Preliminary Results of a Trial of Atabecestat in Preclinical Alzheimer’s Disease

Inadequate efficacy and/or severe side effects in clinical trials with BACE1 inhibitors such as Verubecestat and Atabecestat have been reported.

“Similarly, inadequate efficacy and/or severe side effects in clinical trials with BACE1 inhibitors such as Verubecestat and Atabecestat [638–640] have also been reported.”

All BACE inhibitors tested in randomized clinical trials were discontinued for futility or safety reasons.

“All BACE inhibitors investigated in randomized clinical trials were discontinued for either futility or safety reasons.”

Atabecestat was discontinued after a preclinical Alzheimer disease trial showed frequent hepatotoxicity and worse cognition than placebo.

“Atabecestat was discontinued after a trial in preclinical AD demonstrated frequent hepatotoxicity and worse cognitive outcomes than placebo (Henley et al., 2019).”

The lanabecestat phase 3 investigation was halted due to a lack of efficacy, and the verubecestat and atabecestat trials were halted owing to inefficacy and safety concerns, respectively.

“The lanabecestat phase 3 investigation was halted due to a lack of efficacy, and the verubecestat and atabecestat trials were halted as well owing to inefficacy and safety concerns, respectively.”

All BACE inhibitor treatments reduced cerebrospinal fluid Aβ42 in a dose-dependent manner, but without providing any cognitive or functional benefits, and several were inadequately tolerated and ineffective in subjects with prodromal Alzheimer's disease.

“All the treatments reduced cerebrospinal fluid (CSF) Aβ42 in a dose-dependent manner, but without providing any cognitive or functional benefits, and several of them were inadequately tolerated and ineffective in subjects with prodromal AD.”

Clinical studies with BACE inhibitors such as lanabecestat, verubecestat, and atabecestat have lately been terminated due to unanticipated challenges.

“Due to unanticipated challenges, clinical studies with BACE inhibitors such as lanabecestat, verubecestat, and atabecestat have lately been terminated (Egan et al., 2019, Henley et al., 2019).”

The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness and safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).

“The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).10,32-34”

Clinical trials with the BACE inhibitors lanabecestat, verubecestat, and atabecestat have been recently discontinued due to unexpected difficulties.

“However, the clinical trials with the BACE inhibitors lanabecestat,32 verubecestat,33 and atabecestat34 have been recently discontinued due to unexpected difficulties.”