Meet the Compound: Huntexil

 

Image courtesy of ChemSpider

Image courtesy of ChemSpider

VITAL SIGNS

NAME: Huntexil® (Pridopidine/ACR16)

CHEMICAL FORMULA: C15H23NO2S

MOLECULAR MASS: 281.41 g/mol.

TYPE OF COMPOUND: Dopamine stabilizer

MECHANISMS OF ACTION: Functional antagonism of dopamine type 2 receptors and strengthening of cortical glutamate functions in the central nervous system.


 

Two previous studies that feature Huntexil® are the MermaiHD study and the HART study.

The MermaiHD study was a 26-week, double-blind, controlled trial of 437 HD patients conducted in 2008 through 2009 at 32 centers in Europe1. Study participants were randomized to receive either placebo (n=144) or doses of 45mg (n=148) or 90mg (n=145) of Huntexil per day. The primary outcome measure was the modified motor score, a subset of the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. The 90 mg per day group improved 1.0 points on the modified motor score compared to placebo from baseline to week 26, but the improvement was not statistically significant. The 90 mg per day group showed a statistically significant improvement of 3.0 points in total motor score compared to placebo. Changes in other motor outcomes were not significant across groups.

The HART study was a 12-week, double-blind, controlled trial of 227 HD patients conducted in 2009 through 2010 at 27 centers in Canada and the United States2. Study participants were randomized to receive placebo (n=58) or doses of 20 mg (n=56), 45 mg (n=55), or 90 mg (n=58) of Huntexil per day. As in the MermaiHD study, the primary outcome measure was the modified motor score, but the improvement of 1.2 points on the modified motor score of the 90mg per day group compared to placebo was not statistically significant. The 90mg per day group showed statistically significant improvement of 2.8 points in total motor score compared to placebo. No significant changes in cognition were observed during this 12- week study. In both studies, Huntexil was safe, and well tolerated by participants2,3.


 

Commentary

Justo Garcia de Yebenes, MD

Huntexil is a dopamine stabilizer that was synthesized by Prof. Arvid Carlsson. It can activate dopamine receptors in hypodopaminergic status, and can also block these receptors in cases of dopamine hyperactivity. Huntexil has previously been tested in vitro and in vivo. It showed a good side-effect profile and its pharmacological effect is primarily on extrasynaptic dopamine receptors. Huntexil was first trialed in small groups of Scandinavian HD patients. After four weeks of treatment the results of these studies were primarily an improvement of the modified UHDRS. Following these short-term studies, the MermaiHD trial was organized. Previous studies showed no effect of Huntexil on chorea, dystonia and ocular movements, and so the evaluation of these clinical deficits was thought to ‘dilute’ the significance of the results. For this reason the modified UHDRS was chosen as the primary end-point of the study. That choice eventually proved to be a mistake because the periods of treatment required for improvement of the previously mentioned clinical deficits differ. The results of the study essentially showed no effect of Huntexil treatment at 45 mg per day and a borderline effect of treatment at 90mg per day, using as the defined primary end-point, the modified UHDRS. Additional analysis taking in consideration the number of the patient’s CAG repeats, age, or the total motor score on the UHDRS, showed unequivocal improvement for the group treated with Huntexil at 90 mg per day. Future studies are warranted. With the experience of this study, future studies should be long-term studies, with doses of pridopidine at 90 mg or more per day, using the total UHDRS motor scale as a primary end point, or a more sensitive and global motor scale, if such a rating scale is ever developed.


 

1 de Yebenes JG, Landwehrmeyer B, Squitieri F, et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebocontrolled trial. Lancet Neurol 2011 Dec;10(12):1049-57.

2 A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord 2013 Feb 28.

3 Squitieri F, Landwehrmeyer B, Reilmann R, et al. One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology 2013 Feb 27.