Researchers from the University of Montreal Hospital Research Centre (CRCHUM) and the University of Calgary’s Cumming School of Medicine have discovered a drug that could be used to treat people with amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease.

An article published today in JCI Insight concludes that pimozide is safe and seems to stabilize the progression of ALS in the short term, according to these preliminary results. This neurodegenerative disease leads to progressive paralysis of the skeletal muscles and eventually death an average of three years after the onset of symptoms.

“This is the first drug that seems to relieve symptoms of ALS in animals. Riluzole and edaravone, currently used in humans, have modest effects. Other research has to be conducted to confirm it, but we believe we have found a drug that will be more effective in improving patients’ quality of life,” stated CRCHUM researcher and Université de Montréal professor Alex Parker.

From worm to human

The story began six years ago with a tiny nematode, a millimetre in length, called C. elegans. In his laboratory, Parker genetically modified the worms so that they would have the human form of amyotrophic lateral sclerosis. At the same time, his colleague Pierre Drapeau did the same thing with another model, the zebrafish, a small tropical fish about 5 centimetres in length.

The two scientists received funding from the U.S. Army to test drugs on these worms and zebrafish born with ALS. “We sifted through a library of 3,850 molecules approved for the treatment of other diseases and we found a class of antipsychotic drugs that stabilize mobility in worms and fish. Pimozide works particularly well to prevent paralysis in fish by preserving the junction between the nervous system and the muscles,” explained CRCHUM researcher, Université de Montréal professor and principal investigator of the study Pierre Drapeau.

Professor Richard Robitaille then conducted electrophysiological studies on mice in his laboratory at the Université de Montréal and came to the same conclusion. Pimozide preserved neuromuscular function in three different animal models.

At ALS Canada’s Annual Research Forum in 2012, the Montreal researchers met Dr. Lawrence Korngut, an associate professor at the University of Calgary’s Cummings School of Medicine, a member of the Hotchkiss Brain Institute (HBI) and the director of the Calgary ALS/Motor Neuron Disease Clinic. “Pimozide is a drug that’s been well-known for 50 years, is approved for the treatment of certain psychiatric disorders such as 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,” said the neurologist.

In 2015, an initial Canadian preclinical trial for ALS was carried out with a small group of 25 patients with ALS, with financial support from the Quirk family of Calgary, the HBI and the University of Calgary’s Clinical Research Unit.

“We found the highest dose likely to be tolerated by people with ALS, a dose lower than what is used for other disorders, and we have preliminary proof that pimozide could be helpful,” asserted Korngut.

This first clinical trial was modest. But in only six weeks, the first sign of efficacy was observed. Loss of control of the thenar muscles, located on the palm of the hand between the thumb and index finger, is usually one of the first signs of ALS. For patients who took pimozide, this function remained stable. However, this observation has to be confirmed, given the very limited size and duration of the clinical trial.

“For us, it’s an indication that the therapeutic target is the right one. Pimozide acts directly on the junction between the nervous system and the muscle, like in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it acts only to maintain normal neuromuscular function and at least stabilize the disease. This is also the first time that a drug that may potentially be used for humans has been discovered based on basic research on small organisms such as worms and fish,” stated Drapeau.

The next step is a phase II clinical trial with 100 volunteers starting in the coming weeks and funded by the Ice Bucket Challenge, through a partnership with ALS Canada and Brain Canada. Headed by Dr. Korgnut in Calgary and conducted in nine hospital centres across Canada, this study aims to verify pimozide’s safety and measure its effect on the progression of the disease, symptoms and patients’ quality of life over a six-month period.

Daniel Rompré, a 47-year-old father of two teens, hopes to participate in this new study. He received the terrible diagnosis of amyotrophic lateral sclerosis in March 2016. The muscles of his upper body are weakening, he is starting to have trouble speaking and can no longer use his left arm. “It’s hard to keep my morale up. You think – ‘Why me?’ But at least it’s encouraging to see that research is moving forward. More progress has been made in the last five years than in 100 years of research into the disease,” he said.

It’s too early to conclude with certainty that pimozide is safe and effective. “At this stage, people with ALS should not use the drug. We first have to check to see that it is really safe and useful in the longer term. It’s important to be aware that pimozide is associated with serious side effects. It should be prescribed only as part of a research protocol,” insisted Korgnut.

About this study

The study “Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis” was published on November 16, 2017, in JCI Insight. This research was funded mainly by the United States Department of Defense and the Canadian Institutes of Health Research (CIHR). The authors have declared no conflicts of interest. To learn more, the study is available for consultation: DOI: 10.1172/jci.insight.97152