O3–06–05: Sustained cognitive benefit in patients with mild cognitive impairment (MCI) upon prolonged treatment with CHF5074

CHF5074 is a new microglial modulator that has been shown to prevent brain plaque deposition and attenuate memory deficits in transgenic mouse models of AD. In man, the drug dose-dependently lowers cerebrospinal fluid levels of two biomarkers of neuroinflammation (sCD40L and TNF- a). We monitored the safety and tolerability and cognitive effects of CHF5074 after prolonged treatment in MCI patients. At the end of a 14-week double-blind, placebo-controlled study in 96 MCI patients evaluating three titrated dose regimens of CHF5074 (200, 400 and 600 mg/day), patients were given the option to enter a 76-week open label extension study. Patients received CHF5074 at the dose equal to that of their originally assigned double-blind study cohort. Patients were monitored for vital signs, cardiac activity, neuropsychological performance and safety laboratory parameters. Seventy-four patients entered the open label study: 26, 21 and 27 in the 200,400 and 600 mg/day cohorts, respectively. At Study Week 40, 14 patients dropped out: 4, 2 and 8 in the 200,400 and 600 mg/day cohorts, respectively. Three of drop-outs were for adverse events: two in the 600 mg/day group (serum creatinine elevation and worsening of cognitive function) and one in the 400 mg/day group (pneumonia). The most frequent treatment-emergent adverse events were gastrointestinal disorders, with diarrhea being reported by 1.4% of patients on 200 mg/day, 6.3% of patients on 400 mg/day and 16.0% of patients on 600 mg/day. Interim analysis of cognitive tests of 32 patients reaching Study Week 64 showed statistically significant improvements compared to Baseline on Digit Symbol Substitution Test (+4.8±1.1 matches, p<0.001), Trail Making Test-A (-8.1±2.4 sec, p=0.002), Trail Making Test-B (-14.5±4.6 sec, p=0.004), Immediate Word Recall (+2.9±0.8 words, p=0.001) and Delayed Word Recall (+1.3±0.4 words, p=0.003). APOE4 carriers performed significantly better than APOE4 non-carriers on Immediate Word Recall (+5.4±1.2 vs. +1.4±0.9 words, p=0.012) and Trail Making Test-A (-12.4±2.8 vs. -5.6±3.3 sec, p=0.034) with improvements representing 25–38% of Baseline scores. CHF5074 was well tolerated by MCI patients after prolonged treatment at doses up to and including 400 mg/day. Drug treatment was associated with sustained cognitive benefit in executive function and verbal memory for at least 64 weeks.