Melatonin

▲5月30-31日 第八届广州生物医药创新者峰会 扫码立即报名 注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。3月21日是世界睡眠日，人的生命约有1/3是在睡眠中度过的，睡眠与健康密切相关。睡眠障碍已经成为影响全球人类健康的一个突出问题，失眠症是最常见的睡眠障碍，流行病学研究显示，中国有45.4%的被调查者在过去1个月中曾经历过不同程度的失眠。长期失眠影响个体的正常生活和工作，增加罹患各种健康问题的风险。严重的睡眠缺失将降低患者的工作效率和警觉水平，甚至有可能引发恶性意外事故，造成巨大损失。 目前催眠镇静剂市场规模超48亿，临床仍有较大的未满足需求失眠的治疗方法主要包括心理治疗和药物治疗。心理治疗是首选的治疗方法，但因难以获得和成本高昂等原因应用不广。药物治疗主要包括苯二氮卓类受体激动剂（benzodiazepine receptor agonists，BZRAs）、褪黑素受体激动剂、食欲素受体拮抗剂和具有催眠效应的抗抑郁药物。据药融云数据显示，2022年失眠化药在全国院内市场销售额超48亿元。目前国内失眠化药多为老品种(地达西尼上市前我国失眠行业近16年没有新药获批)，多家仿制药上市，价格偏低，导致国内市场规模始终保持较低水平。2018-2023年全国院内镇静催眠药物市场规模（数据截至2023Q3）截图来源：药融云全国院内销售数据库BZRAs：分为苯二氮卓类药物和非苯二氮卓类药物。BZDs于20世纪60年代开始使用，可非选择性激动γ-氨基丁酸受体A上不同的α1亚基，具有镇静、催眠、抗焦虑、肌肉松弛和抗惊厥的药理作用。20世纪80年代以来，以唑吡坦（zolpidem）和右佐匹克隆（eszopiclone）为代表的non-BZDs先后应用于失眠的临床治疗，它们对γ-氨基丁酸受体A上的α1亚基选择性激动，主要发挥催眠作用，不良反应较BZDs轻，已经逐步成为治疗失眠的临床常用药物。褪黑素和褪黑素受体激动剂：褪黑素参与调节睡眠觉醒周期，可以改善时差变化所致睡眠觉醒障碍、睡眠觉醒时相延迟障碍等昼夜节律失调性睡眠觉醒障碍，但使用普通褪黑素治疗失眠尚无一致性结论，故不推荐将普通褪黑素作为催眠药物使用。食欲素受体激动剂：食欲素又称下丘脑分泌素，具有促醒作用。针对食欲素双受体发挥抑制作用的拮抗剂苏沃雷生（suvorexant），已获得美国食品药品监督管理局批准用于治疗成人失眠（入睡困难和睡眠维持障碍）。其发挥催眠作用的靶点不同于其他催眠药，现有研究数据显示其具有较好的临床疗效和耐受性。抗抑郁药物：部分抗抑郁药具有镇静作用，在失眠伴随抑郁、焦虑心境时应用较为有效。临床上常用具有镇静催眠作用的药物 中国失眠创新药一片蓝海，空间巨大自2007年江苏天士力帝益药业的右佐匹克隆上市以来，中国创新失眠药领域一直面临长期空白，直到2023年浙江京新药业的地达西尼上市后，才打破国内16年来没有治疗失眠障碍创新药上市的局面。2010年以来中国上市失眠创新药Dimdazenil（地达西尼）地达西尼是治疗失眠的1类小分子新药，为为γ-氨基丁酸A型（GABAA）受体的部分正向别构调节剂，通过部分激活GABAA受体，产生促进睡眠的作用。与传统失眠药物相比具有GABAA受体部分激动，避免过度抑制，日间损害和不良反应更小；1h达峰，快速诱导睡眠；半衰期4h，有效维持生理睡眠；主要通过FMO代谢，显著降低药物相互作用风险的特点。截图来源：药融云全球药物研发数据库地达西尼最早由Roche研发，随后德国公司Evotec获得全球独占权并将其开发用于治疗失眠症，于2008年在国外完成I、II期临床。2010年京新药业与Evotec签署协议，获得地达西尼在中国的独家专利许可和开发权。地达西尼在中国的获批上市是基于JX202001-EVT201-III一项评价EVT201胶囊对比安慰剂在失眠障碍患者中疗效和安全性的多中心、随机、双盲III期临床试验。基于统计分析模型，以第13/14晚PSG监测的平均TST值为反应变量，基线TST、年龄为协变量，组别为自变量计算，EVT201胶囊组相对于安慰剂组的优效性成立，EVT201胶囊可快速起效、提高睡眠效率，同时改善次日嗜睡等残留效应。食欲素是一种由下丘脑自然产生的神经肽，食欲素和其受体共同构成的食欲素系统能够刺激唤醒中枢神经系统的目标神经元，然后释放几种促进清醒的化学物质。近年来食欲素及其拮抗剂的研究越来越受到重视，已发现食欲素拮抗剂对失眠具有治疗作用。目前中国在研失眠新药中就是主要以食欲素受体（OX1R、OX2R）为主。中国在研失眠创新药Lemborexant（莱博雷生）Lemborexant是卫材研发的一款双重食欲素拮抗小分子药物，通过竞争性结合OX1R、OX2R，抑制食欲素神经传递，调节睡眠-觉醒节律。双食欲素神经肽信号系统在觉醒中有重要作用，作为一种竞争性拮抗剂，莱博雷生对OX2R具有更强的抑制作用，可抑制REM和非REM睡眠驱动，从而为患者提供更快的睡眠开始、更好的睡眠维持。截图来源：药融云全球药物研发数据库一项为期12个月的全球多中心、随机双盲、平行组的III期临床实验结果显示，莱博雷生与安慰剂相比，对于所有睡眠参数都观察到了显著的益处。与唑吡坦相比，莱博雷生疗法显著改善了睡眠的维持时间，并缩短了下半夜的觉醒时间。同时，相比苯二氮卓类药物的戒断反应，莱博雷生没有出现相关的戒断反应，这表明服药达一年不会产生躯体依赖。Fazamorexant（YZJ-1139）Fazamorexant是扬子江药业子公司上海海雁医药的一款双重食欲素抗体拮抗药物，通过抑制食欲素受体从而改善睡眠，包括加快睡眠速度和延长睡眠时间。同时，fazamorexant拥有吸收快速和半衰期适中的优势，可以达到快速起效和次日残留效应低的效果。截图来源：药融云全球药物研发数据库2021年5月举办的亚洲睡眠医学会第三届睡眠大会（ASSM 2021）公布的该药的Ⅱ期临床试验结果显示，YZJ-1139可剂量相关地改善睡眠效率，各剂量组均可以改善受试者睡眠效率至健康水平。同时，与安慰剂组相比，YZJ-1139未出现明显的中枢神经系统副作用，第二日残留效应低。YZJ-1139 Ⅱ期临床试验的积极结果，为Ⅲ期临床试验提供了有力依据。Daridorexant hydrochloride（达利雷生）Daridorexant是由Idorsia研发的双重食欲素拮抗药。Daridorexant是通过阻断食欲素受体与促觉醒神经肽食欲素的结合，抑制过度活跃的不眠状态。2022年11月先声药业与Idorsia签订独家授权协议，先声药业获得大中华地区开发和商业化独家权益。截图来源：药融云全球药物研发数据库发表于《柳叶刀神经病学》的海外III期临床数据显示，在接受1个月、3个月治疗后，达利雷生较安慰剂显著改善了患者入睡、睡眠维持及自我报告的总睡眠时间，不改变睡眠结构，且未发现依赖性、反跳性失眠、戒断症状和药物滥用证据，显著区分于传统镇静催眠药苯二氮卓类药物。版权声明：本文转自药融云，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 活动推荐  8月 • 第六届CMC-China博览会  关键词：  生物药、小分子创新药、药学CMC&创新&CXO、原辅包（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。

– Reported positive results from ALTO-100 and ALTO-300 Phase 2a studies demonstrating prospective replication of response prediction using Alto’s Precision Psychiatry Platform™ – – Patient enrollment on track across Phase 2b MDD studies for two lead product candidates – – Successful completion of oversubscribed initial public offering; cash position of approximately $210 million as of February 29, 2024 – LOS ALTOS, Calif.--(BUSINESS WIRE)-- Alto Neuroscience, Inc. (“Alto”) (NYSE: ANRO) today reported financial results for the full year ended December 31, 2023, and highlighted recent corporate progress. “2024 is shaping up to be a transformational year for Alto as we advance our mission of redefining the treatment paradigm for patients with neuropsychiatric disorders,” said Amit Etkin, M.D., Ph.D., founder and CEO of Alto Neuroscience. “Our lead product candidates, ALTO-100 and ALTO-300, have demonstrated positive Phase 2a results and we remain focused on clinical execution to deliver value to patients and our shareholders. Looking ahead, we are on track to report data from the Phase 2b depression studies of ALTO-100 and ALTO-300 in the second half of 2024 and the first half of 2025, respectively, in biomarker characterized patients.” Nick Smith, CFO of Alto Neuroscience, added, “As we begin 2024, Alto is in its strongest financial position to date. With the proceeds from our IPO, combined with our existing cash balance, we are well-positioned to read out data from at least four important studies across our clinical-stage pipeline over the next two years.” Full Year 2023 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). In January 2023, Alto reported positive results from a Phase 2a study in which patients with MDD and a cognitive biomarker signature were identified as more responsive to ALTO-100. This signal was prospectively replicated to predict clinical response in an independent, locked, and blinded data set of patients from the same study. Alto is currently evaluating ALTO-100 in a 266-patient Phase 2b study in MDD patients characterized by the 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 a standard antidepressant. ALTO-300 has demonstrated positive results in Phase 2a in patients with MDD in which patients with an EEG biomarker signature were discovered to have more robust response to ALTO-300 compared to those without the biomarker signature. The biomarker signature was prospectively replicated to predict clinical response in an independent, locked, and blinded data set. The Company initiated a Phase 2b study in 200 patients with MDD. In the Phase 2b study ALTO-300 will be evaluated 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: PDE4 Inhibitor in Development for Cognitive Impairment in Schizophrenia (CIAS) ALTO-101 is a novel 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 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 pro improve the overall tolerability pro to other PDE4 inhibitors. The Company expects to report data from a Phase 1 study evaluating the PK properties of the transdermal formulation in the first half of 2024, and subsequently initiate a proof-of-concept study in patients with CIAS. 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 subjective affective clinical measures. ALTO-203 was previously studied in a Phase 1 study and demonstrated significant acute benefits on a scale of subjective positive emotion, compared to placebo. The magnitude of this effect was shown to be equivalent to, or better than modafinil, an active comparator with demonstrated antidepressant activity in clinical trials. In January 2024, Alto received IND clearance for ALTO-203 and expects to initiate a proof-of-concept study in the first half of 2024 in patients with MDD and increased levels of anhedonia. 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. Recent Business Highlights Maha Radhakrishnan, M.D., former Group SVP and Chief Medical Officer at Biogen, was appointed to the Company's board of directors in March 2024. Husseini Manji, M.D., Ph.D., former Global Therapeutic Head for Neuroscience at Johnson & Johnson, was appointed to the Company’s board of directors in February 2024. The Company successfully completed its upsized initial public offering in February 2024, resulting in net proceeds of approximately $133 million. In January 2024 the California Institute for Regenerative Medicine (CIRM) voted to approve a $15 million grant to Alto in support of a proposed Phase 2b study of ALTO-100 in patients with bipolar depression. The Company is evaluating the terms and conditions of the grant and, if accepted, the Company plans to initiate the Phase 2b study in 2024. Upcoming Milestones and Events Near-Term Expected Milestones 1H 2024 — ALTO-101 transdermal formulation pharmacokinetic and safety Phase 1 results 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 Conferences Members of Alto’s scientific team are expected to present data at the following upcoming conferences: Society of Biological Psychiatry American Society of Clinical Psychopharmacology Full Year 2023 Financial Highlights Cash Position: As of December 31, 2023, Alto had cash and cash equivalents of $82.5 million. Following the closing of the Company’s initial public offering, the Company had approximately $210 million of cash and cash equivalents as of February 29, 2024. The Company expects its cash balance to support planned operations into 2027. R&D Expenses: Research and development expenses for the full year ended December 31, 2023 were $30.3 million, as compared to $23.7 million for the same period in 2022. The increase was primarily attributable to costs associated with the Phase 2a clinical studies for ALTO-100 and ALTO-300, which were completed in 2023. G&A Expenses: General and administrative expenses for the full year ended December 31, 2023 were $7.5 million, as compared to $5.5 million for the same period in 2022. The increase was primarily attributable to costs associated with higher headcount to support expanded clinical development efforts and growing operational requirements. Net Loss: The Company incurred a net loss of $36.3 million for the full year ended December 31, 2023, as compared to $27.7 million for the year ended December 31, 2022. 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 the section titled “Risk Factors” in Alto’s Final Prospectus filed with the Securities and Exchange Commission (“SEC”) on February 5, 2024, pursuant to Rule 424(b)(4) under the Securities Act of 1933, as amended, as well as in other filings Alto may make with the SEC in the future, including its Annual Report on Form 10-K for the year ended December 31, 2023. 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. Consolidated Statements of Operations and Comprehensive Loss (in thousands, except share and per share data) (unaudited) Year Ended December 31, 2023 2022 Operating expenses: Research and development $ 30,291 $ 23,688 General and administrative 7,518 5,504 Total operating expenses 37,809 29,192 Loss from operations (37,809 ) (29,192 ) Other income (expense): Interest income 2,349 114 Interest expense (1,370 ) — Change in fair value of warrant liability 525 (369 ) Grant income — 1,737 Total other income, net 1,504 1,482 Net loss $ (36,305 ) $ (27,710 ) Other comprehensive loss: Foreign currency translation (33 ) (24 ) Total other comprehensive loss (33 ) (24 ) Comprehensive loss $ (36,338 ) $ (27,734 ) Net loss per share attributable to common stockholders, basic and diluted $ (9.73 ) $ (8.04 ) Weighted-average number of common shares outstanding, basic and diluted 3,731 3,446 ALTO NEUROSCIENCE, INC. Selected Consolidated Balance Sheet Data (in thousands) (unaudited) December 31, 2023 2022 Cash and cash equivalents $ 82,548 $ 48,344 Total assets 86,628 50,854 Total liabilities 16,823 17,025 Accumulated deficit (76,965 ) (40,660 )