INSYS Therapeutics, Inc.

一位热心股民，将创新脂质体公司告上法庭。 美国伊利诺伊州北达科他州最高法院于2010年3月31日发布的判决书详细记录了事件始末，甚至成为了因退市而淡出公众视线的NeoPharm, Inc.（下称“NeoPharm”）难能可贵的参考资料。毕竟，这家创新脂质体公司因为技术过于前沿以及生不逢时而鲜少出现在当今关于药物递送技术领域的讨论中。 根据判决书，原告在2001年10月31日至2002年4月19 日期间（以下简称“诉讼期间”）购买了被告NeoPharm普通股的人，原告认为NeoPharm、John N. Kapoor、James M. Hussey和Imran Ahmad（统称“被告”）就NeoPharm的实验药物LEP（脂质体封装紫杉醇）做出虚假和误导性陈述。法院裁定，被告的简易判决动议将部分获得批准，部分被驳回。被告的排除动议将遭到驳回，并允许被告在审判前的动议中对其方法提出任何质疑。 简而言之，股民认为NeoPharm的脂质体技术名不副实，要求公司拿出说法。 自原告购买股票到地方最高法院发布完整判决书的十年，也正是生物医药技术在探索中的十年。走过世纪之交的NeoPharm三度易名，历经重组动荡，最后仅有技术留存，供行业后来者继续研究、完善，为创新药物递送系统领域的发展提供灵感与路径指引。 诞生于脂质体技术高速发展期的新秀，一度被临床结果拖累 NeoPharm成立于1990年，于世纪之交在纳斯达克完成上市。原名为OncoMed Inc.，核心脂质体技术获得乔治城大学授权。公司成立时期正值经济、高效的抗真菌和抗癌药物脂质体产品先后投入市场，极大推动脂质体研究与发展的时期。 脂质纳米材料具有独特的亲水、亲油“两亲性”，使得在同一药物里同时添加亲油亲水药物和活性成分成为了可能。但是，科研人员也发现，脂质纳米材料“两亲性”是一把“双刃剑”，它在为载药提供了便利的同时，也增加了量产的难度。因此，脂质纳米材料制备工艺复杂，导致很难去除杂质，中间体及产品难于纯化，因而很难实现量产。也正因技术瓶颈明显，尽管NeoPharm已经有多种药物处于临床开发的不同阶段，但尚未将任何药物推向市场。 但NeoPharm坚信NeoPharm脂质体抗癌剂的市场潜力和销售前景。1998年6月，NeoPharm的 LEP（脂质体封装紫杉醇）和首款脂质体产品脂质体封装阿霉素双双启动临床试验，以验证除了减少传统抗癌疗法的副作用外，脂质体抗癌剂还可以克服化疗的多重耐药性问题。 然而好景不长。2005年至2007年三年合计，NeoPharm的营业亏损总计约9000万美元，甚至公司一度未提交2008年年终财务报告。为此，NeoPharm在2007年末开始实施重组计划，包括聘用新的管理团队、减少现金消耗并精简组织机构。 2009年NeoPharm从纳斯达克退市，并在场外交易市场上市。公司股票一度飙至每股12美元，但在2009年时仅徘徊在30美分左右。《克莱恩报》（Crain's Chicago Business）指出，自2006年该公司宣布一种被市场认为很有前途的脑癌药物的临床试验结果令人失望以来，其股价一直在稳步下跌。 另一边，新团队拼搏势头正足。2010年1月4日，NeoPharm宣布向FDA提交了一份新药研究申请，用于治疗一种致命的肺部疾病特发性肺纤维化，并声明，提交该申请对 NeoPharm 来说是一个“重要里程碑”。 NeoPharm启动的正是IL13-PE的I期临床研究，将以吸入式气雾化液体的形式注入患者肺部。公司随后在6至8个地区开展研究，招募患者32名旨在评估该药物的安全性和最大耐受剂量，以及其对晚期特发性肺纤维化患者的疗效。同年6月，FDA就授予IL13-PE孤儿药资格，用于治疗特发性肺纤维化。受此鼓舞的NeoPharm立刻启动II期临床。 2010年1月6日，NeoPharm公布了LEP（脂质体包裹紫杉醇）治疗转移性乳腺癌患者的 II 期数据。该项试验以Taxol®（即百事美施贵宝紫杉醇）为主要活性成分，在印度的5个试点进行。 其中，16名受试者（46%）肿瘤反应，包括15名部分反应和1名完全反应；10名受试者（29%）病情稳定（平均持续时间为6个周期；范围为2-10 个周期）；9 名受试者（25%）病情有进展。此外，LEP耐受性良好，仅1名受试者（3%）出现3级感觉性多发性神经病，2名受试者（6%）出现3级中性粒细胞减少症，这也是Taxol®（即百事美施贵宝紫杉醇）和 Abraxane®的两种常见毒性。此外，未观察到不良事件或预防性预用药出现的其他输液反应。  人工合成心磷脂， 专攻肿瘤治疗痛点 Neopharm的核心技术在于制备脂质体时采用了一种人工合成的心磷脂——四豆蔻酰甘油心磷脂。由于心磷脂的独特性质，它可以和它可以和亲脂性药物强烈作用强烈作用，将药物稳定地嵌在脂质体膜中，从而提高了药物及制剂在体内外的稳定性。处方中除了心磷脂外还使用了DOPC（作为脂质体制备当中常用的药用辅料）和胆固醇，药脂比大约1：18，制剂粒径150~200nm，包封率可达95%。 ● 心磷脂 Neopharm基于这一专利技术开发了4个产品：LE-SN38、LE-rafAON（反义核酸）、LEM（米托蒽醌脂质体，mitoxantrone）和LEP（紫杉醇脂质体，paclitaxel）。 ● SN-38脂质体LE-SN38 SN38是依利替康（irinotecan）的活性代谢产物，由于SN-38不能溶于常用的药用溶剂，所以无法直接给药，且作为活性代谢产物的SN-38因稳定性等原因应用一直大受限制，而将SN-38 制成脂质体之后，可以解决上述问题。 ● rafAON脂质体LE-rafAON LE-rafAON包裹的是抗c-raf的反义寡核苷酸。LE-rafAON可以抑制肿瘤产生的Raf-1 蛋白，进而抑制肿瘤生长并提高肿瘤对放疗和化疗的敏感性。 ● 米托蒽醌（mitoxantrone）脂质体LEM 米托蒽醌是细胞周期非特异性药物，其抗肿瘤谱较广，临床适用于急性白血病、淋巴瘤、乳腺癌、前列腺癌等各类适应证，本有着巨大的应用前景。但骨髓抑制等不良反应，限制了其临床应用。Neopharm旗下的包载米托蒽醌脂质体（LEM）由冻干脂质与米托蒽醌盐（商品名为Novantrone）混合制成。该产品旨在提高游离诺凡特罗的安全性和有效性。 LEM于2001年进入临床I期，编号为NCT00024492。该试验招募了晚期实体瘤患者（40名参与者），静脉注射LEM。血液药代动力学和肿瘤观察的结果于2004年完成，起初，公司没有公布结果。后续消息显示，因LEM在体内快速释放，引起偶发性感染，临床从而宣告失败。 ● 紫杉醇（paclitaxel）脂质体LEP LEP公开的制备方法重量比为1.8∶9.0∶3.0 ∶0.1∶1的心磷脂、磷脂酰胆碱、磷脂、维生素E和紫杉醇，加热溶解于叔丁醇中，然后通过0.22μm滤膜，分装并冷冻干燥。临床使用时加入生理盐水，随后水化1小时，其后将小瓶振荡十分钟，最后在水浴超声振荡器中以最大频率超声十分钟。此外，LEP需2-8℃ 保存，且配置后室温避光条件下稳定性达24小时。   尚未开花成果的“遗产”， 被卷入另一场官司 2010年时，尽管手握专利技术平台，并有临床结果尚且的管线在持续推进，但Neopharm的资金状况还是支撑不住了。原因与后来的外泌体先驱Codiak的相似：作为一种背负巨大期待的新型技术，仅仅有良好的安全性结果或是疗效中规中矩，是远远不足以填补市场需求和资本厚望的。正所谓“非正面就是负面”，何况Neopharm确实有明显失利的管线。 没过多久，Neopharm等来了自己的退场方式。 同年10月，专注于疼痛和肿瘤学的药物开发公司Insys Therapeutics（下称Insys）宣布将以反向合并的方式收购 NeoPharm，初始股票价值1.35亿美元。私人控股的 Insys 股东将通过预计于11完成的交易最终获得NeoPharm 95%的股份。此后，Insys将成为NeoPharm的全资子公司，但Insys的高管和董事将在合并完成后接替从NeoPharm辞职的领导团队，因此，合并后的公司保留Insys的名字。 Insys与NeoPharm的联系源于John N. Kapoor，他是制药业资深人士和投资者，于2002 年创立了Insys，同时还是NeoPharm董事会主席，此前关于NeoPharm的判决书上也出现过他的名字。 合并后的公司拥有专注于疼痛和肿瘤学的研发管线。最初，公司将NeoPharm针对转移性乳腺癌的管线LEP-ETU推进到的 III 期试验。与此同时，Insys还将同时致力于芬太尼舌下喷雾剂的NDA提交，芬太尼舌下喷雾剂是Insys的主打产品，已于2010年2月完成了一项III 期随机、双盲、安慰剂对照的多中心研究，作为突破性癌症疼痛的治疗方法。而NeoPharm技术平台的加入将有望升级Insys的舌下喷雾给药技术。 遗憾的是，NeoPharm的脂质体技术并未进一步发扬光大。而则Insys专注销售Subsys（芬太尼舌下喷雾剂）和Syndros（屈大麻酚口服溶液、Dronabinol）等产品。 2019年，Insys因涉嫌贿赂医生给病人开出让人上瘾的止痛剂——芬太尼舌下喷剂，助长阿片类药物泛滥，面临多项刑事与民事指控。经过联邦陪审团15天的审议，美国司法部5月宣布，对该公司处罚高达2.25亿美元（约合人民币15.6亿元）的罚款，前董事长和4名员工还要面临最高20年有期徒刑。这是21世纪以来，全世界第一个因为给医生巨额回扣被抓而破产的中大型药企。该案件一经曝光即备受美国各大媒体关注，频频登上报刊头条。 随后，Insys如预料一样破产，对其诉讼却还在继续。而NeoPharm领先的技术平台因“遇人不淑”，在美国陷入死寂。  十年磨一剑， 大洋彼端率先诞生“全球首个” 而NeoPharm的未竟之业，在太平洋另一端迎来曙光。 2022年1月11日，石药集团宣布其附属公司石药集团中诺药业（石家庄）有限公司开发的盐酸米托蒽醌脂质体注射液（10 ml∶10 mg）已正式获得国家药监局颁发的药品注册批件，用于治疗复发或难治的外周T细胞淋巴瘤（PTCL）。据悉，该产品具有完全知识产权，发明专利已在中国、美国、欧洲、日本等十多个国家和地区获得授权。此外，盐酸米托蒽醌脂质体注射液的研发获得了“国家重点研究计划”“国家重大新药创制专项”等多项国家课题的资助。 需要指出的是，NeoPharm之后，北美尚有团队采用柠檬酸梯度法，但因药物无法释放，导致没有治疗效果；不少国内企业也有尝试，但是最终都无法实现技术突破、达成工业生产。 石药集团于2004年着手进军脂质体技术领域，通过不断进行研发投入，打造了具有自主知识产权的脂质体技术平台。石药集团对米托蒽醌进行优化，重新设计工艺。采用了独特的载药、释药技术，保证了给药后纳米粒子可以有效地在肿瘤富集，并合理地释放药物，进而提高药物在肿瘤的生物利用度，从而产生显著改善的疗效和安全性，也避免了容易出现的皮肤毒性和输液反应。 大浪淘沙后，最终是石药集团率先实现了米托蒽醌脂质体的上市。 如果您想对接文章中提到的项目，或您的项目想被动脉网报道，或者发布融资新闻，请与我们联系；也可加入动脉网行业社群，结交更多志同道合的好友。 近 期 推 荐 声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。 动脉网，未来医疗服务平台

SAN MATEO, Calif., March 25, 2024 (GLOBE NEWSWIRE) -- Sagimet Biosciences Inc. (Sagimet, Nasdaq: SGMT), a clinical-stage biopharmaceutical company developing novel fatty acid synthase (FASN) inhibitors designed to target dysfunctional metabolic and fibrotic pathways, today announced the appointments of two biotechnology industry leaders, Tim Walbert and Paul Hoelscher, to the board of directors of the Company, effective April 1, 2024. “We are fortunate to have Tim and Paul join us at this key stage as we prepare to initiate a pivotal, Phase 3 trial for our lead candidate denifanstat in MASH in the second half of 2024,” said Dave Happel, CEO of Sagimet. “With his experience as CEO of public commercial-stage biotechs and service on numerous biotechnology boards, Tim will bring a wealth of strategic, business development, and commercial experience. I also welcome Paul, whose experience in capital markets as well as accounting and finance will be invaluable for Sagimet’s next steps. I anticipate that Tim and Paul’s industry experience and insights will be of tremendous value to achieving our strategic priorities in 2024 as we advance denifanstat into Phase 3 development.” “I am excited to join Sagimet’s board as the company focuses on moving denifanstat into Phase 3 following the successful completion of its Phase 2b studies,” Mr. Walbert commented. “Sagimet is well-positioned for its next stage of growth, with an experienced team and demonstrated clinical results. I look forward to contributing my experience in strategic leadership to help Sagimet achieve its goal to bring denifanstat, with its differentiated mechanism of action as a fat inhibitor, to an underserved patient population.” Mr. Walbert has nearly 30 years of biotechnology and industry experience. He joins Sagimet’s board following a 15-year tenure as president, chief executive officer, and chairman of the board at Horizon Therapeutics, which he built from inception to a leading rare disease company. In 2023, Amgen acquired Horizon for $28 billion, and Mr. Walbert currently serves as a senior advisor to Amgen. Before joining Horizon, he was president, chief executive officer and director of IDM Pharma Inc., a public biotechnology company, which was acquired by Takeda America Holdings Inc. in June 2009. Before IDM, Mr. Walbert served as executive vice president, commercial operations at NeoPharm Inc., a public biotechnology company. From 2001 to 2005, he was divisional vice president and general manager, immunology, at Abbott, now AbbVie, leading the global development and launch of the multi-indication biologic HUMIRA, and served as divisional vice president, global cardiovascular strategy. From 1998 to 2001, Mr. Walbert served as director, CELEBREX North America, and arthritis team leader, Asia Pacific, Latin America and Canada, at G.D. Searle & Company. From 1991 to 1998, he also held sales and marketing roles with increasing responsibility at G.D. Searle, Merck & Co. Inc. and Wyeth. Mr. Walbert currently serves on the boards of Mirum Pharmaceuticals (NASDAQ: MIRM) and Century Therapeutics (NASDAQ: IPSC). Previously, he served on the board of directors for Aurinia Pharmaceuticals, Exicure, Assertio, Raptor Pharmaceutical Corp., which was acquired by Horizon Therapeutics in 2016, XOMA Corporation, and Sucampo Pharmaceuticals Inc., which was acquired by Mallinckrodt Pharmaceuticals in 2018. “I am delighted to join Sagimet’s board at this exciting time in the company’s evolution,” Mr. Hoelscher said. “The company’s commitment to develop therapeutics for currently underserved MASH patients is compelling, and I look forward to working with the other directors and the leadership team on this effort.” Mr. Hoelscher served as executive vice president and chief financial officer of Horizon Therapeutics from 2014 to 2022, prior to the company’s acquisition by Amgen. Prior to joining Horizon, Mr. Hoelscher held multiple financial executive roles in various consumer products, retail and business services companies, as well as working in the audit practice of KPMG LLP. Mr. Hoelscher currently serves on the board and is audit committee chair of Reneo Pharmaceuticals, Inc. (NASDAQ: RPHM). From 2007-2022 he served on the board of trustees of the Illinois Region of The Leukemia & Lymphoma Society, including two terms as board chair. Mr. Hoelscher earned a B.S. in accountancy from the University of Illinois at Urbana-Champaign and is a certified public accountant. Sagimet also announced today that Jinzi Wu, Ph.D. and Rick Rodgers notified the Board that they will not stand for re-election at the upcoming 2024 annual meeting of stockholders. “I have had the pleasure of working closely with both Jinzi and Rick on Sagimet’s Board, and want to sincerely thank each of them for their support and invaluable contributions,” said George Kemble, Executive Chair. “As the CEO of Ascletis, Sagimet’s license partner for denifanstat in Greater China, Jinzi Wu will remain a valued collaborator and we look forward to continuing to work together to make the product available to patients. I look forward to working with Tim and Paul who I know will add great value to our Board of Directors.” About Sagimet Biosciences Sagimet is a clinical-stage biopharmaceutical company developing novel fatty acid synthase (FASN) inhibitors that are designed to target dysfunctional metabolic pathways in diseases resulting from the overproduction of the fatty acid, palmitate. Sagimet’s lead drug candidate, denifanstat, is an oral, once-daily pill and selective FASN inhibitor in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH). FASCINATE-2, a Phase 2b clinical trial of denifanstat in MASH with liver biopsy-based primary endpoints, was successfully completed with positive results. For additional information about Sagimet, please visit www.sagimet.com. About MASH MASH is a progressive and severe liver disease which is estimated to impact more than 115 million people worldwide, for which there is only one recently approved treatment in the United States and no currently approved treatments in Europe. In 2023, global liver disease medical societies and patient groups formalized the decision to rename non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD) and nonalcoholic steatohepatitis (NASH) to metabolic dysfunction-associated steatohepatitis (MASH). Additionally, an overarching term, steatotic liver disease (SLD), was established to capture multiple types of liver diseases associated with fat buildup in the liver. The goal of the name change was to establish an affirmative, non-stigmatizing name and diagnosis. Forward-Looking Statements This press release contains forward-looking statements within the meaning of, and made pursuant to the safe harbor provisions of, The Private Securities Litigation Reform Act of 1995. All statements contained in this press release, other than statements of historical facts or statements that relate to present facts or current conditions, including but not limited to, statements regarding: the expected timing of the presentation of data from ongoing clinical trials, Sagimet’s clinical development plans and related anticipated development milestones, Sagimet’s cash and financial resources and expected cash runway. These statements involve known and unknown risks, uncertainties and other important factors that may cause Sagimet’s actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, these statements can be identified by terms such as “may,” “might,” “will,” “should,” “expect,” “plan,” “aim,” “seek,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “forecast,” “potential” or “continue” or the negative of these terms or other similar expressions. The forward-looking statements in this press release are only predictions. Sagimet has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that Sagimet believes may affect its business, financial condition and results of operations. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, some of which cannot be predicted or quantified and some of which are beyond Sagimet’s control, including, among others: the clinical development and therapeutic potential of denifanstat or any other drug candidates Sagimet may develop; Sagimet’s ability to advance drug candidates into and successfully complete clinical trials, including its FASCINATE-2 Phase 3 clinical trial; Sagimet’s relationship with Ascletis, and the success of its development efforts for denifanstat; the accuracy of Sagimet’s estimates regarding its capital requirements; and Sagimet’s ability to maintain and successfully enforce adequate intellectual property protection. These and other risks and uncertainties are described more fully in the “Risk Factors” section of Sagimet’s most recent filings with the Securities and Exchange Commission and available at www.sec.gov. You should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in these forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, Sagimet operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that Sagimet may face. Except as required by applicable law, Sagimet does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Contact: Maria YonkoskiICR Westwicke203-682-7167maria.yonkoski@westwicke.com

BOSTON & SAN DIEGO--(BUSINESS WIRE)-- Rapport Therapeutics, Inc., a clinical-stage biotechnology company leveraging the science of receptor-associated proteins (RAPs) to advance precision neuromedicines, today announced the appointment of industry veteran Troy Ignelzi as Chief Financial Officer, effective November 1, 2023. This press release features multimedia. View the full release here: Troy Ignelzi (Photo: Business Wire) “We are thrilled to welcome Troy to the Rapport executive team during this time of rapid progress for our company,” said Abraham Ceesay, Chief Executive Officer of Rapport. “With his extensive experience guiding life science companies through major value creation milestones, as well as his demonstrated ability in raising and structuring financings for growth-oriented biotech companies, Troy is the ideal addition to Rapport. As we work to advance and expand our portfolio and ultimately deliver better treatment options for patients living with serious neurological disorders, Troy’s expertise of the biotech financial landscape will help propel us forward.” Mr. Ignelzi joins Rapport with nearly two decades of financial leadership experience in the biotech and pharmaceuticals sectors. Over the course of his career, Mr. Ignelzi has raised an impressive $4 billion-plus in capital for life science companies. Most recently, he was Chief Financial Officer at Karuna Therapeutics, where he led the team in the execution of a private crossover round, the company’s IPO and multiple follow-on financings. Prior to Karuna, Mr. Ignelzi served as Chief Financial Officer at two other companies, Juventas Therapeutics and scPharmaceuticals. He has a long track record of experience in the sector, having started out at Eli Lilly and then moving on to roles of increasing responsibility at companies including Esperion Therapeutics and the former Insys Therapeutics. Previously, Mr. Ignelzi served on the board of CinCor Pharma, Inc., where he advised on the company’s sale to AstraZeneca in early 2023. He currently serves on the boards of Vedanta Biosciences and Abivax. He is a graduate of Ferris State University, where he earned his B.S. in accounting. “There is no question that Rapport has tapped into a potentially transformative way to address unmet need in patients with neurological disorders,” said Mr. Ignelzi. “Rapport’s innovative scientific approach to precision neuromedicine, which creates tremendous opportunity to dramatically improve patient outcomes, is incredibly exciting to me and also signals the potential for significant company growth in the future.” About Rapport ( ) Rapport pursues precision neuromedicine in an effort to give patients better alternatives to current treatments for neurological diseases, which often come with reduced efficacy and side effects that lead to suboptimal dosing, noncompliance and discontinuation. By more precisely targeting the neural circuits and cell types where diseases originate, Rapport’s approach has the potential to reduce the unwanted drug-target interactions that lead to these issues. The company’s platform, built and refined over the past decade by its founding scientific team, achieves precision through the discovery and targeting of receptor-associated proteins, or RAPs, which display regional or neural circuit-specific expression. The company has ongoing clinical programs in seizure and psychiatric disorders.