Quark Pharmaceuticals, Inc.

//  索元生物历经7年，用其全基因组平台找到其在研产品DB104的生物标志物DGM4，且已证明了药物疗效。DB104的治疗群体是难治性抑郁症，其生物标志物DGM4在20%的难治性抑郁症患者中呈阳性。近期索元已经开启对外授权合作的步伐。在5月的2024年DJS创新合作峰会上，索元生物将现场路演。撰文 | 殷丹妮索元生物董事长罗文博士告诉研发客，公司正在和多家国际大药厂接洽合作事宜。这主要得益于DB104治疗难治性抑郁症（TRD）的关键性临床试验积极结果的公布。从2012年成立至今12年，索元终于在首个产品上证明了其精准医疗“基因组学+新药”的研发理念。综观索元的模式，乃是引入临床“失败”新药，利用大数据组学打造的全基因组平台发现生物标志物（biomarker），通过新发现的biomarker筛选患者并重新开展临床试验，验证药物疗效。DB104在2b期临床中证明了对TRD的疗效，也证明了索元模式“biomarker+新药”的可行性。索元生物董事长 罗文罗文认为，如果DB104能成功上市，将是CNS领域第一个精准医疗的突破，类似于当年易瑞沙找到EGFR突变对于肺癌的意义。同时他表示，随着DB104的成功，将有计划重启IPO之路。2017年，索元生物从BMS收购DB104时，研发客就采访过罗文（拓展阅读  索元获AMRI/BMS抗抑郁药全球授权，新模式见真章）。7年过后，索元不仅找到DB104的生物标志物DGM4，且已证明了药物疗效。索元生物首席财务官陈纪正女士将在2024DJS代表公司路演。欢迎参与投票“谁是您最喜爱的路演公司”，投票时间从即日起至5月15日16:00，活动详情见本期次条。或将申请有条件上市研发客：请您介绍一下DB104治疗难治性抑郁症的具体研究情况、疗效如何？罗文：这项关键性国际多中心临床研究ENLIGHTEN，共纳入197例患者，治疗6周后，在基因生物标志物DGM4阳性TRD患者中达到主要临床终点和所有次要终点。其中在主要终点蒙哥马利-阿斯伯格抑郁量表（MADRS）总分相对于基线的变化方面，DB104用药组量表打分相比安慰剂组要低4.4分（p值0.0056）, 将近40%的改善。单从MADRS评分看，DB104疗效与已获批治疗TRD的Spravato疗效相当。Spravato在56mg或84mg剂量的MADRS总分未超过4分。并且DB104在安全性和使用便利性层面也具备优势。Spravato为鼻喷制剂，DB104是每天口服一次的片剂。DB104在2017年被收购前，BMS已开展了11项1期、3项2b期大型临床试验，在上千例患者中验证了产品的安全性和耐受性。而Spravato改良于麻醉剂氯胺酮，上市后因安全性问题和滥用风险被FDA加以黑框警告，只能在医生监督下使用，给药两小时内须由专业人员陪护，一定程度上限制了其临床应用。研发客：DB104将来上市将有多大的市场空间？销售峰值将达多少？罗文：DB104的治疗群体是难治性抑郁症。根据人民日报发布《2022年国民抑郁症蓝皮书》，中国患抑郁症人数超过9500万，其中难治性抑郁症患者占这近1亿例中的约三分之一。且DB104的生物标志物DGM4在20%的TRD患者中呈阳性。20%的比例在生物标志物中已属于较高比例，一些肿瘤突变基因NTRK1、ROS1、RET等只有1%~2%比例，但不妨碍各大药厂投入重金研发。从竞争对手看，Spravato于2019年在美国上市后销量持续上涨，2024年第一季度销售额达2.25亿美金，同比增长72%，成为年销售额超过十亿美金的“重磅炸弹”应该没有悬念。DB104从药物依从性、安全性各方面相较Spravato都有优势。我们预测DB104上市后全球的峰值销售可能会接近20亿美金。研发客：索元生物对DB104进一步的规划是什么？罗文：产品的注册申请程序正在按部就班的进行中。DB104在2b期临床试验获得积极数据，我认为有可能尝试将其作为关键性临床（pivotal trial）结果向药监部门申请有条件上市的批准。此外，我们也正在和一些国际大厂沟通合作事宜。近年国内药企授权出海浪潮正热，一些创新药甚至在临床前就被授权。而且大药厂有强势回归CNS趋势，仅2023年底就有两笔大额收购交易，即BMS以140亿美金收购Karuna、艾伯维87亿美金收购Cerevel。类似于DB104的first-in-class新药，也高度符合MNC的需求，尤其是DB104已获得2b期积极结果。从索元公司本身看，自2012成立至今一直坚持精准医疗，需要有一个突破口证明我们的研发策略是正确的。如今DB104获得重大突破，索元短期将集中所有资源用于这款产品开发。容易检测到的biomarker研发客：可否请您以DB104为例，解释一下索元筛选biomarker的过程？罗文：我们收集了BMS针对DB104开展的两项2b期临床试验，在试验受试者的全血样本中提取DNA，对其中上百例样本进行了全基因组扫描，从上百万个位点中通过大数据分析、人工智能等多种计算工具，历经两年时间，最终发现了一个全新的生物标志物并将其命名为Denovo Genomic Marker4（DGM4）。同时，为验证DGM4是预测疗效的药物基因组生物标志物，而非疾病预后生物标志物。我们在对照组受试者中开展相同的生物标志物分析，结果表明，DGM4是可以预测疗效的生物标志物。索元的生物标志物发现平台研发客：索元生物标志物发现平台的特点和难点是什么？罗文：biomarker的寻找已历经3代，第一代的典型是易瑞沙，药物靶点就是biomarker；第二代的代表是结肠癌治疗药物Erbitux，靶点是EGFR，biomarker则是KRAS。KRAS在EGFR信号传导通路的下游，寻找起来相对复杂。一代和二代生物标志物都是从已有的科学文献推测，属于知识导向。索元模式是第三代，不再局限于已知的生物信息传导通路，而是以数据导向的反向式检索，在全人类基因组中扫描。这也应对了索元生物的英文名称Denovo，完全从头发现，是从0到1的过程。这是索元模式的核心也是难点。人类基因组共有30亿个碱基对，从30亿位点中找出一两个跟药效相关的biomarker，无异于大海捞针。所以，尽管前期我们收购药物时进行了精挑细选，也不能保证每个项目都能找到biomarker。例如DB103，自收购至今6年多时间仍未找到其生物标志物，但我们仍未放弃。索元管线的8款产品（见下图）中，有DB102、DB104和DB107发现了biomarker，分别是DGM1、DGM4和DGM7。而一旦找到了biomarker，其应用就非常容易，普及率很高。以肿瘤生物标志物来做对比。通常抗肿瘤药的伴随诊断所针对的肿瘤突变基因，必须从肿瘤组织提取进行活检。而索元的biomarker是由SNP（单核苷酸多态性）组成的生物标志物，胚系SNP来自父母遗传，存在于全身各个细胞中，因此通过血液、甚至唾液就能检测，不需要获取病灶组织的样本。这种核酸检测简易快捷，方便临床患者，可以做到无创检测。总结起来，找biomarker特别困难，但检测非常容易，这也是索元模式的一大特色。我们在DB104临床入组预筛时就使用过该方法，效率非常高。上市之路可能重启研发客：索元生物的研发理念需要哪些核心技术的融合？罗文：索元生物的研发模式，是一项跨学科的系统工程，将大数据基因组学应用于创新药研发，汇集了大数据、基因组学、分子生物学、临床各类学科人才。而我本身的职业生涯也跨越了多个领域。本科是临床医学，研究生是分子生物学。工作后在蛋白激酶研发前沿公司Sugen（后被辉瑞收购），及Ligand Pharmaceutical从事新药研发。在人类基因组完成的2000年，加入当时最大的基因组学公司Incyte Genomics，对于基因组大数据的价值有切身感受。跨学科的职业经历，也让我认定要将基因组学应用于创新药的研发。研发客：索元生物在关注哪些前沿技术，开展哪些技术合作？罗文：索元生物本身就是商业模式及技术平台超前的研发驱动公司，自然对各类创新技术充满兴趣，也正在和全球最前沿的公司和科研院所合作，不断提升自身研发水平。如，与Nurosene合作，利用AI技术NetraPlacebo帮助解决CNS临床试验中的安慰剂效应，提升试验成功率。索元生物还与哈佛大学、清华大学的脑电波专家合作过。目前CNS临床终点大多是量表打分，例如抑郁症的汉密尔顿抑郁量表、蒙哥马利抑郁量表，而量表打分具有主观性，脑电波是客观的定量指标。不过这些都属于探索性实践合作，真正用于临床还需要获得监管部门的认可，在此之前的临床终点还是必须依据现有国际金标准。研发客：2021年撤回科创板IPO申请后，索元还考虑上市吗？罗文：2021年中国药品市场热点是biosimilar和me-too药物，科创板、港股上市的大部分是这类药企。索元模式至今在全球范围内都没有同类企业，当时更是没有。公司独特的商业模式没有得到验证，这都是挑战。而如今DB104临床成功，核心技术DGM生物标志物发现平台得到验证，我认为公司的上市之路已被打开。同时，DB104对外授权合作也在同步展开，产生的超额收益使公司能够提前进入投资丰收期。而且药监部门一直在支持精准医疗开发。2021年底CDE发布了《生物标志物在抗肿瘤药物临床研发中应用的技术指导原则》，而后在ADC、PD-1/L1、基因治疗等各类指南中都提及生物标志物的重要性。编辑 | 姚嘉yao.jia@PharmaDJ.com  总第2097期访问研发客网站可浏览更多文章www.PharmaDJ.com

CAMBRIDGE, Mass., Jan. 23, 2024 (GLOBE NEWSWIRE) -- Alkeus Pharmaceuticals, Inc. today announced that Seemi Khan, M.D., M.P.H., M.B.A., has joined the Company as Chief Medical Officer. “We are thrilled to welcome Dr. Khan to the Alkeus executive team as we pursue our mission to innovate transformative therapies for degenerative eye diseases,” said Leonide Saad, Ph.D., President and CEO at Alkeus. “An accomplished executive, Dr. Khan has a track record in bringing rare disease treatments to patients in need across multiple therapeutic areas.” Prior to joining Alkeus, Dr. Khan served as Chief Medical Officer at Reata Pharmaceuticals through its acquisition by Biogen, where she oversaw all clinical programs from early stage to commercialization. Dr. Khan was instrumental in the approval and launch of the first treatment for Friedreich’s ataxia. Dr. Khan’s experience also includes senior leadership roles at Mitsubishi Tanabe Pharma America, Quark Pharmaceuticals, Abbott and AbbVie. An internist and nephrologist with expertise in rare disease, immunology and rheumatology, she has served as an Assistant Professor of Medicine at Tufts University School of Medicine. She further has received an M.P.H. from Harvard T.H. Chan School of Public Health and an M.B.A. from Brandeis University. "I am excited to join Alkeus, particularly at a time when gildeuretinol has shown promising advancement toward the treatment of Stargardt disease,” Dr. Khan said. “I’m eager to continue building the team to bring significant impact on the lives of individuals confronted with progressive vision loss. My commitment to medical innovation and patient care aligns seamlessly with Alkeus' mission, and I look forward to driving forward this life-changing treatment." About Alkeus Pharmaceuticals Alkeus Pharmaceuticals is a biopharmaceutical company with headquarters in Cambridge, Mass. Co-founded by Leonide Saad, Ph.D. and Ilyas Washington, Ph.D., Alkeus is focused on developing therapies for serious diseases of the eye with high unmet need. Alkeus’ lead candidate, gildeuretinol (ALK-001), is currently being evaluated in clinical trials for the treatment of Stargardt disease and for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). About Gildeuretinol (ALK-001) Gildeuretinol acetate (ALK-001) is a novel molecule created as a specialized form of deuterated vitamin A designed to reduce the dimerization of vitamin A without disrupting vision. In preclinical studies, gildeuretinol decreased vitamin A dimerization to the normal rate seen in unaffected individuals and prevented retinal degeneration and blindness in animals with Stargardt disease. In addition to the TEASE trials, a Phase 3 study of gildeuretinol in 200 patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) has recently been completed and is expected to read out topline data in 2024. Gildeuretinol has received breakthrough therapy designation and orphan drug designation by the U.S. Food and Drug Administration. For further information, please contact: David Setboun, Chief Operating Officer Email: media01@alkeuspharma.com Website:

Dr. Last brings more than three decades worth of experience leading a variety of life sciences organizations HOUSTON, Texas — November 28, 2023 — CellChorus Inc., the leader in applying artificial intelligence to visually evaluate how cells perform and interact over time, announced the appointment of Andrew Last, PhD, to its board of directors. Dr. Last brings more than three decades of experience leading global life sciences businesses to advise the CellChorus team as it grows the TIMING™ franchise. He currently serves as Executive Vice President and Chief Operating Officer of Bio-Rad Laboratories (NYSE: BIO and BIOb), a global leader of life science research and clinical diagnostic products with nearly $3 billion in revenue. Dr. Last previously served as Chief Commercial Officer at Berkeley Lights. Prior to that he was Chief Operating Officer at both Intrexon Corporation and Affymetrix. Dr. Last has also held senior positions with Becton, Dickinson and Company; Applied Biosystems; Incyte Genomics; and Monsanto Company. He holds a PhD with Agrochemical Specialization and an MS in Bio-Aeronautics from Cranfield University, UK, as well as a BS from the University of Leicester, UK. “Andy has had a front seat at some of the most exciting scientific and commercial advances in life sciences over the past several decades,” said Daniel Meyer, CEO of CellChorus. “We are thrilled to have his guidance as CellChorus advances the next frontier of single-cell analysis to provide scientists with a comprehensive understanding of how their cells interact and perform.” About CellChorus CellChorus® is the leader in applying artificial intelligence (AI) to visually evaluate how thousands of individual immune cells, such as T cells and NK cells, perform over time. The company applies Time lapse Imaging Microscopy in Nanowell Grids (TIMING™) with neural network-based AI to identify cells and evaluate their activity, including how they move, activate, kill and survive. The patent-protected CellChorus platform can link TIMING data and insights with information from other analysis modalities such as single-cell RNA sequencing and flow cytometry to provide a comprehensive understanding of cellular function, state and phenotype for the life sciences industry. Please visit cellchorus.com for more information. Company Contact: Daniel Meyer Chief Executive Officer CellChorus Inc. TIMING@cellchorus.com