EFFECT OF PRIDOPIDINE ON MOTOR FUNCTION IN PATIENTS WITH HUNTINGTON DISEASE: RESULTS FROM THE HART STUDY

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1 EFFECT OF PRIDOPIDINE ON MOTOR FUNCTION IN PATIENTS WITH HUNTINGTON DISEASE: RESULTS FROM THE HART STUDY HSG HART Investigators Presented by Karl Kieburtz, MD, MPH Director, Center for Human Experimental Therapeutics Professor of Neurology, Community and Preventive Medicine and Environmental Medicine University of Rochester

2 Disclosures Research Grants NIH (NINDS, NIA, NEI, NICHD), the Michael J Fox Foundation, Medivation, NeuroSearch, and Pfizer Consulting FDA, VA, NIH (NINDS), Abbott, Biogen-Idec, Boehringer Ingelheim, Ceregene, Clintrex, EMD Serono, Impax, Isis, Lilly, Lundbeck, Merz, Novartis, Orion, Schering-Plough, Siena Biotech, Solvay, Synosia, Teva, UCB Pharma, Xenoport Legal Consulting Welding Rod Litigation Defendants

3 Pridopidine represents a novel therapeutic class of agents: dopamine stabilizers Standard antipsychotic psychomotor activity Pridopidine psychomotor activity High High Normal Normal Low Low

4 Retropulsion Pull Test* Components of the Total Motor Scale of the UHDRS, with Modified Motor Score Highlighted Ocular Pursuit Saccade Initiation Saccade Velocity Dysarthria* Tongue Protrusion* Finger Taps* Pronate/Supinate Hands* Luria (Fist-hand-palm test)* Rigidity arms* Body bradykinesia* Maximal Dystonia Phase II Trial in Huntington Disease Randomized, double-blind, placebo controlled trial n = 58 Pridopidine 50 mg/d (n = 28) Followed for 28 days Maximal Chorea Gait* Tandem Walking* *Component of Modified Motor Score

5 Patients with baseline modified Motor Score >10 Lundin A, et al. Clin Neuropharm 2010;33(5):

6 HART (Huntington ACR16 Randomized Trial) Multi-center, North American, randomized, double-blind, parallel group Phase IIb study 227 subjects treated for 12 weeks Pridopidine 10 mg, 22.5, or 45 mg BID or placebo 1:1:1:1 randomization

7 Primary Objective Assess the effects of pridopidine on voluntary motor function in HD subject Primary Outcome Measure Change from baseline to week 12 in modified motor scale (mms) of UHDRS

8 Secondary Objectives Assess the effects of pridopidine on the CGI-C, cognitive function, behavior, and symptoms of depression and anxiety at 12 weeks of treatment Outcomes: All scales of UHDRS (including TMS), CGI-C, HADS, Trail-Making A (change from baseline to week 12) Assess the safety and tolerability of pridopidine Outcomes: tolerability, adverse events, lab values, vital signs, and ECG

9 Primary Analysis Analysis of covariance model that includes terms for: Treatment group Placebo, 20 mg/day, 45 mg/day, 90 mg/day Baseline mms score Age Sequential testing strategy 90 mg/day vs. placebo 45 mg/day vs. placebo 20 mg/day vs. placebo Handling of missing data LOCF (primary) MMRM (mixed model repeated measures analysis of covariance)

10 Results: Modified Motor Score Comparison Treatment Effect 95% CI P-Value 90 mg/day vs. Placebo 45 mg/day vs. Placebo 20 mg/day vs. Placebo -1.2 (-2.5, 0.1) (-2.5, 0.2) (-1.4, 1.3) 0.98

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12 Results: Total Motor Score Comparison 90 mg/day vs. Placebo 45 mg/day vs. Placebo 20 mg/day vs. Placebo Treatment Effect 95% CI P-Value -2.8 (-5.4, -0.1) (-3.9, 1.5) (-2.9, 2.6) 0.91

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14 Results: Other efficacy measures No significant results

15 Tolerability 92.3% of subjects on study drug completed study at assigned dose 89.3% at 20 mg 96.4% at 45 mg 84.5% at 90 mg 94.8% of subjects on placebo completed study at assigned dose

16 Safety and Tolerability: Adverse Events Placebo ACR16 20mg ACR16 45mg ACR16 90mg Total Total Number of Patients Fall 7 (12.1%) 9 (16.1%) 8 (14.5%) 8 (13.8%) 32 (14.1%) Nausea 4 (6.9%) 2 (3.6%) 1 (1.8%) 5 (8.6%) 12 (5.3%) Headache 3 (5.2%) 3 (5.4%) 3 (5.5%) 3 (5.2%) 12 (5.3%) Diarrhoea 3 (5.2%) 3 (5.4%) 4 (7.3%) 2 (3.4%) 12 (5.3%) Depression 4 (6.9%) 2 (3.6%) 3 (5.5%) 2 (3.4%) 11 (4.8%) Huntington`s chorea 2 (3.4%) 3 (5.4%) 2 (3.6%) 3 (5.2%) 10 (4.4%) Fatigue 5 (8.6%) 1 (1.8%) 2 (3.6%) 2 (3.4%) 10 (4.4%) Nasopharyngitis 1 (1.7%) 2 (3.6%) 2 (3.6%) 3 (5.2%) 8 (3.5%) Excoriation 4 (6.9%) 1 (1.8%) 2 (3.6%) 1 (1.7%) 8 (3.5%)

17 Other Trials: MermaiHD European Phase III trial, n = 437 Results: Trial Comparison groups mms TMS MermaiHD Pridopidine 45 mg BID vs. placebo -1 point p = points p = HART Pridopidine 45 mg BID vs. placebo -1.2 points p = points p = 0.04

18 Conclusions Non-significant trend toward improvement on modified Motor Score Nominally significant improvement in Total Motor Scale Favorable safety/tolerability profile Results similar to other large scale study (MermaiHD) Further research on pridopidine is warranted