How Huntexil works
Huntexil is a dopamine stabilizer, a molecule that binds to the dopamine D2 receptor (D2R) and either activates or blocks 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 — protecting the structure and function of nerve cells by increasing the production of brain-derived neurotrophic factor (BDNF), a protein that may play a role in maintaining neuronal health and in producing 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.
By binding to S1R in the brain, Huntexil 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.
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 either receive Huntexil, at 45 mg or 90 mg, or placebo, once a day for 26 weeks. Huntexil was well-tolerated up to a dose of 90 mg per day. However, as in the HART study, it failed to improve patients’ movement symptoms compared to placebo.
A Phase 2 clinical trial called PRIDE-HD (NCT02006472) evaluated the safety and effectiveness of Huntexil in treating Huntington’s disease patients. It was a 52-week trial of Huntexil twice daily versus placebo that aimed to measure improvements in motor function and effects on disease progression. It 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 also was 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 the findings of the PRIDE-HD study.
An open-label Phase 2 study (NCT02494778), called Open PRIDE-HD and involving patients who took part in the earlier PRIDE-HD study, assessed long-term data on the safety, tolerability, and effectiveness of Huntexil treatment. The results were published in The Lancet Neurology. Treatment with any dose of Huntexil failed to provide significant motor benefits over placebo at week 52. Scores of a physical performance test also revealed no differences. However, patients in the early stages of the disease treated with 45 mg of Huntexil did show an improvement in function at 52 weeks but the authors cautioned that these findings must be replicated.
Some serious adverse side effects also were reported in patients treated with Huntexil. 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).
The authors believe the positive safety profile and the benefit seen with 45 mg of Huntexil at 52 weeks may warrant further investigation.
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