Alto Neuroscience Reports First Quarter 2025 Financial Results and Recent Business Highlights

-- Phase 2 proof-of-concept trials remain on track: Topline data expected from ALTO-203 in MDD in the second quarter of 2025 followed by ALTO-101 in schizophrenia in the second half of 2025 --

-- Late-stage programs advancing: Topline data expected from the Phase 2b trial of ALTO-300 in MDD in mid-2026 followed by the Phase 2b trial of ALTO-100 in bipolar depression in the second half of 2026 --

-- New data presented at recent scientific conferences support Alto's biomarker-driven pipeline and patient stratification approach --

-- Strong cash position of approximately $161.3 million expected to fund planned operations into 2028, and through at least four upcoming clinical study readouts --

MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--May 14, 2025-- 

Alto Neuroscience, Inc. ("Alto") (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today reported financial results for the first quarter ended March 31, 2025, and highlighted recent progress across its pipeline of clinical-stage product candidates.

"In the first quarter of 2025 we took important steps to deliver on our clinical and corporate objectives," said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. "We have continued to execute across each of our four ongoing clinical trials, and in addition we have advanced our biomarker platform to further support our precision psychiatry approach. We believe the recent presentation of our EEG-based placebo response biomarker and dopamine-related biomarkers highlight our leadership position in targeted neuropsychiatric drug development. We look forward to exploring opportunities to maximize the therapeutic impact of our platform to address the high unmet needs of patients. With a strong balance sheet expected to support several key clinical milestones in the coming years, we believe we are well positioned to redefine how neuropsychiatric conditions are treated."

Pipeline Highlights

ALTO-100: Enrollment ongoing in Phase 2b bipolar depression trial; data expected in the second half of 2026.

ALTO-100, a first-in-class, oral small molecule believed to work through enhancing neuroplasticity, is in development for the treatment of bipolar depression (BPD) in patients characterized by a cognitive biomarker.

   -- Enrollment in the randomized, double-blind, placebo-controlled Phase 2b 
      trial remains ongoing with topline data expected in the second half of 
      2026. The Company expects to enroll approximately 200 patients with BPD. 
      Patients will be evaluated over a six-week treatment period and the 
      primary endpoint is the change from baseline on the 
      Montgomery-Åsberg Depression Rating Scale (MADRS) in the patient 
      population characterized by a cognitive biomarker. 
 
   -- In the fourth quarter of 2024, the Company completed the Phase 2b trial 
      evaluating ALTO-100 as a treatment for major depressive disorder (MDD). 
      The clinically meaningful signal in the adjunctive subgroup and evidence 
      of biomarker enrichment in the compliant subset of patients supports the 
      ongoing Phase 2b trial of ALTO-100 as an adjunctive treatment in BPD. 
 
   -- The Company presented additional analyses of the ALTO-100 MDD Phase 2b 
      trial at the Society of Biological Psychiatry (SOBP) Annual Meeting 
      highlighting the utilization of an EEG-based biomarker to account for 
      potential placebo responders. As presented, these results build on the 
      Company's successful identification and prospective replication of an 
      EEG-based biomarker for placebo response in MDD. 
 
          -- The analysis prospectively demonstrated that weighting patient 
             outcomes based on an EEG marker for placebo response resulted in a 
             larger treatment response. These data demonstrate the applications 
             of this biomarker to potentially enable more precise 
             identification of high placebo responders and improve detection of 
             treatment response in a clinical trial. The Company expects to 
             employ this biomarker in the ongoing ALTO-100 BPD trial. 

ALTO-300: Enrollment ongoing in Phase 2b adjunctive major depressive disorder trial; data expected in mid-2026.

ALTO-300, also known as agomelatine, is an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist, and is being developed at 25mg as an adjunctive treatment in the United States for patients with MDD, characterized by an EEG biomarker. Agomelatine is an approved antidepressant medication in Europe and Australia, at both 25mg and 50mg, but has not been approved in the United States. In comparison to the 50mg dose of agomelatine, the 25mg dose has been shown to have equivalent antidepressant efficacy and has not been associated with reversible, low liver enzyme elevations observed with the 50mg dose.

   -- Topline data from the double-blind, placebo-controlled, randomized Phase 
      2b trial is expected in mid-2026. The Company expects to enroll 
      approximately 200 biomarker positive patients for the final analysis 
      sample. The final analysis sample is based on the favorable outcome from 
      the interim analysis announced in February 2025, which resulted in a 
      recommendation to continue the study and increase the biomarker positive 
      sample by approximately 50 subjects. While the trial includes both 
      biomarker positive and biomarker negative patients, the primary analysis 
      will be conducted in the biomarker positive subgroup. 
 
   -- In the ongoing Phase 2b trial, patients who have had an inadequate 
      response to their current antidepressant are randomized to receive either 
      25mg of ALTO-300 or placebo over a six-week treatment period. The study 
      medication is being taken in addition to a patient's background 
      antidepressant. The primary outcome is the change from baseline in MADRS 
      score in patients with the EEG biomarker. 
 
   -- Across the Company's clinical trials, and in clinical practice, 
      agomelatine has demonstrated a favorable safety and tolerability profile. 
      The most common adverse event observed in the Phase 2a trial of ALTO-300 
      was headache. Additionally, the Phase 2a and Phase 2b trials have 
      involved monitoring for elevated liver enzymes (>= 3 times the upper 
      limit of normal), with the Phase 2b trial including a stopping rule for 
      elevated liver enzymes, as measured by liver function tests $(LFT)$. No LFT 
      elevations >= 3 times the upper limit of normal were observed in the 
      Company's 239-patient completed Phase 2a trial, and no patients have been 
      stopped in the ongoing Phase 2b trial due to liver enzyme elevation. 
 
          -- Across three large, United States-based clinical trials in MDD, 
             the 25mg dose of agomelatine (being developed by the Company as 
             ALTO-300) has not led to liver enzyme elevation, exhibiting rates 
             similar to placebo. 
 
          -- Evidence from meta-analyses and real-world clinical care 
             reinforces the consistent safety of the 25mg dose and suggests 
             that higher doses of agomelatine do not result in greater 
             efficacy. The Company believes these data support development of 
             the 25mg dose to optimize clinical efficacy while balancing safety 
             and tolerability. 
 
   -- The Company presented new data at SOBP highlighting the mechanistic link 
      between ALTO-300 and the machine learning-derived, EEG biomarker, used to 
      identify patients who are more likely to respond to treatment. Increasing 
      5-HT2C activity or directly depleting dopamine--both the opposite 
      mechanistic effect of ALTO-300--resulted in greater EEG irregularity, 
      consistent with a biomarker positive profile. 

ALTO-203: Enrollment completed in Phase 2 proof-of-concept MDD trial; data expected in the second quarter of 2025.

ALTO-203, a novel, oral small molecule designed to uniquely act as a histamine H3 inverse agonist, is being developed for the treatment of MDD associated with increased levels of anhedonia.

   -- In February, the Company completed enrollment in the 69-patient Phase 2 
      proof-of-concept (POC) trial in MDD patients with higher levels of 
      anhedonia and expects to report topline data in the second quarter of 
      2025. The trial is the first evaluation of ALTO-203 in a patient 
      population and consists of two sequential, double-blind, 
      placebo-controlled treatment periods to evaluate two different dose 
      levels of ALTO-203 as a monotherapy. 
 
          -- In the first period, patients receive two single-doses of ALTO-203 
             (high-dose and low-dose), and placebo in a randomized, three-way 
             crossover design, and the outcome measures are designed to 
             evaluate pharmacodynamic effects. An acute change in positive 
             emotion is assessed by the alertness and mood components of the 
             Bond-Lader Visual Analog Scale (BL-VAS), an established scale of 
             subjective emotion. The trial is designed to broadly explore the 
             effects of ALTO-203 and is not powered to detect statistical 
             significance on clinical depression outcome scales (e.g., MADRS). 
 
          -- In the second period, patients receive high-or low-dose ALTO-203 
             or placebo once-daily over a 28-day treatment period to further 
             explore the safety and pharmacokinetics of ALTO-203. 
             Pharmacodynamic effects on cognition, EEG, and wearable measures 
             will be evaluated to characterize the profile of ALTO-203 and 
             guide next steps in development. 
 
   -- The Company presented new preclinical data at SOBP demonstrating the 

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