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Original Investigation
January 19, 2021

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial

Author Affiliations
  • 1Brigham and Women’s Hospital, Boston, Massachusetts
  • 2Janssen Research & Development LLC, Titusville, New Jersey
  • 3Indiana University School of Medicine, Indianapolis
  • 4Alzheimer’s Therapeutic Research Institute, University of Southern California, Los Angeles
  • 5Translational Medicine Neuroscience, UCB Biopharma SRL, Braine-l'Alleud, Belgium
  • 6Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  • 7Department of Neurology, University of Virginia, Charlottesville
  • 8Passage Bio, Philadelphia, Pennsylvania
JAMA Neurol. 2021;78(3):293-301. doi:10.1001/jamaneurol.2020.4857
Key Points

Question  What are the short-term effects of atabecestat in preclinical Alzheimer disease (AD), and are adverse effects reversible after stopping treatment?

Findings  In this truncated randomized clinical trial of 557 participants with preclinical AD, atabecestat treatment was associated with statistically significant greater, dose-related cognitive worsening and neuropsychiatric adverse events (AEs) vs placebo. Baseline to last off-treatment cognitive assessment suggested return to baseline cognitive status, and frequency of neuropsychiatric AEs returned to placebo levels after stopping atabecestat.

Meaning  This study’s findings confirm dose-related worsening of cognition and neuropsychiatric AEs in atabecestat-treated participants, with recovery after up to 6 months off treatment.


Importance  Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).

Objective  To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment.

Interventions  Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185).

Main Outcomes and Measures  Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study.

Results  Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, −1.09; 95% CI, −1.66 to −0.53; P < .001) and month 12 (least-square mean, −1.62; 95% CI, −2.49 to −0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, −3.70; 95% CI, −5.76 to −1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups.

Conclusions and Relevance  Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.

Trial Registration  ClinicalTrials.gov Identifier: NCT02569398

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