Positive Results in Phase 2 Trial of BAN2401 for Treatment of Persons With Alzheimer’s Disease
Detailed results of a phase 2 study (NCT01767311) of BAN2401 (Eisai, Woodcliff Lake, NJ and Biogen, Cambridge, MA) were presented at the Alzheimer's Association International Conference (AAIC) 2018 in Chicago, IL. BAN2401 is a monoclonal antibody that targets amyloid-β (Aβ) protofibrils. In the study, 856 patients with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD), which together are considered early AD, who also had confirmed amyloid pathology in the brain. Study subjects were assigned to 1 of 5 dose regimens using Bayesian adaptive randomization. This design uses interim analyses to allocate later enrollees into treatment arms with greater expected efficacies or placebo.
A statistically significant dose-dependent reduction in brain amyloid levels using amyloid-positron emission tomography (amyloid-PET) was seen in all groups. Patients given 10 mg per kg of BAN 2401 every 2 weeks (n = 161) had a mean reduction in brain amyloid accumulation of 74.5 to 5.5 units on the Centiloid scale. Using a mixed-effects model of repeated measures, patients given this dose had a statistically significant mean reduction in amyloid load of 70 units (P < .0001) and 81% of patients in this group converted from amyloid positive to amyloid negative (P <.0001). A dose-dependent reduction in amyloid plaques occurred in all patients given BAN2401that was statistically significant compared to that seen in patients given placebo.
Patients given 10 mg per kg biweekly also had a statistically significant slowing of clinical decline of 30% compared to those given placebo at 18 months (P = .034). A statistically significant slowing of decline on the Alzheimer's Disease Composite Score (ADCOMS) was observed as early as 6 months (P < .05) and at 12 months (P < 0.05). On the Alzheimer's Disease Assessment Scale-cognitive subscale ADAS-Cog this group of patients had a 47% slower decline than those given placebo after 18 months of treatment (P = .017).
BAN2401 demonstrated an acceptable tolerability profile through 18 months of study drug administration. The incidence of treatment-related adverse events was 26.5% for those given placebo arm, and 53.4% (10 mg/kg monthly) or 47.2% (10 mg/kg biweekly) for those given the highest doses of BAN2401. The most common treatment emergent adverse events were amyloid related imaging abnormalities (ARIA) and infusion-related reactions and ARIA-E (edema) occurred in 9.9% of patients given the highest treatment dose (not more than 10% in any BAN2401-treated group). Incidence of ARIA-E in APOE4 carriers was 14.6% at the highest dose. Per protocol, all patients presenting with ARIA-E on MRI were discontinued in the study. The incidence rate of serious adverse events was 17.6% for the placebo arm, 12.3% for the 10 mg/kg monthly treatment arm and 15.5% for the 10 mg/kg biweekly arm.