RAPA-501 Therapy for ALS

This is an open-label, non-randomized, multi-center phase 2/3 study evaluating RAPA-501 T stem cell therapy in pwALS on an expansion cohort. Amyotrophic lateral sclerosis (ALS) is a rare disease that is also considered an orphan disease according to the Orphan Drug Act.

After a subject consents to the study, an apheresis procedure will be performed to collect cells to manufacture the investigational product, RAPA-501 T stem cells. RAPA-501 T stem cells are manufactured ex vivo using epigenetic reprogramming to yield a T stem 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 stem 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.

Inclusion criteria

• Male or female patients ≥ 18 years of age.
• Patients with sporadic or familial amyotrophic lateral sclerosis (ALS) diagnosed as laboratory-supported possible, probable, or definite according to World Federation of Neurology El Escorial Criteria.
• . Less than or equal to 24 months since ALS symptom onset.
• Total ALSFRS-R score between 34 and 45.
• Must have a source of autologous T cells potentially sufficient to manufacture RAPA-501 cells, as defined by a peripheral CD3+ T cell count ≥ 500 cells per μl.
• Patients may continue riluzole (Rilutek®), and/or edaravone (Radicava®), and/or sodium phenylbutyrate/taurusodial (Relyvrio™) if on a stable dose for at least 30 days prior to the screening visit.
• Patients must be ≥ 2 two weeks removed from major surgery or investigational therapy.
• Patients must have recovered from clinical toxicities ([resolution of CTCAE(v5) [version 5] toxicity to a value of ≤ 2].).
• Serum creatinine ≤ less than or equal to 2.0 mg/dL.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN).
• Bilirubin ≤ 1.5 (except if due to Gilbert's disease).
• Pulmonary slow vital capacity (SVC) ≥ 70% of predicted normal.
• No history of abnormal bleeding tendency.
• Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient participant at any time without prejudice to future medical care.

Exclusion criteria

• Active uncontrolled infection.
• Hypertension not adequately controlled by ≤ 3 medications.
• History of documented pulmonary embolus within 6 months of enrollment.
• Clinically significant cardiac pathology, as defined by: myocardial infarction within 6 months prior to enrollment, Class III or IV heart failure according to NYHA, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Patients with history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis.
• HIV, hepatitis B, or hepatitis C seropositive.
• Pregnancy or breastfeeding patients.
• Patients of Subjects of childbearing age, or males who have a partner of childbearing potential, who are unwilling to practice contraception.
• Patients Subjects may be excluded at the Principal Investigator discretion of the PI or if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.