Kv1.1

LONDON--(BUSINESS WIRE)-- EpilepsyGTx, a biotechnology company focused on research and development of cutting-edge gene therapies to treat focal refractory epilepsy, today announced it has raised a total of $10 million in seed funding. The financing was led by the UCL Technology Fund, with participation from Health Technology Holding. The funds raised will be used to complete the preclinical studies for EpilepsyGTx’ lead gene therapy program EPY201, and to prepare a groundbreaking first-in-human, Phase 1/2a clinical study with EPY201 in focal refractory epilepsy. "This funding is a clear vote of confidence from our investors in our vision, the world-class science of the UCL Queen Square Institute of Neurology, and the transformative potential of EPY201 in focal refractory epilepsy. Our mission is to make patients with focal refractory epilepsy seizure-free," said Nicolas Koebel, chief executive officer. Simon Goldman, Partner at AlbionVC, manager of the UCL Technology Fund and EpilepsyGTx Board member, added, “EpilepsyGTx has an objectively world-leading pipeline of genetic therapies for a common and damaging neurological disorder with few treatment options, developed by a globally-renowned clinical, scientific and translational team at the UCL Queen Square Institute of Neurology. We are enormously pleased to have Nicolas Koebel on board as CEO, with a track record of building exceptional global biotech companies from inception to commercial launch. We are excited that this industry-leading team now has the opportunity to translate medicines that have the potential to change the lives of patients with epilepsy and other CNS disorders.” EpilepsyGTx is a spinout company set up with the support of UCL’s commercialisation company UCL Business Ltd (UCLB). Caitriona O’Rourke, UCLB’s Business Manager for EpilepsyGTx commented: “We have been delighted to support Nicolas and his team on their commercialisation journey, and it’s terrific to see them reach this major funding milestone. We are excited by the commercial potential of this technology and its possible contribution to improve the lives of people with focal refractory epilepsy.” Michele Gaiotto, Managing Director at Health Technology Holding, stated, “We were highly impressed by the scientific strategy of the company and the credentials of the leadership team. The targeted, highly localized delivery of gene therapy is the right solution to treat focal refractory epilepsy, and is poised to make an enormous difference in the lives of millions of patients.” About EpilepsyGTx At EpilepsyGTx our mission is to make patients with focal refractory epilepsy seizure-free. We are developing a portfolio of cutting-edge gene therapies which are based on pioneering research from the UCL Queen Square Institute of Neurology. For more information, please visit: About focal refractory epilepsy Focal epilepsy describes a group of disorders in which patients experience seizures that arise from a specific part of the brain. If seizures persist despite trials of at least two tolerated and appropriately chosen antiseizure medicines, epilepsy is deemed refractory. Focal refractory epilepsy (or FRE) affects an estimated 2 million prevalent patients in the United States, the United Kingdom and the European Union, combined. About EPY201 EPY201 is an investigational gene therapy targeting focal refractory epilepsy. EPY201 or AAV9-CAMK2A-EKC uses an AAV9 capsid, an engineered Kv1.1 potassium channel (or “EKC”) and a CAMK2A promoter. EPY201 is delivered directly to the target seizure focus (that is, the part of the brain causing seizures) by intraparenchymal administration. About UCL Technology Fund The UCL Technology Fund exists to help solve the world’s most pressing problems: healthy planet, healthy people and healthy work. It helps UCL innovators across the Physical and Life Sciences scale globally. The Fund supports UCL in achieving the full potential of innovations that have prospects for outstanding societal and market impact, right through the development journey from initial proof of concept to practical commercial application. The Fund is managed by AlbionVC in collaboration with UCL Business. For further information please visit: View source version on businesswire.com: Contacts For enquiries, please contact: communications@epilepsygtx.com Phone: +44 7717 801 246 Source: EpilepsyGTx View this news release online at:

Relay Therapeutics最近的日子可能不太好过，美股市场最新股价11块，市值13亿美金左右，较巅峰期市值缩水了4分之3。截至2023年第一季度末, Relay Therapeutics持有9.378亿美元的现金、现金等价物，低于2022年底的10亿美元。该公司预计这些资金将支持到2025年的运营。 今年4月份，Relay Therapeutics公布了RLY2608的早期临床数据，股价随即大跌40%，RLY-2608是一种异构体选择性PI3K抑制剂，此类药物在安全性和有效性方面都存在挑战，FDA也曾给予黑框警告。RLY2608的一期试验中仅观察到一个患者的部分反应，且RLY-2608的最佳剂量也未确定，这给药物的安全性和有效性带来了不确定性。虽然到目前为止还没有剂量限制性毒性（DLT）的报告，由于仍处于临床试验的早期阶段，随着研究的继续，可能会出现意想不到的不良反应。 Relay公司还有另外两个有前景的资产。首先是RLY-4008（见图2），小分子抑制剂，可靶向晚期或转移性FGFR2改变的实体瘤患者的FGFR2。其首次人体试验的初步数据显示，对FGFR2具有明显的抑制作用，而不受脱靶毒性的限制（如高磷酸血症）。在2022年与FDA讨论后，Relay选择继续进行FGFR2融合CCA treatment-naïve患者的单臂试验设计，以加快审批速度。RLY-4008已获得FDA和EMA的CCA孤儿药指定。 在新药情报库中搜集到2023年5月26号的信息显示，二期推荐剂量为70 mg QD；在分组FGFRi-naïve CCA f/r中，ORR高达55%；在分组Prior-FGFRi CCA f/r中，ORR只有14%；说明接受过FGFRi治疗的患者中，ORR下降比较明显，在不同剂量下，最常见的TRAEs是低级别PPE(57%)、口炎(56%)、口干(38%)、脱发(28%)和眼干(22%)。 其次，GDC-1971(以前的RLY-1971)是Relay的另一个主要资产。该药物靶向晚期或转移性实体瘤患者的SHP2。Ia期试验于2022年完成入组。Relay与Genentech就GDC-1971的开发和商业化达成了合作。 随着诺华SHP2单药临床因有效性不足而失败，多数公司都在积极开展联用。如上图3，在情报库中搜集到2023年7月公开的一项Ib期研究，旨在评估 GDC-1971与奥西替尼联合治疗不可切除的局部晚期或转移性非小细胞肺癌患者，或与西妥昔单抗联合治疗转移性结直肠癌患者的安全性、药代动力学和活性。该临床招募了172名患者，预计2026年12月底结束试验。主要终点为：不良事件参与者的百分比和有剂量限制性毒性的患者人数。 Relay的上述三款抑制剂都出自D. E. Shaw（DESRES首席科学家），三款药物的差异化方向很明确，都是针对特定蛋白具体亚型做出高选择性靶向。三款药物分别是FGFR2抑制剂RLY-4008、PI3Kα变构抑制剂RLY-2608、SHP2抑制剂RLY-1971。 另外，D.E.Shaw还开发了针对自身免疫性疾病和炎症性疾病的小分子抑制剂DES-7114。2022年6月13日，D.E.Shaw Research宣布与礼来公司就Kv1.3抑制剂DES-7114的临床开发和商业化签订了一项全球独家许可协议。礼来将支付6000万美元的首付款，潜在开发和商业里程碑付款高达4.75亿美元，以及全球销售的特许权使用费。 Kv1.3阻断剂的开发难点：对多个亚型需要高度选择性 KV1.3电压门控钾离子通道在质膜和线粒体中参与许多生理过程，主要是在免疫和神经系统中。利用特异性肽和小分子抑制剂靶向KV1.3通道的治疗，在癌症和自身免疫性疾病(如多发性硬化症、I型糖尿病、牛皮癣、接触性皮炎、类风湿性关节炎和重症肌无力)方面显示出巨大的潜力。但是，迄今为止，尚无靶向KV1.3的化合物批准上市。一些具有明确SAR关系的小分子抑制剂已被优化为选择性抑制剂递送到线粒体，这些抑制剂为治疗癌症和自身免疫性疾病提供了治疗潜力。 1999年，小分子WIN17317-3、CP-339818被发现可以靶向Kv1.3通道。然而，这类分子缺乏对通道的选择性和特异性，除 Kv1.3通道外对钠离子通道以及 Kv1.4通道也存在阻断作用，从而导致了潜在的副作用。随后有多种小分子被发现，但都不能很好的解决选择性的问题。除了对钠离子通道和Kv1.4会抑制，对Kv1.1和Kv1.2也会产生阻断。 D.E. Shaw教授表示，DES-7114能够以高选择性的方式抑制离子通道蛋白Kv1.3。临床前研究证明了在几种慢性炎症和自身免疫性疾病(包括溃疡性结肠炎、克罗恩病和特应性皮炎)模型中的有效性，并于2022年初在健康志愿者中成功完成了I期临床试验。但是，时隔一年半，暂时未报道DES-7114临床试验的结果。 靶点Kv1.3的研发进展 如下表1，据智慧芽新药情报库统计，截止2023年09月04日，全球共有11个Kv1.3药物，来自17个机构，覆盖19个适应症，开展4个临床试验，其中有两个小分子和两个多肽。进展最快的公司是selectION, Inc.，他们在临床1期、临床前和非在研阶段都有1个药物在研发中。 对适应症进行分析，如图5所示，目前临床在研适应症均为自身免疫方向，分别是银屑病、银屑病关节炎和特应性皮炎。 美国、欧盟和德国是靶点 Kv1.3 药物研发阶段最高的国家/地区。国内公司中，武汉摩尔生物科技有限公司也在该靶点进行了研发，目前处于临床前阶段。 DES-7114的相关专利 如下图6，在智慧芽新药情报数据库中搜索D. E. Shaw Research和Kv1.3，共发现82组申请，11个INPADOC同族申请，集中在2022年申请了2个（申请日在3月和5月份）、2020年申请了5个，2021年申请了1个，以及2023年申请了两个；而DES-7114在2022年1月份开始进入一期临床。并且早在2013年9月，D.E. Shaw公司就公开了一种筛选电压门控蛋白的方法。目前临床分子DES-7114的结构尚未公开，只能从2021年和2020年6个INPADOC同族申请去寻找蛛丝马迹。 这6篇专利分别是：WO2022076285、WO2021071832、WO2021071812、WO2021071802、WO2021071803、WO2021071821。这几篇专利里面结构的合成难度都不大，不过多数化合物具有几个手性。有一些片段和母核还是比较新的，感兴趣的可以关注一下。 但是，这些专利中的化合物多数只公开了对Kv1.3通道抑制的IC50数据和hERG数据，且都只是一个范围，且没有对其他通道（如Kv1.1和Kv1.2）的选择性数据，想要推断具体的结构还是有难度。 总结 Relay Therapeutics是近年来一家颇有名气的以计算化学为特色的药物发现公司，而Relay管线中的三款药物都来自D.E. Shaw。虽然Relay公司目前3个临床化合物中，有两个在临床试验中磕磕绊绊，其以分子动力学为特色的药物发现平台对药物开发还是起到了巨大的推动作用。 而Kv1.3通道阻断剂的结构类型探索中，20多年来，小分子一直很难做到对Kv1.1和Kv1.2的选择性。D.E. Shaw Research公司在离子通道蛋白亚型的差异化靶向方面具有丰富的经验，除了Kv1.3通道蛋白外，TRPA1阳离子通道蛋白相关专利也有多篇公开。 根据智慧芽新药情报库搜集到的情报，目前Kv1.3阻断剂临床主要用于自身免疫疾病的治疗。为了开发更为安全的治疗药物，需重点关注化合物对Kv1X通道亚型(Kv1.1通道和 Kv1.2通道等)的选择性。 参考资料： 1.https://seekingalpha.com/article/4620984-relay-therapeutics-stock-market-may-be-prematurely-dismissing-rly-2608. 2.Špela Gubič et.al, Discovery of KV1.3 ion channel inhibitors:Medicinal chemistry approaches and challenges.Med Res Rev. 2021;41:2423–2473. 3.Antonio Felipe et.al; Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target.Biochemical Pharmacology 165 (2019) 214-220. 4.智慧芽新药情报库/专利数据库.

Researchers have discovered that extracts from plants used by the Kwakwaka'wakw First Nations peoples in their traditional botanical medicine practices are able to rescue the function of ion channel proteins carrying mutations that cause human Episodic Ataxia. A University of California, Irvine-led team of researchers have discovered that extracts from plants used by the Kwakwaka'wakw First Nations peoples in their traditional botanical medicine practices are able to rescue the function of ion channel proteins carrying mutations that cause human Episodic Ataxia. The study, "Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain" was published in June in Nature Communications. "Episodic Ataxia 1 (EA1) is a movement disorder caused by inherited mutations in the human KCNA1 gene, which encodes Kv1.1, a voltage-gated potassium channel essential for normal function of the human nervous system," said Geoffrey W. Abbott, PhD, vice dean of basic science research and professor in the Department of Physiology & Biophysics at the UCI School of Medicine. "We found that extracts of stinging nettle, bladderwrack kelp and Pacific ninebark can all correct function of the mutation- carrying proteins causing a specific form of ataxia." Abbott's research team also found that two compounds contained in these plants, tannic acid and gallic acid, are each able to rescue activity of the EA1-linked mutation-carrying ion channel proteins. "The plant compounds are the first known compounds to rescue the activity of Kv1.1 carrying EA1-linked loss-of-function sequence variants," said Abbott. "Gallic acid in particular is of therapeutic interest because it is already available over the counter as a nutritional supplement and is very well tolerated in toxicity studies." Individuals with ataxia exhibit abnormal gait, slurring, eye movement abnormalities, difficulties with balance and walking, tremors, and disruption of fine motor skills. "These mutations can cause other disorders, including epilepsy, and so there is therapeutic potential for those conditions as well, " said Abbott. "We have discovered that where modern synthetic drug development techniques have failed to produce a drug that directly rescues EA1-linked mutant channel function, traditional botanical medicine developed by North American First Nation peoples has succeeded." Further research is now needed to explore the efficacy of the plant-derived compounds in preclinical and clinical studies. "We have made a mouse model of a relatively severe form of human EA1 so that we can test the efficacy and safety of gallic acid and also whole plant extracts," said Abbott. "If the preclinical studies go well, our goal is to move to clinical trials. Concurrently, we are synthesizing and testing other plant compounds and derivatives to discover other compounds with potential for treating EA1 and related disorders." There are several forms of ataxia, which is an umbrella term describing loss of coordination or balance. Together with Abbott, the research team comprised Drs. Rian Manville, J. Alfredo Freites, Doug Tobias (UC Irvine) and Richard Sidlow (Valley Children's Hospital). This work was supported by the National Institutes of Health and the National Institute of General Medical Sciences.