Pridopidine (formerly Huntexil) is an investigational oral sigma 1 receptor agonist originally developed by Teva Pharmaceuticals. Prilenia Therapeutics acquired pridopidine from Teva in 2018 for further development to treat symptoms of Huntington’s disease.
How does pridopidine work?
Pridopidine is a small molecule that binds to the sigma 1 receptor (S1R) at low doses. S1R plays a role in neuroprotection — protecting the structure and function of nerve cells by increasing the production of brain-derived neurotrophic factor (BDNF). That protein may play a role in maintaining neuronal health and producing new nerve cells.
In people with Huntington’s, the disease-causing mutation lowers the levels of BDNF. Researchers think this is one of the mechanisms leading to neurodegeneration.
By binding to S1R in the brain, pridopidine may work to activate the receptor and possibly increase the production of BDNF.
Pridopidine in clinical trials
The clinical development of pridopidine initially focused on its potential to reduce the symptoms of Huntington’s disease, including chorea.
HART, a Phase 2b trial, tested the safety and effectiveness of three doses of pridopidine (20, 45, and 90 mg) daily for 12 weeks compared to a placebo. It included a total of 227 patients with Huntington’s disease. Investigators evaluated changes in the patient’s motor function from the start of the study to week 12.
The results showed that although patients tolerated pridopidine well, the treatment failed to improve the symptoms of the disease associated with movement.
MermaiHD was a Phase 3 trial involving 437 patients that investigators assigned randomly to either receive pridopidine, at 45 mg or 90 mg, or a placebo, once a day for 26 weeks.
Participants tolerated pridopidine well up to a dose of 90 mg per day. However, as in the HART study, the treatment failed to improve patients’ movement symptoms compared to placebo.
A Phase 2 clinical trial called PRIDE-HD (NCT02006472) evaluated the safety and effectiveness of pridopidine in treating Huntington’s disease patients. It was a 52-week trial of pridopidine twice daily versus a placebo. The aim was to measure improvements in motor function and the effects of the treatment on disease progression. It tested multiple doses of pridopidine, including higher doses than in previous studies (45, 67.5, 90, and 112.5 mg).
Researchers presented the results at the 69th annual meeting of the American Academy of Neurology (AAN) in April 2017. They showed that pridopidine did not improve patients’ motor function at week 26 compared to the placebo. However, it possibly slowed disease progression, as measured by total functional capacity (TFC). TFC is a rating scale to assess a person’s capacity to work, perform domestic and self-care tasks, and handle finances. No major adverse side effects occurred during the trial, confirming the safety and tolerability of the treatment.
At the same meeting, researchers also presented an exploratory analysis of pridopidine’s effectiveness based on TFC. This analysis included data from a Phase 2 open-label extension study, called OPEN-HART (NCT01306929), in patients who had completed the HART and PRIDE trials. Results suggested a slower decline of functional capacity in pridopidine -treated patients, consistent with the findings of the PRIDE-HD study.
An open-label Phase 2 study (NCT02494778), called Open PRIDE-HD involving patients who took part in the earlier PRIDE-HD study, assessed long-term data on the safety, tolerability, and effectiveness of pridopidine treatment.
The results were published in The Lancet Neurology. Treatment with any dose of pridopidine failed to provide significant motor benefits over a placebo at week 52. Scores of a physical performance test also revealed no differences. However, patients in the early stages of the disease who received 45 mg of pridopidine did show an improvement in function at 52 weeks. However, the authors cautioned that these findings must be replicated. Researchers also reported some serious adverse side effects in patients who received pridopidine. These included falls (in five patients), suicide attempts (in four patients), suicidal thoughts (in three patients), head injury (in three patients), and aspiration pneumonia (in three patients).
Ongoing clinical trials
Researchers are currently investigating pridopidine in a Phase 3 randomized, placebo-controlled trial called PROOF-HD (NCT04556656). The trial aims to recruit an estimated 480 patients, ages 21 and older with early-stage adult-onset HD at more than 60 locations in the U.S., Canada, and Europe. Patients will receive either 45 mg oral doses of pridopidine or a placebo twice a day for 65 to 78 weeks. After completion, patients will be allowed to continue in an open-label extension phase where they will all receive pridopidine.
Researchers will compare changes in the unified Huntington’s disease rating scale–total functional capacity from baseline to week 65 between the treatment and placebo group to determine if pridopidine had a functional benefit. Prilenia announced in October 2020 that the first patient was enrolled in the trial, which is expected to finish in April 2023.
Pridopidine received orphan drug designation in both the U.S. and Europe.
Researchers also are investigating pridopidine as a treatment for amyotrophic lateral sclerosis, neurodegenerative eye disease, Parkinson’s disease, Rett syndrome, Fragile X syndrome, and Alzheimer’s disease.
Last updated: Jan. 20, 2021
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