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Metal-Protein Attenuation With Iodochlorhydroxyquin (Clioquinol) Targeting A Amyloid Deposition and Toxicity in Alzheimer Disease

A Pilot Phase 2 Clinical Trial

Craig W. Ritchie, MBChB, MRCPsych; Ashley I. Bush, MBBS, PhD, FRANZCP; Andrew Mackinnon, PhD; Steve Macfarlane, MBBS; Maree Mastwyk, BN; Lachlan MacGregor, MBBS; Lyn Kiers, MBBS, FRACP; Robert Cherny, PhD; Qiao-Xin Li, PhD; Amanda Tammer, PhD; Darryl Carrington, BSc; Christine Mavros, BSc; Irene Volitakis, BSc; Michel Xilinas, MD, DSc; David Ames, MD; Stephen Davis, MD, FRACP; Konrad Beyreuther, PhD; Rudolph E. Tanzi, PhD; Colin L. Masters, MD

Arch Neurol. 2003;60:1685-1691.

Background  Alzheimer disease (AD) may be caused by the toxic accumulation of -amyloid (A).

Objective  To test this theory, we developed a clinical intervention using clioquinol, a metal-protein–attenuating compound (MPAC) that inhibits zinc and copper ions from binding to A, thereby promoting A dissolution and diminishing its toxic properties.

Methods  A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease.

Results  Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, 25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma A₄₂ levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated.

Conclusion  Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein–attenuating compound.

From the Departments of Pathology (Drs Ritchie, Bush, Macfarlane, Cherny, Li, Tammer, and Masters; Mss Mastwyk, Mavros, and Volitakis; and Mr Carrington), Medicine (Drs MacGregor, Kiers, and Davis), and Psychiatry (Dr Ames), The University of Melbourne, The Mental Health Research Institute of Victoria, Parkville, Victoria (Drs Ritchie, Bush, Mackinnon, Macfarlane, Cherny, Li, Tammer, and Masters; Mss Mastwyk, Mavros, and Volitakis; and Mr Carrington); the Department of Psychiatry and Behavioural Science, Royal Free Campus, University College London, London, England (Dr Ritchie); the Department of Psychological Medicine, Monash University, Clayton, Victoria (Dr Mackinnon); the Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria (Drs MacGregor, Kiers, and Davis); the Institute of Clinical Neuroscience, Göteborg University, Göteborg, Sweden (Dr Xilinas); the Center for Molecular Biology, University of Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Genetics and Aging Research Unit, Massachusetts General Hospital, Boston (Drs Bush and Tanzi). Dr Ritchie has been paid for his time and effort in analyzing the results from the trial sponsor, Prana Biotechnology. Drs Bush and Tanzi are paid consultants, are on the Scientific Advisory Committee, and are stockholders of Prana Biotechnology and had no input into the drafting or review of any portion of the manuscript other than those portions pertaining to study concept and design and consultation on biochemistry and no input into the analysis of the data from the other portions. Drs Macfarlane and MacGregor and Ms Mastwyk were employed by the Mental Health Research Institute through funds provided by Prana Biotechnology. Dr Cherny is a stockholder in Prana Biotechnology. Dr Xilinas has financial and intellectual interests in the development of clioquinol. Dr Beyreuther is on the Scientific Advisory Committee of Prana Biotechnology. Dr Masters is a director of Prana Biotechnology, chairperson of its Scientific Advisory Committee, and a stockholder.

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