QRL-201-01—A Multi-center, Randomized, Double-blind, Placebo-controlled Multiple Ascending Dose Study to Evaluate the Safety and Tolerability of QRL-201 in Amyotrophic Lateral Sclerosis
Angela Genge1, Kristiana Salmon1, John Polzer1, Clarida Martinez1, Bryan Boggs1, Victoria Eon1, Rakhee Ganti1, Sandy Hinckley1, Kristina Johnson1, Daniel Elbaum1
1QurAlis Corporation
Objective:
Evaluate the safety and tolerability of QRL-201 in people living with amyotrophic lateral sclerosis.
Background:
A hallmark of amyotrophic lateral sclerosis (ALS) in >90% of patients, is the presence of cytoplasmic TAR DNA Binding Protein 43 (TDP-43) aggregates and loss of nuclear expression. Loss of nuclear TDP-43 leads to Stathmin-2 (STMN2) mis-splicing, resulting in decreased expression in the majority of people living with ALS. STMN2 is important for neural repair, axonal stability, and neuromuscular junction innervation. Our therapeutic approach is to correct STMN2 mis-splicing, thereby restoring protein function. QurAlis has shown that this can be accomplished using a splice switching antisense oligonucleotide (ASO) in non-clinical studies. QRL-201 is an investigational ASO that rescues STMN2 expression and protein function in QurAlis’ patient-derived neuronal disease models, even in the continued presence of TDP-43 pathology.
Design/Methods:
QRL-201-01 is a double-blind, multiple-ascending dose study in which approximately 64 people living with ALS will receive QRL-201, or matching placebo, in a 6:2 ratio. The study design includes six dose escalation cohorts and two exploratory cohorts. This study includes the collection of data on numerous biomarkers, employs sentinel participant dosing, and includes multiple safety reviews.
Results:
The primary endpoint will be incidence of adverse events. The secondary endpoints will be measurements of multiple dose pharmacokinetics (PK). This study will include multiple exploratory endpoints – 1) biomarkers of neuronal loss and STMN2 biology; 2) clinical outcome measures (ALSFRS-R, ROADS, SVC, HHD, electrophysiology testing); and 3) CSF PK profile.
Conclusions:
QurAlis’ mission is to bring breakthrough precision medicine technology to people living with ALS. QRL-201-01 is designed to evaluate the safety and tolerability of multiple doses of QRL-201 in people living with ALS, and explore the hypothesis that restoration of STMN2 is a suitable disease-modifying approach in ALS.