Literature Review

BACE-1 inhibition worsens cognition in patients with prodromal Alzheimer’s disease

Publish date: April 10, 2019

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Failed trials suggest amyloid is not a practical therapeutic target

“Some trials fail because the experimental treatment proves to be no different than a control or standard intervention,” David Knopman, MD, wrote in an accompanying editorial (N Engl J Med. 2019 Apr 11;380:1476-8). “Others fail because of unacceptable side effects. In this issue of the Journal, an article by Egan et al. and a letter to the editor by Henley et al. (N Engl J Med. 2019 Apr 11;380:1483-5) describe a third reason for failure – a treatment worsens the target symptoms.

Certainly, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibition makes sense when viewed in the light of the current understanding of Alzheimer’s disease neuropathology. The amyloid cascade hypothesis holds that toxic amyloid-beta fragments accumulate in the brain, form dense neuritic plaques, and lead to neuronal death and cognitive decline.

“The model is rooted in the inseparability of Alzheimer’s disease from abundant amyloid-beta pathologic features,” Dr. Knopman wrote. But, “Over the past 2 decades, the amyloid-beta–lowering strategy has been put to the test in trials of antiamyloid antibodies, none of which have been successful.”

Therefore, hitting amyloid at the source – the transmembrane cleavage domain – seemed important and, potentially, effective. But three BACE inhibitors (verubecestat, atabecestat, and lanabecestat) have shown similarly negative cognitive effects. “Together, these results suggest that preserved BACE-1 activity may be critical to normal synaptic functions. These observations place a limitation on how amyloid-beta lowering can be accomplished.”

It is possible that decreasing the level of BACE inhibition might ameliorate off-target effects and neuronal compromise but still be enough to reduce the generation of toxic amyloid-beta fragments, Dr. Knopman said. But, “Adjustments in the dose to a narrow window of BACE-1 inhibition would be difficult to accomplish in a clinical trial until there are peripheral biomarkers that reflect the activity of the agent in the brain.”

Thus far, most of the studied antiamyloid drugs have indeed reduced amyloid-beta levels, but none of those reductions affected cognition. A rethinking of amyloid-beta’s place in dementia progression may be in order.

“The dissociation between amyloid-beta lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”

Dr. Knopman is a clinical neurologist and Alzheimer’s researcher at the Mayo Clinic, Rochester, Minn.

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.

msullivan@mdedge.com

SOURCE: Egan MF et al. N Engl J Med. 2019 Apr 11;380:1408-20.