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钠离子通道蛋白10α亚基（SCN10A），通常被称为Nav1.8，是一种主要表达在外周感觉神经元（尤其是背根神经节，DRGs）中的电压门控钠离子通道亚基。与广谱钠离子通道阻断剂（如利多卡因）不同，选择性Nav1.8阻断剂专门靶向伤害感受（疼痛）信号传导，同时能够完全避免由于阻断Nav1.5 或Nav1.1~1.3所引发的中枢神经系统及心脏毒性。 该药物研发领域迎来重大里程碑：美国 FDA 已批准 Suzetrigine 上市，使其成为全球首个（First-in-class）获批的选择性Nav1.8抑制剂。 一、 突破性/首款获批上市药物 Suzetrigine（原研发代号：VX-548） 研发状态：已获美国 FDA 批准上市。 作用机制：一种强效、口服生物利用度高的非阿片类小分子药物。它对Nav1.8的选择性比对其他钠通道亚型高出约 31,000 倍，通过独特的变构机制阻断该通道。 首要适应症：用于治疗中度至重度急性疼痛（如拇外翻手术或腹壁整形术后的术后疼痛）。 临床价值：其止痛疗效与标准阿片类复合制剂（如氢可酮/对乙酰氨基酚）相当，且完全没有呼吸抑制、镇静或成瘾依赖等阿片类药物常见的副作用。 管线拓展：目前正在针对慢性神经病理性疼痛（包括糖尿病外周神经病变 DPN 和腰骶神经根病）开展临床试验。 二、 下一代及在研临床管线阻断剂 随着 Suzetrigine 的成功，全球制药企业正聚焦于开发具有全新化学骨架的 Nav1.8抑制剂. Latigo Biotherapeutics 管线化合物（如 Ex 35） 研发状态：处于临床前高级阶段 / 早期临床开发阶段。 药物特点：对重组人 Nav1.8通道表现出低于 10 nM 的强效抑制活性（IC50 < 10nM）。该化合物具有高水溶性和外周限制性（不易穿透血脑屏障），用于治疗疼痛、慢性咳嗽及瘙痒。 默沙东（MSD）研发化合物（如 3-氧代哌嗪羧酰胺衍生物） 研发状态：临床前开发。 药物特点：经高度优化后的衍生物，在全细胞电压钳实验中展现出极低的 IC50（仅为 0.7 nM）。靶向用于急性痛、神经病理性痛及难治性咳嗽。 艾立康药业、上海瑛派药业、成都先导等中国药企候选药物 研发状态：1期临床（艾立康药业）、早期管线 、 专利布局阶段。 药物特点：新型小分子抑制剂，除疼痛外，还在探索其在治疗心律失常、尿失禁及多发性硬化症中的潜在疗效。 三、 早期历史/临床前原型药物 在药物发现史上，曾有数个分子为Nav1.8的药理学研究铺平了道路，但因成药性差或药代动力学缺陷而终止： A-803467（雅培实验室）：文献中引用率最高的经典Nav1.8选择性工具化合物之一。虽然在动物炎症痛和神经痛模型中高度有效，但因口服生物利用度极差而未能进入临床。 PF-04531083 / PF-06305591（辉瑞）：临床前选择性阻断剂，展现了强大的靶向结合力。但由于在人体内的药代动力学（PK）性质不理想，在早期临床阶段被终止。 VX-150（Vertex 制药）：Vertex 研发的前期前体药物。尽管在 II 期临床试验中证明了有效性，但由于与标准阿片类对乙酰氨基酚复合制剂相比优势不够显著，最终被终止。 四、 临床局限性与研发挑战 对 Nav1.5的选择性要求极高：由于心脏钠通道 Nav1.5与 Nav1.8具有极高的结构序列相似性，药物发现过程中必须进行高难度优化，以确保新药具备零心脏毒性。 部分镇痛效应天花板：临床数据表明，即使完全阻断单一通道亚型Nav1.8，在 11 分痛觉量表上的临床评分也仅能降低约 1 至 2 分。这表明疼痛信号的传导存在多通道冗余机制（如 Nav1.7和Nav1.9的共同参与）。 参考： https://www.ncbi.nlm.nih.gov/gene/6336； https://www.bjanaesthesia.org/article/S0007-0912(25)00642-7/abstract； https://link.springer.com/article/10.1007/s11916-026-01472-w； https://pubs.acs.org/doi/10.1021/jm061005v； https://pmc.ncbi.nlm.nih.gov/articles/PMC12843740/； https://www.sciencedirect.com/science/article/pii/S0223523425010918； 申报临床 | 艾立康药业全新一代Nav1.8抑制剂获受理：https://news.sohu.com/a/971333674_121123832； https://www.bioworld.com/keywords/37352-nav1-8-blockers；

Key Regulatory Benchmark Met, Differentiating DMX-101 from Traditional Opioid Analgesics Late-Breaking Results to be Presented at CPDD 2026 Annual Meeting San Francisco, California--(News - May 12, 2026) - DIMERx, Inc. ("DIMERx" or "the Company") is a clinical-stage biopharmaceutical company dedicated to addressing the public-health crisis of drug misuse and dependence, with a portfolio of first-in-class, dimer-based pain therapeutics engineered to deliver effective analgesia without the addiction liabilities of conventional opioids. In June 2025, DIMERx was awarded a NIH HEAL Initiative grant to advance its DMX-101 program. The company today announced preclinical data confirming that DMX-101, an orally bioavailable, peripherally acting new chemical entity (NCE) dimer of buprenorphine, is free of the reinforcing effects that drive addiction to traditional opioids. In a self-administration study conducted in accordance with FDA guidance, cocaine- and hydrocodone-trained rats demonstrated that DMX-101 produced no reinforcing behavior characteristic of opioid misuse and dependence. All compounds were administered intravenously to maximize pharmacological exposure, representing a worst-case scenario for misuse potential assessment. Notably, DMX-101 plasma exposure levels in rats were 18-fold higher than the maximum plasma concentration (Cmax) observed in humans following oral dosing, indicating that the absence of rewarding effects was demonstrated at exposures substantially exceeding those expected in clinical use. Even under these rigorous conditions, DMX-101 showed no evidence of addictive behavior, supporting a favorable safety pro respect to misuse liability, overdose risk, and opioid-related morbidity. "DMX-101 is designed to exclusively target peripheral opioid receptors, blocking pain signals at their source without engaging central nervous system pathways linked to reward, sedation, or addiction, and the absence of self-administration behavior observed in this study supports the potential for DMX-101 to provide effective pain relief without the risk of misuse," said Virginia Sanders, PhD, Vice President of Preclinical and Principal Investigator for the NIH grant. "These results, together with prior preclinical and clinical findings, confirm our core hypothesis that peripherally restricted opioid modulation can deliver meaningful analgesia without the liabilities of traditional opioids. As the clinical and societal need for safer pain therapies intensifies, DMX-101 represents a differentiated approach to delivering meaningful analgesia without cognitive impairment or contributing to the addiction epidemic." "DMX-101 could redefine pain treatment. The absence of rewarding effects, even at exposures 18-fold above clinical levels, suggests we are looking at a genuinely differentiated therapy, one with the potential to displace traditional opioids and change the trajectory of the addiction crisis," said Eric C. Strain, MD, Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University School of Medicine and an expert in addiction medicine and Scientific Advisor to DIMERx. DIMERx will present these findings at the College on Problems of Drug Dependence (CPDD) 88th Annual Meeting, June 13-17, in Portland, OR. Virginia Sanders, PhD and Eric C. Strain, MD, will present the data. Poster Details: Title: DMX-101 Does Not Exhibit Reinforcing Effects in a Hydrocodone-Trained Rat Self-Administration Model Session: Poster II Date/Time: Monday, June 15, 2026; 5:00pm-6:30pm Location: OCC, Level 1, Exhibit Hall A About DIMERx, Inc. DIMERx, Inc. is a clinical-stage biopharmaceutical company developing first-in-class, covalently linked dimer-based therapeutics to address major public-health challenges in pain management and the opioid crisis. Co-founded by CEO Nikhilesh Singh, M.Pharm, PhD, and CFO/COO Gregory Beyer, DIMERx is building a pipeline of innovative dimer-based candidates targeting pain and other serious conditions with high unmet medical need. The company's lead asset, DMX-101, is a covalently modified, chemically stable, halogen-free buprenorphine dimer (CAS No: 1820753-68-1) that acts peripherally at the source to provide non-addictive pain relief. DMX-101 is in phase 2 clinical development for chronic lower back pain. Across Phase 1 and Phase 2a studies involving over 400 subjects and patients, it has demonstrated a favorable safety profile, including pancreatic safety, and clear analgesic benefits. The DMX-101 program, which includes a planned human abuse liability study, is supported by a grant awarded by the National Institute on Drug Abuse (NIDA) under the NIH HEAL Initiative. DIMERx's second program, DMX-201, is a covalently linked dimer of arginine and agmatine, a next-generation nitric oxide (NO) donor being developed for conditions involving endothelial dysfunction, such as vaso-occlusive crisis (VOC) pain in sickle cell disease, where treatment options remain dominated by centrally acting opioids. Learn more at . Funding Disclosure and Forward-Looking Statements Research reported in this press release was supported by the National Institute on Drug Abuse of the National Institutes of Health under award number 1 UG3 DA061645-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This press release may contain forward-looking statements, including information about management's view of DIMERx ("the Company"), future expectations, plans and prospects. In particular, when used in the preceding discussion, the words "believes," "expects," "intends," "plans," "anticipates," or "may," and similar conditional expressions are intended to identify forward-looking statements. Any statements made in this presentation other than those of historical fact, about an action, event or development, are forward-looking statements. These statements involve known and unknown risks, uncertainties and other factors, which may cause the results of the Company, its subsidiaries and concepts to be materially different than those expressed or implied in such statements. Unknown or unpredictable factors also could have material adverse effects on the Company's future results. The forward-looking statements included in this presentation are made only as of the date hereof. The Company cannot guarantee future results, levels of activity, performance or achievements. Accordingly, you should not place undue reliance on these forward-looking statements. Finally, the Company undertakes no obligation to update these statements after the date of this release, except as required by law, and also takes no obligation to update or correct information prepared by third parties that are not paid for by DIMERx. Investor Contact Hanover International Inc. Kathy Cusumano, President IR@dimerx.com To view the source version of this press release, please visit