RYR1

关注并星标CPHI制药在线       运动疲劳是发生于多器官、多细胞和多分子水平上的一连串事件，其产生的内在机制非常复杂。根据各种生理诱发因素的作用途径、位点和方式可以将运动疲劳分为外周疲劳和中枢疲劳。外周疲劳通常被定义为肌肉功能的受损，而中枢疲劳是指大脑无法维持产生所需动力或输出所需能量的驱动力，指的是运动神经元和中枢神经系统内部的过程。       虽然中枢疲劳的产生机制仍不完全清楚，但研究表明，中枢疲劳可能与某些神经递质的消耗或积累有关。5-羟色胺(5-HT)在中枢神经系统中主要作为神经递质发挥生理功能，其以色氨酸作为原料在色氨酸羟化酶(TPH)等酶的催化作用下合成。研究认为，5-HT在神经元中的浓度变化与中枢疲劳密切相关，5-HT在脑组织中的累积会造成中枢疲劳。现有研究成果认为，造成5-HT在神经元细胞中的累积主要是通过血脑屏障氨基酸转运体调节的，5-HT的合成前体色氨酸与支链氨基酸（BCAA）竞争性地通过血脑屏障氨基酸转运体从血液进入神经元，在长时间、高强度运动过程中，血液中的BCAA被大量消耗，造成更多的色氨酸进入神经元，产生更多的5-HT以致过量累积，最终造成中枢疲劳。       多巴胺(DA)是中枢神经系统中含量最丰富的儿茶酚类神经递质。研究表明，DA可以抑制5-HT合成途径中的限速酶TPH的活性，进而抑制5-HT的形成。研究发现，中枢神经系统中5-HT/DA较低时可以提升运动表现，而其比例较高时会降低机体的兴奋度，降低运动的协调性和积极性，造成中枢疲劳。另外，根据巴甫洛夫学派的观点，大脑产生的保护性抑制引发了运动疲劳。在高强度的脑力或体力运动时，大量冲动刺激大脑皮质相应的神经元，产生长时间兴奋，为避免糖原等能量物质过多消耗，当达到一定程度时，大脑皮层会产生保护性抑制作用，产生疲劳感提醒身体停止运动，在长时间高强度的运动中，血浆支链氨基酸的含量会减小，使芳香族氨基酸(AAA)/支链氨基酸(BCAA)值增加，此外，疲劳时大脑中的γ-氨基丁酸含量增加，也会导致大脑皮层产生抑制。       能量耗竭、代谢产物蓄积、氧化应激和Ca2+代谢紊乱是当前疲劳产生机制的主流学说，它们对肌肉和中枢神经系统的影响可能直接导致了疲劳的产生。       1、能量物质耗竭       三磷酸腺苷(adenosine triphosphate，ATP)是人体各项生命活动中的直接能源物质， 此外还有糖类、脂肪、蛋白质等营养物质为机体运动间接供能。运动时，磷酸原系统、乳酸能系统、有氧氧化系统为生命活动提供能量。当能量供应充足时，肌肉组织工作正常，从而完成运动过程，随着运动时间的延长或运动强度的提高，机体逐渐依赖肝脏和肌肉中的糖原分解供能。当糖原产生的能量无法维持需求且得不到及时补充时，机体就会出现外周疲劳。       研究发现，机体运动的持续时间和强度是通过影响能源物质消耗速率从而影响运动疲劳产生：在短时间、高强度的运动中，ATP-CP 系统提供主要能量，体内ATP和磷酸肌酸等高能磷酸物含量下降，当疲劳产生时，肌肉中的磷酸肌酸含量降至运动前的20%，在长时间、低强度的运动中，有氧氧化系统提供主要能量，糖原作为储能物质被分解用以供给运动消耗和维持血糖平衡，长时间的运动会大量消耗糖原，产生运动性疲劳。动物实验发现，当狗运动至疲劳时，血糖含量下降，注射肾上腺素，机体对肌组织的糖利用率提高，使血糖浓度升高，狗的运动能力明显恢复。此外，脂肪水解会产生大量的自由脂肪酸，血浆游离脂肪酸的累积会促进游离色氨酸的增加，过多的色氨酸进入脑内则会引起5-羟色胺水平上升，从而抑制大脑工作能力，加强中枢疲劳。       2、代谢产物积累       相对于静息状态下，运动员在高强度运动时消耗更多能源物质，同时也产生更多的代谢产物(乳酸、NH4+、H+等)，如果这些代谢产物不能被及时清除，将会对正常的物质代谢造成通道堵塞，导致肌肉组织运动功能下降，产生运动性疲劳。在高强度运动中，运动员主要通过乳酸能系统供能，体内糖原(葡糖糖)缺氧分解产生乳酸，随着运动强度的增加，体内乳酸含量持续堆积，剧烈运动时，肌肉乳酸含量可达40 mmol/kg湿重， 血乳酸可达18 mmol/L，乳酸解离产生H+降低内环境pH 值，抑制磷酸化酶和磷酸果糖激酶活性，从而抑制乳酸能系统供能，造成ATP供应不足，产生疲劳感。此外，脑细胞对血液酸碱度的变化非常敏感， 血液pH值下降，可造成脑细胞工作能力下降。研究证实，乳酸含量越高，机体运动功能下降越明显，疲劳恢复期增长。人体运动时肌肉收缩还可产生 NH4+(AMP经脱氨酶催化)， 当体内ATP被大量消耗时，体内氨含量增高，氨含量增高可促进糖酵解反应，产生乳酸和 H+，导致一些酶活性降低甚至失活，乳酸和氨共同作用使身体机能下降，产生疲劳。研究表明，体内NH4+的生成与运动强度呈正相关，在运动过程中，由于氨基酸代谢增强及肌肉中二磷酸腺苷浓度升高，引起血氨浓度上升，抑制柠檬酸脱氢酶活性，影响机体能量代谢及运动平衡，甚至引起肌肉痉挛。研究证实，血氨含量升高后可进入脑组织，对大脑细胞有神经毒性作用，破坏谷氨酸和 γ-氨基丁酸的平衡，导致中枢疲劳产生。       3、氧化-抗氧化系统失衡       长时间、高强度运动会导致机体氧化-抗氧化系统的失衡，引发氧化应激症状，造成细胞内自由基的累积，诱发蛋白质、脂类物质的氧化损伤，最终导致运动疲劳。还原型谷胱甘肽(glutathione，GSH)是机体内一种重要的抗氧化物质，其通过清除自由基维持氧化还原稳态。研究表明，马拉松跑和高强度自行车运动后，运动员血浆中的GSH浓度显著下降30%。       运动过程中自由基的生成与肌肉收缩强度有关。短暂或低强度的肌肉收缩诱导生成的活性氧（ROS）/NO水平具有增强骨骼肌收缩相关蛋白如Ca2＋释放通道蛋白（RyR1）和肌钙蛋白I（troponin I）的S-亚硝基化和S-谷胱甘肽酰化作用，从而提高肌原纤维的钙敏感性及增强骨骼肌收缩力量；而运动产生过量ROS/NO时可引起RyR1超S-亚硝基化致使其与亚基calstabin1分裂，肌原纤维的钙敏感性受到抑制，导致骨骼肌收缩功能及力量输出受损。此外，自由基与物质输送有关。在安静状态下，机体内的氧化应激处于较低水平，适量的自由基具有促进血管舒张的作用，增强O2和营养物质的流通；而过高的自由基水平却会抑制血管扩张并且减少血液流量，引起身体各组织器官如骨骼肌、心脏、皮肤和大脑所需的O2和营养物质的供应不足，加速疲劳的产生。       4、Ca2+代谢紊乱       Ca2+在细胞内神经-肌肉信号传导、有氧运动产生的运动性疲劳中为重要的调控因子。研究发现，高浓度的Ca2+长时间存在于胞浆中可以诱发正常肌细胞的凋亡，肌细胞内钙稳态失调最终会导致肌肉疲劳及损伤。此外，运动引起胞浆Ca2+浓度增加，线粒体具有缓冲调节胞浆Ca2+浓度的功能，当疲劳发生时，引发细胞膜系统脂质过氧化反应， 线粒体膜对Ca2+的通透性增加，大量 Ca2+进入线粒体，出现钙反常，过量的钙离子积累又会抑制线粒体的氧化磷酸化过程，使氧化磷酸化脱耦联，ATP 生成减少，进而造成细胞钙离子代谢紊乱， 形成恶性循环，引起不同程度的肌肉疲劳及损伤。       参考资料       [1]赵静.运动疲劳机制及食源性抗疲劳活性成分研究进展[J].食品安全质量检测学报，2021，12(09):3565-3571.       [2]倪冰倩，李秀婷，张成楠等.天然物质抗运动性疲劳活性分子机理的研究进展[J].食品研究与开发，2023，44(10):208-214.       [3]陈慧，马璇，曹丽行等.运动疲劳机制及食源性抗疲劳活性成分研究进展[J].食品科学，2020，41(11):247-258.       作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。【智药研习社课程预告】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~

▎药明康德内容团队编辑本期看点1. “明星”小分子ziftomenib联合标准治疗的早期数据亮眼，特定初治急性髓系白血病（AML）患者100%获得了完全缓解（CR）。2. 用于治疗遗传性血管水肿（HAE）的在研体内CRISPR基因编辑疗法NTLA-2002早期临床数据亮眼，单次给药后使所有患者的月度发作率平均下降了95%。3. 首个获美国FDA许可进入临床试验的RNA外显子编辑疗法ACDN-01被授予快速通道资格。药明康德内容团队整理Ziftomenib：公布1期临床试验数据Kura Oncology公司公布了ziftomenib联合标准治疗，包括阿糖胞苷/达柔比星（7+3）和维奈托克/阿扎胞苷（ven/aza），治疗NPM1突变型（NPM1-m）和KMT2A重排型（KMT2A-r）急性髓系白血病患者的1期临床试验的初步数据。Ziftomenib是一种针对menin与KMT2A/MLL蛋白复合体之间相互作用的在研候选药物，用于治疗有高度未满足需求，携带特定基因突变的AML患者。在临床前模型中，ziftomenib抑制了KMT2A/MLL蛋白复合体，并表现出强大的抗白血病活性。Ziftomenib已获得FDA授予的孤儿药资格，用于治疗AML。这款在研新药曾被猎药人网站（drughunter.com）列为2022年度10大“明星”小分子之一。截至2024年1月11日的数据，在新诊断的NPM1-m型和KMT2A-r型AML患者中，接受ziftomenib联合7+3治疗的CR率为100%；未接受过menin抑制剂治疗的难治/复发（R/R）性AML患者接受ziftomenib联合ven/aza治疗，CR/完全缓解伴部分血液学恢复（CRh）率为56%。安全性方面，连续每天服用200 mg ziftomenib的耐受性良好，其安全性与基础疾病和主要治疗方法的特征一致。NTLA-2002：公布1期临床试验的中期数据Intellia Therapeutics公司在《新英格兰医学杂志》（NEJM）上公布了其在研体内CRISPR基因编辑疗法NTLA-2002的1/2期临床试验的中期分析结果。NTLA-2002旨在使用CRISPR/Cas9技术对激肽释放酶B1（KLKB1）基因进行编辑，该基因负责编码激肽释放酶前体蛋白。通过让KLKB1失活，NTLA-2002可永久性降低激肽释放酶活性，以达到治愈HAE的目的。NTLA-2002包含靶向致病基因的指导RNA（gRNA），和编码Cas9酶的mRNA，它们共同开展精准编辑。结果显示，在最近一次随访中，单次给药NTLA-2002使所有患者（n=10）的HAE月度发作率平均下降了95%；在16周的主要观察期后，所有血浆激肽（kallikrein）水平降低超过60%以上的患者（n=9）仍然完全没有发作，最长的无发作间隔期已达13.0个月，并且还在持续；在所有在使用NTLA-2002后停止长期HAE预防治疗的患者（n=6）中，自停止治疗后还没有报告过HAE发作。此外，NTLA-2002在所有剂量水平上都有良好的耐受性。报告的最常见的不良事件是轻度、短暂的输液相关反应和疲劳。ACDN-01：IND申请获得FDA许可Ascidian Therapeutics公司宣布其在研RNA外显子编辑疗法ACDN-01的IND申请已经获得美国FDA的许可，并被授予快速通道资格。ACDN-01是一种在体内编辑RNA外显子的RNA编辑疗法。它通过单一载体递送，已在非人类灵长类动物的体内实验以及人类视网膜的体外实验中显示出有效且持久的RNA外显子编辑。与其它只修改一个RNA碱基的RNA编辑器不同，ACDN-01的独特之处在于能够重新书写RNA序列，将导致疾病的RNA序列替换为功能正常的RNA序列，具有使用一种疗法，治疗多种基因突变导致的Stargardt病的潜力。此外，RNA编辑疗法与基于CRISPR的基因组编辑疗法相比，由于不会对基因组序列产生永久影响，可能具有更高的安全性。新闻稿指出，ACDN-01是首个获美国FDA许可进入临床试验的RNA外显子编辑疗法，并且是首款专门针对Stargardt病遗传起源的临床期治疗方法。Ascidian预计在2024年上半年开始招募参与ACDN-01针对Stargardt病及其他ABCA4相关视网膜病变的1/2期临床试验STELLAR的患者。JAG201：IND申请获得FDA许可Jaguar Gene Therapy公司宣布，美国FDA已经批准了其用于治疗遗传性自闭症谱系障碍（ASD）和Phelan-McDermid综合征（PMS）的基因疗法JAG201的IND申请。JAG201旨在通过AAV9载体提供SHANK3基因的功能拷贝，持久地恢复学习和记忆所需的突触功能，从而从根本上治疗ASD和PMS。啮齿动物和非人灵长类动物的临床前研究表明，递送功能性SHANK3可改善神经行为、认知和运动功能异常。该公司计划于2024年下半年在美国启动一项1期试验，针对SHANK3突变或缺失的ASD或PMS成人患者。Deltacel：公布1期临床试验中首例患者的数据Kiromic BioPharma公司公布了其在研γ-δ T细胞（GDT）疗法Deltacel用于治疗转移性非小细胞肺癌（NSCLC）的1期临床试验的积极初步数据，该疗法在首例患者中展现出良好的早期疗效结果。Deltacel是一种同种异体细胞治疗产品，由未经修饰的供体来源GDT组成。Deltacel旨在利用GDT的天然效力靶向实体瘤，最初的临床开发重点是NSCLC（约占肺癌病例的80%至85%）。两项临床前研究的数据表明，Deltacel与低剂量放射治疗相结合具有良好的安全性和有效性。积极的初步证据证明了Deltacel在控制NSCLC生长方面的疗效。Deltacel的耐受性仍然良好，进一步证实早期安全性评估结果。首例患者在比佛利山癌症中心（BHCC）接受了治疗，并在开始治疗前三天被确诊为病情进展活跃的患者。接受Deltacel治疗六周后，CT扫描证实了此患者的病情稳定，初步的无进展生存期为一个半月。Risvodetinib：公布1期临床试验数据Inhibikase Therapeutics公司公布了其c-Abl抑制剂risvodetinib治疗老年帕金森病（PD）患者的1期临床试验的数据。结果显示，risvodetinib单次或多次给药在所有受试者中表现出良好的安全性和耐受性。健康受试者中未出现严重不良事件，服用抗PD药物的PD患者也未出现症状恶化。该公司正继续积极招募患者参加其2期试验，以评估risvodetinib对未经治疗的帕金森病患者的治疗效果。ARM210（S48168）：公布1b期临床试验数据ARMGO Pharma公司公布了其靶向ryanodine受体钙释放通道（RyR）的小分子药物ARM210（又称S48168）的1b期研究结果，该药拟用于治疗一种罕见的肌肉疾病——ryanodine受体1型相关肌病（RYR1-RM）。该1b期研究证实了每天服用120 mg和200 mg ARM210在RYR1-RM患者中的安全性和耐受性，并首次在临床上展现了每日服用200 mg ARM210可改善患者疲劳和近端肌力的迹象。此外，该研究还证实了ARM210能够通过修复由突变的RyR1通道造成的细胞内钙泄漏以恢复肌肉功能的作用机制。EC5026：启动1b期临床试验EicOsis Human Health宣布启动一项1b期多剂量递增试验，以评估其小分子候选药物EC5026的安全性。EC5026是一种强效、高选择性的可溶性环氧化物水解酶（sEH）抑制剂，在调节信号脂质的代谢、响应由创伤或疾病引起的炎症和其他应激反应方面发挥着至关重要的作用。通过抑制sEH，EC5026能阻止天然镇痛和抗炎脂肪酸的分解，从而缓解疼痛，是一种治疗中度至重度疼痛的潜在非阿片类药物。临床前研究表明，EC5026不会产生镇静或其他不良行为，也没有成瘾迹象。VTR-297：IND申请获得FDA许可Vanda Pharmaceuticals公司宣布，美国FDA已经批准了其小分子组蛋白脱乙酰酶（HDAC）抑制剂VTR-297用于治疗甲癣的IND申请。VTR-297具有抗皮癣菌和真菌的活性，最开始是作为一种抗真菌抗生素从酵母菌种Streptomyces hygroscopicus中被分离出来，于1976年首次被描述。自2014年以来，美国FDA尚未批准任何新的甲癣治疗方法。启动VTR-297治疗甲癣的临床研究是研究和开发治疗这种常见疾病的潜在新疗法的一个重要里程碑。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Ascidian Therapeutics Announces First-Ever IND for an RNA Exon Editor as FDA Approves Trial Plan and Fast Tracks ACDN-01 in Stargardt Disease and Other ABCA4 Retinopathies. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/ascidian-therapeutics-announces-first-ever-ind-for-an-rna-exon-editor-as-fda-approves-trial-plan-and-fast-tracks-acdn-01-in-stargardt-disease-and-other-abca4-retinopathies-302046287.html[2] ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies. Retrieved January 30, 2024, from https://www.globenewswire.com/news-release/2024/01/29/2818472/0/en/ARMGO-Pharma-Publishes-Positive-Phase-1b-Trial-Results-of-Rycal-ARM210-for-the-Treatment-of-Ryanodine-Receptor-1-Related-Myopathies.html[3] Inhibikase Therapeutics Announces Publication Highlighting Results from its Phase 1 Studies with Risvodetinib. 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Retrieved January 30, 2024, from https://ir.lixte.com/news-events/press-releases/detail/101/first-patient-dosed-with-lixtes-lb-100-and-gsks-immunotherapy-dostarlimab-gxly-in-ovarian-clear-cell-carcinoma-trial[8] Uvax Bio Announces Dosing of First Participant in Phase 1 Clinical Trial Evaluating Two Vaccines to Prevent HIV-1 Infection. Retrieved January 30, 2024, from https://www.businesswire.com/news/home/20240129742089/en[9] EicOsis Initiates Phase 1b Clinical Trial of EC5026. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/eicosis-initiates-phase-1b-clinical-trial-of-ec5026-302047230.html[10] KURA ONCOLOGY REPORTS POSITIVE PRELIMINARY ZIFTOMENIB COMBINATION DATA IN ACUTE MYELOID LEUKEMIA. Retrieved January 31, 2024, from https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-reports-positive-preliminary-ziftomenib[11] Intellia Therapeutics Announces Publication of Positive Interim Phase 1 Data for NTLA-2002 in Patients with Hereditary Angioedema in the New England Journal of Medicine. Retrieved January 31, 2024, from https://www.globenewswire.com/news-release/2024/01/31/2821597/0/en/Intellia-Therapeutics-Announces-Publication-of-Positive-Interim-Phase-1-Data-for-NTLA-2002-in-Patients-with-Hereditary-Angioedema-in-the-New-England-Journal-of-Medicine.html[12] 23andMe Announces FDA Clearance of IND Application for its Dual Mechanism Antibody, 23ME-01473, Targeting ULBP6. Retrieved January 31, 2024, from https://www.globenewswire.com/news-release/2024/01/31/2820995/0/en/23andMe-Announces-FDA-Clearance-of-IND-Application-for-its-Dual-Mechanism-Antibody-23ME-01473-Targeting-ULBP6.html[13] Jaguar Gene Therapy Announces FDA Clearance of IND to Study JAG201 in a Genetic Form of Autism Spectrum Disorder and Phelan-McDermid Syndrome. Retrieved January 31, 2024, from https://www.businesswire.com/news/home/20240131087815/en[14] Vanda Pharmaceuticals Receives FDA Approval to Proceed with Investigational New Drug VTR-297 a Topical Antifungal Candidate for the Treatment of Onychomycosis. Retrieved January 31, 2024, from https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-receives-fda-approval-to-proceed-with-investigational-new-drug-vtr-297-a-topical-antifungal-candidate-for-the-treatment-of-onychomycosis-302049362.html[15] NeuroBo Pharmaceuticals Announces FDA Clearance of IND for a Phase 1 Clinical Trial of DA-1726 for the Treatment of Obesity. Retrieved January 31, 2024, from https://www.prnewswire.com/news-releases/neurobo-pharmaceuticals-announces-fda-clearance-of-ind-for-a-phase-1-clinical-trial-of-da-1726-for-the-treatment-of-obesity-302050383.html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。版权说明：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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies Phase 1b open label trial confirms safety and tolerability of 120 mg and 200 mg dosing of ARM210 daily in patients with Ryanodine Receptor 1 Related Myopathies Provides first signs of clinical efficacy improving fatigue and proximal muscle strength in patients at 200 mg daily Corroborates allosteric mechanism of action of Rycal® ARM210 to restore muscle function by repairing mutated ‘leaky’ Ryanodine Receptor 1 channels January 29, 2024 – ARMGO Pharma, Inc. (ARMGO), a clinical stage biopharmaceutical company advancing a novel class of small molecule drugs known as Rycals®, announced today the publication of the results from a Phase 1b study of its Rycal ARM210 (also known as S48168), for the treatment of Ryanodine Receptor 1 Related Myopathies (RYR1-RM), an orphan muscle disease. The data was published in a paper entitled ‘Rycal S48168 (ARM210) for RYR1-related myopathies: A phase one, open-label, dose-escalation trial’ authored by Dr Joshua Todd et al in the peer reviewed Journal eClinicalMedicine, part of the Lancet family of publications. The paper reviews data from the Phase 1b study of ARM210 and its novel allosteric mechanism of action (MoA) targeting the root cause of RYR1-RM: mutated Ryanodine Receptor 1 (RYR1). The RYR1 gene encodes RyR1, an intracellular calcium-release channel that becomes leaky in muscle diseases. Intracellular calcium leaks caused by mutant RyR1 channels impair muscle contraction leading to muscle weakness and loss of function, and activate toxic pathways that damage muscle, causing the symptoms in RYR1-RM. The Phase 1b, open-label, dose-escalation trial confirmed safety, tolerability and pharmacokinetics of 120 and 200 mg dosing of ARM210 daily over for 29 days in adult men and women affected with RYR1-RM. Importantly, it also demonstrated preliminary efficacy in the higher dose group in two hallmark symptoms of RYR1-RM: 1) significant alleviation of fatigue assessed by PROMIS-fatigue t-scores and 2) improved proximal muscle strength assessed by physical shoulder abduction exam (Medical Research Council grading). These results warrant further development of ARM210 as a potential disease modifying treatment for RYR1-RM in a randomized, placebo-controlled Phase 2 trial. The completed Phase 1b trial was conducted in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) under a Cooperative Research and Development Agreement (CRADA), with the support of the RYR-1 Foundation, Pittsburgh, PA, USA. “We are very pleased with the results of the RYR1-RM trial conducted together with the NIH, as the study has confirmed the safety and tolerability of ARM210, but most importantly, it has demonstrated for the first time that our Rycal®, ARM210, can reverse symptoms of this devastating, chronic muscle disease in a short treatment period. That is very promising”, said Gene Marcantonio, M.D., Ph.D., Chief Executive Officer of ARMGO Pharma. “We look forward, therefore, to rapidly continuing the development of ARM210 to bring this potential first treatment to RYR1-RM patients with the support of the RYR-1 Foundation and the patient community.” Michael F. Goldberg, M.D., M.P.H., Co-Chair of Research of the RYR-1 Foundation added, “We are elated by the publication of this important study, as it represents a beacon of hope for the many individuals and families from around the world who are affected by RYR1-RM. We look forward to the next stages in the development of this important drug.” Further information about this Phase 1b trial can be found online at: https://clinicaltrials.gov/study/NCT04141670. The trial was supported by Intramural Research Programs of the NIH/NINDS, NIH/NINR, a NIH Clinical Center Bench to Bedside Award (2017-551673) and ARMGO’s previous collaboration partner Les Laboratoires Servier. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publication reference: Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial, Todd et al, eClinicalMedicine https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00012-9/fulltext ARM210 (S48168) is a small molecule of the Rycal class, owned and developed by ARMGO for the treatment of Ryanodine Receptor mediated diseases such as RYR1-RM. It is an allosteric modulator that binds preferentially to leaky RyR channels and repairs the leak, as previously demonstrated in vitro in muscle biopsies from RYR1-RM patients. ARM210 (S48168) is currently undergoing Phase 2 clinical development for a second orphan indication, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a genetic arrhythmia caused by mutations in RYR2, the cardiac calcium channel gene. ARM210 (S48168) was awarded orphan drug designation for RYR1-RM in 2018 by the FDA and for CPVT in 2020. ARMGO also has a rare pediatric disease designation for CPVT. ARMGO Pharma, Inc., is a privately held biopharmaceutical company dedicated to developing novel small-molecule therapeutics to treat cardiac, and musculoskeletal disorders characterized by leaky Ryanodine Receptor (RyR) calcium channels. The Company’s proprietary drugs, known as Rycals®, are a new class of oral agents that repair these leaky calcium channels. ARM210, ARMGO’s most advanced Rycal, is currently in clinical development for two rare and orphan diseases, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a life-threatening cardiac disease and RYR1-Related Myopathy (RYR1-RM) a severe muscle disease. ARMGO Pharma has an exclusive, worldwide license from Columbia University for its RyR technology based on the research of founding scientist Andrew R. Marks, M.D. The Pittsburgh, Pennsylvania-based 501(c)(3) public charity was launched in October 2014. It is currently the only organization that exists solely to advocate for and serve the needs of individuals affected by RYR-1-related diseases (RYR-1-RD), the most common cause of congenital myopathy. The RYR-1 Foundation supports research leading to an effective treatment or a cure for RYR-1-RD. To achieve this mission, The RYR-1 Foundation has several goals: 1) Support Research: The RYR-1 Foundation makes grants to researchers interested in RYR-1-RD. Developing a patient registry is also key to promoting clinical trials of potential therapies. 2) Medical Professional Education: The vast majority of medical professionals have never heard of RYR-1-RD. The RYR-1 Foundation raises awareness through resources on our website, including the latest medical literature, as well as direct meetings with medical professionals around the world. 3) Patient/Family Support and Advocacy: Due to the rarity of RYR-1-RD, receiving this diagnosis can be an anxiety-provoking and isolating experience for an affected patient and their families. The RYR-1 Foundation serves as a resource for patients and their families through our website, other forms of social media, and family conferences. The content above comes from the network. if any infringement, please contact us to modify.