Objective: To assess efficacy, safety, and tolerability of multiple doses of pridopidine in HD patients (pts) with signs of motor dysfunction.

Background: Prior trials suggested pridopidine 45 mg twice daily (BID) improved motor function with favorable safety/tolerability. Pridopidine’s activity was initially thought to be mediated by low-affinity D2 receptor binding. However, recent studies show pridopidine having high affinity for sigma-1 receptors (S1R). In-vitro, pridopidine stabilizes medium spiny neurons and BDNF secretion in S1R-dependent fashion suggesting potential beyond improving motor function.

Methods: Pts were randomized to pridopidine 45 mg BID (n=81), 67.5 mg BID (n=82), 90 mg BID (n=81), 112.5 mg BID (n=82), or placebo (n=82) for 52 weeks. Primary efficacy endpoint was total motor score (TMS) change from baseline (BL) to Week (W) 26. Exploratory endpoints included measures of total functional capacity (TFC), among others, at W26 and 52. W52 was measured with the intent to explore long-term symptomatic and functional effects of pridopidine. No correction for type I error for multiple comparisons was applied. Reported P-values are nominal for exploratory endpoints.

Results: TMS showed improvement compared to BL at all doses including placebo at W26 but did not reach significance, possibly due to a large, enduring placebo response.  Less functional decline as measured by TFC was observed at W52 with pridopidine 45 mg BID (n=75) vs placebo (n=81) (least square means difference: 0.87 [95% CI: 0.29–1.45], P=0.003). Compared with placebo (n=62), less functional decline was most evident in early stage (HD1–2) pts taking pridopidine 45 mg BID (n=59; W26: P=0.036; W52: P<0.001). Responder analysis showed a larger proportion of early stage pts receiving 45 mg BID having no deterioration (81% vs 49%, P=0.003) or improvement (27% vs 12%, P=0.099) in TFC compared with placebo. No new safety/tolerability concerns were revealed.

Conclusions: Pridopidine showed improvement in TMS compared to BL but did not differentiate from placebo at W26, possibly due to a large, enduring placebo effect. Compared with placebo in exploratory analyses, 45 mg BID was associated with slowing of functional decline as measured by TFC. Phase III study confirming the potential of pridopidine to slow functional decline, measured by TFC, in HD is warranted.

Presented at: HSG; Nov 3–5, 2016; Nashville, TN, USA

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-safety-and-tolerability-of-pridopidine-in-huntington-disease-hd-results-from-the-phase-ii-dose-ranging-study-pride-hd/