Phase 1/2a, Double-blind, Placebo-controlled Study of Ropinirole Hydrochloride Remedy for ALS (ROPALS trial) Based On The iPSC Drug Repositioning
Shinichi Takahashi1,2,3, Satoru Morimoto1, Kensuke Okada2, Yugaku Daté2, Daisuke Ito2, Jin Nakahara2, Hideyuki Okano1
1Keio University School of Medicine, Physiology, 2Keio University School of Medicine, Neurology, 3Saitama Medical University International Medical Center, Neurology and Stroke
Objective:

In December 2018, we started an investigator-initiated clinical trial (UMIN000034954, JMA-IIA00397) testing ropinirole hydrochloride for amyotrophic lateral sclerosis (ALS). The aims are to assess the safety and tolerability as well as efficacy of ropinirole hydrochloride in patients with ALS.

Background:

No effective treatment has been established for ALS because of a limitation of animal model for drug development. Thus, we performed drug screening using motor neurons (MNs) derived from disease-specific-induced pluripotent stem cells (iPSC) for ALS and we found that ropinirole hydrochloride inhibited reactive oxygen species and the abnormal aggregation of TDP-43 or FUS, improved mitochondrial function, and prevented MN death (Fujimori K, et al. Nat Med 2018).

Design/Methods:
This is a phase I/IIa randomized, double-blind, placebo-controlled, single-center (Keio University, Japan), open-label continuation clinical trial (Morimoto S, et al. Regen Ther 2019). The major inclusion criteria were: 1) "clinically possible and laboratory-supported ALS", "clinically probable ALS" or "clinically definite ALS" according to the criteria for the diagnosis of ALS (El Escorial revised) and within 60 months after disease onset; 2) each ALSFRS-R score ≧2 points; 3) change in total ALSFRS-R score of -2 to -5 points during the 12-week run-in period. The primary aim is to assess the safety and tolerability of ropinirole hydrochloride. Secondary outcomes include: Combined Assessment of Function and Survival (CAFS), ALSFRS-R score, quantitative muscle strength and volume, and an efficacy evaluation using subjects-derived iPSCs/MNs.
Results:

A total of 29 patients have been recruited; 21 of these patients (13 men) are enrolled in the 24-week double-blind phase. At enrollment, the mean±SD disease duration was 20±11 months. ALSFRS-R score was 40±3 (3±1 reduction during the run-in period). The whole trial was completed in July 2020 and the results will be known by April 2021.

Conclusions:

Our trial will be a touchstone trial for iPSC-based drug repositioning and will provide promising data.