Medical Technology

Ropinirole Proves Safe and Tolerable for Patients With ALS

Key Takeaway

  • Ropinirole hydrochloride (ropinirole) is safe and tolerable for patients with amyotrophic lateral sclerosis (ALS).

  • The results encourage a subsequent large-scale trial using ropinirole in ALS worldwide.

Why This Matters

  • ALS is a neurodegenerative disease with a median survival time of approximately 2 years. Muscle weakness eventually leads to respiratory failure and death.

  • Only two drugs have been approved by the US Food and Drug Administration for the treatment of ALS: riluzole (Rilutek) and edaravone (Radicava). Riluzole extends survival by 2-3 months with no reported benefits to muscle strength, whereas edaravone improves short-term functional outcomes but has no statistically significant effect on survival. As a result, the need for effective ALS therapies remains unmet.

  • Compared with other therapeutic areas, drug development for diseases of the nervous system has the second-lowest success rate at the pivotal phase. In particular, neurodegenerative diseases are heterogeneous and the majority of them are sporadic, limiting the translational potential of preclinical animal models.

  • By exploiting induced pluripotent stem cell-derived motor neurons generated from ALS patients, the investigators aimed to enable large-scale drug screening and overcome the limitations of preclinical animal models for the development of drugs to treat highly heterogeneous neurodegenerative diseases.

Study Design

  • Investigators previously used an induced pluripotent stem cell-based drug repurposing approach to demonstrate that ropinirole attenuated ALS-specific pathological phenotypes.

  • In this single-center, randomized feasibility, double-blind, placebo-controlled trial, they assessed the safety and feasibility of ropinirole in ALS patients to verify its efficacy.

  • The trial enrolled 20 participants with ALS Functional Rating Scale-Revised (ALSFRS-R) scores greater than 2 points and randomly assigned them using dynamic allocation to receive ropinirole or placebo for 24 weeks in the double-blind period.

  • Upon completion, participants could opt to participate in the following 24-week open-label active extension period.

  • The primary outcomes were safety and tolerability.

  • The secondary outcomes for the feasibility trial objective were the change in the ALSFRS-R score, composite functional endpoint, combined assessment of function and survival, event-free survival, and time to ≤ 50% forced vital capacity (blinded outcome assessment).

  • This study is registered with the UMIN Clinical Trials Registry, UMIN000034954.

Key Results

  • The primary outcomes of safety and tolerability were demonstrated.

  • Participants in the ropinirole group had lived an additional 27.9 weeks without disease progression events compared with the placebo group (log-rank test, 95% CI, 4.3 – 37.4) at 12 months (secondary outcome).

  • Regarding the feasibility of verifying efficacy, there were no significant differences in the ALSFRS-R score and combined assessment of function and survival scores during the double-blind period for 6 months.

  • Overall, the incidences of adverse events, most of which had been reported previously, were similar within both groups.

  • The incidence of gastrointestinal disorders (mainly, temporary mild nausea and diarrhea) was high at 76.9% in the ropinirole group (14.3% in the placebo group). 

Limitations

  • Interpretations of efficacy analyses in this feasibility study were limited by the small sample size of 20 participants.

  • There was an unexpectedly higher rate of discontinuation in this study than the historical rate in clinical trials of ALS. These discontinuation rates, particularly during the open-label extension phase, were attributable, at least in part, to the COVID-19 outbreak, which accounted for 23% and 29% of the participants in the ropinirole and placebo groups, respectively. The number of participants in the placebo group who discontinued the trial because of a worsening condition (47%) was higher than that in the ropinirole group (23%).

  • The placebo group had more bulbar onset, more female patients, and a lower BMI at baseline, which could be the relevant prognostic factors for ALS.

  • The onset of disease is self-reported and can be influenced by the sensitivity and character of an individual patient, rendering it difficult to confirm the accuracy of the period of disease duration.

Study Disclosures

  • This clinical trial was sponsored by K Pharma, Inc. The study drug, active drugs, and placebo were supplied free of charge by GlaxoSmithKline K.K.

  • Lead author Satoru Morimoto, MD, PhD, reports grants from Keio University School of Medicine during this study.

This is a summary of a preprint research study by Satoru Morimoto, MD, PhD, and colleagues  from Keio University School of Medicine, Tokyo, Japan provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on medRxiv.org.

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