Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies

Abstract

Introduction: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed.

Methods: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout.

Results: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up.

Discussion: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition.

Highlights: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Keywords: APOE; Alzheimer's disease (AD) prevention; BACE inhibitors; amyloid beta lowering; biomarkers; imaging.

FIGURE 1

Participant flow charts. (A) CONSORT Generation Study 1 (GS1) Cohort II. (B) CONSORT Generation Study 2 (GS2). (C) Participant distribution across GS1 and GS2. (A) GS1: 482 participants completed screening, of whom 65 participants were randomized to Cohort I and two participants could not be randomized due to study termination, resulting in 415 participants randomized to Cohort II. *A total of 412 participants were treated, with 249 receiving umibecestat 50 mg and 163 receiving placebo (three not treated). (B) GS2: 1172 participants completed screening, of whom 1145 were randomized and 27 could not be randomized due to study termination. *A total of 1144 participants were treated, including 455 in the umibecestat 50 mg group (one not treated). (C) GS1 and GS2: percentage of mSAF uses SAF as denominator and percentage of "last visit on treatment and after washout" uses mSAF as denominator. Last visit on treatment and after washout: participants who had both a last visit on treatment and a last visit after washout; last visit on treatment is the last assessment (RBANS total score) before or at last day on study drug + 31 days; last visit after washout is the last assessment after last day on study drug + 31 days. mSAF, modified safety analysis set; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; SAF, safety analysis set, which consists of all participants who received study medication; mSAF: consists of all participants of SAF with at least 3 months’ exposure duration.

FIGURE 2

Treatment effect size of change from baseline in RBANS and APCC (modified safety analysis set). A decrease in RBANS and APCC indicates worsening condition. Effect size is calculated using Cohen's d formula (raw, not model‐based, mean to standard deviation [SD] ratio) as the difference between active treatment (umibecestat) and placebo in the mean change from baseline divided by the pooled SD of the change (negative effect size indicates worsening in cognitive score with umibecestat vs placebo). For further details on effect size, CI calculation, and methodology, see Supplementary File. Cohen's d = 0.2 is considered a small, 0.5 a medium, and 0.8 a large effect size. Last visit on treatment is the last assessment before washout (ie, last day on study drug + 31 days). Last visit after washout is the last assessment off treatment after washout. Scheduled visits at Weeks 13 and 26 (as well as Week 52, as shown in Table S3) occurred before study termination; therefore, most participants at these visits were on treatment as per protocol (unless the drug was discontinued for other reasons). Participants who had their last visit on treatment at Week 26 were counted in both Week 26 and last week on treatment analyses. APCC, Alzheimer's Prevention Initiative Preclinical Composite Cognitive test; n, number of participants with non‐missing value; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

FIGURE 3

Change in RBANS total from baseline to last visit on treatment (A) as a function of umibecestat exposure (decline in RBANS score detectable but non‐progressive throughout the treatment period); (B) by neurocognitive domain; (C) proportion of participants in each category of change (modified safety analysis set). Locally estimated scatterplot smoothing (LOESS) estimates were derived using LOESS regression that uses local weighted regression to fit a smooth curve through points in a scatterplot of RBANS total change at last visit on treatment versus exposure. LOESS smooth curve is presented with degree = 1 and smoothing parameter = 0.65. For details on effect size and CI calculation, see figures 2 and 5 legends and Supplementary File. Last visit on treatment is the last assessment before washout (ie, last day on study drug + 31 days). n, number of participants with non‐missing value; N, total number of participants in each treatment group; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.

FIGURE 4

Change in body weight (kilograms) by visit (safety analysis set). Last visit on treatment is the last assessment before washout (ie, last day on study drug + 31 days). Last visit after washout is the last assessment off treatment after washout. Scheduled visits at Weeks 13 and 26 occurred before study termination; therefore, most participants at these visits were on treatment as per protocol (unless the drug was discontinued for other reasons). Participants who had their last visit on treatment at Week 26 were counted in both Week 26 and last week on treatment analyses. n, number of participants with a non‐missing value; N, total number of participants in each treatment group; at each visit, only participants with a non‐missing value at both baseline and that visit are included; SE, standard error.

FIGURE 5

Treatment effect size of percentage volume loss from baseline (Week 26) (modified safety analysis set). Effect size is calculated using Cohen's d formula (raw, not model‐based mean to standard deviation [SD] ratio) as difference between active and placebo in mean change from baseline divided by pooled SD of change (negative effect size indicates worsening in cognitive score with umibecestat vs placebo). For further details on effect size, CI calculation, and methodology, see Supplementary File. Cohen's d = 0.2 is considered a small, 0.5 a medium, and 0.8 a large effect size. For all participants, the scheduled visit at Week 26 occurred before study termination; therefore, most participants at this visit were on treatment as per protocol (unless the drug was discontinued for other reasons).