LRRK2

Innate announced the decision to not reopen the trial’s recruitment in its full-year earnings report. Image credit: Shutterstock/CI Photos. Innate has dropped plans to evaluate lacutamab as a monotherapy in KIR3DL2-expressing refractory/relapsing peripheral T cell lymphoma (r/r PTCL) following disappointing data from a Phase Ib trial. The French biotech, which has both PTCL and cutaneous T cell lymphoma (CTCL) programmes for its anti-KIR3DL2 antibody, highlighted the “prespecified threshold for meaningful activity not being reached” as the reason for the trial’s (NCT05321147) termination. Innate announced the decision to not reopen the trial’s recruitment in its full-year earnings report released on 21 March. Lacutamab has had a bumpy clinical journey. The US Food and Drug Administration (FDA) placed a partial clinical hold on the drug’s trials in December 2023, following a death from a rare haematologic disorder in one of Innate’s CTCL trials evaluating lacutamab. The hold was lifted a month later after an analysis found that Innate’s compound was not to blame. Whilst it is the end of the road for lacutamab as a monotherapy in PTCL, Innate is still investigating its potential use in the cancer type as a combination with the chemotherapy GEMOX – gemcitabine in combination with oxaliplatin. The Phase II KILT trial (NCT04984837) is being led by the Lymphoma Study Association (LYSA). See Also: AnGes files patent for crispr-based method for modifying mutant lRRK2 gene in cells Cellectis files patent for engineered T-cells for immunotherapy with inhibited B2M expression Innate will also press ahead with its CTCL programme as planned. In December 2023, the biotech reported positive final data for its Phase II TELLOMAK study (NCT03902184) in patients with Sézary syndrome, a type of CTCL. The results included a 37.5% objective response rate in patients treated with a median of five prior lines of therapy. Innate has also reported positive interim data from a Phase I trial investigating the drug in patients with mycosis fungoides (MF), also a type of CTCL. The company expects to present topline results from the study later this year. In the financial results release, Innate’s CEO Hervé Brailly also pointed towards recent successes in its natural killer (NK) cell engager programme. Innate has become somewhat of a specialist in NK cell engagers through its ANKET platform. The biotech has a range of NK-targeting therapies in clinical trials being tested as cancer treatments via a collaboration with Sanofi . The big pharma has licensed four NK cell engagers from Innate through a €400m ($437.5m) initial deal and a €15m ($16.4m) expansion . With a view to Innate’s plans for 2024, Brailly said: “We expect notable milestones including final results from the TELLOMAK Phase II trial with lacutamab in mycosis fungoides, and progressing our first proprietary ADC programme, IPH45 towards an IND filing.”

作者｜糯米丁 一说到帕金森，很多人的第一反应就是：抖！手抖！但帕金森只是单纯的手抖吗？这种常见的老年性疾病，如何诊断？又有什么治疗方案呢？  01  帕金森氏症的简介帕金森氏症（图1）是一种慢性神经系统疾病， 国际帕金森和运动障碍协会（IPMDS）将帕金森氏症定义为：“伴有黑质致密神经变性和突触核蛋白沉积的核心临床运动综合征”。帕金森氏症引起的运动障碍包括：动作迟缓、震颤麻痹、不自主运动、僵硬、行走困难、失衡；非运动障碍症状包括：认知功能受损、痴呆、睡眠障碍、疼痛和感觉障碍。 图1 帕金森氏症 图片源自必应  02  帕金森氏症的诊断帕金森氏症最初的诊断是基于帕金森氏症的运动障碍，而没有生理生化检测指标可以进行替代诊断，最近的研究表明，α-突触核蛋白种子扩增测定可以准确区分帕金森患者与健康对照，或能确定疾病的分期。α-突触核蛋白种子扩增测定可以在疾病早期甚至症状出现之前识别帕金森病患者，通过脊髓穿刺可以检测脊髓液中是否存在α-突触核蛋白团块，α-突触核蛋白是在路易体中发现的一种蛋白质，是帕金森病的微观标志物。目前，这项帕金森病检测目前仅在临床前试验阶段，患者出现依从性较差的现象，未来还希望开发新的生物标志物定义帕金森氏症，或使用血样代替脊髓液进行检测，以在生物学基础上为诊帕金森氏症提供诊断依据。  03  帕金森氏症的遗传学和发病机制IPMDS在帕金森氏症的遗传学研究中提出，携带部分基因突变的个体更有可能患帕金森氏症。目前有7个基因被指定为单基因诱因，其中4个导致晚发常染色体显性遗传疾病（LRRK2、CHCHD2、VPS35和SNCA），3个导致早发常染色体隐性遗传疾病（PARKIN、DJ1和PINK1）。此外，基因GBA突变被定义为是帕金森病最常见的遗传风险因素，外显率高达30%。然而，基因检测不能作为帕金森氏症的诊断标准，但它有助于预测家庭成员的患病风险    近年来，对帕金森氏症发病机制的研究逐渐深入，研究表明NR4A2基因的突变与帕金森氏症的发病相关，NR4A2基因是一种转录因子，发生突变后会导致多巴胺能神经元的功能失调，进而引发帕金森氏症的症状。此外，线粒体DNA的缺失和LRRK2基因的突变也与帕金森氏症的发病机制有关，线粒体是细胞内能量产生的主要场所，其缺失会导致能量供应不足，进而损害多巴胺能神经元的功能。LRRK2基因突变则会导致蛋白质异常积聚，从而引发细胞毒性反应。这些发现都为揭示帕金森氏症的发病机制提供了重要线索。帕金森氏症的流行病学研究显示，地理和族群差异对其发病率有一定影响。白种人中帕金森氏症的患病率明显高于其他族群，且在美国东北部和中西部地区患病率较高。这一现象可能与遗传因素和环境的相互作用有关。此外，一些研究还发现，长期暴露于农药和重金属等环境污染物的人群患帕金森氏症的风险较高。这些流行病学数据为帕金森氏症的预防和控制提供了参考依据。  04  未来帕金森氏症治疗的展望帕金森氏症无法治愈，但可以使用药物、手术和康复治疗手段减轻症状。我国于2020年发布了《中国帕金森氏症治疗指南》（图2），帕金森氏症的治疗药物包括复方左旋多巴、多巴胺受体激动剂、抗胆碱能药和金刚烷胺等。尽管多巴胺替代疗法仍然是帕金森病治疗的金标准，但运动障碍对患者的生活影响预示着未来对新的治疗方法的需要。 图2 帕金森氏症的治疗流程 图片源自《中国帕金森氏症治疗指南》神经调控技术在帕金森氏症的康复应用广泛，非侵入性神经调控技术利用声音、光线、电流或磁场等物理和化学因素，对中枢神经系统和周围神经系统进行刺激，改善疾病症状。其中，重复经颅磁刺激（rTMS）和经颅直流电刺激（tDCS）是最常用的非侵入性神经调控技术。rTMS通过刺激脑部神经元来增强大脑皮层的兴奋性，或通过修复异常的神经可塑性来改善运动症状和非运动症状，如认知障碍、睡眠障碍和抑郁等。研究显示，rTMS可以增加帕金森氏症患者运动平衡训练的效果，并且改善患者的整体认知功能。此外，rTMS联合药物治疗可以显著提高帕金森氏症患者的临床疗效，能够改善运动症状和认知功能障碍。tDCS则是通过在特定脑区施加微弱电流来调节神经元的兴奋性。研究发现，在帕金森氏症患者中，tDCS可以辅助运动、改善平衡和步行能力，并且调节前额叶皮层的兴奋性，从而改善认知功能和步态障碍。此外，tDCS还可以结合计算机辅助认知康复训练，改善帕金森氏症患者的认知功能。近年来，机器人科学在医疗领域的应用也取得不错的成果。在康复医疗领域，机器人可以分为自理支持机器人、护理支持机器人、训练支持机器人和就业机器人四类。其中，训练支持机器人是一种将机器人穿戴后进行辅助或替代训练的技术，训练支持机器人在帕金森氏症的康复治疗中应用最广泛。例如，对HY 3级帕金森氏症患者进行了Gait Trainer GT1训练支持机器人的训练，结果显示相较于常规康复训练方法，机器人训练可以改善帕金森氏症患者的步行速度和平衡能力，但对于步态自动性没有显著差异。对HY 2级以上帕金森氏症患者进行了一个月的训练支持机器人训练，发现相较于常规康复方法，机器人训练对于存在冻结步态的帕金森氏症患者更有优势，这与之前的研究结果相似。另外，有研究报道了机器人训练在帕金森氏症患者上肢功能障碍方面的应用。例如，使用Bi-Mnu-Track机器人进行上肢训练，发现上肢的运动功能和灵活性得到了提高。进行了随机对照试验，对帕金森氏症住院患者进行了外骨骼半自主训练，结果发现机器人训练可以显著提高帕金森氏症患者的上肢灵活性、执行功能和整体生活质量。总的来说，机器人训练系统作为一种新的治疗技术，能够客观、精确地控制训练与运动参数，可以稳定、安全地进行重复训练，并提供实时反馈。 图3 患者使用康复机器人 图片源自bing  05  总结研究机构和医学专家正致力于帕金森氏症的研究和治疗，探索新的治疗方法、寻找更有效的药物、开发创新的康复和支持方案，并提高公众对帕金森氏症的认识和理解。未来的帕金森氏症治疗将继续探索多种治疗方式的综合应用，通过科学技术的不断进步和医疗模式的创新，为患者提供更有效的治疗和康复方案，以更好地应对帕金森氏症的全球挑战。 主要参考文献 Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord. 2007;22(13):1901-1911.Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology. 2009;72(13):1121-1126.Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat. 2010;31(7):763-780.Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. Chung-Hsin Tsai et al. "Mutations in NR4A2 associated with familial Parkinson disease." Nature Genetics 36, no. 3 (2004): 225-227.  Cortes-Canteli M et al. "High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease." Proceedings of the National Academy of Sciences 105, no. 34 (2008): 12961-12966. gSamantha J. West et al. "Kinase Activity of Mutant LRRK2 Mediates Neuronal Toxicity." Science 316, no. 5820 (2007): 439-442.  Thomas Gasser. "Genetics of Parkinson Disease: Paradigm Shifts and Future Prospects." Nature Reviews Neurology 7, no. 6 (2011): 306-318.Allison W. Willis et al. "Geographic And Ethnic Variation In Parkinson Disease: A Population-based Study Of US Medicare Beneficiaries." Archives of Neurology 64, no. 9 (2007): 1240-1245.   2024 BiG十周年   6月13-14日，十年一药，日出东方！BiG十周年  关键词：  源头创新与转化、创新技术平台（PROTAC/分子胶；双抗ADC；小核酸药物；AI+大分子）、临床研究&国际化开发策略（肿瘤/CNS/自免/代谢疾病领域）▼关于BiGBiomedical Innovation Group2014年2月，一个专业机构：BiG生物医药创新社（Biomedical Innovation Group）在充满药味的上海张江应运而生，伴随着中国新药的黄金十载，BiG以“开放、民主、平等“的精神为宗旨，旨在为中国生物医药行业的发展创造一个滋养原创的生态环境。共建Biomedical创新生态圈！如何加入BiG会员？

- Awards Dr. Berkowitz an Inducement Grant in accordance with Nasdaq Listing Rule 5635(c)(4) -NEW HAVEN, Conn., March 18, 2024 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, today announced the appointment of Noah Berkowitz, M.D., Ph.D., to the role of Chief Medical Officer and a member of the Executive Committee reporting to President and Chief Executive Officer John Houston, Ph.D. Effective today, Dr. Berkowitz will lead the ongoing clinical development of Arvinas’ PROTAC® protein degrader programs in oncology and neuroscience. “We are thrilled to have Dr. Berkowitz join Arvinas as we continue advancing multiple programs with the goal of improving the lives of patients with serious diseases,” said John Houston, Ph.D., Chairperson, President and Chief Executive Officer at Arvinas. “Noah’s vision, expertise, and proven track record in designing and launching successful clinical programs across all stages of clinical development complement our rapidly advancing portfolio of novel PROTAC protein degraders. His leadership and experience will be invaluable as we approach our first Phase 3 data readout and continue progressing multiple ongoing and planned clinical-stage programs.” Dr. Berkowitz has more than 20 years of experience in advancing programs through early and late stages of development, with proven ability in leading clinical development, regulatory, and medical affairs. He has led multidisciplinary teams and has extensive knowledge of clinical trial design and execution. Dr. Berkowitz joins Arvinas from Bristol-Myers Squibb (BMS), where he was Senior Vice President, Development Unit Head, Hematology. While at BMS, Dr. Berkowitz’s teams achieved initial or subsequent global indications for Abecma®, Breyanzi®, Reblozyl®, Onureg®, and Inrebic®, managed development life cycles for Revlimid®, Pomalyst®, and Sprycel®, and initiated and/or designed registration trials for iberdomide, mezigdomide, and alnuctamab. Prior to BMS, Dr. Berkowitz held roles of increasing responsibility in the areas of oncology, rare diseases, and hematology at Novartis, most recently as Vice President and Clinical Development Head for Hematology. Dr. Berkowitz earned his M.D. and Ph.D. from Columbia University and trained in medical oncology at the National Cancer Institute. “Arvinas is the leader in targeted protein degradation and is on the cusp of its first pivotal data, an important step in potentially bringing an innovative therapeutic approach to patients with serious diseases,” said Dr. Berkowitz. “Arvinas’ progress over the last several years is impressive and I look forward to working with my colleagues, including the strong leadership team at Arvinas, as we prepare for many important upcoming clinical milestones ahead.” The Company also announced that Ron Peck, M.D., who was Chief Medical Officer since joining Arvinas in mid-2019, will be leaving to pursue other opportunities. “In less than five years, Ron built robust clinical development and medical affairs organizations, enabling the planning and initiation of multiple clinical trials across our oncology and neuroscience portfolios,” continued Dr. Houston. “Under Ron’s leadership and in partnership with Pfizer, vepdegestrant has advanced from the start of Phase 1 to multiple ongoing and planned Phase 3 studies in advanced breast cancer. Ron’s teams also progressed our androgen receptor programs, with ARV-766 moving towards Phase 3 initiation, and initiated human dosing of ARV-102, our neuroscience program targeting LRRK2,” said Dr. Houston. “We thank Ron for his tremendous efforts and take confidence in knowing that Dr. Berkowitz is inheriting a high-performing organization.” In connection with the commencement of Dr. Berkowitz’s employment, Arvinas granted Dr. Berkowitz an option to purchase 93,879 shares of common stock and a restricted stock unit award with respect to 63,452 shares of common stock on March 18, 2024, as an inducement material to entering into employment with Arvinas. The option and restricted stock units were granted in accordance with Nasdaq Listing Rule 5635(c)(4) and not pursuant to Arvinas’ stock incentive plan. The option has a 10-year term and an exercise price of $42.60 per share, which is equal to the closing price per share of Arvinas’ common stock on the grant date. The option vests over four years, with 25% of the original number of shares underlying the option vesting on the one-year anniversary of the date of grant and 1/48th of the original number of shares vesting monthly thereafter, and the restricted stock unit award vests in four equal installments on each one-year anniversary of Dr. Berkowitz’s employment start date until the fourth anniversary of Dr. Berkowitz’s start date, subject to his continued service with Arvinas through the applicable vesting dates.  About ArvinasArvinas is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases through the discovery, development, and commercialization of therapies that degrade disease-causing proteins. Arvinas uses its proprietary PROTAC® Discovery Engine platform to engineer proteolysis targeting chimeras, or PROTAC® targeted protein degraders, that are designed to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. In addition to its robust preclinical pipeline of PROTAC protein degraders against validated and “undruggable” targets, the company has four investigational clinical-stage programs: vepdegestrant (ARV-471) for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-766 and bavdegalutamide for the treatment of men with metastatic castration-resistant prostate cancer; and ARV-102 for the treatment of patients with neurodegenerative disorders. For more information, visit www.arvinas.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements with respect to Arvinas’ development plans; the anticipated data readout for Arvinas’ first Phase 3 clinical trial with vepdegestrant (ARV-471); the potential, pending regulatory approval, for vepdegestrant to address an area of significant unmet need and offer patients an innovative therapeutic approach; and the potential advantages and therapeutic benefits of vepdegestrant (ARV-471). All statements, other than statements of historical facts, contained in this press release, including statements regarding Arvinas’ strategy, future operations, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Arvinas may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on such forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Arvinas makes as a result of various risks and uncertainties, including but not limited to: Arvinas’ and Pfizer, Inc.’s (“Pfizer”) performance of the respective obligations with respect to Arvinas’ collaboration with Pfizer; whether Arvinas and Pfizer will be able to successfully conduct and complete clinical development for vepdegestrant (ARV-471); whether Arvinas will be able to successfully conduct and complete development for its other product candidates, including ARV-766, and including whether Arvinas initiates and completes clinical trials for its product candidates and receive results from its clinical trials on its expected timelines or at all; whether Arvinas and Pfizer, as appropriate, will be able to obtain marketing approval for and commercialize vepdegestrant (ARV-471), ARV-766 and other product candidates on current timelines or at all; Arvinas’ ability to protect its intellectual property portfolio; whether Arvinas’ cash and cash equivalent resources will be sufficient to fund its foreseeable and unforeseeable operating expenses and capital expenditure requirements; and other important factors discussed in the “Risk Factors” section of Arvinas’ Annual Report on Form 10-K for the year ended December 31, 2023 and subsequent other reports on file with the U.S. Securities and Exchange Commission. The forward-looking statements contained in this press release reflect Arvinas’ current views with respect to future events, and Arvinas assumes no obligation to update any forward-looking statements, except as required by applicable law. These forward-looking statements should not be relied upon as representing Arvinas’ views as of any date subsequent to the date of this release. Contacts Investors:Jeff Boyle+1 (347) 247-5089Jeff.Boyle@arvinas.com Media:Maurissa Messier+1 (908) 208-9254Maurissa.messier-c@arvinas.com