SARM1

CINCINNATI--(BUSINESS WIRE)-- Asha Therapeutics (Asha) ( ), a life sciences company designing de novo disease modifying medicines for neurodegenerative diseases with high unmet medical need, announced today the nomination of a development candidate, ASHA-624 targeting SARM1 as a potential disease modifying therapy for Amyotrophic Lateral Sclerosis (ALS) with additional indications in Chemotherapy-Induced Peripheral Neuropathy (CIPN), Glaucoma, and traumatic brain and spinal cord injuries. This announcement follows the Company’s presentation of robust efficacy and safety data on its second lead neurology program, ASHA-091 in Alzheimer’s disease and Parkinson’s disease by Chief Scientific Officer & Scientific Co-founder Dr. Bradlee Heckmann earlier this month at the AD/PD 2024 International Conference in Lisbon, Portugal (see full release here). Dr. Michael Gold, MD, MS, a member of Asha’s Scientific Advisory Board noted, “SARM-1 is a well-validated therapeutic target that could yield novel therapies for patients suffering from a range of both central and peripheral nervous disorders. ASHA-624 prevents the activation of SARM-1 using a completely novel approach that has the potential to deliver a therapy with robust clinical efficacy and few, if any, off-target side effects. As a veteran CNS drug developer, I am excited to see this compound continue its progress towards clinical trials.” “Nomination of ASHA-624 as a development candidate for clinical translation in ALS, alongside Asha’s previously nominated ASHA-091 compound with indications in Alzheimer’s disease, Parkinson’s disease, and ALS, is a key juncture for Asha in supporting our mission of providing novel disease modifying therapies for conditions with current treatment options limited largely to symptomatic standard of care. We are committed through our work to the transformation of patient outcomes, and believe ASHA-624 is a significant step forward towards achieving that goal,” commented Dr. Heckmann, PhD. About ASHA-624: ASHA-624 is a first-in-class, novel intra-molecular glue compound that exploits the normal biology of SARM1, a key protein that promotes axonal degeneration and neurodegeneration by selectively “gluing” activated SARM1 into an inactive conformation, leading to robust neuroprotection through the prevention of axon and neuron loss. In ALS, the activation of SARM1 leads to axonal loss, neurodegeneration and ultimately motor dysfunction. ASHA-624 was designed to inhibit SARM1 with hyper selectivity, and in preclinical studies has demonstrated a robust safety pro a functional cure in models of ALS. ASHA-624 therapeutic intervention in preclinical models of ALS reversed motor impairment and dysfunction to similar levels as healthy controls while placebo treated groups exhibited continual and exacerbated decline in motor function. About ALS: Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that affects nerve cells (neurons) in the spinal cord and brain. Loss of motor neurons in ALS patients leads to loss of muscle control, resulting in impaired motor function. ALS ultimately affects the regulation and control of muscles which are required for speaking, eating, and breathing. There is currently no available cure for ALS, and the disease is fatal. Asha anticipates the advancement of ASHA-624 and ASHA-091 into clinical trials by late-2024 for their respective disease indications. About Asha Therapeutics: Asha Therapeutics ( ) is a life sciences company at the forefront of a new era of precision drug design, leveraging the power of its proprietary PRISM™ technology to design de novo compounds to create disease-modifying and curative therapeutics for neurological and infectious diseases with high unmet medical need. Asha's lead therapeutic programs, ASHA-624 and ASHA-091 with indications in Amyotrophic Lateral Sclerosis, Parkinson's disease and Alzheimer’s disease, are anticipated to enter clinical trials by late-2024 and are disease modifying therapeutics. Forward-Looking Statements The matters discussed in this release that are not historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and we intend that such forward-looking statements be subject to the safe harbor created thereby. Forward-looking statements include, but are not limited to, statements containing the words “believes,” “anticipates,” “intends,” “estimates,” “plans,” “expects,” “projects” and words of similar import. Readers are cautioned not to place undue reliance on these forward-looking statements, which are based on the information available to management at this time and which speak only as of the date of this release. The Company undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. These forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results, performance or achievements of the Company or its industry to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. While the Company believes the information contained herein is reliable, the Company makes no representations or warranties regarding the accuracy or completeness of this information.

2017年，李嘉诚在服用了烟酰胺核糖（NR）保健品后，大赞其“服用后感觉回到了20岁”，并一举投资了2500万美元。2019年初，称自己“从不相信保健品”的潘石屹，曾发微博大力宣传了一款保健品，其主要成分也是NR。曾经，只出现在神话故事中的“长生仙丹”竟成为现实，还受到众多大佬投资人的追捧，并被称为“人类的未来”？！究竟是“医学奇迹”还是“狂割韭菜”呢？图源：网络“长寿药”NR到底是什么？NR是重要辅因子烟酰胺腺嘌呤二核苷酸（NAD+）的前体。其实，人们之所以关注NR，更是因为它与NAD+之间密不可分的关系。NAD+是生物体氧化还原反应中非常重要的辅酶，能以还原形式NADH为线粒体电子传递链提供来自糖酵解和三羧酸循环的电子——形象地说，NAD+是“燃料”，使得线粒体中氧化磷酸化过程成为可能，即帮助二磷酸腺苷（ADP）转化为三磷酸腺苷（ATP）。此外，NAD+的另一大作用是：作为多种酶促反应的辅底物。尤其是长寿因子Sirtuins和ADP-核糖基转移酶两大蛋白质家族，在ADP-核糖（ADPR）的使用和烟酰胺（NAM）的释放过程中需要消耗NAD+。除此之外，SARM1、CD38和CD157/BST1均需要消耗NAD+，但释放出NAM和ADPR/环状ADPR。哺乳动物体内NAD+生物合成和代谢的途径鉴于NAD+在代谢、衰老、细胞死亡、DNA修复和基因表达等各种生物学过程中的重要意义，人们开始探究NAD+或NAD+的前体物质（比如NR、β-烟酰胺单核苷酸NMN）作为补充剂带来的潜在健康效益。在细胞水平上，NR的吸收由平衡型核苷转运蛋白家族介导。进入细胞后，NR可以被NR激酶（NRK1和NRK2）磷酸化成为NMN，或者在嘌呤核苷磷酸化酶的作用下脱核糖成为NAM。无论是上述两种情况的哪一种，原则上这些转化都会进入补救合成途径，进一步产生NAD+。多项临床前研究已证实，NR对新陈代谢有益：小鼠模型显示，补充NMN或NR能够显著逆转衰老并延长寿命。紧接着在2016年，科研学者首次在人群中开展了NR相关的临床试验，以测试其作为人体补充剂的安全性和有效性。近年来，为了明确烟酰胺给人体代谢健康和严重疾病的益处，越来越多的试验涌现了出来。那么，作为口服补充剂，NR在人群临床试验中的表现如何？果真是“长寿不老药”吗？最新综述结果令人意外！不过，Science Advances上最新综述结果却给了大家“当头一棒”！来自哥本哈根大学健康和医学科学学院的研究团队评估了目前已发表的25篇前沿文献，均与人类NR补充剂的临床试验有关。总结来说，口服NR补充剂几乎没有临床相关效果，同时这些研究结果有“夸大”的嫌疑。当然，也不能全盘否定NR，其在减轻炎症状态和治疗严重疾病的方面具有一定的潜力。但如果想将NR视作“唐僧肉”，可能要大失所望了。DOI: 10.1126/sciadv.adi4862在这篇综述中，研究者依次论述了25项人体临床试验，包括没有安慰剂组的试验、设有安慰剂对照的平行设计试验、设有安慰剂对照的交叉设计试验，以及NR与紫檀芪（PT）联合使用的临床试验。本文中论述的第一篇文章还要追溯到2016年，Trammel等人首次开展了NR补充剂的人类临床试验。这是一项未设安慰剂组的试验，更准确地来说本项试验的样本数为1——一名体重为65kg的52岁健康男性，在一周内每天早上服用1000mg的NR。结果显示，在服用NR后，这名参与者的外周血单核细胞（PBMCs）中的NAD+和NAAD水平稳定增长。此外，尿液中的NAM、MeNAM、Me2PY和Me4PY均有所增加，说明补充NR后NAD相关化合物的排泄量也会有所增加。为了更有说服力，研究者又开展了一项包含12名参与者的小型人体试验，使用100-1000mgNR。在口服NR的前24和8个小时内，分别观察到NAD+和NAAD水平的增加，但NAM和NMN则没有变化。也就是说，口服NR能增加PBMC中NAD代谢物含量，但并未说明其“延寿”的作用。全部文章总结不过，在一项针对帕金森病患者的试验中，研究者观察到，每天接受1000mgNR能够增加大脑中NAD，提高脑脊液中Me2PY水平；而在肌肉中，NR治疗还增加了NAAD、NAMOX、Me2PY和Me4PY的水平。因此，该研究的作者认为，NR治疗能够增加脑内NAD及其代谢物，或能改善帕金森病。然而，在心力衰竭试验中，连续12周接受从500mg/天持续升至2000mg/天的NR，并未观察到呼吸以及炎症标志物的变化。同时，针对12名老年人的交叉设计试验显示，每天补充1000mgNR几乎无法改变肌肉的生物利用度，比如肌肉线粒体功能、底物利用率或血流、GTT期间的抓地力，甚至肝、肾和甲状腺功能标志物均没有改变。......综合来看，得到的结论令人大跌眼镜：补充NR的临床效果可以说是微乎其微。回顾历史，自2016年首次开展人体NR试验以来的7年多时间里，有不少试验涌现了出来。然而，总结迄今为止的大部分试验可以发现，NR唯一一个具有可重复性的健康益处是：减少全血或免疫细胞中的炎症标志物。有部分试验显示，口服NR补充剂能够增加全血中的NAD+以及相关代谢物，偶尔也能增加PBMCs中的NAD+。而除了血液之外，绝大多数的研究局限于大脑和肌肉——在大脑中，NR对NAD的促进作用还是非常鼓舞人心的，但没有证据显示口服NR能提高肌肉中NAD+水平。本综述的作者强调，事实上，有些文献的结果有些“言过其实”，即过度解读了口服NR补充剂的意义。举例来说，在某些研究中，NAAD、MeNAM、Me2PY和Me4PY水平的增加被视作“NAD+代谢增加”的指标；但真实情况是，这些NAD相关代谢物不一定非要经过NAD+的通量。口服补充NR后，主要循环NAD+前体是NA和NAM。理论上来说，NAM会被回收并进入NAD+库，但也可以直接甲基化从而排出体外。在肌肉中，这一现象变得尤为明显。虽然NAM能被肌肉有效吸收，但却不能很好地转化为NAD+。也就是说，肌肉中的MeNAM、Me2PY和Me4PY水平增加并不是通过NAD+的通量，而是意味着囤积了大量的NAM且急需排出。因此，口服NR无法等价于“补充肌肉中NAD+水平”，自然也不能很好地改善肌肉力量、线粒体功能和运动表现。读到这儿，相信大家对于口服NR补充剂有了更深的了解。是“灵丹妙药”还是“对韭当割”？大家的心中应该已经有了自己的答案。但对于NR也不必“一棒子打死”，在降低血液中炎症标志物、治疗某些严重的疾病以及高血压等方面还是具有一定的前景的，值得后续深入的研究。参考资料：[1]Damgaard MV, Treebak JT. What is really known about the effects of nicotinamide riboside supplementation in humans. Sci Adv. 2023 Jul 21;9(29):eadi4862. doi: 10.1126/sciadv.adi4862. Epub 2023 Jul 21. PMID: 37478182; PMCID: PMC10361580.撰文 | Swagpp编辑 | Swagpp● 补充这种常见的维生素，真能抗癌？Nature子刊：能激活抑癌基因，诱导血管正常化，提高免疫疗效● 国家卫健委：新冠可能在本月回升！乙流占比超甲流，疼到骨头里，乙流是王中王？31%网友反复中招，为了老人，有人过年不回家了● 这个禁食法，有效减重7kg！国人研究团队：禁食不仅能有效减肥，还改变了大脑和肠道菌群！版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。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。点击下方「阅读原文」 立刻下载梅斯医学APP！

- NB-4746 is being developed as a neuroprotective therapy for neurological diseases - Milestone marks Nura Bio’s transition to a clinical-stage company SOUTH SAN FRANCISCO, CA, USA I August 25, 2023 I Nura Bio, Inc. (Nura Bio), a biopharmaceutical company developing neuroprotective, small molecule therapies for the treatment of debilitating neurological diseases, today announced the initiation of the Phase 1 clinical trial of its SARM1 inhibitor, NB-4746. NB-4746 is believed to be a first-in-class, oral, brain-penetrant, neuroprotective SARM1 inhibitor with broad therapeutic potential across diseases of the central, peripheral, and ocular nervous systems. NB-4746 confers significant structural and functional protection in several preclinical disease models including Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Traumatic Brain Injury (TBI), and Chemotherapy-Induced Peripheral Neuropathy (CIPN). In preclinical models, NB-4746 significantly reduced and in some cases prevented, an increase in levels of the axonal injury-dependent, disease-associated biomarker neurofilament light (NfL). “We are excited about the potential of NB-4746,” said David Lau, PhD, Senior Vice President, Development Sciences, Nura Bio. “We expect to enter clinical trials in a patient population in 2024, to evaluate the impact of NB-4746 on axonal injury and NfL levels.” The Phase 1 clinical trial is a randomized, double-blind, placebo-controlled, single ascending dose and multiple ascending dose study to assess the safety, tolerability, and pharmacokinetics of NB-4746 in healthy volunteers. “The initiation of the Phase 1 trial of NB-4746 marks Nura Bio’s transition to a clinical-stage company,” said Shilpa Sambashivan, PhD, Chief Scientific Officer, Nura Bio. “With our strong scientific foundation and dedicated team, we are rapidly progressing NB-4746 through early development. We also continue advancing additional molecules through our pre-clinical pipeline, with the goal of delivering novel and potentially life-changing neuroprotective medicines.” About NB-4746 NB-4746 is the lead asset in Nura Bio’s small molecule pipeline. NB-4746 targets SARM1, a neuronally enriched NAD hydrolase that has emerged as an important axon-intrinsic metabolic sensor and central driver of axon degeneration. Axon degeneration is an early hallmark of several neurological diseases. Halting axon degeneration early can confer significant structural and functional neuroprotection and has tremendous potential in the treatment of several neurological diseases. About Nura Bio Nura Bio, Inc. (Nura Bio) is a clinical-stage biopharmaceutical company developing neuroprotective therapies for the treatment of a broad range of neurological diseases. Nura Bio’s research and early development small molecule pipeline spans discovery through Phase 1. Nura Bio’s efforts are focused on developing therapies that halt axon degeneration and/or modulate microglial responses to degeneration and injury, with the goal of conferring neuroprotection, across diseases of the central, peripheral, and ocular nervous systems. For more information, visit www.nurabio.com . SOURCE: Nura Bio