Viewpoint Cite This: Biochemistry XXXX, XXX, XXX−XXX
pubs.acs.org/biochemistry
Light at the End of the Amyloid Tunnel Published as part of the Biochemistry series “Biochemistry to Bedside” Dennis J. Selkoe* Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
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apolipoprotein E4-positive and E4-negative subjects, because E4 carriers have a higher prevalence and somewhat earlier onset of clinical AD and possibly a more rapid course. However, the European Medicines Agency (EMA) decided early on (in July 2014) to remove from the trial any apoE4+ patients in the highest dose arm (10 mg/kg bimonthly) who had not yet reached month 6, and they also prevented any more apoE4+ patients from entering that arm. The regulators apparently did this because they feared an excess of subjects developing the common adverse event of amyloid-clearing mAbs, ARIA-E (amyloid-related imaging abnormality-edema), which occurs much more frequently in ApoE4+ than E4− subjects. This forced discontinuation skewed the distribution of apoE4+ subjects away from the highest dose and toward the next highest dose (10 mg/kg monthly). The trial continued, and a 12-month interim analysis identified the highest dose (10 mg/kg bimonthly) as the best, having a 98% probability of being superior to a placebo; the second highest dose was the next best. This result follows earlier mAb trials that showed that higher doses are far more effective. After 18 months, there was a significant, dose-dependent reduction of PET amyloid burden across all doses. Accordingly, BAN2401 significantly converted positive scans to negative, with 81% of subjects on the highest dose read as amyloid-negative at 18 months. Importantly, there was a dosedependent reduction in cognitive decline in the ADCOMS test, starting at 6 months and achieving a 30% reduction from a placebo (p = 0.034) at the highest dose. The widely used ADAS-cog test showed a dose-dependent reduction in decline starting at 6 months, reaching a 47% reduction versus a placebo after 18 months on the highest dose. Placebo subjects declined at a similar rate as other large AD trial populations. With regard to biomarkers in a CSF substudy, BAN2401 bound Aβ1−42, yielding a dose-dependent increase in its CSF level and thereby demonstrating target engagement. CSF tau levels decreased slightly but significantly at the top two doses. With regard to safety, the principal treatment-attributable adverse event (other than occasional mild infusion reactions) was ARIA-E. As expected from earlier mAb trials, this change in MRI scans was more prevalent at high doses (but still occurred in
