Phase 2/3 Trial of Autologous Hybrid TREG/Th2 Cell (RAPA-501) Therapy for Amyotrophic Lateral Sclerosis

This is an open-label, non-randomized, multi-center phase 2/3 study evaluating RAPA-501 T cell therapy in pwALS on an expansion cohort.

After a subject consents to the study, an apheresis procedure will be performed to collect cells to manufacture the investigational product, RAPA-501 T cells. RAPA-501 cells are manufactured ex vivo using epigenetic reprogramming to yield a T cell population that is enriched for a dual anti-inflammatory phenotype based on hybrid TREG and Th2 differentiation. RAPA-501 cells express both the TREG and Th2 transcription factors FOXP3 and GATA3, are enriched for expression of the ATP ectonucleotidase molecules CD39 and CD73, are enriched for the T cell homing molecule CD103, and suppress both effector T cell inflammatory molecules and CNS microglial cell inflammatory molecules.

This study consists of a phase 2/3 expansion cohort that is evaluating RAPA-501 T cell therapy at the dose of 80 x 10EE6 cells per infusion, with up to 4 infusions separated by six weeks between doses (infusion at time 0, and then after week 6, 12, and 18). Study subjects are then followed at the treatment site at 24 weeks and 30 weeks on-study; then, subjects are followed remotely using surveys for two years to capture major clinical events and assess survival. The primary objective in the expansion cohort is to determine the feasibility and safety of the highest established safe dose of RAPA-501 (80 x 10EE6 cells per infusion) in patients with standard-risk ALS (as defining by study entry values of: SVC greater than or equal to 70% of predicted normal; time interval since first ALS symptom, 24 months or less; and ALSFRS-R score between 34 and 45). Secondary study objectives relate to assessing the potential efficacy of RAPA-501 therapy through monitoring of ALSFRS-R scores, SVC values, time to King's stage transition, and survival. To enhance an ability to determine potential efficacy, these parameters will be compared to two comparator arms using machine learning algorithms developed by Origent Data Sciences, namely: (1) a virtual intra-patient control cohort (patient serves as own control); and (2) a comparator arm developed by prognostic mapping to the PRO-ACT database. In addition, secondary study objectives relate to study of pre- and post-therapy blood samples (serum and cells) for markers of inflammation and neurodegeneration.

In the initial phase 1/2 study design, patients received therapy on Cohort 1 (low-dose RAPA-501; 20 x 10EE6 cells per infusion), Cohort 2 (high-dose RAPA-501; 80 x 10EE6 cells per infusion), and Cohort 3A (low-dose RAPA-501 when administered after a 3-day host conditioning regimen consisting of pentostatin plus cyclophosphamide. At the time of study amendment to add the expansion cohort, some patients already enrolled to the phase 1/2 aspect of the trial will continue to receive their initially designated cohort therapy and follow-up evaluation.