Latest news with #ALTO-101
Business Wire
3 days ago
- Business
- Business Wire
Alto Neuroscience Reports Second Quarter 2025 Financial Results and Recent Business Highlights
MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--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 quarter ended June 30, 2025, and highlighted recent progress across its pipeline of clinical-stage product candidates. 'We have had an exciting past few months marked by a promising addition to our pipeline with ALTO-207 and encouraging clinical data that provide further validation of our biomarker-driven approach to drug development,' said Amit Etkin, M.D., Ph.D., Founder and CEO of Alto Neuroscience. 'The robust clinical effects of pramipexole observed in the PAX-D study give us strong conviction in the therapeutic potential of ALTO-207 to become a meaningful option for patients with treatment resistant depression (TRD), and we look forward to initiating a potentially pivotal Phase 2b trial by mid-2026. We continued our diligent execution across our pipeline to enroll high-quality subjects and are looking forward to the upcoming clinical study readouts.' Dr. Etkin continued, 'The recent data from our exploratory study of ALTO-203 highlights our ability to better guide indication selection and trial design through our use of biomarkers, which we believe will drive better patient outcomes. Recent clinical readouts in cognitive impairment in schizophrenia (CIAS) further our view that this is an area of incredible unmet need. To our knowledge, ALTO-101, which previously demonstrated pro-cognitive effects, now represents the most advanced therapeutic candidate in a space with no currently approved treatments. We look forward to completing the ongoing study this year to further guide its development.' Pipeline Highlights ALTO-207: Acquired novel combination product with robust clinical validation; Phase 2b trial, designed to be a potentially pivotal study, in patients with treatment resistant depression expected to initiate by mid-2026. 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 TRD. The planned Phase 2b trial of ALTO-207, designed to be a potentially pivotal study, is expected to initiate by mid-2026. In May 2025, the Company acquired from Chase Therapeutics Corporation (Chase) a portfolio of potentially best-in-class dopamine agonist combination product candidates, including ALTO-207, formerly known as CTC-501. The link to the conference call replay is accessible on the Company's website and here. Prior to the acquisition by Alto, Chase completed a randomized, placebo-controlled Phase 2a clinical trial evaluating CTC-501 in 32 patients with depression. The primary endpoint was achieved in the study. Patients randomized to receive CTC-501 reached a mean dose of 4.1mg per day, with 67% of patients achieving the highest allowable dose of 5mg/day. CTC-501 was generally well tolerated in the maintenance period of the study. The clinical efficacy measures were evaluated as secondary endpoints and across measures CTC-501 demonstrated large, clinically meaningful effects. CTC-501 demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo on depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale, or MADRS (LSM Δ vs. placebo at Week 8 = -8.2, p=0.025, Cohen's d=1.1). CTC-501 also demonstrated a significantly greater improvement compared to placebo on the Clinician Global Impression Scale of Severity, or CGI-S (LSM Δ vs. placebo at Week 8 = -0.76, p=0.04, Cohen's d=1.0). The acquisition of ALTO-207 was prompted by Alto's novel insights on dopamine biomarkers in TRD patients and the robust antidepressant effects of pramipexole exhibited in the PAX-D study conducted by the University of Oxford. Results, which were recently published in The Lancet Psychiatry, showed pramipexole augmentation of antidepressant treatment, at a target dose of 2.5mg, demonstrated a large (Cohen's d =0.87) reduction in symptoms relative to placebo at 12 weeks, but was associated with a high rate of adverse effects. The link to the online publication can be found here. The Company plans to collaborate with the National Health Service network, including PAX-D clinical sites for the planned Phase 2b trial of ALTO-207. ALTO-101: Enrollment is ongoing in Phase 2 POC CIAS trial; topline data expected in the second half of 2025. ALTO-101, a brain-penetrant PDE4 inhibitor designed as a novel transdermal formulation, is being developed for the treatment of CIAS. The novel formulation is designed to retain the desired brain effects shown with the oral formulation while avoiding the tolerability challenges and adverse effects known to be associated with PDE4 inhibitors. Enrollment remains ongoing in the Phase 2 POC trial in CIAS, with topline data expected in the second half of 2025. The Phase 2 POC trial consists of a dose-escalating treatment with ALTO-101 and is designed to enroll approximately 70 adult participants with schizophrenia between the ages of 21 and 55. The primary outcome in the study is the effect of ALTO-101 on theta band activity, the EEG measure shown to be most clearly associated with CIAS in replicated analyses of large schizophrenia datasets. Objective cognitive performance is also being evaluated. 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 major depressive disorder (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. 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. In May 2025, the Company presented additional analyses at the American Society of Clinical Psychopharmacology Annual Meeting (ASCP) Annual Meeting supporting the unique biomarker opportunity for patient stratification and reinforcing the well-established safety and tolerability profile for ALTO-300 in MDD. The most common adverse event observed in the completed 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. No liver function test (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, which remains blinded. The ALTO-300 biomarker signal likely reflects increased neural noise due to elevated 5-HT2C tone and reduced dopaminergic activity. Increasing 5-HT2C activity in a preclinical rodent model or directly depleting dopamine in a healthy human volunteer study—both the opposite mechanistic effect of ALTO-300—resulted in greater EEG irregularity, consistent with a biomarker positive profile. These data reinforce the direct link between ALTO-300 and the EEG biomarker used to identify MDD patients who are more likely to be responders to treatment. 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 MADRS in the patient population characterized by a cognitive biomarker. The completed Phase 2b trial evaluating ALTO-100 as a treatment for MDD demonstrated a clinically meaningful signal in the adjunctive subgroup and evidence of biomarker enrichment in the compliant subset of patients. These data support the ongoing Phase 2b trial of ALTO-100 as an adjunctive treatment in BPD. ALTO-203: Reported topline results from Phase 2 POC MDD trial. ALTO-203 is a novel, oral small molecule designed to uniquely act as a histamine H3 inverse agonist, designed to modulate circuits underlying cognition, wakefulness, and alertness. In June 2025, the Company announced the identification of a patient selection biomarker and positive pharmacodynamic results from its exploratory Phase 2 POC trial of ALTO-203 in MDD patients with elevated levels of anhedonia. The findings in the study replicated results from the Phase 1 study in healthy volunteers, where ALTO-203 treatment led to improvements in sustained attention and reductions in the EEG theta/beta ratio. Baseline EEG theta/beta ratio predicted attentional benefits of ALTO-203 in both the Phase 1 study and Phase 2 POC trial. Alto plans to report additional results from this exploratory study at a future medical meeting and expects to determine the next development steps for ALTO-203 following the complete analysis of the data set. Corporate Updates In August 2025, the Company appointed to its Board of Directors, Raymond Sanchez, M.D., a highly accomplished executive with a strong background in medicine and over 20 years of strategic experience in the life sciences industries. With the addition of Ray, Alto's Board has increased to six members. Upcoming Milestones and Events Near-Term Expected Milestones 2H 2025 — ALTO-101 Phase 2 POC CIAS trial topline data Mid-2026 — ALTO-300 Phase 2b MDD trial topline data Mid-2026 — ALTO-207 Phase 2b TRD trial initiation 2H 2026 — ALTO-100 Phase 2b BPD trial topline data Upcoming Conferences The Company is expected to present at the following upcoming conferences: H.C. Wainwright 27th Annual Global Investment Conference: September 8-10, 2025 Baird 2025 Global Healthcare Conference: September 10, 2025 TD Cowen's 5th Annual Novel Mechanisms in Neuropsychiatry & Epilepsy Summit: September 17-18, 2025 Second Quarter 2025 Financial Highlights Cash Position: As of June 30, 2025 the Company had cash, cash equivalents, and restricted cash of approximately $148.1 million, compared to approximately $168.7 million in cash, cash equivalents, and restricted cash as of December 31, 2024. The Company expects its cash balance to support planned operations into 2028. R&D Expenses: Research and development expenses for the quarter ended June 30, 2025 were $13.1 million, as compared to $13.2 million for the same period in 2024. G&A Expenses: General and administrative expenses for the quarter ended June 30, 2025 were $5.6 million, as compared to $5.2 million for the same period in 2024. Net Loss: The Company incurred a net loss of $17.7 million for the quarter ended June 30, 2025, as compared to $16.0 million for the quarter ended June 30, 2024. 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, and schizophrenia, and other mental health conditions. For more information, visit 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 with regard to the potential benefits, activity, effectiveness and safety of its product candidates and Precision Psychiatry Platform ('Platform'); Alto's expectations with regard to the 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 and regulatory development plans for its product candidates, including the timing or likelihood of regulatory filings and 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 clinical development of Alto's product candidates; the risk that Alto may not realize the intended benefits of its Platform; availability and timing of results from clinical trials; whether initial or interim results from a clinical trial will be predictive of the final results of the trial or the results of future 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 Alto's Annual Report on Form 10-K for the fiscal year ended December 31, 2024 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. Availability of Information on Alto's Website Alto routinely uses its investor relations website to post presentations to investors and other important information, including information that may be material. Accordingly, Alto encourages investors and others interested in Alto to review the information it makes public on its investor relations website.
Ottawa Citizen
28-04-2025
- Health
- Ottawa Citizen
Alto Neuroscience Presents New Data at the Society of Biological Psychiatry Annual Meeting Underscoring Precision Psychiatry Approach
Article content – Identified and prospectively replicated an EEG-based biomarker for placebo response in MDD – Article content Article content – New data strengthen the mechanistic link between ALTO-300 and the EEG biomarker being used for patient selection; biomarker signature induced by activating 5-HT2C or depleting dopamine directly – Article content – Preclinical ALTO-101 rescue study underscores the therapeutic potential of this novel PDE4 inhibitor, and validates EEG theta response as a robust translational biomarker for CIAS – Article content Article content MOUNTAIN VIEW, Calif. — Alto Neuroscience, Inc. ('Alto') (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced multiple presentations at the Society of Biological Psychiatry (SOBP) Annual Meeting, in Toronto, Canada, held April 24-26, 2025. Article content 'The biological and clinical insights we presented at SOBP support our precision psychiatry pipeline and mark important advancements for the field,' said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. 'To address the longstanding challenge of high placebo response in neuropsychiatric clinical development, we have successfully identified and prospectively replicated an EEG biomarker that captures placebo response patterns in patients with major depressive disorder. We believe this biomarker has the potential to reduce noise and improve the detection of true therapeutic effect.' Article content Dr. Etkin continued, 'We enhanced our understanding of 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. We showed that 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. Additionally, in a preclinical rescue study we demonstrated that ALTO-101 increased theta response, demonstrating its robustness as a translational biomarker for cognitive impairment associated with schizophrenia and potential pro-cognitive drug effect. We look forward to leveraging these findings to drive meaningful innovation in psychiatry and enhance clinical outcomes for patients.' Article content Background and Rationale: High placebo response is a major challenge in clinical trials for patients with major depressive disorder (MDD), yet no validated biomarker exists for reliably identifying high placebo responders. A shared predictor across diverse established antidepressant treatments was hypothesized to approximate a placebo response. Prospective replication was conducted in two randomized trials, including placebo and active arms. Within the two randomized trials, the ability to increase drug-placebo effect size was evaluated by incorporating placebo response predictions as sample weights. Key Takeaways: An EEG-based biomarker capable of predicting non-specific treatment response across multiple interventions and independent datasets was developed and validated. The placebo biomarker yielded significant predictions for the open-label ALTO-100 and sertraline treatment response, both analyzed prospectively. Additional prospective analyses in two randomized-controlled MDD studies were conducted to further validate the previously identified EEG-based placebo biomarker (ALTO-100 Phase 2b trial and the EMBARC sertraline trial) on both placebo response and drug-placebo differences. In the ALTO-100 placebo arm, the biomarker significantly predicted MADRS score change across all weeks with correlation ranging from 0.29 to 0.19 (p=0.001 to p=0.029; Cohen's d=0.49 to d=0.41) at weeks 2 and 6 respectively. In the EMBARC placebo arm, the biomarker significantly predicted HAMD score change, with a partial correlation ranging from 0.24 to 0.31 (p=0.009 to p=0.001) at weeks 6 and 8 respectively. Drug-placebo treatment effect sizes were enhanced across diverse drug mechanisms when accounting for individual differences in predicted placebo response, as demonstrated by both the Phase 2b trial of ALTO-100 and EMBARC trial of sertraline. This biomarker has the potential to enable more precise identification of high placebo responders in MDD trials, reduce trial variability, and enhance detection of treatment effects. Intellectual Property: Alto has patent protection covering the use of EEG biomarkers to predict placebo response. Article content Background and Rationale: ALTO-300 is an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist. ALTO-300 has been shown to enhance dopaminergic and noradrenergic input to the frontal cortex and rescue anhedonia-like behavioral deficits. Greater gamma sample entropy (SE), or EEG irregularity, was previously shown to predict antidepressant response to ALTO-300 in MDD. Increasing 5-HT2C activity or directly depleting dopamine (both the opposite mechanism of ALTO-300) was hypothesized to increase gamma SE and create a more biomarker positive EEG pattern. Key Takeaways: Administered two different 5-HT2C agonists (R0-0175 and YM348) in independent preclinical studies and revealed a dose-related increase in SE. 5-HT2C agonism also led to an anhedonic phenotype as demonstrated by a sucrose preference test. In a double-blind, placebo-controlled, cross-over study, healthy participants consumed a nutritionally balanced amino acid mixture (placebo) and a mixture deficient in the dopamine precursors tyrosine and phenylalanine (APTD) in a counterbalanced order. SE was significantly larger in the APTD condition compared to the placebo condition (p<0.01, Cohen's d=0.94), indicating that dopamine depletion drives a biomarker positive EEG pattern. The ALTO-300 biomarker signal likely reflects increased neural noise due to elevated 5-HT2C tone and reduced dopaminergic activity. The mechanism of action of ALTO-300 involves an increase in dopamine in part through 5-HT2C antagonism. These findings therefore provide a direct link between ALTO-300 and the EEG biomarker used to identify MDD patients who are more likely to be responders to treatment. Article content Background and Rationale: Cognitive Impairment Associated with Schizophrenia (CIAS) remains a high unmet need, with no approved treatments specifically targeting these deficits. Theta EEG response, measured by inter-trial coherence (ITC), is reproducibly disrupted in patients with schizophrenia and was previously identified as a promising marker for CIAS. Theta response strongly correlated with cognitive deficits in patients in multiple datasets. N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a key role in CIAS pathophysiology. A rodent model was used to evaluate the effects of ALTO-101 on theta response following administration of MK-801, an NMDAR antagonist. Key Takeaways: Administration of MK-801 reduced theta response, modeling neural and behavioral abnormalities in schizophrenia. Administration of ALTO-101 led to a dose-dependent rescue of the theta response abnormality induced by MK-801 and was statistically significant at the highest dose of 0.1 mg/kg (p<0.001). Results are consistent with the completed Phase 1 trial in healthy volunteers, where ALTO-101 demonstrated robust, dose-dependent effects on theta response and cognitive test performance. The effects on these two measures were also correlated. Taken together, results validate theta response as a robust translational biomarker and underscore the potential cognitive benefits of ALTO-101 for patients with CIAS.
National Post
28-04-2025
- Health
- National Post
Alto Neuroscience Presents New Data at the Society of Biological Psychiatry Annual Meeting Underscoring Precision Psychiatry Approach
Article content – Identified and prospectively replicated an EEG-based biomarker for placebo response in MDD – Article content Article content – New data strengthen the mechanistic link between ALTO-300 and the EEG biomarker being used for patient selection; biomarker signature induced by activating 5-HT2C or depleting dopamine directly – Article content – Preclinical ALTO-101 rescue study underscores the therapeutic potential of this novel PDE4 inhibitor, and validates EEG theta response as a robust translational biomarker for CIAS – Article content Article content MOUNTAIN VIEW, Calif. — Alto Neuroscience, Inc. ('Alto') (NYSE: ANRO) a clinical-stage biopharmaceutical company focused on the development of novel precision medicines for neuropsychiatric disorders, today announced multiple presentations at the Society of Biological Psychiatry (SOBP) Annual Meeting, in Toronto, Canada, held April 24-26, 2025. Article content 'The biological and clinical insights we presented at SOBP support our precision psychiatry pipeline and mark important advancements for the field,' said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. 'To address the longstanding challenge of high placebo response in neuropsychiatric clinical development, we have successfully identified and prospectively replicated an EEG biomarker that captures placebo response patterns in patients with major depressive disorder. We believe this biomarker has the potential to reduce noise and improve the detection of true therapeutic effect.' Article content Dr. Etkin continued, 'We enhanced our understanding of 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. We showed that 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. Additionally, in a preclinical rescue study we demonstrated that ALTO-101 increased theta response, demonstrating its robustness as a translational biomarker for cognitive impairment associated with schizophrenia and potential pro-cognitive drug effect. We look forward to leveraging these findings to drive meaningful innovation in psychiatry and enhance clinical outcomes for patients.' Article content Background and Rationale: High placebo response is a major challenge in clinical trials for patients with major depressive disorder (MDD), yet no validated biomarker exists for reliably identifying high placebo responders. A shared predictor across diverse established antidepressant treatments was hypothesized to approximate a placebo response. Prospective replication was conducted in two randomized trials, including placebo and active arms. Within the two randomized trials, the ability to increase drug-placebo effect size was evaluated by incorporating placebo response predictions as sample weights. Key Takeaways: An EEG-based biomarker capable of predicting non-specific treatment response across multiple interventions and independent datasets was developed and validated. The placebo biomarker yielded significant predictions for the open-label ALTO-100 and sertraline treatment response, both analyzed prospectively. Additional prospective analyses in two randomized-controlled MDD studies were conducted to further validate the previously identified EEG-based placebo biomarker (ALTO-100 Phase 2b trial and the EMBARC sertraline trial) on both placebo response and drug-placebo differences. In the ALTO-100 placebo arm, the biomarker significantly predicted MADRS score change across all weeks with correlation ranging from 0.29 to 0.19 (p=0.001 to p=0.029; Cohen's d=0.49 to d=0.41) at weeks 2 and 6 respectively. In the EMBARC placebo arm, the biomarker significantly predicted HAMD score change, with a partial correlation ranging from 0.24 to 0.31 (p=0.009 to p=0.001) at weeks 6 and 8 respectively. Drug-placebo treatment effect sizes were enhanced across diverse drug mechanisms when accounting for individual differences in predicted placebo response, as demonstrated by both the Phase 2b trial of ALTO-100 and EMBARC trial of sertraline. This biomarker has the potential to enable more precise identification of high placebo responders in MDD trials, reduce trial variability, and enhance detection of treatment effects. Intellectual Property: Alto has patent protection covering the use of EEG biomarkers to predict placebo response. Article content Background and Rationale: ALTO-300 is an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist. ALTO-300 has been shown to enhance dopaminergic and noradrenergic input to the frontal cortex and rescue anhedonia-like behavioral deficits. Greater gamma sample entropy (SE), or EEG irregularity, was previously shown to predict antidepressant response to ALTO-300 in MDD. Increasing 5-HT2C activity or directly depleting dopamine (both the opposite mechanism of ALTO-300) was hypothesized to increase gamma SE and create a more biomarker positive EEG pattern. Key Takeaways: Administered two different 5-HT2C agonists (R0-0175 and YM348) in independent preclinical studies and revealed a dose-related increase in SE. 5-HT2C agonism also led to an anhedonic phenotype as demonstrated by a sucrose preference test. In a double-blind, placebo-controlled, cross-over study, healthy participants consumed a nutritionally balanced amino acid mixture (placebo) and a mixture deficient in the dopamine precursors tyrosine and phenylalanine (APTD) in a counterbalanced order. SE was significantly larger in the APTD condition compared to the placebo condition (p<0.01, Cohen's d=0.94), indicating that dopamine depletion drives a biomarker positive EEG pattern. The ALTO-300 biomarker signal likely reflects increased neural noise due to elevated 5-HT2C tone and reduced dopaminergic activity. The mechanism of action of ALTO-300 involves an increase in dopamine in part through 5-HT2C antagonism. These findings therefore provide a direct link between ALTO-300 and the EEG biomarker used to identify MDD patients who are more likely to be responders to treatment. Article content Background and Rationale: Cognitive Impairment Associated with Schizophrenia (CIAS) remains a high unmet need, with no approved treatments specifically targeting these deficits. Theta EEG response, measured by inter-trial coherence (ITC), is reproducibly disrupted in patients with schizophrenia and was previously identified as a promising marker for CIAS. Theta response strongly correlated with cognitive deficits in patients in multiple datasets. N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a key role in CIAS pathophysiology. A rodent model was used to evaluate the effects of ALTO-101 on theta response following administration of MK-801, an NMDAR antagonist. Key Takeaways: Administration of MK-801 reduced theta response, modeling neural and behavioral abnormalities in schizophrenia. Administration of ALTO-101 led to a dose-dependent rescue of the theta response abnormality induced by MK-801 and was statistically significant at the highest dose of 0.1 mg/kg (p<0.001). Results are consistent with the completed Phase 1 trial in healthy volunteers, where ALTO-101 demonstrated robust, dose-dependent effects on theta response and cognitive test performance. The effects on these two measures were also correlated. Taken together, results validate theta response as a robust translational biomarker and underscore the potential cognitive benefits of ALTO-101 for patients with CIAS.
