Engrail Therapeutics, Inc.

The first-in-human Phase 1 clinical study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic profile of ENX-104 in healthy volunteers SAN DIEGO, Sept. 18, 2024 (GLOBE NEWSWIRE) -- Engrail Therapeutics, a precision neuroscience company focused on the development of transformational therapies to improve the lives of patients, today announced initiation of a Phase 1 single ascending dose clinical study for ENX-104 in healthy volunteers. ENX-104 is a potent and selective dopamine D2/D3 receptor antagonist designed to enhance dopamine neurotransmission by preferential autoreceptor inhibition at low doses. The lead indication for ENX-104 is the treatment of major depressive disorder (MDD) characterized by anhedonia (aMDD). Anhedonia is the inability to experience pleasure in normally pleasurable activities and is a core symptom of MDD that is largely unresponsive to currently approved antidepressants. “Dysregulation of dopamine in the reward centers of the brain is believed to underlie anhedonia which is experienced by 60-70% of MDD patients. ENX-104 provides a novel and targeted approach to enhancing dopamine modulation and represents a potential new therapeutic modality for the treatment of patients with aMDD,” said Vikram Sudarsan, PhD, chief executive officer of Engrail. “The initiation of this Phase 1 study is a significant step forward for ENX-104 and an important milestone for Engrail as our second clinical-stage program.” The ENX-104 Phase 1 study is a randomized, double-blind, placebo-controlled single ascending dose clinical study that is expected to enroll up to 48 healthy adult volunteers. The primary objective is to evaluate the safety and tolerability of ENX-104 after a single oral administration of increasing doses in separate cohorts. Each dose cohort will include 8 subjects, with 6 subjects randomized to ENX-104 and 2 to placebo. The study is also designed to measure pharmacokinetics and explore the pharmacodynamic effects of ENX-104 on biomarkers associated with changes in dopamine neurotransmission in order to ascertain target engagement. About ENX-104ENX-104 is a potent dopamine D2/D3 receptor antagonist in development for major depressive disorder (MDD) characterized by anhedonia (aMDD). Dysregulated dopaminergic neurotransmission, particularly in brain reward systems, is believed to underlie anhedonia, a hallmark symptom of MDD. ENX-104 was designed to directly modulate dopaminergic transmission in brain reward systems by increasing dopamine release via potent antagonism of presynaptic D2/D3 autoreceptors at low doses. ENX-104 is in Phase 1 clinical development. About Engrail TherapeuticsEngrail is a clinical-stage pharmaceutical company with a rich pipeline of precision-targeted neuroscience programs designed to improve the lives of patients with neuropsychiatric and neurodevelopmental diseases. ENX-102, a next-generation GABAA positive allosteric modulator, is in Phase 2 clinical development for the treatment of generalized anxiety disorder. ENX-104, a potent dopamine D2/D3 receptor antagonist, is in Phase 1 clinical development for the treatment of major depressive disorder characterized by anhedonia. Additional programs in development are intended to address significant unmet medical needs for the treatment of posttraumatic stress disorder, anxiety-, mood- and stress-related disorders and rare neurological conditions. At Engrail, we apply precision chemistry and pharmacology to develop transformative medicines for patients who are underserved by existing treatments. For more information, visit engrail.com. Media Contact:Anil Vootkur, PharmDEngrail Therapeuticsanil@engrail.com

▎药明康德内容团队编辑 针对难以成药靶点的药物开发虽具挑战，但也充满机遇。近年来，科学进步和技术创新大大拓展了可成药的靶点边界，有望为广泛难治性疾病带来突破性疗法。当前全球大型药企有近10款针对难以成药靶点的创新疗法已处于临床3期，早期管线则折射出业界攻克更广泛靶点的希望；此外，今年上半年共19家致力于解决难以成药靶点或专注于相关技术的新锐获得共约10.7亿美元的早期投融资，高于去年同期。 在这篇文章中，我们将为大家回顾2024上半年产业在解决难以成药靶点方面以及基于相关策略开发疗法的进展与趋势，并展望下半年有望实现全球首批的多款疗法。扫描文中二维码或点击文末“阅读原文”可申请获取完整报告，包括已获批及即将获批疗法梳理、大型药企管线列表、融资新锐列表和介绍等详尽信息。 ▲长按扫描二维码或点击文末“阅读原文/Read more”，即可填写问卷，申请获取难以成药靶点研发进展完整报告 注：本文关注范围涵盖明确针对难以成药靶点（包括近年已有突破但仍产业仍在进一步开发的靶点）的疗法，或使用共价/别构机制、蛋白降解、蛋白稳定等创新技术研发的疗法，这些技术也有助于拓展其他靶点的成药性。 临床在研疗法蓬勃发展，有望攻克更多靶点 近3年来，全球范围内已有10余款基于共价/别构机制开发的新药获批，其中包括FDA批准的首款TYK2抑制剂，也不乏“first-in-class”新药或是针对特定患者群体的里程碑式突破。在2024上半年，EGFR共价抑制剂瑞必达（瑞齐替尼）在中国获批，为非小细胞肺癌（NSCLC）治疗带来全新选择，展望下半年，还有3款KRAS抑制剂有望在中国实现全球首批。 同时，从全球大型药企丰富的管线储备来看，更多创新疗法正在涌现。针对难以成药靶点或基于相关技术，大型药企管线中有40款疗法正处于临床研究或拓展适应症阶段。 ▲大型药企针对难以成药靶点或采用相关机制开发的管线分布 注：数据来源为各药企公开信息，截至2024年6月。20家大型药企参考行业媒体Fierce Pharma 2024年4月榜单。部分疗法已有适应症获批，但仍在推进更多适应症/地区的研究与监管申请：包括4款临床3期共价剂、1款注册阶段共价剂；1款临床3期别构剂。 多款临床3期候选疗法有望改写数个靶点治疗现状，包括2款KRAS抑制剂、1款TYK2抑制剂、4款雌激素/雄激素受体降解剂、1款针对癌症相关蛋白Ikaros/Aiolos的Cereblon E3连接酶调节剂（CELMoD，分子胶类）。 多样化的技术也正在解决更多靶点的成药性。比如，迈入1期临床的有，阿斯利康针对知名癌症相关靶点p53的T细胞受体（TCR）-T细胞疗法，百时美施贵宝基于CELMoD技术开发的Helios降解疗法，以及针对WRN、SHP2等靶点的在研疗法。 整体而言，这些疗法的治疗方向高度集中在癌症领域，其次为自身免疫性疾病、中枢神经系统（CNS）疾病、罕见病。 ▲大型药企针对难以成药靶点或采用相关机制开发、已处于临床后期的候选疗法；所有临床期管线列表请扫描文中二维码申请获取 早期融资回暖，成药性解决方案多样化 初创生物技术公司是产业创新重要源泉。2024上半年共19家致力于解决难以成药靶点或专注于相关技术的新锐获得共约10.7亿美元的早期投融资，高于去年同期，在二季度明显回暖。 这些新锐所聚焦的疾病领域大多为癌症，所涉及技术多样化，包括基于非自然界氨基酸的共价蛋白疗法、大环类药物、调节蛋白-蛋白相互作用的疗法、蛋白降解剂-抗体偶联药物（DAC）等；其次为开发别构剂治疗CNS疾病。多家新锐基于人工智能/机器学习技术平台进行药物设计与筛选，加速疗法研发。 其中3家开发共价剂/别构剂的新锐获得≥1亿美元的高额融资： Engrail Therapeutics完成1.57亿美元B轮融资，针对严重神经系统疾病开发精准靶向疗法，核心在研疗法ENX-102是精准靶向GABAA的正向别构调节剂，治疗广泛性焦虑障碍，正处于临床2期试验阶段； Alterome Therapeutics完成1.32亿美元B轮融资，通过机器学习平台开发具有突变选择性和异构体选择性的分子，以更有效抑制关键的癌症驱动因子。核心管线包括AKT1 E17K共价选择性抑制剂、KRAS异构选择性抑制剂，前者即将进入临床试验阶段。 Enlaza Therapeutics完成1亿美元A轮融资，开发共价蛋白疗法，以改变癌症和其他严重疾病的治疗。其专有平台“War-Lock”能结合非自然界氨基酸、生成具有高度特异性的治疗性蛋白，与靶点形成共价键。该平台生产的蛋白药物可以携带各种有效载荷，并特异性递送至目标组织。 同时值得关注的是，蛋白设计先驱David Baker教授联合创立的Vilya宣布A轮融资扩展至7100万美元，Vilya基于人工智能平台从头设计大环分子，专注于既往难以成药的治疗靶点。 针对难以成药靶点，2024下半年有望获批的疗法 劲方医药/信达生物：氟泽雷塞（fulzerasib，GFH925，IBI-351） 氟泽雷塞为劲方医药与信达生物合作开发的一款新型KRASG12C不可逆共价抑制剂，氟泽雷塞的上市申请已于2023年11月获得中国国家药监局（NMPA）受理，并被纳入优先审评，用于单药治疗携带KRASG12C突变的晚期NSCLC患者，这些患者既往至少接受过一种系统性治疗。 其上市申请主要基于一项在中国开展的临床2期单臂注册研究结果，在标准治疗失败或不耐受且携带KRASG12C突变的晚期NSCLC中，氟泽雷塞单药治疗的客观缓解率（ORR）为46.6%、疾病控制率（DCR）为90.5%、中位无进展生存期（mPFS）为8.3个月。 益方生物/正大天晴：格舒瑞昔（garsorasib，D-1553） 格舒瑞昔是益方生物与正大天晴合作研发的一款新型、高效的KRASG12C共价不可逆抑制剂。2023年12月，该疗法上市申请获NMPA受理并被纳入优先审评，适用于既往经一线系统治疗后疾病进展或不可耐受的、并且经检测确认存在KRASG12C突变的局部晚期或转移性NSCLC患者。 发表于Journal of Thoracic Oncology的一项单臂、多中心1/2期临床试验结果显示，格舒瑞昔治疗KRASG12C突变的NSCLC，患者ORR为40.5%，DCR为91.9%，mPFS为8.2个月。 加科思：戈来雷塞（glecirasib，JAB-21822） 戈来雷塞是加科思通过自有的诱导变构新药发现平台设计的KRASG12C不可逆抑制剂。2024年5月，其上市申请获NMPA正式受理并被纳入优先审评，用于治疗二线及以上治疗带有KRASG12C突变的晚期或转移性NSCLC患者。 戈来雷塞的2期注册性临床研究达到主要研究终点，在单药二线治疗NSCLC患者中，确认ORR为47.9%（56/117），36例患者肿瘤缩小超过50%，DCR为86.3%。mPFS为8.2个月，中位总生存期（mOS）为13.6个月。中位缓解持续时间（mDoR）数据还未成熟，6个月和12个月的缓解持续时间比例分别为73.6%和56.6%。 ▲长按扫描二维码或点击文末“阅读原文/Read more”，即可填写问卷，申请获取难以成药靶点研发进展完整报告 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Private funding for biotechnology startups rose during the first three months of the year, suggesting some of the sectors momentum has translated to stepped-up investment in young drugmakers.Twenty-six companies closed private fundraising rounds worth more than $100 million, according to data from HSBC Innovation Banking shared with BioPharma Dive. While venture rounds have grown in size in recent years, $100 million is typically viewed as a significant threshold.Eight of those 26 biotechs were cancer drugmakers, while five were startups developing programs for neurological conditions, said Jon Norris, a managing director with HSBC. Overall, biotechs across the U.S. and Europe raised $6.8 billion in venture capital funding during the first three months of the year, nearly $1 billion more than the most active quarter in 2023.This is a good number for representing strong biopharma activity, Norris said. If you see another big increase, Id be a little worried that wed be trying to return ourselves to the 2021 cycle, he added, referring to a boom year in biotech funding.Venture firms are continuing to seek out surer bets, though. While some seed and Series A rounds are being built around more cutting-edge technology, many more are for tried-and-true management teams working to improve existing platforms, like antibody-drug conjugates or radiopharmaceuticals.Among the most active investors currently are OrbiMed, Arch Venture Partners, GV, RA Capital Management and Cormorant Asset Management, according to William Blair. Several life sciences investment firms have closed new funds in the first quarter of 2024, including TCGX, Scion Life Sciences and Goldman Sachs a sign of industry interest.“Round sizes continue to increase given heightened focus from investors on providing sufficient 'inflection capital,'“ William Blair analysts wrote in a recent report.Eighteen of the 26 private financing rounds identified by HSBC involved companies in preclinical or Phase 1 drug trials. That contrasts with the firms having the most success pricing initial public offerings, which have mostly been biotechs in mid-to-late testing so far this year.There remain a number of very hungry buyers for the right IPO story and promising clinical data, Norris said.The apparent uptick in private funding also stands out in comparison to this time last year, when IPOs dropped off and venture funding became harder to secure. Then, life sciences companies were forced to turn more often to so-called insider rounds, or cash infusions from their existing backers.Now, new investors are returning and often joining through large syndicates. Mirador, a startup birthed by former Prometheus executives, recently pulled in $400 millionfrom 17 venture investors.When markets arent as strong, you want like-minded insiders who are going to have a pragmatic approach, said Brian Matesic, a principal at Norwest Venture Partners. In March, Norwest co-led a $157 million Series B round for psychiatric drug developer Engrail Therapeutics.M&A really started this rebound, Matesic said. Blockbuster deals brokered at the end of last year included AbbVies $8.7 billion acquisition of Cerevel Therapeutics and $10.1 billion buy of ImmunoGen, Roches $7.1 billion purchase of Telavant and Bristol Myers Squibbs $14 billion deal for Karuna Therapeutics. '