GYS1

Announcement coincides with WORLD Symposium™ presentation highlighting knockdown of GYS1 mRNA and protein in muscle, as well as favorable safety and tolerability profile, in normal healthy volunteers PHILADELPHIA, PA, USA I February 05, 2025 I Aro Biotherapeutics , a clinical-stage biotechnology company working to develop potent and tissue-targeted medicines, today announced that it has received U.S. Food and Drug Administration (FDA) clearance of the Investigational New Drug Application (IND) for ABX1100, a novel therapy currently being investigated in a phase 1 study in late-onset Pompe disease (LOPD) patients. Additionally, Aro will present data at the 2025 WORLD Symposium™ in San Diego, Calif., from a phase 1 study in normal healthy volunteers (NHVs) in which ABX1100 provided durable knockdown of glycogen synthase 1 ( GYS1 ) messenger RNA (mRNA) and protein in the muscle. ABX1100 also was well-tolerated and exhibited predictable pharmacokinetics (PK) in the Phase 1 trial in NHVs. “FDA clearance of our IND application, combined with the encouraging data from our phase 1 healthy volunteer trial, provide tremendous momentum for the ABX1100 clinical development program,” said Susan Dillon, Ph.D., co-founder, president and chief executive officer of Aro. “Attainment of these milestones bolsters our confidence as we continue to enroll patients with late-onset Pompe disease in our ongoing Phase 1 trial.” Individuals with LOPD have a genetic deficiency in the enzyme that breaks down muscle glycogen, a stored form of sugar used for energy. As a result, these individuals have excess levels of glycogen stored in muscle tissue, leading to disease. Using Aro’s Centyrin technology, ABX1100 is designed to deliver a short-interfering RNA (siRNA) therapeutic payload directly to muscle tissue in order to inhibit the production of GYS1, a key enzyme required for synthesizing glycogen. By reducing the production of glycogen, Aro hopes to bring a new treatment to patients. Aro recently announced the dosing of the first patient in its open-label Phase 1 clinical trial of ABX1100 in patients with LOPD in Canada. In the completed phase 1 NHV study, ABX1100 exhibited dose- and time-dependent GYS1 mRNA and protein reduction in muscle biopsy samples relative to baseline pre-dose levels. The investigators observed approximately 70% knockdown of GYS1 mRNA and protein at 10 weeks following two doses of ABX1100 at days 1 and 29, indicating potentially therapeutic levels of GYS1 reduction and supporting the rationale for quarterly maintenance dosing following loading doses. Pharmacokinetic analysis demonstrated rapid clearance from the plasma but durable persistence in the muscle. “The phase 1 results demonstrate consistent and dose-dependent delivery to the muscle, allowing ABX1100 to knock down GYS1 with a long duration of effect,” commented Karyn O’Neil, Ph.D., co-founder and chief scientific officer of Aro. “This provides the first clinical evidence translating from the bench to bedside for our Centyrin-siRNA platform.” ABX1100 was well-tolerated at all dose levels, with no serious adverse events (SAEs) reported through 85 days post-treatment, and no early discontinuations due to adverse events (AEs). Most AEs were transient and mild. There were no reports of anemia in the study. About ABX1100 ABX1100, an investigational treatment for Pompe disease, is comprised of a CD71 receptor-binding Centyrin conjugated to a short-interfering RNA (siRNA) that specifically interferes with expression of GYS1 messenger RNA (mRNA) in the muscle tissues, thereby reducing levels and overall activity of GYS1, a key enzyme required for synthesizing glycogen. ABX1100 is in early-stage development for the treatment of Pompe disease (Clinicaltrials.gov #NCT06109948) and has received Orphan Drug Designation and Rare Pediatric Disease status from the FDA. About LOPD Pompe disease is a rare neuromuscular disorder caused by a genetic deficiency of alpha-glucosidase, which leads to a toxic buildup of glycogen in the muscle. This buildup leads to progressive loss of muscle function, weakness, and disability that can eventually progress to death from respiratory failure. 1 Late-onset Pompe disease (LOPD) is a subtype of Pompe that is typically diagnosed during adolescence or adulthood. The current standard of care for LOPD is enzyme replacement therapy, which aims to restore a genetic deficiency in the enzyme that breaks down muscle glycogen. However, the standard of care has shown limited efficacy, and is also associated with significant treatment burden of long intravenous (IV) infusions multiple times a month. About Aro Biotherapeutics Aro Biotherapeutics is a biotechnology company working to develop potent and versatile tissue-targeted genetic medicines with a platform based on a proprietary protein technology called Centyrins. The company is developing a wholly owned pipeline of Centyrin-based therapeutic candidates for tissue-specific targeting of therapeutics for a diverse set of diseases. For more information, visit www.arobiotx.com . Reference SOURCE : Aro Biotherapeutics

1月7日，距获得D轮融资不过一个月，Maze Therapeutics向美国证券交易委员会（SEC）提交上市申请。这家总部位于湾区的biotech没有公布计划发行的股票数量和价格，只提到希望通过上市进一步推动公司肾病候选药物的发展。 申请文件显示，Maze申请在纳斯达克上市，股票代码为MAZE。与之前的 D 轮融资一样，此次募集的资金将用于推进MZE829和MZE782的临床开发。 MZE829 是口服APOL1抑制剂，目前正在进行针对APOL1 肾病的试验，计划最晚于2025 年第一季度开始 II 期试验。 MZE782是口服SCL6A19抑制剂，目前正在进行针对健康受试者的I期试验。申请文件显示，Maze 计划在慢性肾病和苯丙酮尿症领域继续开发该药物。 剩余资金将用于进一步开发心血管、肾脏和代谢适应症领域（Maze的重点领域）的 “其他常见疾病项目”，“包括临床前研究、IND-enabling研究和启动临床试验”。 Maze 还希望利用 IPO 来推动公司Compass™平台的发展，该平台利用人类基因变异来精确定位致病基因，从而确定潜在的新药靶点。   01   关于Maze Therapeutics 成立于2018年，是一家临床阶段公司，开发治疗常见疾病的小分子精准药物，拥有3个临床阶段项目，并通过Compass™平台开发多个药物研发项目。Maze Therapeutics 正在开发的药物旨在模仿罕见的、自然发生的保护性基因变异作用，帮助阻止肾脏疾病的发展，并有可能逆转肾脏疾病的影响。进展最快的项目是用于治疗APOL1 肾病的MZE829。 正在推进的项目有两个：MZE829和MZE782。 2024年10月25日，Maze报告MZE829作为APOL1 肾病 (AKD) 潜在治疗药物，在I期健康志愿者临床试验中取得正向首次人体试验数据。   02   35天从融资过渡到申请IPO 去年12月3日，Maze在新闻稿中宣布获得 1.15 亿美元的 D 轮融资，由Frazier Life Sciences 和 Deep Track Capital 共同领投，Janus Henderson Investors 、Logos Capital 以及包括 Third Rock Ventures、ARCH Venture Partners 和 Matrix Capital Management 等在内的现有投资者共同参与。 Maze首席执行官Jason Coloma博士表示：“有了此次融资提供的额外资源，我们就能够优化即将开展的MZE829的II期试验，进一步挖掘两个先导项目的潜力。此次融资在我司发展史上标志着重要一步，对我们旨在服务的患者亦是如此。” 继 2019 年首次融资 1.91 亿美元和 2022 年融资 1.9 亿美元后，经过此次D轮融资，Maze 的总融资额达到了近5亿美元。   03   与赛诺菲的合作半道崩殂 说起2023年医药圈大事件，肯定有一件是美国联邦贸易委员会（FTC）否决了赛诺菲与Maze Therapeutics的合作。 当年5月1日，赛诺菲提出购买Maze Therapeutics的糖原合成酶1 (GYS1) 项目，包括刚完成的一项针对庞贝病患者的 I 期试验，预付现金和生物奖金金额高达7.5亿美元。 原本此次授权可以为赛诺菲的管线增加一种处于临床阶段的罕见病药物。罕见病目前约占赛诺菲管线的15%。作为交换，Maze也可以获得 1.5 亿美元的预付现金和股权，以及高达 6 亿美元的里程碑付款。 此前不久，Maze 报告了在健康志愿者中进行MZE001 I 期试验的最新数据，发现该药物耐受性良好，剂量可达每天两次，每次 720 毫克。Maze 还发现，这种药物能降低血液糖原和肌糖原水平，而这两项潜在生物标志物正说明对庞贝病产生了治疗效果。根据当时的协议，赛诺菲将负责启动该药的II期试验。 除了MZE001，赛诺菲本还可以获得其他适应症或GYS1后备项目的知识产权或 “专有技术”，并可以决定是否扩大MZE001的使用范围。 但人算不如天算，2023年12月12日，FTC阻止了这一授权交易。面对采取行动阻止该交易的FTC，赛诺菲的选择是退出，而不是花力气解决横亘在它与MZE001之间的反垄断问题。 FTC在披露打算阻止该交易的声明中称，该协议将 “消灭一个新生竞争者，而该竞争者能够挑战赛诺菲在庞贝病治疗市场的垄断地位”，并在一份经过大量删节的申诉中进一步阐述了这一点。 对此，赛诺菲表示不同意，称与Maze的交易本可以利用赛诺菲的 “资源、知识和专长加速MZE001的开发”……FTC的决定 “推迟了潜在进展，可能影响患者生命”。 不过，赛诺菲选择不对FTC阻止交易的举动提出异议。据赛诺菲之言，之所以终止协议，是因为 “漫长诉讼延宕纠葛，提出异议不符合患者的最佳利益”。 此案也标志着FTC针对的交易类型发生了变化。以前，公司通常只需担心反垄断问题阻碍大型收购，例如，安进（Amgen）斥资 278 亿美元收购Horizon Therapeutics。相对而言，小型收购和授权交易作为biotech的主要收入来源、风投公司的主要退出渠道，受到的FTC审查却要少得多。 在FTC看来，“赛诺菲试图收购 Maze，而不是与Maze竞争”，赛诺菲认识到，这家biotech的 “创新产品有可能取代自己的主导地位”。申诉中被删节的部分讨论了赛诺菲对MZE001在竞争对手手中可能占据多少市场份额做了预测，以及Amicus Therapeutics 最近获批的庞贝病药物对赛诺菲能形成多大威胁。   04   MZE001花落盐野义 然而，对于Maze来说，塞翁失马，焉知非福。就在FTC否决赛诺菲收购 Maze Therapeutics 庞贝病项目五个月后，日本盐野义制药（Shionogi）成功收购了这项资产。梦碎赛诺菲，花落盐野义。 去年5月10日上午，盐野义透露以 1.5 亿美元的预付价格收购MZE001。这个金额远超去年3月盐野义支付给日本biotech FunPep的预付款。FunPep开发了一种抗IgE抗体诱导肽，可治疗季节性过敏性鼻炎，盐野义为授权交易支付了3亿日元（约合190万美元）预付款。 盐野义CEO吉田达守则博士说，Maze的MZE001与盐野义 “战略上高度契合”。 “这将有助于切实推进我们的承诺，开发创新药物，满足医疗需求缺口，补充盐野义在中期业务计划指定重点领域迅速扩大的产品线。” 盐野义指出，MZE001有可能成为第一款治疗庞贝症的口服药物。如果获批，GYS1 抑制剂既可作为单一疗法，也可作为酶替代疗法的附加疗法，而酶替代疗法正是目前治疗该病的标准疗法。 或许赛诺菲的CEO韩保罗 (Paul Hudson) 对此交易也是乐见其成的，毕竟他此前曾表示，担心赛诺菲获取授权失败可能会危及该药物的未来。 在2024年的摩根大通医疗健康大会 (J.P. Morgan Healthcare Conference) 上，韩保罗曾表示：“我们对庞贝病最直接的担心是项目可能无法继续。有时资金难以到位，有时专业知识不及，有时这些小公司的愿望就只是把项目做到这一步。”   05   又是艰难的一年, 2025会好吗？ 2024年，A股市场上只有5家医药公司成功上市，分别是海昇药业、爱迪特、小方制药、益诺思和健尔康。这个数字在2023年是22家，2022年是50家，2021年是63家。其中固然有部分缘由是一些企业转战港交所或北交所，但依然改变不了处境艰难的底色。美股方面，2024年较2023年有所回暖，由Maze Theraeutics上市开局的2025年，会更好吗？  这个问题的答案关系到无数候选药物的前景和biotech从业者的生计。分析师们在2025 年展望中已经做出了预测：任何期望出现戏剧性反转的人现在都应该“风物长宜放眼量”。 2024年，尽管IPO投资规模远低于2020和2021的繁荣时期，风投的融资额也延续始于 2022 年的下滑趋势，分析师对交易活动的描述也是 “低迷”二字。但是与灾难性的2022和2023相比，复苏迹象已显。IPO的数量和融资额都有所增加，风投轮数也有所上升。过去数年经历挑战的公司获批在望。分析师眼中，Cytokinetics的aficamten和Insmed的brensocatib名列2025年潜在最重要上市新药榜单。 分析师们认为，去年年底美国大选前后，IPO 活动有所暂停。今年，预计IPO活动将再次加快步伐。这些分析师表示，“私营公司”存在压抑许久的巨大需求，但预计只有最安全的申请和得到现有投资者大力支持的公司才会在今年头几个月上市。 分析师们还认为，虽然许多人预测2025年IPO的统计数据将再次上升，但很少有人预测闸门会突然开启。分析师们称："股市变幻莫测，像12月初 BioAge 这样的爆仓无助于提高biotech的声誉。” 要想进一步打开IPO窗口，市场条件必须发生变化。分析师们表示，“在特朗普政府就职并制定坚定的政策方向之前”，这种转变不太可能发生，这表明IPO活动仍将受到抑制，直至最早2025年晚些时候。 IPO窗口未完全打开时，一些私营公司就需要向风投公司寻求资金，通过收购控制股权实现退出。2024 年的并购活动出现下滑，截至11 月中，交易数量和交易额远低于 2023 年同期水平。但分析师们认为，2025 年并购上升 “几乎不可避免，因为大型制药公司董事会面临实现长期增长的压力”。   写在最后   Maze Therapeutics的IPO不仅为自身发展输入了新鲜血液，也为2025年biotech IPO开了个好头。“月盈则亏，月缺则盈”是古人对周期的智慧，事物发展到一定程度就会向相反的方向转化。《基督山伯爵》最后一章有这么一段话：“这个世界上既无所谓幸福也无所谓不幸，只有一种状况和另一种状况的比较，如此而已。只有体验过极度不幸的人，才能品尝到极度的幸福。”面对冰塞川、雪满山、行路难、多歧路，我们所需要的智慧不过就是怀抱希望、等待时机而已。 参考资料： Fierce biotech. Maze Therapeutics looks for IPO lodestar to guide kidney disease assets through clinical trials. Fierce biotech. Maze Therapeutics looks to steer lead kidney disease assets through the clinic with $115M series D. Fierce biotech. Sanofi bets $750M to enter glycogen-lined Maze deal with lead asset waiting in the middle. Fierce biotech. Sanofi scraps Maze deal after FTC throws up antitrust obstacles. Fierce biotech. After FTC stalled Sanofi deal, Shionogi secures Maze's Pompe disease drug for $150M. Fierce biotech. Analysts predict M&A, IPO uptick in 2025 but don't expect 'floodgates to suddenly open'. Maze Therapeutics官网 药企IPO观澜 . 见底了，回顾2024年医药IPO的7大关键词. 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Trial aims to establish safety and provide proof of concept for GYS1 inhibition as promising new treatment strategy in patients with late-onset Pompe disease Dosing milestone extends momentum of ABX1100 development program, with data from normal healthy volunteers to be presented at WORLD Symposium™ in February PHILADELPHIA, PA, USA I January 23, 2025 I Aro Biotherapeutics , a clinical-stage biotechnology company working to develop potent and tissue-targeted medicines, today announced the dosing of the first patient in its clinical trial of ABX1100, a novel treatment for late-onset Pompe disease (LOPD). “We are excited to initiate dosing in the Phase 1b trial, the results of which should provide the first proof of concept for GYS1 inhibition as a therapeutic strategy in Pompe disease,” said Susan Dillon, Ph.D., co-founder, president and chief executive officer of Aro. “The results build on promising data from healthy volunteers.” ABX1100 is uniquely designed to deliver a glycogen synthase 1 (GYS1)-specific short-interfering RNA (siRNA) therapeutic payload directly to muscle tissue. Once inside the muscle tissue, the siRNA inhibits the production of GYS1, a key enzyme required for synthesizing glycogen. When combined with enzyme replacement therapy (ERT) of the genetically deficient enzyme, ABX1100 has shown significant reductions in glycogen in preclinical models and may reduce the need for frequent infusions of ERT. “The Pompe disease community has long awaited the development of a treatment that overcomes the limitations of enzyme replacement therapy,” said Brad Crittenden, executive director of the Canadian Association of Pompe. “We are eager to see how well muscle-targeted GYS1 reduction with ABX1100 works to treat the disease.” The Phase 1b portion of the ABX1100 clinical trial is an open-label study evaluating the drug’s safety, tolerability, pharmacokinetics, and pharmacodynamics in LOPD patients who are currently receiving ERT. LOPD patients will receive one dose of ABX1100 on Day 1 of the study and a booster dose on Day 29, and will be followed for 16 weeks to assess response. “Results from the ongoing Phase 1b study will provide the first clinical insights into safety and activity of GYS1 reduction in muscle tissues as a new therapeutic approach for Pompe disease,” commented Glenn Crater, M.D., Chief Medical Officer at Aro. “We look forward to expanding the study beyond the current sites in Canada to other countries and anticipate reporting the results from this study later this year.” More information about the trial is available at ClinicalTrials.gov using the identifier NCT06109948. About ABX1100 ABX1100, an investigational treatment for Pompe disease, is comprised of a CD71 receptor-binding Centyrin conjugated to a short-interfering RNA (siRNA) that specifically interferes with expression of GYS1 messenger RNA (mRNA), thereby reducing levels and overall activity of the GYS1 enzyme in muscle tissues. ABX1100 was well tolerated in a recently completed Phase 1a trial conducted in normal healthy volunteers, and demonstrated durable GYS1 mRNA knockdown in muscle biopsies, supporting the potential for quarterly dosing. ABX1100 has received Orphan Drug Designation and Rare Pediatric Disease status from the United States Food and Drug Administration (FDA). About Pompe Pompe disease is a rare neuromuscular disorder caused by a genetic deficiency of alpha-glucosidase, which leads to a toxic buildup of glycogen in the muscle. This buildup leads to progressive loss of muscle function, weakness, and disability that can eventually progress to death from respiratory failure. 1 Late-onset Pompe disease (LOPD) is a subtype of Pompe that has onset later in life. The current standard of care for LOPD is enzyme replacement therapy, which aims to restore genetically deficient enzymes. However, the standard of care has shown limited efficacy. ERT is also associated with significant treatment burden of long intravenous (IV) infusions multiple times a month. About Aro Biotherapeutics Aro Biotherapeutics is a biotechnology company working to develop potent and versatile tissue-targeted genetic medicines with a platform based on a proprietary protein technology called Centyrins. The company is developing a wholly owned pipeline of Centyrin-based therapeutic candidates for tissue-specific targeting of therapeutics for a diverse set of diseases. For more information, visit www.arobiotx.com . Reference SOURCE: Aro Biotherapeutics