Agomelatine

– Initiated Phase 2 study of ALTO-203 in patients with MDD and anhedonia – – Reported positive Phase 1 data with transdermal formulation of novel PDE4 inhibitor, ALTO-101; achieved significantly greater drug exposure with improved tolerability compared to oral administration – – Patient enrollment on track across Phase 2b MDD studies for ALTO-100 and ALTO-300 – – Strong cash position of approximately $206 million expected to support planned operations into 2027 – LOS ALTOS, Calif.--(BUSINESS WIRE)-- Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) today reported financial results for the first quarter ended March 31, 2024, and highlighted recent corporate progress. “Our team’s commitment to developing personalized therapies for the brain is exemplified by our continued clinical execution and the recent progress across our pipeline,” said Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience. “We are proud to have initiated five Phase 2 clinical studies since Alto’s inception, and we look forward to reporting results from our depression studies for ALTO-100, ALTO-300, and ALTO-203, over the coming 12 months.” Dr. Etkin added, “The Phase 1 data we recently reported for ALTO-101 showcase the depth and diversity of our clinical pipeline. We are excited to have a proprietary formulation that enables greater drug exposure while substantially reducing the typical PDE4-related adverse events. Our planned proof-of-concept study in schizophrenia with ALTO-101 will mark an important step forward for this program.” First Quarter 2024 and Recent Business Highlights ALTO-100: Ongoing Phase 2b Study in MDD ALTO-100, a first-in-class, oral small molecule believed to work through enhancing neural plasticity, is in development in Phase 2b for the treatment of major depressive disorder (MDD). Alto is currently evaluating ALTO-100 in a 266-patient Phase 2b study in MDD patients characterized by a memory-based cognitive biomarker. The study is evaluating ALTO-100 compared to placebo over a 6-week double blind treatment period. The primary endpoint is the change from baseline on the standard regulatory clinical endpoint in depression, the Montgomery-Åsberg Depression Rating Scale (MADRS). Enrollment is ongoing and the Company expects to report topline data in the second half of 2024. ALTO-300: Ongoing Phase 2b Study in MDD ALTO-300 (agomelatine), an oral small molecule that is believed to act as a melatonin agonist and 5HT2C antagonist, is being developed as a new treatment for patients with MDD as an adjunctive treatment to an antidepressant to which they had an insufficient response. Alto is currently evaluating ALTO-300 in a 200-patient Phase 2b study in MDD patients characterized by an EEG biomarker signature. The study is evaluating ALTO-300 compared to placebo over a 6-week treatment period, and the primary outcome will be the change from baseline in MADRS score. Enrollment is ongoing and the Company expects to report topline data in the first half of 2025. ALTO-101: In Development for Cognitive Impairment Associated with Schizophrenia (CIAS) ALTO-101 is a novel brain-penetrant PDE4 inhibitor currently in Phase 1 clinical development for the treatment of CIAS. In December 2023, the Company reported positive results from a Phase 1 study in healthy volunteers in which ALTO-101 was shown to positively impact key brain pharmacodynamic markers relevant to cognition that are indicative of potential clinical benefit. PDE4 inhibitors have demonstrated, as a class, a propensity to induce significant adverse events, historically limiting their development in CNS disorders. Alto is developing ALTO-101 as a novel transdermal formulation in partnership with MedRx Co., Ltd. to potentially enhance the pharmacokinetic (PK) pro improve the overall tolerability pro to other PDE4 inhibitors. In April 2024, the Company reported positive results from a Phase 1 study evaluating the pharmacokinetic and tolerability pro transdermal administration of ALTO-101 compared to oral administration. Overall, ALTO-101 demonstrated a favorable pharmacokinetic and tolerability profile. The novel transdermal formulation delivered significantly greater drug exposure with substantially fewer adverse events typically associated with PDE4 inhibitors. The drug exposure demonstrated by the transdermal formulation is expected to be sufficient to achieve the desired 30-40% target occupancy, which has been shown through positron emission tomography (PET) to be the relevant occupancy to induce the brain effects observed with oral administration of ALTO-101. The Company expects to initiate a Phase 2 proof-of-concept study with ALTO-101 in CIAS in the first half of 2024. ALTO-203: Histamine H3 Inverse Agonist in Development for MDD with Anhedonia ALTO-203 is a novel, oral small molecule that uniquely acts as a histamine H3 inverse agonist, a histamine receptor primarily expressed in the brain. The Company is developing ALTO-203 as a novel treatment for patients with MDD and increased levels of anhedonia given the demonstrated effects of ALTO-203 on dopamine release in the reward system and on positive subjective emotional measures in humans. In April 2024, Alto announced the initiation of a Phase 2 proof-of-concept study to evaluate ALTO-203 in patients with MDD and higher levels of anhedonia. The study consists of two sequential double-blind, placebo-controlled treatment periods with two dose levels of ALTO-203 being studied as monotherapy. The first period uses a randomized single-dose treatment design to evaluate patient pharmacodynamic responses to ALTO-203 compared to placebo. The powered primary outcome is measured by an acute change in positive emotion assessed by the alertness and mood components of the Bond-Lader Visual Analog Scale (BL-VAS), an established scale of subjective emotion also used in a prior Phase 1 study of ALTO-203. The second period uses a 28-day, multi-dose exposure design to assess the safety of ALTO-203 in patients with MDD. Exploratory, non-powered objectives for the multi-dose period will evaluate changes in measures of depression, anhedonia, and other clinical symptoms, along with cognition, EEG, and wearables. Alto expects to enroll approximately 60 adult participants with MDD and evidence of anhedonia, and report topline data from this study in the first half of 2025. ALTO-202: NMDAr Antagonist in Development for Depression ALTO-202 is a novel, oral small molecule believed to specifically target the GluN2b subunit of NMDA receptors, acting as a selective NMDA receptor antagonist. Alto plans to develop ALTO-202 for patients with depression. Corporate Updates The Company successfully completed its upsized initial public offering in February 2024, resulting in net proceeds of approximately $133 million. Upcoming Milestones and Events Near-Term Expected Milestones 1H 2024 — ALTO-101 Proof-of-Concept CIAS study initiation 2H 2024 — ALTO-100 Phase 2b MDD study topline data 1H 2025 — ALTO-300 Phase 2b MDD study topline data 1H 2025 — ALTO-203 Proof-of-Concept MDD study topline data 2025 — ALTO-101 Proof-of-Concept CIAS study topline data Upcoming Scientific Conference Presentation Members of the Alto Neuroscience team are expected to present data highlighting the breadth of the Company's pipeline and Precision Psychiatry Platform™ at the American Society of Clinical Psychopharmacology annual meeting. First Quarter 2024 Financial Highlights Cash Position: As of March 31, 2024, Alto had cash and cash equivalents of $205.9 million. The Company expects its cash balance to support planned operations into 2027. R&D Expenses: Research and development expenses for the quarter ended March 31, 2024 were $10.0 million, as compared to $5.6 million for the same period in 2023. The increase was primarily attributable to costs associated with the ALTO-100 and ALTO-300 Phase 2b clinical studies, which were initiated in January 2023 and June 2023, respectively. G&A Expenses: General and administrative expenses for the quarter ended March 31, 2024 were $4.4 million, as compared to $1.6 million for the same period in 2023. The increase was primarily attributable to costs associated with higher headcount to support expanded clinical development efforts, growing operational requirements, and costs associated with operating as a public company. Net Loss: The Company incurred a net loss of $13.4 million for the quarter ended March 31, 2024, as compared to $7.3 million for the quarter ended March 31, 2023. 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 depression, PTSD, schizophrenia, and other mental health conditions. For more information, visit or follow Alto on X (Twitter). 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,” “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; and Alto’s business strategy, financial position and the sufficiency of its financial resources to fund its operations through expected milestones. 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 does not accept the CIRM grant; 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, 2023 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. ALTO NEUROSCIENCE, INC. Condensed Consolidated Statements of Operations and Comprehensive Loss (in thousands, except per share amounts) (unaudited) Three months ended March 31, 2024 2023 Operating expenses: Research and development $ 9,952 $ 5,609 General and administrative 4,434 1,592 Total operating expenses 14,386 7,201 Loss from operations (14,386 ) (7,201 ) Other income (expense): Interest income 1,558 230 Interest expense (346 ) (324 ) Change in fair value of warrant liability (243 ) 11 Total other income (expense), net 969 (83 ) Net loss $ (13,417 ) $ (7,284 ) Other comprehensive loss Foreign currency translation (5 ) (19 ) Total other comprehensive loss (5 ) (19 ) Comprehensive loss $ (13,422 ) $ (7,303 ) Net loss per share attributable to common stockholders, basic and diluted $ (0.76 ) $ (1.97 ) Weighted-average number of common shares outstanding, basic and diluted 17,600 3,691 ALTO NEUROSCIENCE, INC. Selected Condensed Consolidated Balance Sheet Data (in thousands) (unaudited) March 31, December 31, 2024 2023 Cash and cash equivalents $ 205,895 $ 82,548 Total assets 209,922 86,628 Total liabilities 16,818 16,823 Accumulated deficit (90,382 ) (76,965 )

– Breadth of Alto’s pipeline and Precision Psychiatry Platform™ will be highlighted across twelve posters and presentations at the Society of Biological Psychiatry and American Society of Clinical Psychopharmacology Annual Meetings – – Presented comprehensive identification and prospective replication of neurobiological markers linked to cognitive impairment associated with schizophrenia; Results inform design of planned ALTO-101 proof-of-concept study in CIAS – – Importance of developing ALTO-100 in depression characterized by poor cognition highlighted through new analyses demonstrating baseline cognition does not moderate response for vortioxetine and poor cognition in turn drives functional impairment in depression – LOS ALTOS, Calif.--(BUSINESS WIRE)-- Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) today announced upcoming data presentations that highlight the company’s precision psychiatry pipeline and biomarker-based analyses at the Society of Biological Psychiatry (SOBP) and American Society of Clinical Psychopharmacology (ASCP) Annual Meetings, to take place May 9-11 in Austin, TX, and May 28-31 in Miami Beach, FL, respectively. “The vast amount of clinical and biomarker data we’ve generated to date enables our team to make important contributions to the scientific community and develop novel compounds for patients in need, in both depression and schizophrenia,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “Alto’s precision psychiatry platform continues to get stronger with each new dataset we analyze. Importantly, we have systematically identified and prospectively replicated neurobiological markers linked to cognitive impairment associated with schizophrenia in a comprehensive analysis inclusive of all major candidate biomarkers. Our rigorous data science approach derives its impact from prospectively validating important discoveries. In this case, doing so enables us to identify the most pertinent and consistent signals to use as primary outcome measures for proof-of-concept studies – with theta response as a notable example of this in the planned ALTO-101 study.” Summary of Data Presentations Across Clinical Programs ALTO-100: Data from the completed Phase 2a study highlight the identification, and prospective replication, of a memory-based cognitive marker predicting greater antidepressant response to ALTO-100. New analysis of vortioxetine Phase 3 data demonstrates that baseline cognitive performance is not a moderator of response to vortioxetine. Vortioxetine does not show greater benefit in patients with poor baseline cognitive performance despite its reported benefits for aspects of cognition. New analysis of a large depression trial demonstrates that poor memory predicts worse functional outcomes in depression – further highlighting the need for better treatment options for this underserved population. ALTO-101: Data from a completed randomized, double-blind, placebo-controlled Phase 1 study in healthy adult volunteers demonstrate significant effects of ALTO-101 on electrophysiological measures relevant to cognitive processing, including theta response, as well as information processing speed, an important area of cognitive impairment associated with schizophrenia. A new analysis of the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) studies identified, and prospectively replicated, theta response as the EEG marker best linked to schizophrenia diagnosis and cognitive impairment in patients. A notable relationship between theta response and processing speed, which is thought to underpin cognitive impairment in schizophrenia, was observed. ALTO-300: Data from the completed Phase 2a study highlight the identification, and prospective replication, of an EEG-based cognitive marker predicting greater response to ALTO-300. The details of each presentation follow: Society of Biological Psychiatry Annual Meeting Thursday, May 9, 2024 Poster Session I: 5:30-7:30 p.m. CT, Griffin Hall Presentation Title: Identification and Prospective Replication of a Cognitive Biomarker for Predicting the Antidepressant Effect of ALTO-100, a Novel Pro-plasticity Drug Candidate, in Patients with Major Depression: Results from a Large Phase 2a Study Poster Authors: Joshua T. Jordan, Ph.D., Nicholas J. Cooper, Ph.D., Faizan Badami, M.S., Jessica Powell, Wei Wu, Ph.D., Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. Presentation Title: Identification and Prospective Replication of Electrophysiological Markers Linked to Cognitive Impairment in Schizophrenia Poster Authors: Chao Wang, Ph.D., Sam Goncalves, M.S., Joshua T. Jordan, Ph.D., Maimon Rose, Ph.D., Akshay Sujatha Ravindran, Ph.D., Mike Avissar, M.D., Ph.D., Greg Hajcak, Ph.D., Faizan Badami, M.S., Yueqi Guo, Ph.D., Wei Wu, Ph.D., Jessica Powell, Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. Presentation Title: Verbal Memory and Inhibitory Control Predict Functional Capacity in Major Depressive Disorder: A Secondary Analysis of the ReMIND SWITCH Trial Poster Authors: Joshua T. Jordan, Ph.D, Li Shen, Ph.D, Wei Wu, Ph.D., Adam J. Savitz, M.D., Ph.D., Amit Etkin, M.D., Ph.D. Friday, May 10, 2024 Concurrent Symposia: 4:00-6:00 p.m. CT, JW Grand Ballroom 2 Session Title: Bringing Precision Psychiatry out of the Lab and Into the Clinic: Developing Biomarkers for Diagnosis, Drug Development, Treatment Selection and Tracking Clinical Status Speakers: Amit Etkin, M.D., Ph.D., founder and CEO of Alto will serve as Chair, and Adam Savitz, M.D., Ph.D., CMO of Alto, will serve as Co-chair of the session. Additional presenters include Daniel Mathalon, M.D., Ph.D., University of California, San Francisco; Magali Haas, M.D., Ph.D., Cohen Veterans Bioscience; Katharine Dunlop, Ph.D., University of Toronto Dr. Etkin will present from 5:25-5:50 p.m. CT: Development and Prospective Replication of Biomarkers for Predicting Treatment Outcome With ALTO-100 and ALTO-300 in Major Depression: Data from Multiple Phase 2 Programs. Dr. Savitz will serve as a discussant for the panel. Poster Session II: 6:00-8:00 p.m. CT, Griffin Hall Presentation Title: Identification and Prospective Replication of an EEG Biomarker for Predicting the Antidepressant Effect of ALTO-300 in Patients with Major Depression: Results from a Large Phase 2a Study Poster Authors: Maimon Rose, Ph.D., Joshua T. Jordan, Ph.D., Chao Wang, Ph.D., Faizan Badami, M.S., Jessica Powell, Fadi Abdel, M.D., Wei Wu, Ph.D., Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. Presentation Title: Baseline Cognition is Not Associated with Depression Outcomes with Vortioxetine for Major Depressive Disorder: Findings from Placebo-Controlled Trials Poster Authors: Joshua T. Jordan, Ph.D., Li Shen, Ph.D., Nicholas J. Cooper, Ph.D., Samantha V. Goncalves, M.S., Madhukar H. Trivedi, M.D., Alan F. Schatzberg, M.D., Wei Wu, Ph.D., Adam J. Savitz, M.D., Ph.D., & Amit Etkin, M.D., Ph.D. Saturday, May 11, 2024 Poster Session III: 5:00-7:00 p.m. CT, Griffin Hall Presentation Title: Identification of Brain/Behavior-based Pro-cognitive Pharmacodynamic Effects for ALTO-101 in Healthy Volunteers: Results from a Randomized, Double-blind Phase 1 Study Poster Authors: Akshay Ravindran, Ph.D., Guhan Sundar, Samantha Goncalves, M.S., Chao Wang, Ph.D., Li Shen, Maimon Rose, Ph.D., Joshua T. Jordan, Ph.D., Nicholas J. Cooper, Ph.D., Sebastian Marquez, Ph.D., Faizan Badami, M.S., Wei Wu, Ph.D., Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. American Society of Clinical Psychopharmacology Annual Meeting Tuesday, May 28, 2024 Pharmaceutical Pipeline Session: 2:00-4:00 p.m. ET, Salon 3 Presentation Title: Pro-cognitive Pharmacodynamic Effects of ALTO-101: Results from Brain and Behavioral Outcomes in a Randomized, Double-blind Phase 1 Study Poster Authors: Akshay Ravindran, Ph.D., Guhan Sundar, Samantha Goncalves, M.S., Chao Wang, Ph.D., Li Shen, Ph.D., Maimon Rose, Ph.D., Joshua T. Jordan, Ph.D., Nicholas J. Cooper, Ph.D., Sebastian Marquez, Ph.D., Tabitha Carreira, MPH, Jessica Powell, Faizan Badami, M.S., Wei Wu, Ph.D., Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. Workshop: 4:15-6:15 p.m. ET, Poinciana 3-4 Presentation Title: Good News/Bad News: Precision Neuroscience and the Clinical Trials Ecosystem Speakers: Mark Opler, Ph.D., M.P.H. (Chair); Adam Savitz, M.D., Ph.D., Alto Neuroscience; Seth C. Hopkins, Ph.D., Sumitomo Pharma America; John Carlos Diaz, GeoSera; John Sonnenberg, Ph.D., Uptown Research Institute; Barbara Echevarria, Ph.D., WCG; George Garibaldi, M.D., Garibaldi Consulting GMBH Wednesday, May 29, 2024 Individual Research Reports: 3:00-4:30 p.m. ET, Salon 2 Presentation Title: Baseline Cognition is not Associated with Depression Outcomes with Vortioxetine for Major Depressive Disorder: Findings from Placebo-controlled Trials Poster Authors: Joshua T. Jordan, Ph.D., Li Shen, Ph.D., Nicholas J. Cooper, Ph.D., Samantha V. Goncalves, M.S., Madhukar H. Trivedi, M.D., Alan F. Schatzberg, M.D., Wei Wu, Ph.D., Adam J. Savitz, M.D., Ph.D., & Amit Etkin, M.D., Ph.D. Thursday, May 30, 2024 Poster Session II: 12:30-2:15 p.m. ET, Salon 4 Presentation Title: A Biomarker-Based Enrichment Strategy for Neuropsychiatric Drug Development: Examples from Two Ongoing Phase 2b Studies Poster Authors: Michael Avissar, M.D., Ph.D., Joshua T. Jordan, Ph.D., Nicholas Cooper, Ph.D., Maimon Rose, Ph.D., Chao Wang, Ph.D., Faizan Badami, M.S., Peter Emmel, Kaitlly Zhu, Jessica Powell, Fadi Abdel, M.D., Amit Etkin, M.D., Ph.D., Adam J. Savitz, M.D., Ph.D. Presentation Title: Prevalence and Correlates of Cognitive Impairment in Depression: Findings from the Texas Resilience Against Depression Study Poster Authors: Joshua T. Jordan, Ph.D., Li Shen, Ph.D., Cherise Chin-Fatt, Ph.D., Adam J. Savitz, M.D., Ph.D., Amit Etkin, M.D., Ph.D., & Madhukar H. Trivedi, M.D. 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 depression, PTSD, 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,” “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 for the timing, progress, and results of its studies. 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 Alto’s studies 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 the section titled “Risk Factors” in Alto’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 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.