Gilgamesh Pharmaceuticals, Inc.

A new psychedelic-focused startup incubator is debuting, backed by an investor behind some of the most prominent biotechs in the space. The main theme of the companies it wants to build? No tripping. Negev Labs is an offshoot of Negev Capital. Founded in 2022 and equipped with $30 million in assets, New Jersey-based Negev Labs jumped out of stealth Wednesday with a library of compounds from the Alexander Shulgin Research Institute and the ophthalmology program from Beckley Psytech. The goal is to build a suite of venture-backed biotechs focused on developing neuroplastogens, an up-and-coming class of psychedelics that can change the brain’s structure and function, but without the hallucinations that can come with other psychedelics. Delix Therapeutics, one of Negev Capital’s portfolio companies, is an example of the science Negev Labs hopes to advance. Delix raised one of the largest private rounds for a psychedelic company and counts RA Capital as a Series A investor. “It’s not possible just one company, even [a] great company like Delix, will cover all the market,” Ken Belotsky, co-founder of both Negev Labs and Negev Capital, said in an interview. At Negev Labs’ disposal will be “two families of compounds” from the Alexander Shulgin Research Institute. The psychedelic research center was born out of work by Sasha Shulgin, who was a pioneer in the field and colloquially known as “the godfather of ecstasy.” Shulgin’s work synthesizing methylenedioxymethamphetamine (MDMA) helped usher in a new wave of research supporting its therapeutic use, despite being listed as a schedule 1 substance by the US Drug Enforcement Agency. When Shulgin passed away, he left the institute with about 500 finished psychedelic compounds, known as the “Shulgin vault,” fellow institute co-founder Nicholas Cozzi said in a separate interview. He, Paul Freeman Daley and Sasha’s wife Ann carried on Shulgin’s mission before Ann died in 2022. Cozzi and Daley have carried the torch since then. Cozzi said that Negev will have access to “some of the compounds, but so far, it’s just a limited set.” Shlomi Raz, a partner at Negev Labs, told Endpoints that the target of almost every drug that the firm will develop will be the serotonin 2A receptor, which is associated with the brain’s ability to restructure its neural networks. Raz also helped negotiate Negev Labs’ acquisition of the ophthalmology program from Beckley Psytech, where he was the chief business officer. Data from Beckley suggested that “sustained delivery depots” into the fluid that lines the eye at amounts that would not spur a psychedelic effect could still produce significant benefits for a handful of ocular diseases. Negev Labs has not yet announced its first company but plans to do so soon, Raz teased, saying it will focus on Parkinson’s. As for future financing, the firm is now “fully funded by external investors,” Belotsky said. In fact, Negev Capital no longer invests, after deploying the roughly $30 million first fund it closed in 2022 and failing to raise a second in 2023. Belotsky said he’s still supporting those companies — including Delix, Gilgamesh and atai Life Sciences — but most of his focus is on getting Negev Labs off the ground. “I just decided, ‘OK, we don’t have results in fundraising, but we have wonderful results in Negev Labs. And we have investors who are interested in this business model,’” he said.

An AbbVie schizophrenia drug acquired as part of a multi-billion dollar deal has failed two mid-stage studies, dealing a setback to the company’s plans to compete with a Bristol Myers Squibb medication that was recently approved in schizophrenia and is projected to become a blockbuster seller across several psychiatric indications. The preliminary results announced Monday are from two placebo-controlled Phase 2 studies designed to evaluate multiple doses of emraclidine, a once-daily drug, over the course of six weeks. The main goal was to show a reduction in score from baseline (a lower score indicates improvement) compared to placebo, according to the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), a rating scale used to assess schizophrenia symptoms. AbbVie said both studies show the experimental drug achieved numerical improvements in score compared to a placebo, but the changes were not enough to be statistically significant. The company added that the drug was well tolerated with a safety profile comparable to what was observed in Phase 1b testing. Many currently available schizophrenia drugs work by blocking dopamine type 2 (D2) receptors. But these drugs offer limited efficacy while introducing side effects that make it hard for patients to stay on treatment. Drug developers have been looking for other targets. Emraclidine gave AbbVie entry into a group of companies developing drugs targeting muscarinic receptors, which are receptors in the central nervous system that play key roles in neuronal functions. Emraclidine is an agonist of the muscarinic acetylcholine receptor type 4, or M4 receptor. By selectively targeting and activating this receptor, the drug is intended to treat schizophrenia in a way that does not hit D2 receptors. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Emraclidine was initially developed by Cerevel Therapeutics, which had advanced the drug to the Phase 2 studies EMPOWER 1 and EMPOWER 2 when AbbVie reached an $8.7 billion deal to acquire the biotech late last year. Weeks after that announcement, BMS announced a $14 billion deal to buy Karuna Therapeutics, whose M1- and M4-targeting schizophrenia drug was already under FDA review. The September approval of that twice-daily pill, now named Cobenfy, made it the first muscarinic-receptor targeting drug to pass the FDA’s regulatory bar. Though emraclidine trailed the BMS product, AbbVie hoped to offer better safety and more convenience with once-daily dosing. Now AbbVie must figure out how to proceed with emraclidine, which is also in Phase 1 testing in Alzheimer’s disease psychosis. “While we are disappointed with the results, we are continuing to analyze the data to determine next steps,” Roopal Thakkar, executive vice president, research and development, chief scientific officer, AbbVie, said in a prepared statement. In a note sent to investors Monday, Leerink Partners analyst David Risinger described emraclidine’s PANSS scores as “surprisingly low.” Looking across trials, he noted that the AbbVie drug’s reduction in score was significantly lower than what was reported for Cobenfy’s Phase 3 test. The AbbVie drug’s studies also had higher placebo responses compared to the placebo group in the BMS drug’s study. Risinger added that emraclidine’s failure to show dose-dependent efficacy across the multi-dose studies is concerning. William Blair analysts Myles Minter and Matt Phipps said the “absolute miss” of emraclidine in Phase 2 is a surprise, given the strength of the drug’s Phase 1 data. The failure all but removes a multi-billion dollar product from the AbbVie pipeline and calls into question the $8.7 billion Cerevel acquisition, they said. Sponsored Post The Future of Hospitals and Pharma Companies Will Depend on Strength of Healthcare Analytics Insights PurpleLab® stands out from others in this sector by providing its data analytics services to several different groups of users across healthcare and pharma companies. By Stephanie Baum “While additional details are necessary to fully understand the EMPOWER study outcomes, the results may suggest M1 and M4 agonism are needed to drive maximum benefit for patients, expanding Cobenfy’s first-mover advantage and ultimate market opportunity,” Minter and Phipps wrote. Despite emraclidine’s disappointing Phase 2 results in schizophrenia, AbbVie still has more shots on goal from its Cerevel acquisition and from other deals. This past April, Cerevel reported its drug candidate tavapadon met the main goals of its Phase 3 study in Parkinson’s disease. In May, AbbVie paid startup Gilgamesh $65 million up front to begin an R&D alliance focused on psychedelic medications for diseases and targets that were not disclosed.

艾伯维又出手了，这次是神经科学领域！ 10月28日，艾伯维宣布与 Aliada Therapeutics达成协议，以14亿美元收购这家聚焦中枢神经系统 (CNS) 疾病的biotech。艾伯维也获得了其在研的一款针对阿尔茨海默病的潜在best-in-class产品ALIA-1758。 这是继8月份87亿美元收购神经科学生物技术公司Cerevel Therapeutics之后，艾伯维在神经科学领域的又一重要战略布局。 就在10月30日，艾伯维公布了三季度财报，其神经科学产品组合营运层面增长16.0%，带来了23.63亿美元净收入，这也是今年以来艾伯维在神经科学领域连续三个季度取得了双位数高增长。神经科学已经成为推动艾伯维未来发展的关键增长领域之一。 另据报告披露，三季度艾伯维全球净收入144.60亿美元，营运层面增加4.9%。其中肿瘤学领域营运层面增长13.0%，净收入16.87亿美元；免疫产品组合营运层面增长4.8%，净收入70.46亿美元；眼科和美学产品则分别贡献了5.25亿美元、12.39亿美元。 可以看到，在Skyrizi和瑞福的稳定、高速的业绩助推下，艾伯维已经摆脱对修美乐的依赖，多领域齐头并进，重拾新增长曲线。 01 重金押注，这次是神经科学领域 在神经科学领域，艾伯维建立了丰富的产品管线，包括3款偏头痛药物Botox、Ubrelvy、Qulipta，精神分裂症药物Vraylar，以及帕金森病药物Vyalev。在2023年，艾伯维神经科学板块实现收入77.17亿美元，是仅次于自免板块的第二大收入来源。 从三季度财报来看，精神分裂症药物Vraylar、偏头痛药物Ubrelvy、Qulipta的销售额稳步增长，分别为8.75亿美元（+16.6%）、2.69 亿美元（+15.3%）、 1.76 亿美元（+33.6%）。其中，Botox、Vraylar和Ubrelvy是艾伯维在2019年豪掷630亿美元收购艾尔建而获得。 值得关注的是，帕金森病药物Vyalev刚刚在10月17日获美国FDA批准，用于治疗晚期帕金森病（PD）成人患者的运动症状波动。这也是FDA批准的首款基于左旋多巴的皮下24小时持续输注疗法。 除了Vyalev，另一款帕金森病药物Tavapadon是艾伯维以87亿美元收购 Cerevel Therapeutics时获得的。艾伯维同时还拿下了潜在best-in-class的新一代抗精神病药物Emraclidine，目前正在推进用于治疗精神分裂症的研究。 而以14亿美元收购Aliada Therapeutics，艾伯维则是获得了其在研的一款可能成为阿尔茨海默病最佳疾病疗法的新药ALIA-1758。对于艾伯维而言，本次收购一方面补充了阿尔兹海默病管线，但更为主要的原因则是借助Aliada的递送平台去赋能整个神经药物管线。正如艾伯维研发执行副总裁兼首席科学官Roopal Thakkar博士所言：“Aliada的新型血脑屏障（BBB）穿透技术也增强了我们的研发能力，使我们能够加快开发治疗神经系统疾病和其他疾病的下一代疗法。” 在更早的5月，艾伯维斥资20亿美元与Gilgamesh Pharmaceuticals达成合作，开发治疗精神疾病的新一代疗法，后者拥有两项处于临床阶段的资产，针对情绪障碍和焦虑症等多种精神疾病。 随着全球人口老龄化的加剧，神经系统疾病的发病率不断上升，神经科学领域的治疗需求随之攀升。据Frost & Sullivan预测，全球神经科学药物市场规模将从2022年的1600亿美元增长到2028年的2200亿美元。 面对庞大的市场，没有哪一家MNC能保持淡定，除了自研，纷纷通过买管线、并购等方式加码神经药物赛道。 在“钞能力”的加持下，艾伯维在神经科学领域的扩张不断提速，布局也趋于完善，拥有了更为丰富的产品管线，涵盖精神分裂症、偏头痛、帕金森病和阿尔茨海默病等。 随着布局的不断完善，艾伯维的神经科学板块将迎来高增长态势，成为艾伯维未来的重要发力点之一。 02 布局实体瘤，细分市场寻求突破 当前，艾伯维拥有3款已上市的血液肿瘤产品，包括Venclexta（维奈克拉）、Imbruvica（伊布替尼）和Tepkinly（epcoritamab）。三季度，艾伯维肿瘤学产品组合全球净收入16.87亿美元， 营运层面增长13.0%。其中，维奈克拉全球净收入6.77亿美元，营运层面增长18.2%，增势迅猛。 维奈克拉是一种口服的B细胞淋巴瘤-2（BCL-2）抑制剂，也是目前全球唯一一款上市的Bcl-2抑制剂。自上市以来，因其在血液肿瘤治疗中的显著效果而受到市场的认可。随着临床试验进展和新适应症的获批，维奈克拉的市场潜力将不断放大。艾伯维预测，维奈克拉的销售峰值有望在2026年达到60亿美元。 Tepkinly作为艾伯维血液肿瘤板块另一款创新产品，欧盟已授予Tepkinly有条件上市许可，作为单药用于治疗接受过二线或多线既往治疗后复发或难治性（r/r）滤泡淋巴瘤（FL）的成人患者。Tepkinly是首个在欧盟条件性批准的单药皮下双特异性抗体，适用于治疗已接受过二线或多线治疗的r/r FL和r/r大B细胞淋巴瘤（DLBCL）。去年5月，Tepkinly首次获得美国FDA批准(商品名Epkinly)，治疗R/R DLBCL。 在血液肿瘤领域，艾伯维处于领先的市场地位，因此推进实体瘤领域差异化产品管线，在细分市场寻求新的突破，就成为艾伯维的“必选课”。据艾伯维财报披露，欧洲药品管理局（EMA）人用药品委员会（CHMP）建议批准Elahere（mirvetuximab soravtansine）新适应症的上市许可，用于治疗接受过一至三线既往治疗的叶酸受体α（FRα）阳性、铂耐药及高分化浆液性上皮卵巢、输卵管或原发性腹膜癌成人患者。Elahere这一适应症的EC决定预计将在今年晚些时候做出。此前，美国FDA已批准Elahere用于治疗先前接受过1-3种系统性治疗的FRα阳性、铂类耐药性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者。Elahere是艾伯维以101亿美元收购ImmunoGen后，获得的“first-in-class”抗体偶联药物（ADC）。ImmunoGen的管线包括用于多种不同实体瘤和血液恶性肿瘤治疗的潜在项目。 此外，财报披露，艾伯维已向FDA提交申请，请求对Teliso-V（telisotuzumab vedotin）进行加速批准，用于治疗在既往接受过治疗的局部晚期或转移性表皮生长因子受体（EGFR）野生型、非鳞状非小细胞肺癌（NSCLC）中c-Met蛋白过表达患者。目前尚无专门针对c-Met过表达NSCLC的批准抗肿瘤治疗，如果获得批准，Teliso-V将成为该患者群体的首创新疗法。 就在财报公布后不久，艾伯维在11月1日宣布和EvolveImmune Therapeutics达成一项约15亿美元的合作和许可选择协议，旨在共同开发针对肿瘤学多个靶点的多特异性生物制品。这一发现合作伙伴关系将利用EvolveImmune的T细胞参与平台，为实体瘤和血液恶性肿瘤开发新的基于抗体的疗法。 作为全球千亿美元赛道的最主要竞赛场，肿瘤赛道历来是兵家必争之地。相对于艾伯维的自免板块，肿瘤板块的“想象空间”还很大。随着众多MNC巨头肿瘤赛道战略大调整，艾伯维此时入局，投资更具潜力和性价比的项目，不失为一手好棋。押注肿瘤赛道，或许是艾伯维未来重回高增长轨道的“胜负手”。 03 接棒修美乐，Skyrizi和瑞福在路上 说起自免，艾伯维必定是那个“别人家的孩子”。作为在这个领域最成功的药企，它正在迈过“人生低谷”。 三季度，艾伯维免疫产品组合全球净收入70.46亿美元，营运层面增加4.8%。其中，Skyrizi净收入32.05亿美元，营运层面增长51.5%，显示出其强劲的动力和潜力；瑞福（Rinvoq）净收入16.14亿美元，营运层面增长47.4%；修美乐业绩虽然下滑，但也取得了22.27亿美元的净收入。 业界预计，Skyrizi全年收入将达到110亿美元，成为艾伯维培育的第二个百亿“药王”；而瑞福全年收入将超过50亿美元。艾伯维则预计到2027年，Skyrizi和瑞福的总收入将超过270亿美元。 有了修美乐珠玉在前，艾伯维是懂得如何保持产品优势的。SKYRIZI和瑞福作为未来顶梁柱，艾伯维对它们的期待从未停步。 就在7月27日，欧盟批准SKYRIZI（risankizumab）用于治疗对传统药物治疗或生物制剂治疗应答不足、失应答或不耐受的中度至重度活动性溃疡性结肠炎成人患者。这项上市许可，也标志着Skyrizi在欧盟的第四个适应症获批。此前获批的3个适应症包括克罗恩病、中重度斑块状银屑病，以及成人活跃银屑病关节炎。在中国，早在2023年艾伯维就提交了SKYRIZI关于克罗恩病的上市申请。今年6月，艾伯维又提交了新的适应症申请，外界推测可能与溃疡性结肠炎相关。 而瑞福目前在全球已经获批皮科、消化、风湿等领域的9个适应症，还有红斑狼疮、斑秃、白癜风、巨细胞动脉炎等三期临床研究正在进展中。 从今年艾伯维在自免领域的动向来看，艾伯维从没有满足于现有的成就，它希望更积极地投资，以扩大其在免疫学领域的市场领导地位。例如收购Landos Biopharma、Celsius Therapeutics，与明济生物合作，加码炎症性肠病(IBD)这个患者群体数量庞大且有着巨大的未满足临床需求的领域。 可以看到，通过战略重塑，在更加明确加码神经科学领域和肿瘤领域、继续深耕免疫领域后，艾伯维正立足新的起点，在“新动能”的加持下全方位“提速”，实现华丽转身。 一审| 黄佳 二审| 李芳晨 三审| 李静芝