Dexpramipexole Dihydrochloride

▎药明康德内容团队报道 根据中国国家药监局药品审评中心（CDE）官网以及公开资料，本周（9月16日~9月22日），有15款1类创新药首次在中国获得临床试验默示许可（IND），药物类型包括了小分子药物、单抗、双抗、多特异性抗体以及抗体偶联药物（ADC）、放射性药物等。这些产品拟用于治疗各类实体肿瘤、白血病、渐冻症、哮喘、终末期肾病等。本文将根据公开资料对这些产品进行介绍。 图片来源：123RF 恒瑞医药：注射用HRS-2183；HRS-2129片 作用机制：化药1类新药 适应症：革兰阴性菌引起的严重感染；急性疼痛 恒瑞医药两款1类新药首次获批临床，其中注射用HRS-2183拟开发用于革兰阴性菌引起的治疗选择有限或无治疗选择的严重感染（包括碳青霉烯耐药菌感染）；HRS-2129片拟开发用于急性疼痛。目前尚未从公开渠道查询到这两款产品的作用机制，从受理号可知两款产品均为化药。 挚盟医药：CB03-154片 作用机制：KCNQ2/3选择性开放剂 适应症：成人ALS 挚盟医药1类新药CB03-154片获批临床，拟开发治疗成人肌萎缩侧索硬化（又称“渐冻症”，ALS）。公开资料显示，这是挚盟医药研发管线中的一款针对中枢神经的创新药，为一款KCNQ2/3钾离子通道开放剂，它具有较好的离子通道选择性、化学和代谢稳定性、抗神经过度兴奋等活性。该产品此前治疗ALS适应症已经获得美国FDA授予孤儿药资格。 CSL Behring：CSL300（clazakizumab） 作用机制：靶向IL-6配体的单克隆抗体 适应症：终末期肾病透析患者 CSL Behring公司申报的clazakizumab获批临床，拟开发用于降低接受维持性透析的成人患者的心血管死亡和心肌梗死风险，他们有系统性炎症证据并且患有动脉粥样硬化性心血管疾病或糖尿病。公开资料显示，clazakizumab是一种靶向白细胞介素-6（IL-6）配体的单克隆抗体，拟开发适应症包括治疗慢性活动性抗体介导的排斥反应（AMR）， AMR是肾移植受者长期排斥反应的主要原因，目前在国际范围内处于3期临床阶段；以及用于终末期肾病(ESKD)透析患者，目前在国际范围内处于2期临床阶段。 普方生物：注射用PRO1286 作用机制：EGFR与cMET靶向双特异性ADC 适应症：实体瘤 普方生物（已被Genmab公司收购）1类新药注射用PRO1286获批临床，拟用于治疗实体瘤患者。根据普方生物公开资料，这是一款在研的EGFR与cMET靶向双特异性抗体偶联药物（ADC）。它由一种对EGFR和cMET具有微调亲和力的双特异性人IgG1抗体和专有的基于拓扑异构酶1抑制剂的连接药物sesutecan组成。Sesutecan是普方生物研发的新型亲水性载荷连接子，它极其亲水稳定并可裂解的，有望改善了小分子载荷的疏水性，并优化了ADC的整体理化性质。 信诺维：注射用亚胺培南西司他丁钠福诺巴坦 作用机制：抗菌药物复方制剂 适应症：医院获得性细菌性肺炎和呼吸机相关性细菌性肺炎 信诺维医药申报的注射用亚胺培南西司他丁钠福诺巴坦获批临床，拟用于18岁及以上的患者，治疗由对本品敏感的革兰阴性菌，包括鲍曼不动杆菌，大肠杆菌（如肺炎克雷伯杆菌，大肠埃希菌），铜绿假单胞菌引起的以下感染：医院获得性细菌性肺炎和呼吸机相关性细菌性肺炎（HABP/VABP）。公开资料显示，亚胺培南、西司他丁钠均为抗生素产品，福诺巴坦（XNW4107）是信诺维正在研发的新一代β-内酰胺酶类广谱抗耐药菌药物，目前正在进行全球多中心3期临床研究。 强生：Bleximenib胶囊 作用机制：Menin-KMT2A相互作用抑制剂 适应症：急性髓系白血病 强生（Johnson & Johnson）1类新药bleximenib胶囊获批临床，拟用于治疗携带组蛋白-赖氨酸N-甲基转移酶2A重排（KMT2Ar）或核磷蛋白1基因突变（NPM1m）的复发/难治性急性髓系白血病（AML）成人患者。公开资料显示，bleximenib是一款Menin-KMT2A相互作用抑制剂，正在国际范围内开展1/2期临床研究。目前，Menin抑制剂被认为是一种治疗白血病的有前景的新疗法，尤其是对那些携带KMT2A基因重排或NPM1基因突变的AML患者。 希格生科：SIGX1094R片 作用机制：靶向FAK的创新药 适应症：晚期实体瘤 希格生科1类新药SIGX1094R片获批临床，拟开发治疗晚期实体瘤。根据希格生科新闻稿介绍，这是该公司整合类器官疾病模型与AI研发出的针对FAK的创新靶向药物，拟用于治疗弥漫性胃癌及其他晚期实体瘤。该产品在弥漫性胃癌以及晚期腹水的临床前模型中表现出较好的治疗潜力，并在卵巢癌、三阴性乳腺癌及胰腺癌等恶性转移性癌症的治疗中展现出优异效果。目前该药物已获美国FDA和中国NMPA的IND批件，即将在中美开展临床试验。 Areteia Therapeutics：dexpramipexole片 作用机制：小分子嗜酸性粒细胞成熟抑制剂 适应症：重度嗜酸性粒细胞性哮喘 Areteia公司申报的dexpramipexole片获批临床，拟用于成人和≥12岁青少年重度嗜酸性粒细胞性哮喘患者的新型（非甾体类）口服附加维持治疗。公开资料显示，dexpramipexole是一种口服小分子药物，研究人员在临床开发过程中验证该产品具有嗜酸性粒细胞靶向作用，它可以通过抑制骨髓中的嗜酸性粒细胞的成熟和释放，治疗嗜酸性粒细胞性哮喘。该产品目前正在开展国际多中心3期临床研究，是一款潜在“first-in-class”嗜酸性粒细胞成熟抑制剂。 蓝纳成生物：18F-LNC1007注射液 作用机制：双靶点放射性体内诊断药物 适应症：诊断FAP和αvβ3阳性的成人实体瘤 蓝纳成生物1类新药18F-LNC1007注射液获批临床。这是一种新型双靶点放射性体内诊断药物，同时靶向成纤维细胞活化蛋白（FAP）和整合素αvβ3（αvβ3)，拟用于诊断FAP和αvβ3阳性的成人实体瘤。根据蓝纳成新闻稿介绍，18F-LNC1007可以进一步提高肿瘤的诊断效率，在临床前研究和临床转化研究中，该产品能够显著延长肿瘤摄取时间、提升肿瘤靶向效率，并具有良好的肿瘤成像质量，有希望在未来成为一种非侵入性示踪剂用于FAP和/或αvβ3阳性表达患者的临床诊断。 正大天晴：TQB2253注射液 作用机制：生物制品1类新药 适应症：晚期恶性肿瘤 正大天晴1类新药TQB2253注射液获批临床，拟开发治疗晚期恶性肿瘤。目前尚未从公开渠道查询到该产品的作用机制，从受理号可知这是一款生物制品新药。 汇宇海玥医药：注射用HY07121 作用机制：靶向PD-1/TIGIT/IL-15的三靶点抗体融合蛋白 适应症：晚期实体瘤 根据汇宇制药公告，注射用HY07121（项目研发代号为HY-0007）为该公司全资子公司汇宇海玥自主研发的抗PD-1、抗TIGIT、IL-15/IL-15Rα双抗融合蛋白。体外药效学研究表明，该产品通过特殊设计获得的多抗分子在等摩尔数情况下，刺激人免疫细胞因子IFN-γ分泌水平比三个靶点联合用药表现出更优的潜力。该产品具备增强肿瘤免疫治疗疗效及克服免疫耐药的作用机制，本次获批临床的适应症为晚期实体瘤。 康方生物：AK137注射液 作用机制：CD73/LAG-3双抗 适应症：晚期恶性肿瘤 康方生物1类创新药AK137注射液获批临床，适应症为晚期恶性肿瘤。公开信息显示，AK137注射液是一款CD73/LAG-3双特异性抗体。根据公开渠道查询，目前全球以CD73或以LAG-3为靶点的在研新药已经处于后期临床研究阶段，但尚无同时靶向CD73及LAG-3的双抗新药获批临床。 百利药业：GNC-077多特异性抗体注射液 作用机制：多特异性抗体 适应症：实体瘤 百利药业申报的GNC-077多特异性抗体注射液获批临床，拟用于包括但不限于非小细胞肺癌、小细胞肺癌、鼻咽癌、头颈癌、食管癌、结直肠癌、乳腺癌等实体瘤。根据百利天恒早前公布的招股书资料，这是百利天恒基于多特异性抗体开发平台（GNC平台）开发的创新多特异性抗体分子。其分子结构中有靶向T细胞CD3及靶向T细胞免疫检查点的抗体结构域，以及靶向肿瘤抗原的抗体结构域。GNC-077可有效诱导naïve T细胞的激活、分化、增殖，可引导激活的T细胞靶向杀伤肿瘤抗原阳性的肿瘤细胞。 百济神州：注射用BGB-C354 作用机制：靶向B7-H3的ADC 适应症：晚期实体瘤 百济神州1类新药注射用BGB-C354获批临床，拟开发治疗晚期实体瘤患者。公开资料显示，BGB-C354是一款靶向B7-H3的ADC，是百济神州在实体瘤领域布局的一款新分子实体。百济神州此前已经在美国和澳大利亚启动一项1期临床研究，评估BGB-C354单独或与抗PD-1抗体替雷利珠单抗联合用于晚期实体瘤患者的安全性、耐受性、药代动力学和初步抗肿瘤活性。 参考资料： [1]中国国家药监局药品审评中心（CDE）官网. Retrieved Sep 21，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]各公司官网及公开资料 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

The new program's forthcoming database will fill in the knowledge gaps by first compiling existing data from various entities. In 2015, after spending nearly four decades grinding his way up the ladder at one of the world’s most prolific construction equipment companies, Ed Rapp was nearing its apex. He had risen from humble beginnings in a town of fewer than 800 people to presiding over Caterpillar Inc.’s massive Resource Industries division. He was in the running to become CEO.   Then the rug was pulled out from under him. Rapp was diagnosed with the incurable neurodegenerative disease amyotrophic lateral sclerosis—also known as ALS, or Lou Gehrig’s disease—and forced into early retirement.    “Thirty-seven years at Cat, you know, two sick days and 12 months from potentially being the CEO of the company, when you get an ALS diagnosis, and you’ve got two to five years to live,” he recalled to Fierce Biotech Research in an interview.   Rapp, 67, has clearly outlived that prognosis and has taken advantage of the extra time by channeling his ambition into the quest to find better therapies and diagnostic tools for ALS. Now, he’s co-chair of a working group in a new effort to change how the disease is diagnosed and treated: the Accelerating Medicines Partnership in Amyotrophic Lateral Sclerosis, or AMP ALS, a five-year, $60 million public-private partnership announced May 21 by Foundation for the National Institutes of Health (FNIH), an independent nonprofit that supports the work of the NIH. “This is the first time we’re going to have all the leading organizations working in ALS from the for-profit side and the non-profit side working together,” Alessio Travaglia, Ph.D. director of neuroscience at the FNIH, said. “That’s the main reason why this initiative is going to be so powerful.” Slow progress   Despite advances in research, therapies and massive awareness campaigns, the prognosis for ALS patients hasn’t moved much in the last few decades, Dave Shulman, 46, a Wells Fargo executive who was diagnosed with ALS in 2023, told FBR.  “[When I was first diagnosed,] I wondered, 'Why are we 10 years out from the Ice Bucket Challenge, over 80 years out from Lou Gehrig’s famous speech, and more than 150 years out from when ALS was first identified by a researcher, and we’re still not at a place where we can meaningfully slow, stop or reverse the disease?'” he said. “And what are the underlying reasons why so many ALS clinical trials fail?” Recent years have seen some big steps forward, like the 2023 FDA approval of Biogen and Ionis Pharmaceuticals’ Qalsody, or tofersen, which slows symptom progression in ALS patients with a mutation in the protein SOD-1. But that subgroup makes up just 2% of the disease population. The two drugs that are FDA-approved for all ALS patients, Covis Pharma’s Rilutek and Mitsubishi Tanabe’s Radicava, have only “modest” effects, according to James Berry, M.D., a neurologist and ALS researcher at Massachusetts General Hospital.  “We are lucky to be in an era when we have seen the development of newer more effective therapies for ALS than ever before,” Berry said in an email. But the tempered efficacy of ALS drugs that work across subtypes suggests that they might be acting on mechanisms that occur after damage-causing cascades are already underway, he explained, which limits how much of an impact they can have, even if they do apply to all patients.   Other major drawbacks, like the removal of Amylyx’s ALS drug Relyvrio from the market in April, underscore the challenge of developing ALS drugs.     “So, while we do have more treatment options today than we have ever had in the past, we still have a long way to go,” Berry said.   ALS is a complicated disease, to put it mildly. And while decades of research have lent insight into the basic mechanisms and the contribution of factors like SOD-1 mutations, there’s still a black box around its natural course and what kinds of biomarkers are associated with progression, Steph Fradette, vice president and head of neuromuscular development at Biogen and a steering committee member of AMP ALS, told FBR.   “The foundational challenge is that we’re still coming to understand the underlying pathophysiology of ALS,” she said. “There are exceptions to that rule and we are making a lot of progress as a field, but we still have a lot of uncertainty about what is actually causing the disease, what are the downstream implications of that cause and then, of course, how to address it.”   The win with Qalsody aside, Biogen like other companies has weathered its share of ALS drug failures, most recently with an Ionis-partnered candidate called BIIB105. That drug wasn’t as far along as the company’s first attempt at an ALS therapy—dexpramipexole—which failed a phase 3 trial in 2013, but it suffered from the same blind spots with regards to efficacy.  “Over the past several years we’ve found ourselves, like with dexpramipexole, in a situation where we have false positive and false negative trial results,” Fradette said. That has led to conversations within the field about what endpoints are really indicative of progress as well as about the tools used to measure them, she added. That’s not to say there’s been no improvements, of course: Qalsody was approved on the basis of reductions in a marker called plasma neurofilament light chain (NfL), a protein that is increasingly being used as an indicator of neuronal damage in neurological drug trials.    But it took longer to get NfL assays out of academic labs and into industry practice than if an initiative like AMP ALS had existed, Fradette said. And it’s hard to go further without knowing how the disease progresses naturally—which is impossible without biological samples from patients, both living and deceased. Although there are currently disparate efforts to collect these on the part of government and nonprofit organizations, there are still too few, Travaglia said.   “We don’t have enough post-mortem samples or longitudinal samples. We have to rely on just one single data point, meaning we take patients today and analyze those samples, but we don’t know how those biomarkers are going to progress,” he explained.   Beyond a shot in the dark     The ALS AMP’s database will fill in the knowledge gaps by first compiling existing data from various entities then getting more from patients and those at risk of ALS based on what’s missing. Seven biotechs, seven nonprofits and two government agencies—the FDA and the NIH's National Institute of Neurological Disorders and Stroke—are involved in the creation of the database. Representatives from the entities will sit on a steering committee that decides what information is needed, then the FNIH and NIH will put out requests for proposals and issue grants to researchers to collect it. “More than anything, I think that bringing together these different datasets and knowledge across the different people at the table will help accelerate that understanding in a way that anyone or group of us can do on our own,” Fradette said.   Besides identifying biomarkers and therapies that might be useful for ALS patients in general, the effort may also delineate groups of patients with certain genetic factors that cause them to develop ALS, like those with the SOD-1 mutation. This could eventually make it possible to treat ALS with personalized medicines like the ones used for cancer, Julie Gerberding, M.D., president and CEO of the FNIH, said in an email.  “The program will focus on comprehensive data collection and analysis that can help identify subgroups within the ALS population,” Gerberding said. “These subgroups might have distinct underlying causes that will allow researchers to develop targeted therapies specific to the subgroups.”  For Rapp, Shulman and many other patients who are involved in AMP ALS, progress can’t come soon enough.   “There is pretty good acceptance that ALS is not a single disease—it’s more like cancer where you have different variations,” Rapp said. “But until you understand that, I think any drug trials are a bit of a shot in the dark because you’ll never know if you have the right subgroup of patients.” Editor's note: This article was updated May 29 to clarify that the FNIH is an independent nonprofit and to update the number of biotechs, partners and nonprofits participating in AMP ALS, as well as to adjust some details about how the program works. Travaglia's last name was also misspelled in an earlier version and was corrected.