#AANAM – Findings Due in Japan Study of Repurposed ALS Therapy

Editor’s note: The ALS News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

Treatment is complete in 20 patients enrolled in the randomized ROPALS clinical trial assessing the safety, tolerability and early efficacy of ropinirole hydrochloride as a repurposed oral therapy — identified through stem cell work — for amyotrophic lateral sclerosis (ALS).

Full results from this part of the Phase 1/2a study (UMIN000034954) in Japan, which finished in July 2020, are expected this year.

The treatment’s potential was discovered via patient-derived, induced pluripotent stem cell (iPSC) motor neurons, which were used to screen a library of known molecules to highlight those that might best be used for ALS, its researchers stated. 

Ropinirole hydrochloride, under the brand name Requip, is approved to treat motor symptoms of Parkinson’s disease, including stiffness, tremors, muscle spasms, and insufficient muscle control. 

This trial update was presented by Shinichi Takahashi, MD, of Keio University School of Medicine at the 2021 American Academy of Neurology Annual Meeting, in the poster, “Phase 1/2a, Double-blind, Placebo-controlled Study of Ropinirole Hydrochloride Remedy for ALS (ROPALS trial) Based On The iPSC Drug Repositioning.”

Research in ALS often relies on mouse models carrying disease mutations to evaluate potential treatments. But these models do not reproduce the spinal cord damage observed in patients, the scientists wrote in their poster, attributing this as a reason both for the “failure of many previous clinical trials” and their cell-based approach to drug discovery.

iPSCs are mature cells, usually taken from the skin or blood, that are reprogrammed to behave like stem cells. Given the right cues and growth conditions, iPSCs can become many different cell types, including spinal motor neurons — the nerve cells that control voluntary movement and are damaged in ALS.

As these cells retain the genetic signature of patients, they may be a better platform than animal models for screening therapies for their potential in ALS. 

Gene mutations underlying the development ALS “have not yet been identified,” making it “difficult to establish useful [animal] models,” the researchers wrote in an earlier study that described their use of patient-derived iPSC-derived motor neurons to test existing medicines.

That cell work identified ropinirole hydrochloride as a promising candidate.

Ropinirole was seen to reduce the presence of harmful ALS-associated substances, including reactive oxygen species and TDP-43 or FUS protein clumps, while boosting cellular energy production and motor neuron survival.

Based on these promising findings, the ROPALS trial was launched to investigate ropinirole in treating ALS patients.

Eligible participants were those diagnosed within five years, and with a drop of two-to-five points in their Revised ALS Functional Rating Scale scores (ALSFRS-R, lower scores indicate poorer function) over a study run-in period of 12 weeks.

Those enrolled had a mean age of 65.6 years and a mean disease duration of 20 months. 

They were randomly assigned to either once-daily ropinirole hydrochloride extended-release tablets (at doses ranging from 2–16 mg) or to a placebo for 24 weeks (about six months). The study was double-blinded, meaning neither patients nor researchers knew who received the treatment.

Following this randomized period, participants could enter an open-label, extension phase and either continue or start treatment with ropinirole hydrochloride for another 24 weeks.

Mean ALSFRS-R scores decreased from 42.9 to 39.5 points during the run-in period. This scale measures a patient’s physical abilities, from swallowing and using utensils to climbing stairs and breathing. 

While the trial’s main goals are to assess the safety and tolerability of ropinirole hydrochloride in ALS patients, secondary goals  look at changes in the Combined Assessment of Function and Survival, ALSFRS-R scores, and muscle strength and volume. Evidence of treatment efficacy will also be evaluated using motor neurons derived from iPSCs from these patients.