BACE-1 inhibition worsens cognition in patients with prodromal Alzheimer’s disease
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Atabecestat
In a research letter in the same issue of the New England Journal of Medicine (2019 Apr 11;380:1483-5), David Henley, MD, senior director of Janssen’s Alzheimer’s clinical development core, released similarly negative results from an interim analysis of EARLY (Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia) trial, a randomized study of the BACE-1 inhibitor candidate, atabecestat.
The phase 2 trial enrolled 557 patients with prodromal Alzheimer’s disease. The primary cognitive end point was change from baseline in the Preclinical Alzheimer’s Cognitive Composite (PACC) score.
This trial was discontinued in May 2018 because of liver-related adverse events, although safety follow-up continues. The research letter did not disclose details of the hepatic events, but a company press release from May 2018 referred to them in a general sense.
“Elevations of liver enzymes, which were serious in nature, have been observed in some study participants who received the Janssen BACE inhibitor, atabecestat. After a thorough evaluation of all available liver safety data from our studies, Janssen has concluded that the benefit-risk ratio is no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.”
Patients in EARLY were randomized to 5 mg, 25 mg, or placebo. As in the verubecestat trial, those randomized to placebo did better. The mean changes from baseline in the PACC score were −1.44 in the 25-mg group, −0.58 in the 5-mg group, and −0.32 in the placebo group.
“At month 6, the difference between the 25-mg group and the placebo group was −1.12 and the difference between the 5-mg group and the placebo group was −0.26, favoring placebo over the higher dose,” the authors said.
This theme reemerged in a secondary end point, the Repeatable Battery for the Assessment of Neuropsychological Status. The 25-mg group declined 3.58 points more than placebo, and the 5-mg group, 1.43 points more.
Adverse events were more common in the active groups and included depression, effects on sleep and dreams, and anxiety.
“The differences in cognitive performance between the groups are of uncertain clinical significance; however, given similar findings favoring placebo over BACE-1 inhibitors in other trial, we are communicating this potential signal of worsening cognitive function in the treated groups,” Dr. Henley said.
SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.
