Atabecestat Associated With Dose-Related Cognitive Worsening in Preclinical AD

Treatment with atabecestat, a nonselective oral β-secretase inhibitor, was associated with dose-related cognitive worsening in patients with preclinical Alzheimer disease (AD), and these effects were observed as early as 3 months following the start of therapy, according to study results published in JAMA Neurology.

In this double-blind, phase 2b/3 study conducted at 143 centers across 14 countries, 557 patients who were amyloid-positive but cognitively normal (mean age, 70.4 years) were randomly assigned to atabecestat at 5 mg (n = 189), 25 mg (n=183), or placebo (n=185). The study did not enroll its originally planned 1650 participants because it was prematurely stopped due to hepatic-related adverse events (AEs).

The primary outcome was the change in the Preclinical Alzheimer Cognitive Composite score from baseline. Additional secondary outcomes included the change in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score from baseline. The study investigators also monitored safety during the study.

Treatment with 25 mg atabecestat was associated with significant cognitive worsening compared with placebo for the Preclinical Alzheimer Cognitive Composite at 6 months (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P <.001) and 12 months (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P <.001). The 25 mg atabecestat therapy was also associated with worsening for the Repeatable Battery for the Assessment of Neuropsychological Status at 3 months (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P <.001).

While there were no deaths during the study, the study researchers highlighted a high incidence of serious treatment-emergent AEs with atabecestat compared with placebo. Treatment with atabecestat was also associated with higher rates of neuropsychiatric-related AEs, including depression-related, cognition-related, sleep/dream-related, and anxiety-related AEs.

Treatment with the 25 mg dose of atabecestat was associated with greater mean decreases in weight at 12 months compared with the 5 mg and placebo groups (-1.68 kg vs 0.41 kg vs 0.21 kg, respectively). Findings indicated new-onset transaminase elevations more than 3 times the upper limit of normal in 7 participants from 20 to 110 days following the discontinuation of atabecestat dosing. Transaminase levels eventually returned to normal.

The study investigators added that recovery became apparent after up to 6 months following treatment discontinuation. In an exploratory analysis, whole-brain volume decreased at 6 months and 12 months in the 25 mg atabecestat group compared with the placebo arm.

A limitation of this study was truncation, predominantly due to the premature discontinuation of atabecestat dosing.

The study investigators concluded that considering oral antiamyloid agents show “tremendous potential benefit” in preventing AD, the study findings “can be instrumental in better understanding the mechanisms underlying transient cognitive worsening and to explore whether there exists a path forward for low-dose BACE inhibition in the future.”

Disclosure: This clinical trial was supported by Janssen. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Sperling R, Henley D, Aisen PS, et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: A truncated randomized phase 2b/3 clinical trial. Published online January 19, 2021. JAMA Neurol. doi:10.1001/jamaneurol.2020.4857