Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults (≥25 years old) with early-stage to mid-stage Huntington's disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests (Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) and scores on eight individual cognitive tests (the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with ClinicalTrials.gov, NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35) at 19 research centres in Australia and the USA. 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study. Six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 (89%) participants on PBT2 250 mg, 30 (79%) on PBT2 100 mg, and 28 (80%) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg (least-squares mean 0·02, 95% CI -0·10 to 0·14; p=0·772) nor PBT2 250 mg (0·07, -0·05 to 0·20; p=0·240) significantly improved the main composite cognition Z score between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17·65 s, 0·65-34·65; p=0·042) but not in the 100 mg group (0·79 s improvement, -15·75 to 17·32; p=0·925); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited.
|Number of pages||9|
|Journal||The Lancet Neurology|
|State||Published - Jan 1 2015|
Bibliographical noteFunding Information:
ERD has received grants from Prana Biotechnology; grants and personal fees from Huntington Study Group, Lundbeck, and Medtronic; and personal fees from Clintrex, Roche, Optio, Transparency Life Sciences, and Amgen. HDR has received a research contract from Prana Biotechnology and personal fees from Pfizer. CH and DAn are employees of and shareholders in Prana Biotechnology. CWR and ME-D have received personal fees from Prana Biotechnology. DO, SGa, AW, KB, and CL have received grant support from Prana Biotechnology. JS has received grants from Prana Biotechnology and CHDI Foundation, personal fees from Roche and Prana Biotechnology, research contracts from Teva Pharmaceuticals and Omeros, and personal fees and non-financial support from GlaxoSmithKline. IL has received grants from Monash University. CSt is an employee of Prana Biotechnology. RR has received grants from CHDI Foundation, DFG, EU-FP7, European Huntington's Disease Network, DZNE, and BMBF; has been an advisory board member for Novartis, Pfizer, Siena Biotech, Ipsen, Teva, Lundbeck, ISIS Pharma, and CHDI Foundation; has received honoraria from Novartis, Pfizer, Siena Biotech, NeuroSearch, Ipsen, Teva, Lundbeck, ISIS Pharma, CHDI Foundation, Wyeth, Link Medicine, Prana Biotechnology, Medivation, MEDA Pharma, Temmler Pharma, and AOP Orphan Pharmaceuticals; has received consultancy payments from Pfizer, Siena Biotech, NeuroSearch, Ipsen, Teva, Lundbeck, ISIS Pharma, CHDI Foundation, Wyeth, Link Medicine, and Prana Biotechnology; and has provided clinical trial services or quantitative motor analyses for Novartis, Teva, Pfizer, Ipsen, CHDI Foundation, BMBF, and DZNE. SH has received grants and personal fees from Prana Biotechnology; and personal fees from Pfizer and Azevan Pharmaceuticals. RM has received grants from Prana Biotechnology, Neurocrine, Medivation, and Teva. DAm was a member of a data safety and monitoring board for Prana Biotechnology. KM has received grants from CHDI Foundation, HDSA, the National Institutes of Health 1 UL 1 RR024156, P0412196, NS036630 , and Parkinson's Disease Foundation. CSi has received personal fees from Lundbeck. SK's institution received research funding from Prana Biotechnology through the University of Rochester for this study; financial support from NeuroSearch for participation in HART-HD and OPEN-Hart; financial support from Auspex Pharmaceutical for participation in the First HD and Arc HD trials; and funding for participation in the ENROLL-HD. SK has received grants from Huntington's Disease Society of America, Lundbeck, NuroSearch, Auspex Pharmaceuticals, and CHDI Foundation, and personal fees from Lundbeck. PC's institution has received financial support from Prana Biotechnology through the University of Rochester for participation in the Reach2HD study. PC has received grant support from Teva Pharmaceuticals. MN has received grants from Prana Biotechnology through the University of Rochester, Teva, NeuroSearch, Medivation/Pfizer, Impax Pharmaceuticals, Schering-Plough, Biotie, and personal fees from Lundbeck. MSLD has received grants from Prana Biotechnology, Omeros, Auspex, and CHDI Foundation; and personal fees from Lundbeck, UCB Pharma, Teva, USWorldMeds, Mayo Clinic, and Elsevier. AD's institution received research funding from Prana Biotechnology through the University of Rochester for this study; from NeuroSearch in conjunction with the Huntington Study Group for participation in HART-HD and OPEN-Hart; and from Auspex Pharmaceutical in conjunction with the Huntington Study Group for participation in First HD and Arc HD. AD has received grants from Huntington's Disease Society of America, and funding from CHDI Foundation for participation in ENROLL-HD. PM has received personal fees from Novartis Pharma, Bayer, and Roche. SE has received personal fees from Huntington Study Group, Prana Biotechnology, Millennium/Takeda, Pfizer, Roche, Novartis, Achaogen, Averion, Massachusetts General Hospital, Harvard Clinical Research Institute, TARIS, Boston University, Alcon, Cubist, Merck, Chelsea Therapeutics, Mannkind, QRx Pharma, IMMPACT, Intermune, Genentech, Affymax, FzioMed, CIS Biotech, Auspex, Sunovion, GlaxoSmithKline, Boehringer Ingelheim, Alcon, American Statistical Association, American Neurological Association, Beth Israel Deaconess Medical Center, US Food and Drug Administration, Osaka University, Statistical Society of Australia, Interfarma, Muscle Study Group, Society for Clinical Trials, Harvard Medical School, Biopharmaceutical Applied Statistics Symposium, Phamaceutical Education and Research Institute, Graybill Conference, Deming Conference, Midwest Biopharmaceutical Statistics Workshop, New Jersey Chapter of American Statistical Association, American Statistical Association, Drug Information Association, Merck, Johns Hopkins University, Schering-Plough, HIV/AIDS Network Coordination, HIV Neurobehavioral Research Center, and grant funding from the National Institutes of Health and Fogarty International Center. BRL has received personal fees from Prana Biotechnology, Novartis, Isis Pharmaceuticals, Pfizer, Neurosearch, Teva, Lundbeck, Roche, Aequus, Auspex, and Omeros. RT reports personal fees from Prana Biotechnology. ST reports personal fees and equity interest from Prana Biotechnology; grants from Pfizer, Forum Pharmaceuticals, and Civitas Pharmaceuticals; and personal fees from Functional Neuromodulation. MW, MM-L, SF, CV, EK, KH, CC, CO, JC-B, PKP, AG, PA, AC, SJ, VS, RK, KA, CD, EM, SC, SGl, JGo, LLe, NY, MM, RC, HMa, NP, DG, LLi, HMo, BH, SGu, AI, BJ, JGr, AF, and SW declare no competing interests.
This study was funded by Prana Biotechnology. Development of the huntingtin assay was supported by a National Institutes of Health grant NS071789 (SMH and MML). The 2B7 antibody was provided by the Novartis Institute for Biomedical Research. We thank Byron L Lam for his help undertaking ophthalmological assessments in the study.
© 2015 Elsevier Ltd.
ASJC Scopus subject areas
- Clinical Neurology