Blog Post from the ALS Association

Pimozide Identified as a Potential ALS Therapeutic

Dr. Pierre Drapeau and team of Université de Montréal recently published an important paper in JCI Insight showing how basic animal models are used to identify ALS potential therapeutics. They found that pimozide, a neuroleptic drug, was the most potent in impacting animal model mobility. A short clinical trial was then conducted in sporadic ALS patients, which demonstrated that the drug hit its target and safe at a specific dose. Evidence from these studies paved the way for the current randomized pimozide phase II clinical trial that began enrollment this month in Canada. We are proud to support these studies through the Lawrence and Isabel Barnett Drug Development Program, and your donations.

What is pimozide?

Pimozide is a FDA approved neuroleptic drug used to treat psychosis, Tourette syndrome, and resistant tics. Exactly how the drug works is up for debate. It has been shown to target dopamine receptors, calcium channels, and enhance autophagy, a type of cell degradation system.

Study summary

The initial goal of Dr. Drapeau’s team was to identify compounds that stabilize motor function and could represent possible ALS therapeutics. To achieve their goal, they conducted a high-throughput screen of 3,850 small molecules (compounds) in C. elegans harboring a known TDP-43 mutation that is conserved in humans. C. elegans are microscopic nematodes (worms) that have short lifespans, are inexpensive to maintain, and have human genes conserved, including ALS-associated gene TDP-43. From the screen they identified multiple compounds that rescued C. elegan motor dysfunction. These compounds were then validated in another ALS animal model, zebrafish, a small vertebrate also harboring a known TDP-43 mutation. Together, they confirmed 10 active compounds in zebrafish and identified pimozide as the most potent lead compound.

The effects pimozide was then further explored in the above models and additional models, including zebrafish expressing other known ALS mutant genes, including SOD1 and FUS, and in SOD1 mice (SOD1G37R). Importantly, they found that pimozide acutely restored neuromuscular transmission (motor neuron to muscle cell signal transmission) at the neuromuscular junction (NMJ) in the tested C. elegans, zebrafish, and mouse models. Next, they team found that pimozide acts on a specific type of calcium channel in cells, called T-type Ca2+channels, to enhance activity at the NMJ.

Given the positive results in animal models, Dr. Drapeau’s team took this study another step further to test the impact of pimozide on people living with sporadic ALS. They conducted a randomized phase II study over a 6-week period. The drug was tested in 25 people, with one active treatment patient discontinuing the study due to death. They found that pimozide was safe and tolerable at a 4 mg/day dose, and obtained preliminary evidence of target engagement at the NMJ. Due to the small study size and short duration, along with promising results, they concluded that a larger clinical should be conducted over a longer time period to understand whether pimozide is effective to treat people living with ALS.

“This is an extremely exciting publication highlighting the systematic process from identifying a potential treatment approach in a model system and taking this into the clinic to test in people living with ALS. Having a readout that can be translated from a model system, in this case the neuromuscular junction, to the clinic is crucial to confirm target engagement. I am excited to learn whether this treatment approach is beneficial in the larger ongoing trial.” – Dr. Lucie Bruijn, Chief Scientist of The ALS Association

Next steps

The next randomized phase II clinical trial of pimozide is now enrolling in Canada. The goal is to enroll 100 people living with ALS to further test the safety, tolerability, and efficacy of pimozide at a 4 mg/day dose. For more information about the current clinical trial visit: clinicaltrials.gov NCT03272503.

*These studies were funded under the ALS Research Program at the Department of Defense and The ALS Association. ALS Canada sponsors the clinical trial. The ALS Association is currently funding this project to identify additional ALS compounds that show improved properties.

Paper citation – paper is open-access