Clioquinol Treatment in Familiar Early Onset of Alzheimer’s Disease

Ibach et al.’s recent report of Alzheimer’s disease (AD) stabilization with Clioquinol (CQ) 250 mg bid [the first in class Metal-protein attenuating compound (MPAC)] provides further evidence of the potential importance of this target for rational therapeutic intervention [3].

Their own study is limited by the difficulty in generalising from two patients. However, there is cause for some optimism as this represents the third, independent report of efficacy with this drug [5] [6]. Importantly, each study has noted an impact of the drug on the presumed pathological hallmarks of the disease, namely Aβ and tau protein in both CSF [3] [5] and plasma [6]. The inconsistent pattern of alteration in these parameters between these three studies highlights the dynamic relationship between disease severity and alterations in biomarker levels with the further complication of the effect of genetic mutations on the natural history of these changes.

From Ibach’s work, it is interesting to note that both patients in the study deteriorated slightly before stabilising. One wonders whether this was an effect of withdrawal of their standard acetylcholinesterase/memantine treatment as it is not clear in the report whether these drugs were stopped prior to the commencement of CQ. In our study [6], despite noted treatment failure with donepezil before entering the trial, we had a strong effect noted at week 4 in the CQ group which we had attributed to neutralisation of a toxic more soluble pool of Aβ. Finally, Ibach’s report is particularly noteworthy as it is the first to show an effect through functional neuroimaging of CQ, providing more concordant evidence of this drug’s pathophysiological effect.

There is now a small but gathering evidence base with regard to this drugs potential efficacy in AD. Unlike Ibach’s proposition that these drugs should be a ‘last resort’, it is our belief that given the strong pre-clinical and accumulating evidence of their mode-of-action, this class of drugs would ideally find a place in managing AD at the earliest clinical juncture.

The risk of sub-acute myelo-optic neuropathy with CQ is believed now to be small [7] and given that this drug and similar drugs in its class may be effective in other neurodegenerative conditions [2] as well as cancer [1], there is a pressing need for further critical evaluation of their use and to this end, Phase 1 studies of the next generation of MPAC drugs are ongoing [4].

Clinicians and academics using these drugs as Ibach has are encouraged to report their experience, if for no other reason than to minimise the risk of publication bias that could encourage false optimism with regard to their clinical utility.

References

• 1 Ding W Q, Liu B, Vaught J L, Yamauchi H, Lind S E. Anticancer activity of the antibiotic clioquinol.  Cancer Res. 2005;  65 3389-3395
• 2 Doraiswamy P M, Finefrock A E. Metals in our minds: therapeutic implications for neurodegenerative disorders.  Lancet Neurology. 2004;  3 431-434
• 3 Ibach B, Haen E, Marienhagen J, Hajak G. Clioquinol treatment in Familiar Early Onset of Alzheimer’s Disease.  Pharmacopsychiatry. 2005;  38 178-179
• 4 Prana Biotechnology: http://www.pranabio.com/company_profile/press_releases_item.asp?id = 89. 
• 5 Regland B, Lehman W, Abedini I. et al . Treatment of Alzheimer’s disease with clioquinol.  Dement Geriatr Cogn Disord. 2001;  12 408-414
• 6 Ritchie C W, Bush A I, MacKinnon A. et al . Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer’s disease: a pilot phase 2 clinical trial.  Arch Neurol. 2003;  60 1685-1691
• 7 Ritchie C W, Bush A I, Masters C L. Metal-protein attenuating compounds and Alzheimer’s disease.  Expert Opin Investig Drugs. 2004;  13 1585-1592