Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease

Abstract

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. RESULTSOf 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.

Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer’s disease in humans

“…However, with excessive or prolonged exposure, these protective effects of Aβ could transition to the well-established neurotoxic effects of high Aβ concentrations, overwhelming glial-mediated Aβ clearance pathways, leading to extracellular Aβ deposition. This nuanced interpretation wherein BACE1 and Aβ monomers serve a protective role is consistent with findings from controlled trials in which BACE1 inhibitors paradoxically worsened cognitive decline,[175, 176] despite markedly decreasing CSF Aβ (see description in Table S1 ). [177]…”

Accelerated long‐term forgetting is a BACE1 inhibitor‐reversible incipient cognitive phenotype in Alzheimer’s disease model mice

“…Concerning the failure of recent clinical trials, it should be noted that BACE1 inhibitor drugs showed dose‐dependent cognitive worsening (rather than improvement) in prodromal AD populations. 6 , 7 , 8 This was observed for multiple BACE1 inhibitors at the highest dose, most likely indicative of side effects associated with excessive BACE1 inhibition rather than compound‐specific effects. The current clinical dosage achieving up to 90% Aβ reductions seems far higher than needed, given that an APP mutation (A673T) that lowers Aβ in plasma by only 28% can protect against AD and age‐related cognitive decline.…”

“… 3 However, BACE1 inhibitor clinical trials have been failing to show beneficial cognitive outcomes first in patients with mild‐to‐moderate AD 4 , 5 and more recently in those with early stages of mild AD or amnesic mild cognitive impairment (MCI) due to AD (prodromal AD). 6 , 7 , 8 Clinical studies are shifting to target further earlier stages such as secondary prevention (presymptomatic populations) and primary prevention (before amyloid build‐up preceding symptoms by ~ 15 years 9 ) of AD. These efforts are, undoubtedly, indispensable for determining the disease stage to start successful BACE1 inhibitor interventions for clinical efficacy, while evaluating the cognitive benefits (if any) in asymptomatic subjects at a risk of developing AD is challenging.…”

Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

“…Finally, the mild AD population enrolled may have been too far along in their disease process to respond to a BACE inhibitor treatment. A BACE inhibitor trial was terminated in the preclinical AD population due to findings of dose-related cognitive worsening and neuropsychiatric adverse events [ 31 ], though it has been hypothesized that a viable low dose BACE inhibition regimen could be identified in the future [ 32 ]. A number of other trials, such as the A4 study [ 33 ] or the AHEAD 3–45 Study (NCT04468659) are attempting to target the amyloid pathway with other mechanisms of action in preclinical AD.…”