ALTO-101

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 third quarter ended September 30, 2024, and highlighted recent corporate progress. “We have sharpened our clinical focus, which we expect will propel us forward to multiple near-term milestones, including MDD readouts anticipated in the first half of 2025 for ALTO-300 and ALTO-203,” said Amit Etkin, M.D., Ph.D., founder and chief executive officer of Alto Neuroscience. “While we were disappointed that the ALTO-100 Phase 2b study did not achieve the primary outcome, there are important findings within the data, which we believe will enable us to enhance the likelihood of success with our other ongoing clinical studies. We are encouraged by the potential benefit of ALTO-100, as demonstrated in the adjunctive population, and of our biomarker approach in patients with confirmed drug compliance, showing that enrichment resulted in a meaningful difference and greater improvement in patients with the cognitive biomarker. I am proud of our team for completing this study—which we believe was the first large-scale, double-blind, biomarker driven trial in psychiatry—and plan to incorporate learnings from this data set across our other programs. With a strong cash runway into 2027, we are well positioned to drive forward our differentiated pipeline, targeting unique, biomarker-defined patient populations.” Third Quarter 2024 and Recent Business Highlights ALTO-100: Phase 2b in Bipolar Depression ongoing, reported topline data from Phase 2b MDD study. ALTO-100, a first-in-class, oral small molecule believed to work through enhancing neural plasticity, is in development for mood disorders. In October 2024, the Company reported topline results in a Phase 2b trial evaluating ALTO-100 as a treatment for major depressive disorder (MDD). The cognitive biomarker-defined MDD (biomarker positive) patient group treated with ALTO-100 did not demonstrate a statistically significant improvement in depressive symptoms compared to placebo in the overall modified intention to treat (mITT) population (n=196 biomarker-positive, including those receiving ALTO-100 or placebo as a monotherapy or adjunctive to an antidepressant to which they had an inadequate response). ALTO-100 continued to demonstrate a favorable safety and tolerability profile, with no new safety signals observed in this study. Overall, placebo response was well-managed and the biomarker did not enrich for a larger placebo response in the study. In a pre-specified analysis of biomarker positive patients taking ALTO-100 or placebo adjunctively to a stable background antidepressant (n=61), ALTO-100 demonstrated a clinically meaningful effect compared to placebo at week 6 (Cohen’s d=0.47, p=0.09). The pre-specified analysis of this population was not powered to achieve statistical significance. In the Phase 2b trial there was a higher-than-anticipated level of non-compliance with taking study medication in the monotherapy group, which was not evident in the adjunctive treatment group. In a subset of patients that had evidence of taking ALTO-100 through blood sample analysis, the patients with the ALTO-100 cognitive biomarker demonstrated a greater improvement than those without the biomarker. Alto does not currently intend to advance ALTO-100 in MDD. ALTO-100 is currently being evaluated as an adjunctive treatment in a Phase 2b study in bipolar depression with topline data expected in 2026. ALTO-300 (agomelatine): Enrollment on track in Phase 2b adjunctive MDD trial. ALTO-300, an oral, small molecule designed to act as a melatonin agonist and 5-HT2C antagonist, is being developed 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, but has not been approved in the United States. Enrollment in the Phase 2b MDD trial remains on track with topline data expected in the first half of 2025. The double-blind, placebo-controlled, randomized study is expected to enroll 200 patients characterized by an EEG biomarker signature. Patients will receive ALTO-300 or placebo in addition to a background antidepressant, to which they have had inadequate response, over a 6-week treatment period. The primary outcome is the change from baseline in MADRS score. This study builds on positive results from Alto’s completed Phase 2a trial and data from completed trials of agomelatine by other sponsors that demonstrated effects on depression symptoms. Approximately 50% of patients with MDD are estimated to be positive for the ALTO-300 EEG biomarker. ALTO-203: Enrollment on track in Phase 2 proof-of-concept MDD trial. 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. Enrollment in the Phase 2 proof-of-concept (POC) trial in MDD patients with higher levels of anhedonia remains on track with topline data expected in the first half of 2025. Alto expects to enroll approximately 60 patients in the study, which consists of two sequential double-blind, placebo-controlled treatment periods with two dose levels of ALTO-203 as a monotherapy. In the first period, patients will receive a single-dose of ALTO-203 or placebo, and the outcome measure is designed to evaluate pharmacodynamic effects. An acute change in positive emotion will be 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 trial of ALTO-203. In the second period, patients will receive ALTO-203 or placebo once daily over a 28-day treatment period to evaluate the clinical activity and safety of ALTO-203. The study is powered based on the outcomes being evaluated in the first period. The clinical outcomes, e.g., MADRS, are not powered to detect statistical significance. ALTO-101: Phase 2 proof-of-concept CIAS trial ongoing, topline data on track for 2H 2025. ALTO-101, a brain-penetrant PDE4 inhibitor designed as a novel transdermal formulation, is being developed for the treatment of Cognitive Impairment Associated with Schizophrenia (CIAS). Through this unique formulation, ALTO-101 is designed to retain the desired brain effects shown with the oral formulation and avoid tolerability challenges and adverse effects known to be associated with PDE4 inhibitors. Topline data from the Phase 2 POC trial is expected by the end of 2025. The Phase 2 POC trial consists of a cross-over, double-blind, placebo-controlled, dose-escalating treatment with ALTO-101 and Alto expects to enroll approximately 70 adults with schizophrenia. The primary outcome in the study is the effect of ALTO-101 on theta band activity, the EEG measure shown to be best related to CIAS in replicated analyses of large schizophrenia datasets. Objective cognitive performance will also be evaluated. Upcoming Milestones and Events Near-Term Expected Milestones 1H 2025 — ALTO-300 Phase 2b MDD trial topline data 1H 2025 — ALTO-203 Phase 2 MDD trial topline data 2H 2025 — ALTO-101 Phase 2 CIAS trial topline data 2026 — ALTO-100 Phase 2b bipolar depression trial topline data Upcoming Conferences Members of the Company’s management team are expected to present at the following upcoming conferences: Stifel 2024 Healthcare Conference: fireside chat on Monday, November 18, 2024 at 3:00 pm ET Jefferies London Healthcare Conference: fireside chat on Wednesday, November 20, 2024 at 3:00 pm GMT International Pharmaco-EEG Society (IPEG): November 21-24, 2024 American College of Neuropsychopharmacology (ACNP): December 8-11, 2024 Third Quarter 2024 Financial Highlights Cash Position: As of September 30, 2024 the Company had cash, cash equivalents, and restricted cash of approximately $182 million. The Company expects its cash balance to support planned operations into 2027. R&D Expenses: Research and development expenses for the quarter ended September 30, 2024 were $13.1 million, as compared to $8.0 million for the same period in 2023. The increase was primarily attributable to costs associated with the Phase 2b clinical studies for ALTO-100 and ALTO-300, and the Phase 2 POC studies for ALTO-203 and ALTO-101. G&A Expenses: General and administrative expenses for the quarter ended September 30, 2024 were $5.8 million, as compared to $1.8 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. The increase in personnel costs includes $0.9 million of non-cash stock-based compensation expense. Net Loss: The Company incurred a net loss of $16.8 million for the quarter ended September 30, 2024, as compared to $9.1 million for the quarter ended September 30, 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 www.altoneuroscience.com 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 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 Quarterly Report on Form 10-Q for the fiscal quarter ended June 30, 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. ALTO NEUROSCIENCE, INC. Condensed Consolidated Statements of Operations and Comprehensive Loss (in thousands, except per share amounts) (unaudited) Three months ended September 30, Nine months ended September 30, 2024 2023 2024 2023 Operating expenses: Research and development $ 13,060 $ 7,967 $ 36,196 $ 20,648 General and administrative 5,826 1,751 15,417 5,396 Total operating expenses 18,886 9,718 51,613 26,044 Loss from operations (18,886 ) (9,718 ) (51,613 ) (26,044 ) Other income (expense): Interest income 2,500 714 6,716 1,611 Interest expense (349 ) (363 ) (1,042 ) (1,014 ) Change in fair value of warrant liability — 226 (243 ) 359 Change in fair value of Convertible Grant Agreement (48 ) — (48 ) — Total other income (expense), net 2,103 577 5,383 956 Net loss $ (16,783 ) $ (9,141 ) $ (46,230 ) $ (25,088 ) Other comprehensive loss Foreign currency translation (6 ) (10 ) (16 ) (40 ) Total other comprehensive loss (6 ) (10 ) (16 ) (40 ) Comprehensive loss $ (16,789 ) $ (9,151 ) $ (46,246 ) $ (25,128 ) Net loss per share attributable to common stockholders, basic and diluted $ (0.62 ) $ (2.44 ) $ (1.94 ) $ (6.75 ) Weighted-average number of common shares outstanding, basic and diluted 26,959 3,742 23,878 3,717 ALTO NEUROSCIENCE, INC. Selected Condensed Consolidated Balance Sheet Data (in thousands) (unaudited) September 30, December 31, 2024 2023 Cash, cash equivalents, and restricted cash $ 182,201 $ 82,548 Total assets 191,608 86,628 Total liabilities 26,556 16,823 Accumulated deficit (123,195 ) (76,965 )

百时美施贵宝的精神分裂症新药Cobenfy（xanomeline/trospium，即KarXT）于今年9月底顺利获得FDA批准，是几十年来精神分裂症领域首个新型作用机制的药物（M1/M4毒蕈碱激动剂）。 就在获得批准前夕，杰富瑞(Jefferies)分析师预测，Cobenfy仅精神分裂症适应症的年销售额最高将达到35亿美元，所有适应症的销售额将达到62亿美元。高盛分析师预测，到2035年，Cobenfy精神分裂症销售额将达到37亿美元。 Cobenfy作为其他精神分裂症药物的辅助药物正在进行Ⅲ期试验，预计将于2025年获得结果；治疗阿尔茨海默病精神病Ⅲ期试验预计将于2026年获得数据。百时美施贵宝还计划启动Cobenfy治疗双相情感障碍、阿尔茨海默病相关躁动和阿尔茨海默病的试验。Cobenfy已计划于2025年启动与自闭症相关的认知障碍研究项目，并计划于2025年底或2026年初启动另一个针对与自闭症相关烦躁的研究项目。 尽管精神分裂症市场有超过20种抗精神病药物可供患者选择，似乎已经非常饱和，但是患者对现有治疗药物非常不满意，主要原因是这些抗精神病药物只对大约30%的患者有效。 与传统针对多巴胺2（D2）受体的非典型抗精神病药物相比，Cobenfy具有差异化的疗效、安全性和耐受性，有望成为该治疗领域游戏规则的改变者。 延伸阅读：70年来精神分裂症First in Class新药KarXT将于9月下旬获FDA批准 与此同时，在精神分裂症新药研发管线中，除了传统抗精神病药物外，Cobenfy还面临着同类机制的追赶者、新机制的突破者以及505(b)(2)挑战者。 追赶者：直接数据PK NBI-1117568 就在今年8月底，Neurocrine公司公布了其开发的口服选择性M4毒蕈碱激动剂NBI-1117568Ⅱ期临床试验结果：尽管该药物可改善精神分裂症的症状，但只有在最低剂量达到主要终点。即每日一次 20 mg 剂量治疗第 6 周时阳性和阴性症状量表 (PANSS) 总分较基线有临床意义和统计学显着降低，安慰剂调整后平均降低 7.5 分；在此剂量水平下，疾病的严重程度也得到了改善。所有其他剂量组（30mg、40mg和60mg）均未达到试验的主要终点。 该公司股价在结果公布后下跌了20%，部分原因是其PANSS评分低于竞争对手。 Cobenfy在3项关键的Ⅲ期临床试验（EMERGENT-1、2、3）主要终点方面，EMERGENT-3中治疗第五周PANSS总分降低了8.4分，略低于EMERGENT-2中的9.6分和EMERGENT-1的11.6分。 Neurocrine仍旧计划于2025年初把NBI-1117568推进到Ⅲ期临床试验，未来试验数据有待于进一步观察。 不过，该公司还具有丰富的毒蕈碱激动剂组合：M1激动剂NBI-1117567、M4激动剂NBI-1117569和M1/M4双重激动剂NBI-1117570都正在进行Ⅰ期临床试验。Neurocrine在未来有充足的选择机会。 Emraclidine 艾伯维于2023年12月以87亿美元收购Cerevel，从而获得了M4毒蕈碱激动剂Emraclidine，目前处于II期EMPOWER - 2研究开发阶段。不过该研究因为比一般的II期试验规模大得多（招募372例患者），因此被认为具有可用于上市申请潜力。 根据2022年发表于《柳叶刀》杂志上的Ⅰb期试验结果，Emraclidine对精神分裂症成年人治疗六周后PANSS总分出现了具有临床意义和统计学意义的改善。 突破者：多种机制齐出击 ALTO-101 Alto Neuroscience正在开发的新型磷酸二酯酶4(PDE4)酶抑制剂ALTO-101来治疗精神分裂症认知症状。 PDE4抑制剂已获批上市用于治疗慢性阻塞性肺病（COPD ）和银屑病。有趣的是，PDE4酶在大脑中高表达，被认为是治疗神经系统疾病的潜在靶点。 Alto于2024年6月启动了ALTO-101的II期研究，计划招募约70名年龄在21至55岁精神分裂症和明显认知障碍的患者。预计2025年下半年将获得主要数据。 在I期研究中，该候选药物对认知和与认知功能相关的脑电图(EEG)测量结果表现出积极作用。该公司报告称，ALTO-101透皮制剂比口服制剂具有更大的全身药物暴露量。透皮ALTO-101将在Ⅱ期试验中进行测试。 MK-8189 PDE10A是一种主要存在于纹状体多巴胺能神经元中的磷酸二酯酶，可终止多巴胺与D1和D2受体结合所诱导的细胞内信号，因此，被认为是治疗精神分裂症的潜在靶点。 默沙东也在开发的治疗精神分裂症的强效选择性PDE10A抑制剂MK-8189。MK-8189在随机概念验证临床试验的初步结果表明：与安慰剂相比，MK-8189在治疗4周后患者PANSS总分相对于基线的变化呈改善趋势。目前正处于Ⅱb期临床开发阶段。 延伸阅读：辉瑞、武田、灵北“三连败”后：默沙东MK-8189初步看到更广泛潜力 Iclepertin 勃林格殷格翰正在开发一种甘氨酸转运蛋白1(GlyT1)抑制剂iclepertin，用于治疗与精神分裂症相关的认知症状。GlyT1被认为在调节抑制性和兴奋性神经传递方面发挥重要作用。 Ⅱ期临床试验结果显示，与安慰剂相比，Iclepertin 2-25 mg剂量组患者的认知功能均较基线改善，其中10 mg和25 mg组患者的认知功能改善幅度最大。所有剂量的Iclepertin总体安全性及耐受性都是良好的。 iclepertin目前正在进行三项大型随机对照Ⅲ期临床试验研究，预计将于2025年公布结果。 505(b)(2)挑战者：最直接威胁 不过，对于百时美施贵宝，Cobenfy最为直接的挑战者可能是Terran Biosciences。 由于Cobenfy两种活性成分xanomeline和trospium都属于“老药”，化合物已失去专利保护。 Terran Biosciences公司正在通过开发xanomeline和trospium前药的组合，有望在未来挑战百时美施贵宝。 为了成功克服xanomeline和trospium的药代动力学局限性，Terran组建了一支由全球药物化学专家组成的团队，设计了10000多种新型前药。Terran的PK建模团队针对各种不同的配方设计和释放曲线开发了xanomeline和trospium的预测模型，以确定最佳药代动力学参数和比例。Terran利用200名化学家组成的团队合成了500多种前药，然后进行了临床前测试，包括285项体外研究和365项体内研究。 Terran目前正在开发Cobenfy的两种前药版本，一种是每日一次的口服候选药物TerXT，另一种是数月注射剂TerXT LAI。长效注射剂可以大大改善精神分裂症患者服药依从性问题。   Terran已通过505(b)(2)审批途径将TerXT提交给FDA申请，目前正在接受FDA审查。 Terran正计划分别针对两个版本启动两项I期试验，以确认安全性和药代动力学。不过，该公司仍需要等待百时美施贵宝的五年市场独占期结束，才能将其产品推向市场。新的制药化学实体从FDA批准开始，将获得五年的市场独占期，以防止仿制药竞争。 当药物的原始成分专利到期时，制药公司可以开发药物前体版本，以绕过原始药物配方或组合的任何其他专利。开发药物前体会创造一种新的可获得专利授权保护的分子，使公司能够重新获得该药物前体的20年专利保护。只要原始成分专利到期，药物前体就可以获得批准和上市，而不会受到原始药物配方其他专利的阻碍。 今年5月20日，Terran称已收到美国专利商标局 (USPTO) 专利权利要求保护全球首款xanomeline前药的物质成分专利申请通知。 备注：本文同时刊载于《医药经济报》，有删改。 本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。 免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。 限于作者水平和专业知识所限，如有谬误，欢迎指正！