Highlights
- •Ropinirole, identified via iPSC screens, was tested for safety/efficacy in ALS
- •Ropinirole is safe and well tolerated in ALS patients
- •Lipid peroxide in the CSF is a potential biomarker to assess disease progression
- •Ropinirole potentially inhibits the SREBP2-cholesterol synthesis pathway
Summary
iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in respiratory failure and death. There are currently three Food and Drug Administration (FDA)-approved drugs for ALS, but they only provide limited benefits, and there remains a need for effective therapies. Drug development for nervous system diseases has a low success rate, and preclinical animal models have limited translational potential. Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from ALS patients can overcome these limitations for drug screening. Ropinirole hydrochloride, a dopamine D2 receptor (D2R) agonist commonly used for Parkinson’s disease, was identified as a treatment candidate for ALS in a drug screening analysis. Previously, we established iPSCs derived from 32 sporadic ALS (SALS) patients and induced LMNs. Among 32 LMNs, 22 of 24 LMNs with cell damage and neurite regression demonstrated increased apoptosis. Finally, we confirmed that ropinirole hydrochloride improved multiple phenotypes of ALS in 16 of 22 LMNs (72.73%).
Here, we present the results of the ropinirole hydrochloride remedy for ALS (ROPALS) single-center, randomized, placebo-controlled phase 1/2a feasibility trial, which evaluated the safety, tolerability and efficacy of ropinirole with the following parameters: the revised ALS functional rating scale (ALSFRS-R) score, composite functional endpoints, event-free survival, and time to ≤50% forced vital capacity (FVC) of the ropinirole hydrochloride extended-release tablet (Requip CR) in participants with ALS (Figure 1).
Results
Characteristics of participants
From December 3, 2018 to September 12, 2019, we screened 29 participants, of whom 21 completed the run-in period and were randomized. Before drug administration, one participant withdrew because of protocol deviation. Among the remaining 20 participants, 13 received ropinirole, and 7 received a placebo. Of the 18 participants who completed the last dose at week 24 in the double-blind period, 8 completed follow-up visits 24 days after the last dose at week 48 in the open-label active extension period (Figure 2). This was a small-scale phase 1/2a randomized control trial. Two more participants were allocated to the placebo group than planned originally (3:1) due to dynamic allocation; as a result, the number of participants in the placebo group was seven instead of five, with an allocation ratio of 2:1. According to Kang et al., at the initial stages of a clinical study or for trials with small sample sizes, simple randomization can cause an extreme imbalance among the treatment groups by random chance alone.
