An early clinical trial headed by researchers at Keio University School of Medicine has shown that the Parkinson’s disease drug ropinirole is safe to use in patients with the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), and delayed disease progression by an average of 27.9 weeks. The study demonstrated that some patients were more responsive to ropinirole treatment than others, and the researchers were able to predict clinical responsiveness in vitro using motor neurons derived from patient stem cells. A Phase III study is now being planned.

“ALS is totally incurable, and it’s a very difficult disease to treat,” said physiologist Hideyuki Okano, MD, PhD, at Keio University School of Medicine “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.”

Okano is senior author of the team’s published paper in Cell Stem Cell, which is titled “Ropinirole hydrochloride for amyotrophic lateral sclerosis: A single-center, randomized, double-blind, placebo-controlled phase 1/2a feasibility trial.”

Amyotrophic lateral sclerosis is a neurodegenerative disease that results in respiratory failure and death, the authors wrote. The three currently FDA-approved drugs for ALS provide only limited benefits, and there remains a need for effective therapies. Okano and colleagues had previously applied induced pluripotent stem cell (iPSC)-based drug screening to identify the Parkinson’s disease drug, ropinirole, as a potential candidate for ALS treatment.

Their newly reported single center, randomized placebo-controlled Phase I/IIa ropinirole hydrochloride remedy for ALS (ROPALS) trial was designed to evaluate the safety, tolerability and therapeutic effects of ropinirole in patients with sporadic ALS, who were receiving care at Keio University Hospital. None of the 20 enrolled participants carried genes predisposing to the disease, and, on average, they had been living with ALS for 20 months.

The trial was double blinded for the first 24 weeks, so that neither the participants nor the doctors knew which patients were receiving ropinirole and which were receiving a placebo. Then, for the following 24 weeks, all patients who wished to continue with the trial were knowingly administered ropinirole.

Many patients dropped out along the way—in part due to the COVID-19 pandemic. “… 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 team noted. A number of patients in the placebo group dropped out because of their worsening condition, the investigators also pointed out. In total, seven of the thirteen ropinirole-treated participants, and one of seven participants who had initially received placebo and then continued on ropinirole, were monitored for the full year. None of the participants dropped out due to safety reasons.

To determine whether the drug was effective at slowing the progression of ALS, the team monitored a variety of different measures throughout the trial and for four weeks after treatment concluded. These included the ALS functional rating scale-revised (ALSFRS-R) score, which assesses the functional status of ALS patients. Overall, the team monitored changes in the patients’ self-reported physical activity and ability to eat and drink independently, activity data from wearable devices, and physician-measured changes in mobility, muscle strength, and lung function.

Researchers tested the safety and efficacy of ropinirole in ALS patients in an early-phase clinical trial paired with stem cell research to explore ropinirole’s mechanism of action. [Morimoto et al/Cell Stem Cell]

Patients who received ropinirole during both phases of the trial were more physically active than patients in the placebo group. They also showed slower rates of decline in mobility, muscle strength, and lung function, and they were more likely to survive. “The estimated effect size of ropinirole on the ALSFRS-R score over 48 weeks was 1.46–9.86 points, resulting in a 21–60% slower rate of functional decline, which is considered clinically meaningful,” the team noted.

“We found that ropinirole is safe and tolerable for ALS patients and shows therapeutic promise at helping them sustain daily activity and muscle strength,” said first author Satoru Morimoto, MD, a neurologist at the Keio University School of Medicine.

The benefits of ropinirole relative to the placebo became increasingly pronounced as the trial progressed. However, placebo group patients who began taking ropinirole halfway through the trial did not experience these improvements, which suggests that ropinirole treatment may only be useful if treatment is started earlier and administered over a longer duration.

The team in addition investigated the potential mechanisms behind ropinirole’s effects and looked for molecular markers of the disease. To do this, they generated induced pluripotent stem cells from the patients’ blood and grew these cells into motor neurons in the lab. Compared to healthy motor neurons, they found that motor neurons from individuals with ALS showed distinct differences in structure, gene expression, and metabolite concentrations, but ropinirole treatment reduced these differences.

Specifically, motor neurons derived from the iPSCs of individuals with ALS had shorter neurites compared to healthy motor neurons, but these axons grew to a more normal length when the cells were treated with ropinirole. The team also identified 29 genes related to cholesterol synthesis that tended to be upregulated in motor neurons from ALS patients, and found that ropinirole treatment suppressed their gene expressions over time. “These 29 genes were significantly enriched in enzymes involved in cholesterol synthesis (CS) in the endoplasmic reticulum,” they noted. “Transcription factor analysis of the 29 genes identified SREBF2 as the greatest contributor.”

The results also identified lipid peroxide as a good surrogate marker for estimating the effect of ropinirole both in vitro and clinically. “CSF NfL, a marker of neuronal damage, was decreased in the group in which CSF lipid peroxide was decreased by ropinirole treatment,” they noted. “Moreover, ALSFRS-R was suppressed in the group in which CSF lipid peroxide was decreased. Thus, CSF lipid. peroxide may be a surrogate marker for determining the efficacy of ropinirole.”

“We found a very striking correlation between a patient’s clinical response and the response of their motor neurons in vitro,” said Morimoto. “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.”

The researchers say their results suggest that the strategy of growing and testing motor neurons from patient-derived induced pluripotent stem cells could be applied clinically to predict how effective the drug would be for a given patient. It’s unclear why some patients are more responsive to ropinirole than others, but the researchers think that there may be genetic differences, which they hope to pinpoint in future studies.

“… an extremely important result of this study for iPSC drug discovery is the possibility that in vitro drug efficacy evaluation can predict clinical drug efficacy,” the team stated. “In other words, we confirm that it is possible to use iPSCs and the induction products themselves as surrogate markers of drug efficacy or patient-stratified biomarkers of therapeutic response.”

Noting limitations of their study, the researchers concluded, “To the best of our knowledge, the ROPALS trial is the representative touchstone of iPSC-based drug repurposing-enabled trials to define the feasibility of iPSC models in predicting clinical outcomes and replacing failure-prone preclinical transgenic mouse models of ALS.”

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