Parkinson’s Drug Slows ALS Progression in Small Clinical Trial

Results from a small clinical trial show that the Parkinson’s disease drug ropinirole delayed the progression of amyotrophic lateral sclerosis (ALS) by an average of 27.9 weeks. The study is published in Cell Stem Cell.

New, effective ALS therapies needed

ALS, also known as Lou Gehrig’s disease, is a rare and fatal neurological disease that causes degeneration of the motor neurons that control the movement of our muscles. The disease is progressive, and patients gradually lose control of their muscles, leading to reduced mobility, speech problems and difficulty breathing.

There is no cure for ALS and no treatments capable of reversing the disease. The drug riluzole is approved for ALS patients but shows only modest benefits. As a result, research to find drugs capable of effectively slowing down the progression of ALS is sorely needed.

Previous studies have screened existing drugs already approved for other conditions to assess if any may also be beneficial for ALS. Ropinarole, a drug used in Parkinson’s disease, was identified in a screen that used motor neurons derived from induced pluripotent stem cells (iPSCs) of ALS patients. Now, researchers in the current study report the findings from a clinical trial of ropinirole in a small number of ALS patients, with its findings suggesting ropinirole slowed disease progression over a six-month period.

Slowing disease progression

The researchers recruited 20 patients with ALS that were being treated at Keio University Hospital in Japan. On average, the participants had been living with ALS for 20 months, and they also had no genetic markers predisposing them to the disease.

The study was double-blinded for an initial 24-week period where patients and researchers did not know who received ropinirole and who received a placebo. This was followed by a 24-week open-label phase in which participants wanting to continue the study, including those who initially received the placebo, knowingly received ropinirole.

However, many patients left the study during this second phase, in part due to the COVID-19 pandemic; no patients left due to safety concerns. Only 7 of 13 participants in the ropinirole group and 1 of 7 participants in the placebo-then-ropinirole group completed the full 48-week follow-up period.

The researchers used a variety of measures to assess how effective ropinirole was at slowing ALS progression, including participants’ physical activity, their ability to eat and drink on their own and changes in mobility, muscle strength and lung function.

Patients who received ropinirole during both phases of the trial gained the most benefit. They had higher physical activity and experienced a slower decline in mobility, muscle strength and lung function compared to those in the placebo group.

To find out the mechanism behind this effect, the researchers grew motor neurons in the lab derived from the participants' iPSCs. They found that ropinirole could reduce differences in the structure, gene expression and metabolite concentrations observed in ALS-affected neurons compared to healthy neurons.

For example, ropinirole increased the length of neurites (small processes found on developing neurons), which were shortened in the ALS neurons compared to healthy ones. Ropinirole treatment also decreased the expression of 29 genes related to cholesterol synthesis which were elevated in neurons from ALS patients. Finally, they also identified a potential biomarker, lipid peroxide, which could be used to estimate the effect of ropinirole both in vitro and in the clinic.

“We found a very striking correlation between a patient’s clinical response and the response of their motor neurons in vitro,” said Dr. Satoru Morimoto, lead author of the study. “Patients whose motor neurons responded robustly to ropinirole in vitro had a much slower clinical disease progression with ropinirole treatment, while suboptimal responders showed much more rapid disease progression despite taking ropinirole.”

Validation in further studies

The authors also acknowledge the limitations to the study as a result of the small sample size and high drop-out rate. “Interpretations of efficacy analyses in this study were limited by the small sample size of 20 participants. This was further compounded by the unexpectedly higher rate of discontinuation in this study compared with the historical rate in clinical trials of ALS […],” they write in the paper.

The researchers note that these lab-grown motor neurons could be used to predict how patients may respond to ropinirole, as it remains unclear why some respond differently to others. They hope to identify the underlying cause in future studies.

“ALS is totally incurable, and it’s a very difficult disease to treat,” said Prof. Hideyuki Okano, senior author of the study and physiologist at the Keio University School of Medicine in Tokyo. “We previously identified ropinirole as a potential anti-ALS drug in vitro by iPSC drug discovery, and with this trial, we have shown that it is safe to use in ALS patients and that it potentially has some therapeutic effect, but to confirm its effectiveness we need more studies, and we are now planning a Phase III trial for the near future.”

Reference: Morimoto S, Takahashi A, Ito D, et al. Ropinirole hydrochloride for amyotrophic lateral sclerosis: A single-center, randomized, double-blind, placebo-controlled phase 1/2a feasibility trial. 2023. Cell Stem Cell. doi: 10.1016/j.stem.2023.04.017

This article is a rework of a press release issued by Cell Press. Material has been edited for length and content.