Alto Neuroscience’s ALTO-100 Fails to Beat Placebo in Improving Depressive Symptoms

Credit: Adobe stock/ LIGHTFIELD STUDIOS

Only 9 months after Alto Neuroscience’s biotech went public, phase 2b data revealed the depression treatment, ALTO-100, failed to beat placebo.¹

Alto Neurosciences was one of the first biotechs of 2024 to IPO and raised $128.6 million in early February. Yesterday evening the company reported that its phase 2b trial did not meet its primary endpoint, and its shares dropped 60% in after-market trading.

“While the Phase 2b results did not replicate the clinical results observed in the Phase 2a trial, we believe our approach to collecting and stratifying based on biomarkers represents an innovative approach to developing neuropsychiatric drugs,” said Adam Savitz, MD, PhD, chief medical officer of Alto Neuroscience, in a statement. “We are deeply grateful to the patients, physicians, trial site staff, and advocacy partners for their support.”

Investigators conducted the randomized, double-blind, placebo-controlled phase 2b study across 34 sites in the US to evaluate ALTO-100 in 31 adults with major depressive disorder (MDD). The primary endpoint was the change from baseline to the end of the 6-week double-blind treatment period on the Montgomery-Åsberg Depression Rating Scale (MADRS.

Ultimately, the biotech shared the phase 2b study found ALTO-100 did not provide statistically significant improvement in depressive symptoms compared to placebo with a memory-based cognitive biomarker. The treatment also did not perform better than placebo in pre-specified key secondary analyses.

“The clear top-line miss of ALTO-100 in MDD undoubtedly will cast investor doubt on Alto’s Precision Neuropsychiatry approach to pair specific mechanisms of action to patient biomarkers of drug response,” wrote William Blair analysts.²

Nevertheless, the favorable safety and tolerability profile of ALTO-100 was consistent with earlier trials.¹ The most common adverse events were headache, nausea, and abnormal dreams, but these were all similar rates to placebo.

“We still think the Alto precision psych approach has merit, and we do note that all drugs within the pipeline operate by fundamentally different mechanisms of action,” Stifel analysts wrote.² “In our view, better patient selection, and ‘homogenizing’ trial populations, is still a winning strategy in CNS, and for this reason, we do think Alto’s other shots-on-goal for fundamentally different assets should not be written off.”

The company expects to have enough funds for planned operations into 2027, which will include their upcoming trials on ALTO-203 and ALTO-300 for MDD expected in the first half of 2025. ¹ As of June 2024, the company reported having $193.6 million.²

Before the biotech works on their next operations, they need to finish analyzing the full dataset of this phase 2b trial.

“We are disheartened by the results from this study as the unmet need in this patient population is immense,” said Amit Etkin, MD, PhD, founder and chief executive officer of Alto Neuroscience.¹ “While the results are surprising and disappointing, I am proud of our team for conducting a first-of-its-kind precision biomarker-based study in psychiatry. We will move quickly to evaluate the full data set to better understand these findings and incorporate learnings from this large data set across our platform.”

References

1. ^{Armstrong, A. Alto Depression Therapy Fails Mid-Stage Trial, 9 Months After IPO. BioSpace. October 23, 2024. https://www.biospace.com/drug-development/alto-depression-therapy-fails-mid-stage-trial-9-months-after-ipo. Accessed October 23, 2024.}
2. ^{Alto Neuroscience Reports Topline Results from a Phase 2b Trial Evaluating ALTO-100 as a Treatment for Major Depressive Disorder. Business Wire. October 22, 2024. https://www.businesswire.com/news/home/20241022197716/en/Alto-Neuroscience-Reports-Topline-Results-from-a-Phase-2b-Trial-Evaluating-ALTO-100-as-a-Treatment-for-Major-Depressive-Disorder. Accessed October 23, 2024.}