Mexiletine Hydrochloride

horillaz/ Getty Images With its recent data drop for an oligonucleotide candidate, Dyne Therapeutics signals it may become a frontrunner in this disease space alongside Avidity Biosciences, Lupin and AMO Pharma. Last month, Dyne Therapeutics announced positive results in a Phase I/II trial of its candidate DYNE-101. The milestone places Dyne among the companies closest to developing a disease-modifying treatment for myotonic dystrophy type 1. Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy caused by DMPK mutations on chromosome 19. It affects muscles and many organs across multiple systems that depend on muscular activity. Also known as Steinert disease, it is characterized by the inability to relax muscles at will. DM1 affects 140,000 people in the United States alone, and although there are drugs that address its symptoms, there are no currently approved disease-modifying treatments for the condition. There are, however, more than two dozen investigational drugs in development for DM1. Among the companies looking to fill the unmet need is Dyne, whose DYNE-101 is an antisense oligonucleotide fused with a fragment antibody that binds to the transferrin receptor 1 in muscles. In the Phase I/II ACHIEVE trial , key findings included DMPK RNA level reductions, CASI-22 improvements, early and sustained improvement in myotonia as measured by grip myotonia assessment, and multiple other strength and timed assessments. The trial utilized a multiple ascending dose cohort to identify 6.8 mg/kg every 8 weeks as the optimal dose for future studies. Dyne stated in its press release that it plans to initiate a global registrational expansion cohort of the trial to potentially support a submission for FDA Accelerated Approval in the first half of 2026. Meanwhile, Avidity Biosciences is developing AOC 1001, an antibody oligonucleotide conjugate that targets the DMPK gene to treat DM1. Also known as del-desiran, this investigational treatment is currently being studied in the Phase III HARBOR trial and Avidity has announced plans to submit marketing applications in 2026. In March 2024, Avidity announced positive long-term del-desiran data from the Phase II MARINA-OLE trial showing reversal of disease progression in people living with DM1 across multiple endpoints compared to a matched natural history study population over one year. Those endpoints included grip myotonia assessment, muscle strength and activities of daily living. According to Avidity, additional data from the ongoing Phase I/II MARINA trial for AOC 1001, in which patients were split into placebo-controlled single-dose and multiple ascending dose arms, will be released in the first quarter of this year. While clinical-stage investigational oligonucleotide-based therapy candidates are catching up, repurposed drugs such as metformin, tideglusib and mexiletine are also undergoing Phase III trials to treat DM1. Metformin , a biguanide currently approved for type 2 diabetes mellitus, is currently slated for Phase III trials in DM1. In previous Phase II trials, metformin increased the 6-minute walking distance for DM1 patients versus placebo. While it has positive benefits ranging from anticancer effects to cardiovascular protection to neuroprotection, metformin is also associated with adverse effects such as gastrointestinal discomfort and lactic acidosis in high doses. Another approach is AMO Pharma ’s tideglusib (also known as AMO-02), a glycogen synthase kinase 3 beta inhibitor currently in Phase III clinical trials. Despite not reaching its primary endpoint in the Phase II/III REACH-CDM trial due to a strong placebo effect, tideglusib had achieved clinically and statistically significant benefits in various functional and objective assessments as of May 2024. As a result, after meeting with the FDA, AMO Pharma is forging ahead with a Phase III trial of tideglusib. Elsewhere, Lupin is working on repurposing mexiletine, a class I antiarrhythmic drug that is currently in Phase III trials for DM1. In contrast to previous trials that used mexiletine capsules for immediate-release effects, Lupin intends to use mexiletine granules for prolonged-release oral suspension formulations for its Phase III HERCULES and ATLAS trials. Like tideglusib, mexiletine reached Phase III despite less-than-stellar mid-stage results. In its case, Phase II trial data demonstrated no significant change in 6-minute walk distance at 6 months for patients on mexiletine capsules compared to placebo. Also worthy of mention is ARTHex. While clinical data is scant for the company’s ATX-01, it was enrolling patients into its Phase I/IIa ArthemiR trial as of October 2024. The drug is based on microRNA technology. As progress currently stands, antibody-oligonucleotide conjugates appear to be more effective at targeting the genetic source of DM1 and have a more convincing mechanism of action than small molecules and repurposed drugs. However, even though genetic therapies are advancing quickly, the DM1 space is risky. Consider that Ionis Pharmaceuticals stopped working on its antisense compound IONIS-DMPK-2.5Rx in January 2017 after failing to achieve adequate concentration levels in muscles in Phase I/II trials. If all goes well in the late-stage gene therapy space for DM1, expect new treatments to hit the market within the next three to four years at the earliest.

关注并星标CPHI制药在线 2025年1月30日，Vertex Pharmaceuticals宣布FDA批准Suzetrigine上市，用于治疗中至重度急性疼痛，这也是20多年来首款非阿片类镇痛药。 Suzetrigine(VX-548)是 NaV1.8 通道的靶向抑制剂。NaV1.8 是一种电压门控钠通道，选择性地表达于外周痛觉神经元，传递疼痛信号。Suzetrigine 通过高选择性抑制 NaV1.8通道，能有效缓解疼痛。 本次获 FDA 批准，Suzetrigine 的疗效验证主要基于 2 项针对急性手术疼痛的随机、双盲、安慰剂和活性的对照试验。一项试验是在腹部整形术后，另一项是在拇囊切除术后。 2 项试验的都表明，与安慰剂相比，高剂量（初始剂量 100mg，之后以 50mg/12h 维持治疗）的Suzetrigine 可在 48 小时内有效减轻疼痛；与安慰剂相比，两组 SPID48（48 小时内疼痛强度差异的时间加权总和评分）的平均差异分别为 48.4 和 29.3。 新机制镇痛靶点：Nav1.8 疼痛作为心脑血管疾病和肿瘤之后的第三大健康挑战，驱动了止痛药市场的快速增长，该市场扩张速度紧跟肿瘤药物之后，反映出临床中对更有效镇痛方案的迫切需求。据Mordor intelligence调查显示，2021年全球疼痛管理市场价值794亿美元，预计到2027年将增长至1207亿美元，复合年增长率为7.39%，因此镇痛药市场被认为是继GLP-1减肥药之后的下一个千亿金矿。 鉴于阿片类药物滥用与成瘾问题严峻，医药界正集中力量探索新型非阿片类、无成瘾性的高效镇痛药物。疼痛信号传递机制与细胞膜上的电压控制钠离子通道（Nav）密切相关，尤其是通过调控Nav通道活性可以干预疼痛过程。Nav通道家族包含九个亚型（Nav1.1至Nav1.9），这些亚型分布广泛，其中Nav1.8和Nav1.9主要存在于外周神经系统。尽管抑制这些通道活动是疼痛治疗的一个方向，但由于Nav亚型的多样性及其在心脏、中枢神经系统等关键部位的存在，导致现有非选择性Nav抑制剂（例如拉莫三嗪、拉科酰胺、美西律）可能产生广泛的副作用，限制了它们的临床应用和安全性。 Nav1.7作为镇痛研究的重点之一，因其在人类遗传学研究中的良好验证而受到广泛关注。研究表明，Nav1.7的突变与遗传性疼痛综合症密切相关，这使得其成为了潜在的治疗靶点。然而，多个Nav1.7抑制剂化合物在临床试验中的表现不尽如人意，主要包括未能有效作用于脊柱分布、靶点占位不足、生物利用度差等问题。这些因素导致了Nav1.7抑制剂在实际应用中的局限性。此外，临床实验设计和靶点选择性也影响了开发结果，使得研究者们面临着重重挑战。这使得Nav1.7作为镇痛药物开发的靶点逐渐被取代，研究者们将注意力转向了Nav1.8这一亚型。 Nav1.8在痛觉信号传导中发挥着关键作用，主要表达于伤害感受神经元，并且属于对河豚毒素不敏感的钠离子通道。与Nav1.7不同的是，Nav1.8不参与中枢神经系统的活动，其抑制剂能够在提供有效镇痛效果的同时，避免成瘾性和对运动功能的不良影响。因此，Nav1.8成为了具有高选择性的疼痛治疗靶点。研究显示，通过靶向Nav1.8，可以有效减轻慢性疼痛而不引发依赖或其他副作用，这为新一代镇痛药物的开发提供了新的方向。 Vertex开了一个好头 Vertex曾经陆续将4款NaV1.8抑制剂(VX-128、VX-961、VX-150、VX-584)推进到临床试验阶段，其中VX-128和VX-961皆因I期临床试验PK和安全性问题分别于2018年和2020年终止。VX-150虽然PK和暴露量有所改善且也通过临床概念验证试验，但因2021年VX-584在I期临床试验中具有更明显安全性、PK和暴露量优势，因此VX-150亦遭放弃，Verte进而继续开发VX-548并最终取得临床试验成功。 在行业媒体Evaluate发布的盘点文章中，VX-548疗法被列为潜在重磅疗法。有Leerink Partners分析师表示，当前的疼痛市场与两年前的肥胖市场有着相似之处，他预计到2030年VX-548的年销售额可能会达到51亿美元。 然而，真正的临床需求并不是另一种急性疼痛药物，因为患者已经有很多现有且便宜的药物得到了有效且安全的的治疗（例如阿片类药物）但是对于慢性疼痛而言，非阿片类的镇痛药物意义就很重大了。VX-548有可能成为一种新的有效的慢性疼痛治疗方法，这是患者需求最大的领域，VX-548同时布局了性糖尿病神经病变（DPN）和慢性腰骶神经根病（LSR)。 DPN方面，尽管去年12月宣布了积极结果，但该试验的样本量不足以显示与临床对照药物普瑞巴林的疗效对比，并且没有安慰剂组。因此，Vertex宣布他们计划在2024年下半年启动一个更全面的III期项目。 LSR方面，在2期研究中VX-548虽然达到主要终点——即显著减轻了疼痛。然而，安慰剂组同样显示出明显的疼痛减轻（约 2 分），治疗组与安慰剂组之间的差异并不显著，仍需推向III20期临床进一步确定疗效。 Vertex钠离子通道抑制剂管线 图片来源: Vertex官网 总体而言，VX-548此次虽然顺利获批急性疼痛适应症，但在更具商业潜力的慢性疼痛适应症的开发上仍任重道远。 在Vertex的镇痛管线中，除了VX-548在急性镇痛和慢性镇痛上的布局外，还正在开发第三代NaV1.8抑制剂VX-993和VX-973，旨在提供更安全、有效的非阿片类镇痛方案。这两种化合物已进入I期临床阶段，正在健康受试者中评估其安全性、耐受性和药代动力学特性。VX-993和VX-973有望优化药效以实现良好的镇痛效果。 据丁香园 Insight 数据库显示，全球共有 30 款靶向 NaV1.8 的在研新药（仅统计活跃状态），有 12 款在研 NaV1.8 抑制剂已进入针对疼痛适应症的临床阶段。在国内，目前也有多款 NaV1.8 抑制剂已经进入临床阶段，包括恒瑞（Ⅱ 期）、济民可信（Ⅱ 期）、健康元（Ⅰ 期）、海博为（Ⅰ 期）。 图片来源:贝壳社 JMKX000623是上海济煜自主研发的高选择性NaV 1.8）抑制剂,其针对糖尿病周围神经痛的Ⅱ 期临床正在进行中。早在2022年JMKX000623就实现出海，芬兰药企ORION以1500万欧元首付款买下了这款药物的海外权益,足以体现此产品的不俗价值。 巧合的是，海博为药业的HBW-004285片也在近期完成了Ⅰ期临床。从已获得的临床研究数据显示，相比全球首个刚刚获批上市的Nav1.8抑制剂Journavx（即VX-548），HBW-004285片安全性更高（无任何一级以上不良反应）、起效速度更快，药代动力学更优，且无性别差异，有望超越VX-548；在临床前头对头对比实验中，HBW-004285无论是生物活性还是药代动力学性质，都显著优于Vertex下一代Nav 1.8 抑制剂 VX-993，是具有成为Best In Class潜力的药物分子。 参考来源： 1. 各企业官网 2. CDE官网 扫码领取CPHI & PMEC China 2025展会门票 【智药研习社近期直播】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~