FDA-Approved Schizophrenia Medicine Orap Appears to Benefit ALS Patients, Canadian Study Reports

The schizophrenia therapy Orap (pimozide) may be able to prevent the progression of ALS, Canadian researchers report.

The team confirmed in a clinical trial of 25 ALS patients the results it saw in studies with worms, fish and mice. An antipsychotic drug, Orap is used to treat other psychiatric conditions in addition to  schizophrenia.

A key finding was that Orap preserved the function of a muscle between the thumb and index finger whose dysfunction is one of the first signs of amyotrophic lateral sclerosis.

To validate their preliminary findings, the researchers have started a Phase 2 trial (NCT03272503) with more patients. They are still recruiting people for it.

“This medication alleviates the symptoms of ALS in animal models,” Dr. Alex Parker, a medical professor at the University of Montreal, said in a press release.

The ALS therapies Rilutek (riluzole), which is made by Sanofi, and Mitsubishi Tanabe Pharma’s Radicava (edaravone) improve patients’ symptoms, he said. “But we believe that we’ve found a medication [Orap] that may prove to be more effective in improving patients’ quality of life,” added Parker, the study’s lead author.

He and the other researchers published their findings in the Journal of Clinical Investigation (JCI) Insight. The title is “Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.”

The team from the University of Montreal Hospital Research Center and the University of Calgary’s Cumming School of Medicine first developed simple genetic models of ALS – in a millimeter-long worm called C. elegans and in a five-centimeter-long tropical zebrafish. They used the models to identify therapies approved for other diseases that doctors might be able to treat ALS with as well.

“We sifted through a library of 3,850 molecules approved for the treatment of other diseases, and found a class of antipsychotic drugs that stabilize mobility in worms and fish,” said Dr. Pierre Drapeau, a study co-lead author who was one of the Montreal researchers.

Orap proved to be the most potent of the 13 antipsychotics — or neuroleptics — that the screening identified as possible ALS treatments.

“Pimozide works especially well in preventing paralysis in fish by preserving the neuromuscular junction,” Drapeau. As the name implies, a neuromuscular junction is where nerve cells and muscle fibers meet.

The U.S. Food and Drug Administration has approved Orap as a treatment for chronic psychosis, a nerve-related psychiatric disorder known as Tourette syndrome, and brain-triggered involuntary movements known as tics.

Pimozide also improved mice’s neuromuscular function, according to work that Dr. Richard Robitaille of the University of Montreal conducted.

The results of the animal studies prompted the team to conduct a clinical trial of Orap in 25 ALS patients in 2015.

“Pimozide is a drug that has been well-known for 50 years,” said Dr. Lawrence Korngut, an associate professor at the University of Calgary medical program. “It was approved for treating certain types of psychiatric conditions, like schizophrenia, and costs only 9 cents per pill. Other recent studies have shown genetic links between schizophrenia and ALS. The next logical step was to test it on human volunteers with ALS.”

Korngut led the clinical trial investigation. A key finding was that within six weeks of the start of treatment, Orap preserved ALS patients’ thenar muscle function. Dysfunction in this muscle, which is located between the thumb and index finger, is one of the initial signs of ALS.

“We found the highest dose most likely to be tolerated in individuals with ALS — a lower dose than that used in other conditions — and we have preliminary proof showing that pimozide may be useful,” Korngut said.

“For us, this is an indication that we found the right therapeutic target,” Drapeau said. “Pimozide acts directly on the neuromuscular junction, as shown in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it only preserves normal neuromuscular function to at least stabilize the disease. This is also the first time that a potential drug for human patients was discovered based on basic research on small organisms such as worms and fish.”

Researchers hope to recruit 100 participants for the Phase 2 trial that Korngut is leading. The study (NCT03272503) will be conducted at nine hospital centers across Canada. It will evaluate Orap’s safety and ALS patients’ outcomes after five months of treatment.

Participants will be randomly assigned to one of two groups. One group will receive Orap and the other a placebo.

The primary objective of the trial is to see whether Orap improves patients’ scores on an index known as the ALS Functional Rating Scale-Revised.

Daniel Rompré, who was diagnosed with ALS in March 2016, hopes to participate in the trial. The father of two teenage girls is already developing muscle wasting and speech impairments.

“It is hard to maintain a positive outlook,” he said. “You ask yourself: Why me? But at least it’s encouraging to see that research is advancing. There has been more progress in the last five years than in 100 years of research on the disease.”

Because the results obtained so far are preliminary,” at this stage, people with ALS should not use this medication,” Korngut said. “We must first confirm that it is really useful and safe in the longer term. It is also important to be aware that pimozide is associated with significant side effects. Therefore, it should only be prescribed in the context of a research study.”