The pridopidine paradox in Huntington's disease

In this issue the Huntington’s Disease (HD) ACR-16 Randomized Trial (HART) investigators of the Huntington Study Group (www.huntington-studygroup.org) report a formally negative randomized, double-blind, parallel-group, multicenter trial of pridopidine (previously “ACR-16”) in HD (NCT00724048; n 5 227 randomized patients). The HART study failed its prespecified primary endpoint, the change in the “modified Motor Score” (mMS) after 12 weeks of treatment; the mMS is a subset of the “Unified Huntington’s Disease Rating Scale Total-Motor-Score” (UHDRS-TMS) not including the assessments of eye movements and dystonia. The mMS was selected as primary endpoint based on post hoc efficacy observations in an earlier smaller phase II safety and tolerability trial of pridopidine in HD. Notably, HART reports that the UHDRS-TMS, a secondary outcome, significantly improved in the group treated with 90 mg/day by 22.8 points (P 5 .04). No significant effects were seen in the 20 mg/day or 45 mg/day groups compared to matching placebo. Pridopidine was generally well tolerated. HART confirms the results of MermaiHD, a phase III randomized, double-blind, parallel-group, multicenter trial (NCT00665223; n 5 437 randomized patients) conducted by the investigators of the European Huntington’s Disease Network (www.eurohd.net). In MermaiHD the prespecified primary endpoint mMS also failed to show a significant change at 24 weeks in the full analysis set (FAS), although there was a trend in the 90 mg/day group with 20.99 points (P 5 .042; not significant [n.s.] after Bonferroni correction); notably, the per-protocol population (PPP; n 5 357) significantly improved in the 90 mg/day group by 21.29 points (P 5 .014). In addition, the UHDRSTMS significantly improved in the 90 mg/day group by 22.96 points (P 5 .004) for FAS and by 22.93 points (P 5 .009) in the PPP. Interestingly, these amplitudes of change in the motor scales were virtually identical to the treatment effects observed in the 90 mg/day arm of the HART study. Overall, although the primary endpoints in both studies were negative, these observations suggest a reproducible beneficial effect of pridopidine on motor symptoms in HD. However, there are a few inconsistencies that should be acknowledged. In HART the mMS showed a trend toward improvement in both the 45 mg/day (21.19 points) and the 90 mg/day (21.17 points) groups compared to placebo with similar amplitudes of change for both doses. The change in the UHDRS-TMS, however, was observed in the 90 mg/day group only. In MermaiHD, the UHDRS-TMS effect in the 90 mg/day group was seen after 24 weeks only; a post hoc analysis revealed no change at 12 weeks, which is inconsistent with the HART data. In addition, MermaiHD reported no effect in the 45 mg/day group on the mMS and the UHDRS-TMS. In spite of the fact that overall the UHDRS-TMS is thought to have a good interrater reliability and that motor raters in both the HART and MermaiHD trials were certified by the European Huntington’s Disease Network (EHDN) UHDRS-TMS annual online certification, interrater and intrarater variability and lack of sensitivity of the UHDRS-TMS may at least partly account for these inconsistencies. The interpretation of the HART and MermaiHD data should take into account that different statistical analysis plans were used in both trials. In HART, formal hypothesis testing was performed in a prespecified -----------------------------------------------------------*Correspondence to: Dr. Ralf Reilmann, Chair Huntington Center, Dept. of Neurology, University Clinic Muenster (UKM), University of Muenster, Albert Schweitzer Campus 1 Building A1, 48149 Muenster, Germany; r.reilmann@uni-muenster.de