The dopaminergic stabilizing drug pridopidine showed signs of improving motor function without worsening chorea in patients with Huntington’s disease, despite failing to meet its primary end point in an industry-sponsored phase III trial.
The drug also failed to improve nonmotor outcomes for both secondary and tertiary end points that measured cognitive and functional deficits, Dr. Justo Garcia de Yebenes of the department of neurology, Hospital Ramón y Cajal, Madrid, and his associates reported online Nov. 7 in the Lancet Neurology.
However, the higher of the two doses of pridopidine that the investigators tested in this international trial produced significant improvement in the tertiary end point of total motor score in the Unified Huntington's Disease Rating Scale (UHDRS), they noted.*
Pridopidine belongs to a new class of drugs known as dopaminergic stabilizers, which act primarily at dopamine type 2 receptors. In vivo studies have shown that the drug "normalizes dysregulated psychomotor functions while having only subtle effects on normal psychomotor activity." In animal models, it has been reported to improve signs of depression, anxiety, and motor dysfunction.
Dr. Garcia de Yebenes and his colleagues performed the MermaiHD trial (Multinational European Multicentre ACR16 Study in Huntington’s Disease) to explore pridopidine’s usefulness in treating symptoms of Huntington’s disease. The double-blind trial involved 437 ambulatory patients recruited from 32 clinics in Austria, Belgium, France, Germany, Italy, Portugal, Spain, and the United Kingdom.
The study subjects were randomly assigned to receive 45 mg oral pridopidine (148 patients), 90 mg pridopidine (145 patients), or matching placebo (144 patients) daily for 26 weeks. They were allowed to take concomitant therapies including antidepressants and other psychotropic drugs as long as they had been receiving a stable dose of those agents for at least 6 weeks before randomization.
The primary outcome measure was improvement in a shortened version of the total motor score on the UHDRS, which was assessed at baseline and weeks 4, 8, 12, and 26. This modified score addressed dysarthria, tongue protrusion, finger tapping, pronate and supinate hands, fist-hand-palm sequencing, arm rigidity, body bradykinesia, gait, tandem walking, and retropulsion pulling. It did not assess eye movements, dystonia, or chorea.
The mean age of all patients in the study was nearly 51 years, and it had been an average of nearly 5 years since they had been diagnosed with Huntington’s disease.
At baseline, the mean modified motor score was 18-20 points in the three study groups. At week 26, that had decreased in the 90-mg group (–0.99 points) relative to the placebo group, but not to a significant degree. However, in a per-protocol analysis, the decline in mean modified motor score (–1.29 points) was significant relative to placebo, the investigators wrote (Lancet 2011 Nov. 7 [doi: 10.1016/S1474-4422(11)70233-2]).*
There were no significant differences between either dose of pridopidine and placebo in any of the secondary outcomes, which included improvement in clinical global impression-improvement scores, total UHDRS scores, and anxiety and depression scores.
A single tertiary outcome – mean change in UHDRS total motor score – was significantly better in the 90-mg pridopidine group than in the placebo group. Patients who took the 90-mg dose had a mean score that was 2.93 points lower than the score for placebo-treated patients; the baseline UHDRS total motor score was 41-43 points. This difference in scores was attributed to improvements in change was primarily because of improvements in eye movements, dystonia, hand movements, and gait and balance, but not chorea.*
"Pridopidine was well tolerated and had an adverse event profile similar to that of placebo," the researchers wrote.
Overall, 38% of the low-dose group, 44% of the high-dose group, and 45% of the placebo group reported adverse events judged to be related to the study drug. The rates of serious adverse events were 7%, 6%, and 8%, respectively.
Although these results "fell short of" success, the improvements in UHDRS total motor score "have been reproduced in a phase IIb trial run in parallel with our study," and may warrant further investigation, Dr. Garcia de Yebenes and his colleagues wrote.
This study was funded by NeuroSearch A/S, a European biopharmaceutical company that makes pridopidine and other CNS drugs. Dr. Garcia de Yebenes reported receiving institutional funding from NeuroSearch, and several of his coauthors are employees of NeuroSearch. Other colleagues reported receiving payments for services to NeuroSearch and payments or research support from numerous industry sources, foundations, research networks, and patient advocacy groups.
* Corrections, 11/15/2011: An earlier version of this article misstated the statistical significance of items in the trial's tertiary endpoint, the total motor score in the UHDRS. It also misstated the mean difference in scores at week 26 between the group taking 90 mg pridopidine and the placebo group on the primary end point of the mean modified motor score and the tertiary end point of the total motor score in the UHDRS.