IPL-344

编者按：数据显示，每90分钟就会有人被确诊为“渐冻症”。患病者会逐渐失去说话、进食、甚至呼吸能力，最终被疾病无情吞噬，患者平均生存时间为2至5年。所幸，科学界不懈努力，持续向这一顽疾发起挑战，多款药物面世为患者带来了生活的改善，且当下近百款ALS管线也进入临床阶段，为迫切需要创新疗法的患者带来新的希望。作为全球医药及生命科学行业创新的赋能者，药明康德多年来也一直在支持包括渐冻症在内的神经系统疾病新药开发，以一体化、端到端的CRDMO服务平台，助力全球合作伙伴加速新药造福病患。每年6月21日被定为“世界渐冻人日”，这一天是二十四节气中的夏至，气温逐渐增高，可以融化冰块。这个日子不仅呼吁人们关注渐冻症这一疾病，更是一种寄托——希望温暖炙热的阳光，能够融化“渐冻症”患者逐渐僵硬的身体和心灵。“渐冻症”是肌萎缩侧索硬化症（ALS）的俗称，这是一种罕见的进行性神经退行性疾病，主要影响运动神经元，患病者会面临肌肉逐渐萎缩和无力，以至瘫痪，似乎身体被逐渐冻住一般，从无法行走到无法说话、吞咽、呼吸，最终导致呼吸衰竭。ALS协会数据显示，每90分钟就有一人被诊断出患有这种疾病。ALS患者的平均生存时间为2至5年，也有一些患者生存期可能更长。来自Mayo Clinic的数据显示，约10%的ALS患者是家族性遗传原因，其他患病原因尚不明确，目前大多理论集中在基因和环境因素的复杂相互作用方面。家族性遗传ALS可由多种基因突变引起，例如SOD1是常见的突变基因之一。“渐冻症”已被发现200多年，但治疗方法突破尚且有限。近30年来，一些治疗药物逐步面世，例如利鲁唑（riluzole）、依达拉奉（edaravone）、Relyvrio(苯丁酸钠和牛磺酸二醇口服固定剂量配方）和托夫生（tofersen）等，以延缓患者的病程进展并以及改善症状。尤其托夫生获批用于治疗具有超氧化物歧化酶1（SOD1）突变的患者，成为FDA批准的首款治疗遗传性ALS的反义寡核苷酸（ASO）疗法，也是首款基于生物标志物加速批准的ALS疗法。但由于疾病机制本身的复杂性等挑战，现有疗法依然无法完全阻止或逆转患者的神经退行性病变，临床上依然存在巨大未被满足的治疗需求。通过公开资料梳理，当下有近百款新药正处于积极的临床研究，探索治疗渐冻症的潜力。这些药物中，小分子占比过半，还包括寡核苷酸和多肽药物、细胞和基因治疗药物、抗体药物等。整体来看，随着对ALS疾病前沿研究的突破，新靶点和新机制药物正在不断涌现。图片来源：123RF新分子治疗ALS潜力凸显，寡核苷酸疗法率先突破在“渐冻症”新药领域，寡核苷酸药物的进展颇引人瞩目。渤健和Ionis Pharmaceuticals联合开发的托夫生于2023年获FDA批准上市，代表了这一疾病治疗领域的重要进展。托夫生注射液作为一种ASO药物，可通过减少SOD1蛋白合成，减少毒性SOD1蛋白的蓄积，从而减轻运动神经元的损伤，减缓疾病进展。这一获批是寡核苷酸药物用于治疗“渐冻症”的率先突破，更为SOD1突变患者带来了靶向治疗方案。Ionis Pharmaceuticals研发的另一款ASO疗法ulefnersen（又名jacifusen）也进入了3期临床研究阶段，该产品正在被开发用于治疗由融合肉瘤（FUS）基因突变引起的ALS患者。大冢制药于去年11月通过合作获得该产品的全球权益。研究显示，FUS突变在家族性ALS中的致病比例为5%。今年5月，《柳叶刀》发表的一项研究显示，jacifusen可显著降低FUS-ALS患者脑脊液中神经丝轻链（NfL，其升高是神经元/轴突损伤和退行性病变指标）浓度多达82.8%。在核酸药物领域，还有多款在研ALS疗法处于早期临床阶段，涵盖多个靶点。比如：uniQure 在研的AMT-162，其可表达一种可降低突变SOD1蛋白的miRNA，有望减缓甚至阻止SOD1-ALS的进展；中美瑞康在研的siRNA疗法RAG-17，旨在靶向并沉默SOD1基因的mRNA；QurAlis在研的靶向STMN2的ASO疗法QRL-201，STMN2为一参与神经修复和轴突稳定的蛋白质。研究表明，STMN2缺失导致轴突退化和肌肉内神经支配的丧失，是导致ALS患者瘫痪的主要功能缺陷；Amylyx在研的ASO疗法AMX0114靶向calpain-2，calpain-2是ALS轴突变性途径的关键因素，轴突影响神经元传递。该产品今年6月获FDA授予治疗ALS的快速通道资格。此外，今年4月另一则ALS新药进展也颇引人注意：Immunity Pharma的IPL344治疗ALS患者的2a期试验显示，与历史数据相比，IPL344治疗组患者的ALS功能评分量表修订版（ALSFRS-R）进展速度显著减缓58%至64%；接受治疗至少两个月的患者NfL水平降低27%；IPL344组未经调整的中位生存期为43.4个月，而历史对照组为19.1个月。IPL344是一种生物活性肽，能直接激活ALS患者体内受损的Akt通路，可针对ALS关键病理机制发挥作用。实际上，以寡核苷酸、肽类为代表的新分子不仅在“渐冻症”领域取得突破，也是更广泛的罕见疾病新药研发的重要方向。这类药物的研发和生产技术门槛高，创新突破还面临不少挑战。而且，由于ALS等罕见疾病患者数量有限，新药研发成本更高、周期更长，也一直是行业重大挑战。这些，都需要创新生态圈的共同应对。作为创新的赋能者，药明康德多年来通过其一体化、端到端的CRDMO新药研发平台，通过技术创新、高效协同和全链条服务，为全球合作伙伴提供从药物发现、开发、到商业化生产的全方位支持，助力提高新药研发效率，降低成本，并加速造福病患。例如在多肽、寡核苷酸领域，药明康德旗下专注于寡核苷酸和多肽及相关化学偶联药物的WuXi TIDES平台，正在赋能全球合作伙伴为各类罕见病药物开发提供重要支持。研发管线丰富，小分子占半壁江山小分子药物也是ALS新药研发的主要突破方向。在目前的ALS研发管线中，小分子数量过半，且有近十款小分子新药已经进入ALS研究的3期或2/3期临床阶段。进展较快的产品例如：NEUVIVO公司在研的小分子药物NP001 (sodium chlorite infusion)，已经于2024年12月向FDA递交上市申请，用于治疗ALS。NP001是一种小分子前药，在细胞内转化为taurine chloramine（TauCl），这一种经临床验证的调节剂，可以平衡先天免疫系统的促炎和抗炎过程，有望成为从免疫机制治疗ALS的药物。MediciNova在研的小分子药物MN-166 (ibudilast) 也进入治疗ALS的2/3期临床阶段，它可抑制4型磷酸二酯酶（PDE4）和炎性细胞因子，包括巨噬细胞迁移抑制因子（MIF），有望治疗多种神经退行性疾病如ALS；InFlectis BioScience在研的能穿透血脑屏障的小分子IFB-088（icerguastat）也在2a期试验中展示出良好安全性和潜在疗效。它能够选择性抑制真核翻译起始因子2B（eIF2B）的去磷酸化，增强综合应激反应，为细胞提供对抗各种应激的保护屏障。此外，抗体药物、基因治疗药物等更多类型的新药也陆续迎来新进展。比如：神济昌华研发的以TRIM72为靶点的基因治疗药物SNUG01在美国获批IND，适应症为ALS。福贝生物开发的抗体药物4B02-01注射液已经在中国获批临床，该产品有望通过特异性激活TrkB受体的下游信号通路，起到神经保护和修复作用。创新技术助力，加速ALS以及CNS疾病新药研发进程根据文献报道，当前“渐冻症”新药研发呈现出新的趋势和突破方向。例如，随着对ALS遗传驱动因素、异常压力反应和免疫机制等病理因素认识的逐渐深入，靶点研发呈现多元趋势，作用机制也向多通路干预转变；基于基因突变、脑脊液蛋白或影像学将患者人群细分，生物标志物如NfL作为疾病进展预测指标，也被越来越多用于临床试验设计。尤其值得注意的是，ALS作为一种神经系统疾病，其治疗必须将药物送入中枢神经系统（CNS），因此血脑屏障穿透技术的进步对该领域的新药研发突破至关重要。在合力突破的过程中，药明康德都以全方位的支持，助力合作伙伴加速疾病创新疗法的开发。以CNS疾病领域的血脑屏障穿透技术为例，公开信息显示，药明康德DMPK自2009年起开始进行CNS相关研究，拥有超过15年的临床前CNS药物研发经验，建立了针对CNS药物体外血脑屏障通透性评价的特色且准确性较高的“漏斗”模型。对于主要通过被动扩散入脑的CNS药物，“漏斗”模型的评估准确性为100%。通过完善的体外、体内测试平台，药明康德DMPK能够快速、准确、高效地对CNS药物进行全方位药代动力学相关评价，筛选出具有良好的脑通透性及稳定性的CNS候选药物。根据早前公开信息，该平台已完成包括常规小分子、治疗性蛋白、寡核苷酸等新分子实体类型项目百余项，成功助力全球客户多个CNS药物进入临床阶段。 再以当下多款在研ALS疗法采用的鞘内注射技术为例，这是一种将药物直接注入蛛网膜下腔（脑脊液循环系统）的技术，能够绕过血脑屏障，使药物快速作用于CNS。公开资料显示，药明康德DMPK突破传统技术局限，建立了一套特色鞘内递送系统，在大小动物模型中实现腰椎鞘内插管精准定位给药，将操作成功率提升至100%。该系统为临床前CNS药物的研发提供了标准化、高可靠性的技术能力，加速CNS靶向药物的研发进程。 当下，仍有大量ALS患者缺乏有效的治疗手段，这种致命疾病也仍有无数谜团需要科学家们探索。但我们相信，在创新和合作的驱动下，科学的进展终将冲破疾病的阴霾。期待更多创新疗法研发顺利，早日造福更多渐冻症患者。参考资料：[1]Amyotrophic lateral sclerosis (ALS) Overview.Retrieved May 16，2024, From https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022[2] Understanding ALS. Retrieved May 16，2024,  from https://www.als.org/understanding-als[3]Immunity Pharma Presents New Data Supporting the Efficacy of IPL344 in ALS. Retrieved Apr 07, 2025.From https://www.prnewswire.com/news-releases/immunity-pharma-presents-new-data-supporting-the-efficacy-of-ipl344-in-als-302421483.html[4]Amylyx Pharmaceuticals Receives U.S. FDA Fast Track Designation for AMX0114 for the Treatment of Amyotrophic Lateral Sclerosis .Retrieved Jun 3, 2025.From https://www.amylyx.com/news/amylyx-pharmaceuticals-receives-us-fda-fast-track-designation-for-amx0114-for-the-treatment-of-amyotrophic-lateral-sclerosis[5] NEUVIVO SEEKS FDA APPROVAL FOR ITS BREAKTHROUGH ALS TREATMENT NP001.Retrieved Oct 7, 2024.From https://www.neuvivo.com/news/neuvivo-seeks-fda-approval-for-its-breakthrough-als-treatment-np001[6]What are the current trends in Amyotrophic Lateral Sclerosis treatment research and development? .Retrieved Mar 12, 2025.From  https://synapse-patsnap-com.libproxy1.nus.edu.sg/article/what-are-the-current-trends-in-amyotrophic-lateral-sclerosis-treatment-research-and-development[7]演讲回顾 | 药明康德科学论坛广州站：“漏斗”模型助力CNS药物渗透性评估.Retrieved Dec 4，2024, From https://mp.weixin.qq.com/s/MXvyakDs2oQnt66VWWofsA[8]从腰椎到大脑：大鼠鞘内插管技术助力中枢神经系统（CNS）药物精准递送.Retrieved May 16，2024, From https://mp.weixin.qq.com/s/02lDYedix9yQnFwtBcBOEg版权说明：本文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：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。

Results from phase 2a trial in ALS patients were published in Muscle and Nerve. Statistically significant 58% to 64% slower ALSFRS-R progression rate in IPL344-treated patients compared to the matched PRO-ACT records. NfL was reduced by 27% for patients treated for at least two months. Unadjusted median survival for participants in the IPL344 group was 43.4 months compared with 19.1 months in the historical control group. IPL344 was safe and well-tolerated. JERUSALEM, April 7, 2025 /PRNewswire/ -- The results of a phase-2a clinical trial of IPL344 were published in Muscle and Nerve, the leading American scientific journal specializing in ALS and neuromuscular diseases. Slower ALSFRS-R Progression Following Treatment The nine study participants were treated for varying durations, averaging 11 months per participant, including one individual treated under a compassionate use protocol with comparable dose ranges. Multiple statistical methods were applied to assess the results of this study, primarily through comparison with PRO-ACT, the largest ALS clinical trials dataset available. ALSFRS-R progression rate was reduced by 58% (median, P=0.04) between each participant and their individually matched PRO-ACT control group (116 participants in a group on average). Adjustment for disease stage and rate-indicating covariates indicated a 64% slower ALSFRS-R progression (p = 0.034). All participants except one—who was treated for less than two months—exhibited slower disease progression than their matched controls, with 7 of the 9 progressing at least 40% slower. NfL Reduction and Survival Neurofilaments light chain (NfL), a biomarker for neuronal damage with increasing prominence in the evaluation of ALS studies, was measured before and after treatment. Six participants had blood sampling past the initial 28-day dose-escalating study. In these participants, plasma NfL concentrations were reduced from an average of 79.7 pg/mL at baseline to 58.6 pg/mL following treatment; a mean reduction of 27%. Unadjusted median [95% CI] survival for participants in the IPL344 group, including follow-up beyond treatment period, was 43.4 months [20.5, NA] compared with 19.1 months [17.4, 23] in a historical control group (the placebo group of the ceftriaxone study, selected as control for its particularly long duration). Additional Treatment Benefits IPL344 treated participants gained weight (+0.47 kg/month), while those in the historical PRO-ACT placebo control lost weight (−0.39 kg/month); the difference was statistically significant (p = 0.02) when corrected for covariates. With respect to the respiratory function, measured by slow vital capacity (SVC) adjusted for covariates, IPL344 treated participants had an adjusted mean change of −1.6% per month compared to −2.8% per month in the historical placebo, which is 44% slower. The preliminary data indicate that IPL344 was safe and well-tolerated. "There is a pressing need for therapies that can slow the progression of ALS beyond current options. The results observed in this open-label, small trial with IPL344 are good pilot data to inform design of next clinical trial, I do believe there are both scientific rationale and data to support going to a larger, randomized placebo- controlled trial." said Prof. Merit Cudkowicz, Executive Director, Mass General Brigham Neuroscience Institute, Massachusetts Boston. "I am pleased to share this publication with the broader community. The study participants were specifically selected for their rapid disease progression, and these initial results are encouraging. I am looking forward to seeing this drug evaluated in a larger clinical trial."" said Prof. Marc Gotkine, Principal Investigator of the study and Head of Neuromuscular and EMG Unit at Hadassah Medical Center, Jerusalem. "Despite the small size of study, we were able to demonstrate clinically meaningful improvements in the 5 endpoints assessed. We are encouraged by the magnitude and the consistency of the results. We thank Prof. Schoenfeld of Harvard medical school, for developing the statistical methods and performing the statistical analysis for this study. We also thank Prof. Shefner, the cofounder of NEALS and Prof, Cudkowicz for supporting our study design and evaluation" said Dr. Ilana Cohen, VP of R&D, Immunity Pharma. "We thank the study participants and their families for their partnership and support. We are encouraged by the potential of IPL344 to be transformative in the fight against ALS, given its initial efficacy across multiple clinical endpoints. This efficacy is driven by its unique mechanism of action that targets key biological processes underlying ALS. We are currently preparing for a large, placebo-controlled clinical trial to further evaluate IPL344 efficacy. If the current results will be reproduced in the larger study, they could offer meaningful benefits to individuals living with ALS." said Eran Ovadia, Immunity Pharma's CEO. Paper details: Marc Gotkine, David A. Schoenfeld, Ilana Cohen, Jeremy M. Shefner, Yossef Lerner, Irun R. Cohen, Colin Klein, Eran Ovadia and Merit E. Cudkowicz, "Akt Activation with IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open-Label Study". Muscle and Nerve. 19 March 2025. About the Phase 1/2a ALS Clinical Trial The Phase 1/2a trial is an open-label, dose-ranging study with once-daily IPL344 IV treatment (at home) for up to 3 years. The study includes a 28-day Phase 1 portion, followed by the Phase 2a portion of the study. The study was conducted at the Hadassah Medical Center, Jerusalem. All participants were rapidly progressing ALS patients. About IPL344 IPL344 is Immunity Pharma's lead drug candidate. IPL344 was discovered in the Weizmann institute of Science, Israel, at Prof. Irun Cohen's Laboratory. IPL344 is being developed as an intravenous injection for the treatment of ALS. IPL344 received orphan drug designation from FDA and EMA which grants exclusivity for at least seven years. About Immunity Pharma Immunity Pharma Ltd. (IPL) is a privately-held clinical-stage neurology-focused biopharmaceutical company that develops therapies for neurodegenerative diseases, with an initial focus on ALS. IPL's drugs are small biologically active peptides that stimulate therapeutic cell-signalling processes including activation of the Akt pathway which is down-regulated in neurodegenerative diseases. These drugs mitigate progression of neurodegenerative diseases by inducing survival-supporting processes and mitigating stress conditions. IPL's drugs are being developed as treatment for ALS, Parkinson's disease and other neurodegenerative diseases. For more information, please visit Contact: Eran Ovadia, [email protected] WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED