Resmetirom

2024年3月15日，Madrigal Pharmaceuticals开发的first-in-class药物瑞司美替罗(resmetirom) 获得FDA批准，用于治疗伴有肝纤维化的非酒精性脂肪性肝炎（NASH，现称为代谢功能障碍相关脂肪性肝炎“MASH”）患者。瑞司美替罗的获批不仅打破了40年来NASH领域的空白，更标志着THR-β 激动剂这一类全新作用机制的药物迎来商业化的曙光。  一款新药的商业化成功取决于该款药物能否在专利保护期内兑现市场空间。那么瑞司美替罗的专利布局情况如何呢？让我们使用Pharma ONE数据库一探究竟吧。  笔者使用瑞司美替罗作为药物的关键词在Pharma ONE全球药物专利页面检索到25组专利同族，其中最早的专利是由罗氏于2006年申请的，后由罗氏转让至Madrigal Pharmaceuticals（下文简称为“Madrigal”）。瑞司美替罗从研发到上市历经近20年的漫长岁月，属于少有的核心化合物专利到期较早的药物，其化合物专利将于2026年到期，距其上市仅有两年时间，可能引发仿制药的快速跟进。 图1 瑞司美替罗的相关专利 来源：Pharma ONE智能药物大数据分析平台 Madrigal通过外围专利策略，比如：晶型、制剂、用途等专利，将相关保护期至2033年以后，构筑了严密的专利城墙，一定程度上缓解了核心化合物专利过早到期的压力。 图2 瑞司美替罗的原研专利 来源：Pharma ONE智能药物大数据分析平台 尽管如此，瑞司美替罗仍然吸引了一部分国内企业的关注，他们对其分子结构改造或修饰以突破原研专利。笔者在Pharma ONE专利页面检索到，THR-β激动剂的相关化合物PCT专利在国内处于活跃法律状态的有39组同族。 图3 THR-β 激动剂的化合物专利格局 来源：Pharma ONE智能药物大数据分析平台 瑞司美替罗是由内源性活性物质T3（三碘甲腺原氨酸）改造而来。T3是甲状腺激素中活性程度较高的一种。T3对胆固醇和甘油三醇的有益代谢作用主要是通过甲状腺激素受体 (THR) 介导。THR 分为 α 和 β 两种亚型，目前认为，甲状腺激素对心脏和骨骼的不利作用主要与THR-α 有关，而对代谢的有益作用则由THR-β 所介导。THR-α和THR-β 配体结合域只有一个氨基酸不同：Asn331 (THR-β) / Ser227 (THR-α)，而Asn331能与T3的酸性部分形成氢键。 回顾瑞司美替罗的设计思路，研究人员用哒嗪酮替代T3衍生物的苯酚，以消除苯酚在代谢上产生诱变硝化衍生物的安全隐患，并且在对侧链上的羧酸进行构效分析后发现氰基氮杂嘧啶具有最高的选择性和活性。此外，瑞司美替罗的氰基氮杂嘧啶与Arg320有直接相互作用，相比与T3的羧酸需要通过水桥介导与Arg320的互作，具有更小的脱溶剂化损失。 图4  T3和瑞司美替罗在分子结构、以及与THR-β 结合位点的对比 来源：J Med Chem. 国内药企推出的THR-β 激动剂一部分追随瑞司美替罗的路线，在保留母核不变的基础上，海创使用了氘代策略、泽璟制药使用前药策略，明德新药在哒嗪酮上继续环化。而歌礼制药则是追随Viking公司的步伐，在T3类似物上做成磷酸酯前药。 图5  部分国内企业的THR-β 激动剂 通过对THR-β 激动剂的专利格局分析，我们观察到国内药企对fast-follow策略的娴熟应用。然而随着竞争的加剧，fast-follow跟随节点已前移至早期临床甚至临床前阶段，该策略的风险也逐渐提升。而一款全面、准确的专利数据库能够帮助企业快速获取行业动态，分析竞争对手的专利布局，从而制定出更为科学和前瞻性的研发策略。Pharma ONE全球药物页面收录了近1200万同族专利，涵盖了药物、适应症、作用机制等多维度标签，帮助用户全面掌握和跟踪药物的全球专利格局。 END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

VANCOUVER, Washington, June 27, 2024 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTCQB: CYDY) ("CytoDyn" or the "Company"), a biotechnology company developing leronlimab, a CCR5 antagonist with the potential for multiple therapeutic indications, announced today that its preclinical MASH study with SMC Laboratories, Inc. (“SMC”) has commenced, with results expected in the fall of 2024. CytoDyn believes its prior MASH study demonstrated a statistically significant benefit of leronlimab at a dosing level of 350 mg. To clarify the optimal dosing and evaluate the potential for combination therapy, SMC will be conducting a twelve-week preclinical mouse study evaluating both 350 and 700 mg dose levels, alone and in combination with Resmetirom, a drug recently approved by the FDA. The study will evaluate leronlimab’s potential role in preventing and/or reversing liver fibrosis. CytoDyn’s CEO, Dr. Jacob Lalezari, stated, “in addition to clarifying dosing and efficacy, the goal of this study is to eventually use the results to pursue partnerships in the MASH space. Although CytoDyn will be primarily focused on oncology and inflammation in the coming months, we do believe that leronlimab could have a significant role in the treatment of MASH, whether as a standalone therapeutic or in a combination therapy approach.” About CytoDyn CytoDyn is a clinical-stage biotechnology company focused on the development and commercialization of leronlimab, an investigational humanized IgG4 monoclonal antibody (mAb) that is designed to bind to C-C chemokine receptor type 5 (CCR5), a protein on the surface of certain immune system cells that is believed to play a role in numerous disease processes. CytoDyn has studied leronlimab in multiple therapeutic areas, including infectious disease, cancer, and autoimmune conditions. Forward-Looking Statements This press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements may include statements about leronlimab, its ability to provide positive health outcomes, the Company's ability to implement a successful operating strategy for the development of leronlimab and thereby create shareholder value, the ability to obtain regulatory approval of the Company’s drug products for commercial sales, and the strength of the Company’s leadership team. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties, including: (i) the regulatory determinations of leronlimab’s safety and effectiveness to treat the diseases and conditions for which we are studying the product by the U.S. Food and Drug Administration (the “FDA”) and various drug regulatory agencies in other countries; (ii) the Company’s ability to raise additional capital to fund its operations; (iii) the Company’s ability to meet its debt and other payment obligations; (iv) the Company’s ability to recruit and retain key employees; (v) the Company’s ability to enter into partnership or licensing arrangements with third parties; (vi) the timely and sufficient development, through internal resources or third-party consultants, of analyses of the data generated from the Company’s clinical trials required by the FDA or other regulatory agencies in connection with applications for approval of the Company’s drug product; (vii) the Company’s ability to achieve approval of a marketable product; (viii) the design, implementation and conduct of the Company’s clinical trials; (ix) the results of any such clinical trials, including the possibility of unfavorable clinical trial results; (x) the market for, and marketability of, any product that is approved; (xi) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company’s products; (xii) regulatory initiatives, compliance with governmental regulations and the regulatory approval process; (xiii) legal proceedings, investigations or inquiries affecting the Company or its products; (xiv) general economic and business conditions; (xv) changes in foreign, political, and social conditions; (xvi) stockholder actions or proposals with regard to the Company, its management, or its board of directors; and (xvii) various other matters, many of which are beyond the Company’s control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and risk factors or cautionary statements included in subsequent Form 10-Qs and Form 8-Ks, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release. CONTACT Investor Relations CytoDyn Inc. ir@cytodyn.com