Alzheimer Metal Chelator Shows Some Promise in Phase II
Abstract & Commentary
Source: Ritchie CW, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685-1691.
The zinc and copper chelating compound clioquinol has been shown to reduce beta-amyloid deposits in the brain of transgenic mice and is consequently being tested as a treatment for Alzheimer’s disease (AD). The compound has been found to promote solubilization and clearance of beta-amyloid in laboratory studies and may also inhibit potentially harmful copper-amyloid interactions. Clioquinol has been used as an antibacterial and antifungal agent in the past but was withdrawn from clinical use after several thousand cases of subacute myelo-optic neuropathy developed in Japan, possibly as a result of clioquinol-induced B-vitamin deficiency.
Relying on careful monitoring to reduce the risk of toxicity, Ritchie and colleagues carried out a 36-week phase II test of the efficacy of clioquinol in reducing plasma beta-amyloid levels and slowing cognitive decline in patients with moderately severe AD. The study had randomized, placebo-controlled and double-blind design and examined 36 AD patients with a mean ADAS-Cog score of approximately 26 at baseline. Despite the involvement of a relatively small number of subjects, Ritchie et al chose to stratify the subjects into 2 groups by severity of cognitive impairment for the purposes of analysis.
No significant effects on cognition were observed in the treated patients overall or in the more mildly affected group. Among the more severely affected patients (baseline ADAS-Cog score greater than 25), a statistically significant effect was seen at weeks 4 and 24 on the ADAS-Cog but not other weeks. No significant differences were seen on the Minimental State Examination at any time point. Plasma beta-amyloid levels did show change significantly with treatment, although there was wide individual variation in levels across subjects. Five serious adverse events were observed, including one case of visual changes that was considered possibly treatment related.
Ritchie et al concluded that their results were sufficiently promising to warrant further trials of clioquinol or a modified version of this compound for treatment of AD.
Commentary
A phase II trial such as this is generally designed to establish proof of concept, providing minimal information on whether there is enough of a treatment effect relative to tolerance to warrant further studies. The results of this trial look respectable in terms of reduction of plasma beta-amyloid levels by clioquinol, while the primary outcome measure of cognition shows less impressive changes but noteworthy trends. Ritchie et al point out that demonstrating a comparable treatment effect with the current generation of cholinesterase inhibitors requires trials with more than 300 patients. The practicality of using a medication that was withdrawn from clinical use owing to side effects in patients with dementia is a cause for concern. Larger studies will be needed to delineate the efficacy and safety profile of clioquinol in a more representative AD population. The use of copper and zinc chelation as a treatment for AD is novel, and the relative merits of this approach compared to other emerging techniques for altering brain amyloid burden remain to be determined. — Norman R. Relkin
Dr. Relkin, Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital- Cornell Campus, is Assistant Editor of Neurology Alert.
Relying on careful monitoring to reduce the risk of toxicity, Ritchie and colleagues carried out a 36-week phase II test of the efficacy of clioquinol in reducing plasma beta-amyloid levels and slowing cognitive decline in patients with moderately severe Alzheimer's disease.
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