Intermediate-Size Expanded Access Trial of Autologous Hybrid TREG/Th2 Cell Therapy (RAPA-501) of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症是一种由神经炎症加速的致命性神经退行性疾病。目前FDA批准的 疗法的益处不大，而且不能解决炎症问题。为了解决这个问题，Rapa Treeutics，LLC (RAPA)已经开发出一种自体T细胞疗法(RAPA-501)，可以减少炎症，目标是 减少肌萎缩侧索硬化的发病率和死亡率。体外制造RAPA-501以获得双重Treg/Th2抗 炎症活性和T干细胞表型，允许T细胞治疗而不需要条件化疗。在……里面 一项正在进行的RAPA-501在ALS(PwALS)患者(NCT04220190)的临床试验中发现，RAPA-501细胞 安全(没有产品相关的不良事件)，生物活性(pwALS的多种抗炎作用)， 并显示出稳定肺功能下降的早期趋势。添加了2/3阶段扩展队列 以评估RAPA-501在标准风险pwALS中是否有效。 我们将把RAPA-501疗法扩展到不符合正在进行的2/3期试验或其他ALS试验的pwALS， 这几乎普遍要求参与者的慢肺活量(SVC)值为预测的≥的50% 很正常。拟议的EAP将招收SVC值为50%的pwALS。这群pwal是 被认为是“高风险”(约50%的几率在180天内发生呼吸衰竭或死亡)，因此特别适合 用于实验性免疫疗法，如RAPA-501。此外，RAPA-501-EAP将不排除pwALS ALS相关症状持续时间较长或ALSFRS-R得分较低的患者。参赛者将获得四个 RAPA-501静脉输注(以确定的安全剂量，每42天一次，80×106细胞/输液)。本RAPA-501-EAP 将进一步评估该疗法的安全性，扩大对RAPA-501治疗机制的了解 并使用标准方法和方法评估pwALS这一真实人群中的疗效信号 Origent Data Science机器学习ALS预测算法。 RAPA-501 EAP将由马萨诸塞州综合医院(MGH；Dr.Berry，Babu和 Paganoni)，由负责RAPA-501制造和FDA监管的RAPA赞助 根据现有IND 019480标准提交的文件(保荐人福勒博士)。临床试验现场调查人员有经验 RAPA-501疗法(MGH、哈肯萨克大学医学中心和亚利桑那州梅奥诊所)或其他细胞 治疗。地点的地理位置不同，可能会产生大量服务不足的pwALS(U 爱荷华州大学；爱达荷州大学；俄勒冈州波特兰普罗维登斯医院；加州大学欧文分校；哥伦比亚大学，纽约市)。此外，还有几个 研究合作将源于对临床注释的、有价值的研究的密集研究 从RAPA-501EAP获得的样本。

ALS is a lethal neurodegenerative disease accelerated by neuroinflammation. Current FDA-approved therapies have modest benefits and do not address inflammation. To address this, RAPA Therapeutics, LLC (RAPA) has developed an autologous T cell therapy (RAPA-501) that reduces inflammation, with the goal of reducing ALS morbidity and mortality. RAPA-501 are manufactured ex vivo to attain dual TREG/Th2 anti- inflammatory activity and a T-stem phenotype that permits T cell therapy without conditioning chemotherapy. In an ongoing clinical trial of RAPA-501 in people with ALS (pwALS) (NCT04220190), RAPA-501 cells were found to be safe (no product-related adverse events), biologically active (diverse anti-inflammatory effects in pwALS), and showed early trends toward stabilizing pulmonary function decline. A phase 2/3 expansion cohort was added to the trial to assess whether RAPA-501 is efficacious in standard-risk pwALS. We will extend RAPA-501 therapy to pwALS not eligible for this ongoing phase 2/3 trial or other ALS trials, which nearly universally require that participants have a slow vital capacity (SVC) value of ≥50% of predicted normal. The proposed EAP will enroll pwALS who have SVC values <50%. This population of pwALS is considered “high risk” (~50% chance of respiratory failure or death within 180 days) and thus particularly suitable for experimental immune therapies such as RAPA-501. In addition, the RAPA-501-EAP will not exclude pwALS who have a prolonged time from ALS-related symptoms or low ALSFRS-R scores. Participants will receive four RAPA-501 IV infusions (every 42-days at established safe dose, 80 x 106 cells/infusion). This RAPA-501-EAP will further evaluate the safety of this therapy, expand an understanding of the RAPA-501 therapeutic mechanism of action, and evaluate signals of efficacy in this real-world population of pwALS using standard methods and Origent Data Sciences machine learning ALS prediction algorithms. The RAPA-501 EAP will be led by investigators at Mass General Hospital (MGH; Drs. Berry, Babu, and Paganoni) and sponsored by RAPA, which is responsible for RAPA-501 manufacturing and FDA regulatory filings under existing IND 019480 (Dr. Fowler, Sponsor). Clinical trial site investigators have experience with RAPA-501 therapy (MGH; Hackensack University Medical Center; and Mayo Clinic Arizona) or other cells therapies. Sites are geographically diverse and likely to accrue a significant number of underserved pwALS (U of Iowa; U of Idaho; Providence Hospital, Portland, Oregon; UC-Irvine; Columbia, NYC). In addition, several research collaborations will emanate from the intensive study of the clinically-annotated, valuable research samples obtained from the RAPA-501 EAP.