And another one bites the dust. Yesterday, Janssen, the pharmaceutical division of Johnson & Johnson, announced that it would end clinical development of the BACE inhibitor atabecestat. Serious elevations in liver enzymes were detected in some patients taking the drug. “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,” according to a company press release.
Janssen has stopped screening, randomization, and dosing in the Phase 2/3 EARLY trial and also in a Phase 2 long-term safety study. More than 600 people in these trials have received either drug or placebo. Janssen will update the study protocol to monitor patients after they discontinue treatment.
“Certainly, this is another disappointment,” said Paul Aisen, University of Southern California, San Diego. “The EARLY trial was a very exciting project and it’s disappointing that it will not continue to its conclusion.” Aisen is one of the clinical leaders of the trial.
Aisen does not see this latest development as an indictment of the study design, or of BACE inhibitors as a class. He noted there are other BACE inhibitors being tested that seem to be free of hepatotoxicity. “We need to continue to advance early intervention and early anti-amyloid therapies, including anti-BACE approaches, in sporadic and in familial AD, and I don’t think this announcement changes that,” he said.
This news comes three months after Merck stopped development of its BACE inhibitor, verubecestat, for prodromal AD, citing lack of efficacy (Feb 2018 news). There was no indication of serious liver toxicity from verubecestat. However, in 2013 Eli Lilly halted development of its BACE inhibitor, LY2886721, because of liver abnormalities. Aisen acknowledged that hepatotoxicity has been seen with some, but not all, drugs in this class. “It occurs with a number of drugs, including some already on the market,” he said.
Whether liver toxicity turns out to be a function of BACE inhibition or an off-target effect remains to be seen. Novartis, AstraZeneca/Eli Lilly, and Biogen/Eisai also have BACE inhibitors in clinical trials.—Tom Fagan
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