those in the placebo group. These side effects are commonly associated with other PDE4 inhibitors, such as roflumilast and Amgen’s psoriasis drug Otezla. The company said this similarity suggests that the therapy could have better tolerability than other drugs in its class. However, a high rate of application site skin reactions was observed in both treatment and placebo groups.
Following the trial results, Alto confirmed it will not advance ALTO-101 in its current or modified forms without securing a development partner. The company had also been working on a modified-release oral version of the drug, but this program will likewise not be pursued unless a partnership is established.
Alto stated that it will now shift its focus to ALTO-207, a combination therapy consisting of the approved Parkinson’s disease medication pramipexole and the nausea prevention drug ondansetron. The company expects to initiate a phase 2b study of ALTO-207 for treatment-resistant depression.
Commenting on the results, Alto CEO Amit Etkin, M.D., Ph.D., said, “While we are disappointed that the ALTO-101 data did not deliver the signal we were seeking, it is an exploratory program, and we remain heavily focused on ALTO-207, our most advanced program in development for treatment-resistant depression—which is supported by strong prior clinical data and external validation.”
Etkin also stated that the company is excited about the oral, modified-release formulation of ALTO-101 to potentially provide benefit to patients and intends to seek partnering opportunities to drive future value for the program.
Analysts at William Blair described the outcome as disappointing but indicated that expectations for the program had been limited. They explained that the study was considered high risk due to its signal-finding nature, short duration, and the difficulty of treating cognitive impairment associated with schizophrenia, and that minimal value had been assigned to ALTO-101 in their model. The analysts also noted that investor focus remains on ALTO-207 and the major depressive disorder candidate ALTO-300.
The update follows a previous phase 2 setback for Alto’s depression therapy ALTO-203. The histamine H3 receptor inverse agonist was unable to demonstrate a placebo-adjusted improvement in alertness and mood, although the company continues to list the asset in its pipeline.
What Happened in the Alto Neurosciences Trial?
Alto Neurosciences evaluated ALTO-101 in a Phase 2 proof-of-concept study targeting cognitive impairment in schizophrenia. The primary endpoint focused on improvements in brain activity markers and cognitive performance.
However, Alto Neurosciences reported that ALTO-101 failed to demonstrate statistically significant improvements compared to placebo, leading to the discontinuation of the program.
About ALTO-101 and Its Mechanism
Alto Neurosciences developed ALTO-101 as a novel PDE4 inhibitor designed to improve cognitive function by targeting brain signaling pathways. The Alto Neurosciences approach included biomarker-driven patient selection and the use of EEG-based endpoints to measure treatment response.
Despite early promise, Alto Neurosciences was unable to translate these mechanisms into meaningful clinical outcomes in the Phase 2 trial.
The discontinuation of ALTO-101 marks a critical turning point for Alto Neurosciences. While the company remains financially stable, it is shifting focus toward next-generation candidates such as ALTO-207.
Alto Neurosciences continues to leverage its precision psychiatry platform, but this failure highlights the risks associated with neuroscience drug development.
Market and Industry Implications
The Alto Neurosciences setback underscores broader challenges in developing treatments for cognitive impairment in schizophrenia—a condition with limited therapeutic options.
Alto Neurosciences’ experience reflects the difficulty of translating biomarker-driven approaches into successful clinical outcomes, a key issue across the biotech industry.
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