HIGH DOSE DONEPEZIL WITH SOLIFENACIN (CPC-201) IMPROVES SAFETY AND INITIAL EFFICACY IN ALZHEIMER’S DISEASE

Abstract

Cholinesterase inhibitors (ChEIs) remain the therapeutic mainstay for dementia of the Alzheimer’s type (DAT) despite dose-limiting adverse events (AEs) and modest efficacy. Nevertheless, PET studies indicate that ChEIs, at maximum tolerable dose (MTD), inhibit the target CNS enzyme by only about 30%, while non-clinical and clinical results suggest higher ChEI doses confer greater cognitive benefit. Moreover, Phase I studies supported hypothesis that co-administration of a peripheral anticholinergic reduces dose-limiting AEs, enabling the safe/tolerable use of higher ChEI doses and thus potentially improving antidementia efficacy. A phase IIa single-blind, crossover trial was conducted to further evaluate this hypothesis in 41 moderate (MMSE 10-20) DAT patients being successfully treated with 10 mg/day donepezil. The anticholinergic solifenacin was first titrated to 15 mg/day and then donepezil escalated to each patient’s MTD or protocol limit (40 mg/day). Patients continued at their MTD for 3 additional months. At the end of dose titration (week 14), the median MTD of donepezil (primary endpoint), given orally with solifenacin as CPC-201, increased to 40 mg/day (p <.0001; n = 33 in ITT population); 88% of patients reached this maximum allowable dose, which did not change significantly during following 3 months. Cognitive function, measured by the ADAS-cog scale at end of dose titration and during dose maintenance (weeks 18, 22 and 26 in n = 23 per protocol population) was consistently improved compared with baseline; adjustment for natural disease progression and the previously realized response to 10 mg donepezil (approximated from published RCT results) yielded a mean (± SEM) benefit of 5.4 ± .84 points (p < .05) compared to historic placebo (trial not powered for secondary efficacy measures). Combined Clinical Global Impression (CGI-I) scores from investigators and caregivers at 26 weeks averaged 3.1 ± .20 points, thus improving by .94 ± .20 points (p < .001; n = 16). At MTD, the frequency of gastrointestinal AEs declined by over 80% of that reported in trials of 10 and 23 mg donepezil. No drug-related drop-outs or SAEs, and no new AEs or evidence of solifenacin toxicity occurred. Attenuating donepezil AEs with soifenacin enables the safe/tolerable administration of higher ChEI doses that could improve antidementia efficacy.