Parkinson’s therapy ropinirole may slow ALS progression: Trial data
Slower functional decline seen in patients given therapy at start of study
Early treatment with ropinirole, a medication used to treat Parkinson’s disease, may slow disease progression in amyotrophic lateral sclerosis (ALS) patients, according to recently published data from a Phase 1/2 trial.
Patients given the therapy showed slower functional declines and delayed disease progression over those who started treatment after a six-month delay.
“With this trial, we have shown that [ropinirole] 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 3 trial for the near future,” Hideyuki Okano, MD, PhD, a physiologist at the Keio University School of Medicine, Tokyo, and the study’s senior author, said in a news release.
The study, “Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery,” was published in Cell Stem Cell.
Sold under the brand name Requip, ropinirole is approved to treat the motor symptoms of Parkinson’s disease. It mimics the activity of the nerve signaling chemical molecule dopamine in the brain.
Researchers have recognized that ropinirole could suppress ALS-associated cellular damage in patient-derived motor neurons, the nerve cells that are progressively lost in ALS. This has suggested the treatment may benefit people with the condition.
To investigate, the researchers launched the ROPALS Phase 1/2 trial (UMIN000034954) in 2018, which enrolled 20 adults with sporadic ALS at a single center in Japan. The patients had begun having their first symptoms about two years before enrolling.
Slowing ALS disease progression
The participants were randomly assigned to receive 2-16 mg ropinirole (13 people) or a placebo (seven people), once a day for 24 weeks, or about six months. Seventeen participants then entered an open-label extension phase, where all continued receiving ropinirole up to an additional six months. Seven people in the ropinirole group and one originally assigned to a placebo completed an entire year.
No study discontinuations were related to side effects, with the treatment being found generally safe and well tolerated. Common side effects associated with ropinirole during the main trial included constipation (61.5%), nausea (38.5%), sleepiness (30.8%), and headache (23.1%).
Those given ropinirole had significantly higher daily physical activity levels relative to the placebo group in the main trial, although both groups had similar rates of functional declines, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R).
Differences began to emerge between the groups during the extension phase, however, where those who started on ropinirole exhibited a significant slowing of ALSFRS-R declines relative to those initially on a placebo. Early starters lost a mean of 7.64 points in their ALSFRS-R scores over the main trial and extension period. This was significantly less than the 17.51 points lost by those who started treatment six months later.
The findings were similar when ropinirole-treated patients were compared to a matched external group from an ALS patient registry who weren’t given the treatment.
Other measures of disease severity, including lung function, muscle strength, and a combined assessment of functional decline and survival, tended to favor ropinirole over a placebo.
These functional benefits were associated with about a twofold lower risk of disease progression. The time to reaching a specific disease progression event or dying was also significantly prolonged by an additional mean 27.9 weeks — a little over six months.
Predicting treatment response in vitro
To learn more about ropinirole’s mechanisms in ALS, the researchers used stem cells from participants to grow motor nerve cells in the lab. They found motor nerve cells from ALS patients showed distinct differences from cells derived from healthy people, some of which ropinirole was able to normalize.
Specifically, it normalized nerve cell projection (neurite) lengths, which are reduced in ALS, and reduced the activity of genes related to cholesterol synthesis, which is also abnormal in ALS.
Still, “the precise mechanism of action of ropinirole in ALS warrants further investigation,” the researchers wrote.
The cells from patients who responded best to treatment in the clinical trial also showed the greatest changes in response to ropinirole in the lab.
“We found a very striking correlation between a patient’s clinical response and the response of their motor neurons,” said Satoru Morimoto, MD, a neurologist at Keio University and the study’s first author. “Patients whose motor neurons responded robustly to ropinirole in vitro [in the lab] had a much slower clinical disease progression with ropinirole treatment, while suboptimal responders showed much more rapid disease progression despite taking ropinirole.”
Levels of a molecule called lipid peroxide — which is involved in the metabolism of fats like cholesterol — was found to be a good biomarker for estimating ropinirole’s effectiveness in patients and lab studies.
The findings support the potential utility of repurposing ropinirole for ALS, but also illustrate that patient-derived cell models can supplement trials’ clinical research by examining mechanisms and predicting which patients may be most responsive to treatment, the researchers said.
They noted the small sample size, inclusion of participants with largely early-stage ALS, and high dropout rate in the extension phase, which were believed to be due to the COVID-19 pandemic, limit the ability to interpret the data.
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