Huntexil (pridopidine) is an investigational oral dopamine stabilizer that Teva Pharmaceuticals is developing to possibly treat symptoms of Huntington’s disease.

How Huntexil works

It is a dopamine stabilizer. These are molecules that bind to the dopamine D2 receptor (D2R) and either activate it or block it depending on the biological status of the cell.

Although the exact mechanism of action of Huntexil is not well-understood, it is thought to work by binding to a protein called sigma 1 receptor (S1R). S1R plays a role in neuroprotection, or in protecting the structure and function of nerve cells. It does so by increasing the production of brain-derived neurotrophic factor (BDNF), a protein that may play a role in maintaining neuronal health and in creating new nerve cells.

In people with Huntington’s disease, the disease-causing mutation lowers the levels of BDNF. This is thought to be one of the mechanisms leading to neurodegeneration.

Huntexil, by binding to S1R in the brain, may work to activate the receptor and possibly increase the production of BDNF.

Huntexil in clinical trials

The clinical development of Huntexil was initially focused on its potential to reduce the symptoms of Huntington’s disease, including the involuntary twitchy movements called chorea.

Two clinical trials were conducted, one in North America called HART (NCT00724048), and one in Europe called MermaiHD (NCT00665223).

HART, a Phase 2b trial, tested the effectiveness and safety of three doses of Huntexil (20, 45 and 90 mg) given daily for 12 weeks compared to 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 Huntexil was well-tolerated by patients, it failed to improve the symptoms of the disease associated with movement.

MermaiHD was a Phase 3 trial involving 437 patients randomly assigned to receive Huntexil, at 45 mg or 90 mg, or placebo, once a day for 26 weeks. Huntexil was well-tolerated up to the 90 milligrams per day dose, but as in the HART study, it failed to improve patients’ movement symptoms compared to placebo.

After these failures, the Phase 2 PRIDE-HD study (NCT02006472) was undertaken.

PRIDE-HD was a 52-week trial of Huntexil twice daily versus placebo that aimed to measure improvements in motor function and effects on disease progression. This study included multiple doses of Huntexil, including higher doses than used in previous studies (45, 67.5, 90, and 112.5 mg). Results presented at the 69th Annual Meeting of the American Academy of Neurology (AAN) in April 2017  showed that Huntexil did not improve patients’ motor function at week 26 compared to placebo. However, it was found to possibly slow disease progression, as measured by total functional capacity (TFC). (TFC is a rating scale used to assess a person’s capacity to work, perform domestic and self-care tasks, and handle finances). No major adverse side effects were reported during the trial, confirming the safety and tolerability of the treatment.

An exploratory analysis of Huntexil’s effectiveness based on TFC was also presented at the same meeting, which 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 Huntexil-treated patients, consistent with PRIDE-HD study findings.

Teva is continuing to evaluate Huntexil in Huntington’s patients.

A Phase 1 open-label study (NCT03019289) in Germany is currently evaluating the binding of Huntexil to S1R and to the dopamine-2 receptor in the brains of healthy volunteers and Huntington’s patients. This study aims to recruit 38 participants; enrollment information is available by clicking on its identification number.

An open-label Phase 2 study (NCT02494778), called Open PRIDE-HD and involving patients who took part in the earlier PRIDE-HD study, is assessing long-term data on the safety, tolerability, and effectiveness of Huntexil treatment. The study is expected to finish in late January 2018.

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