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Clinical Effects of Oral Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification.

Abushakra and colleagues (1) report on the effects of oral tramiprosate on apolipoprotein E (APOE) ε 4 allele (APOE4) homozygotes. Tramiprosate is an oral amyloid anti-aggregation agent that reduces oligomer formation and fibrillar (plaque) amyloid deposition in transgenic animal models (1–4). Tramiprosate has been shown to inhibit β -amyloid (A β ) fibrillation and to reduce soluble A β . It prevents A β formation and deposition by interfering with glycosaminoglycans. It has also been reported to inhibit the inflammatory response. More recently, tramiprosate has been shown to modulate “conformational flexibility of amyloid beta A β 42, leading to the prevention of oligomer seed formation and thus aggregation” (4). Phase 2 studies of tramiprosate showed promising data, with evidence of stabilization. Tramiprosate was then evaluated in two 78-week phase 3 trials in patients with mild to moderate Alzheimer’s disease (AD). However, the results of the North American trial, which became available in 2007, did not show efficacy in the overall study population (5). The present report is a substudy of that primary analysis. In the substudy, APOE4 homozygotes were selected. The substudy reports the results from the North American and European Union studies of 2 doses (tramiprosate 100 mg twice daily and 150 mg twice daily) and matching placebo in each study. The APOE4/4 sample comprised 257 subjects. In the mild subgroup identified using the Mini-Mental State Examination (MMSE), tramiprosate proved to be significantly superior to placebo at weeks 52, 65, and 78 (p≤0.01), as indicated by Alzheimer’s Disease Assessment Scale (ADAS) scores. It proved to have statistically significant benefit (p<0.05) at weeks 52, 65, and 78 as indicated by Clinical Dementia Rating (CDR) scale scores, and it proved to be of some benefit at week 78 as indicated by Disability Assessment for Dementia (DAD) scale scores. These data suggest a pharmacogenomically driven effect in a subcohort of AD.