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Adverse cognitive and psychiatric effects seen associated with the investigational Alzheimer’s drug atabecestat were reversed within 6 months of treatment cessation, according to follow-up results from a truncated clinical trial.
A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.
A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.
In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Sperling and colleagues found.
Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.
Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
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Questions Surround BACE Inhibitors
Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.
Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.
While no BACE inhibitor is currently in the pipeline for Alzheimer’s — trials of these agents have been stopped for futility or toxicity — Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue.
“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
Research Should Continue
Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.
“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”
Vassar noted that, with both doses of atabecestat, Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.
“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Vassar said.
Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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