A year after announcing an early end to the EPOCH trial of the BACE inhibitor verubecestat in mild to moderate Alzheimer’s disease, Merck pulled the plug on the APECS study, a trial of prodromal AD patients. In a February 13 press release, the company said the trial would shut down a year early based on the results of an interim safety analysis. An external data-monitoring committee judged it “unlikely that positive benefit/risk could be established,” according to the release. Researchers at Merck did not respond to requests for comment, and the future for verubecestat’s clinical development remains unclear.
Scientists in the field said the results were disappointing but not surprising, given that animal studies have now shown that BACE inhibitors do little to halt the growth of established plaques (Jan 2018 news). People with cognitive symptoms are already nearing the plateau of amyloid plaque deposition, noted Robert Vassar at Northwestern University in Chicago. They have had amyloid deposition in their brains for well over a decade. Stefan Lichtenthaler at the German Center for Neurodegenerative Diseases (DZNE) in Munich voiced the prevailing view. “Prodromal AD is simply not early enough,” he wrote to Alzforum. Inclusion criteria for APECS included evidence of brain amyloid, a history of subjective cognitive complaint, and impaired episodic memory.
Like other BACE inhibitors in development, verubecestat slashes production of Aβ42, lowering levels in cerebrospinal fluid and blood by up to 90 percent (Nov 2016 news). Nonetheless, for AD patients in the EPOCH trial, the compound provided no clinical benefit. Treatment nudged down plaque load by 4 percent, but some side effects cropped up, most notably skin rashes and behavioral changes such as anxiety, insomnia, and falls (Dec 2017 conference news).
These EPOCH data fueled the debate over how early BACE inhibitors would have to be given to be effective. The APECS results now push this proposed treatment window to even earlier stages. Vassar said the findings support the idea that inhibitors will have their greatest effect near the beginning of amyloid deposition, and will most likely need to be taken at low doses for years.
For his part, Jochen Herms at DZNE noted that the age of participants could be a complicating factor. He believes participants should be at most 70, because older adults often have comorbidities such as α-synuclein, TDP-43, or vascular pathology that could cloud cognitive outcomes. “It is unlikely that a trial will ever be positive if we continue to enroll very old MCI/AD patients,” Herms predicted (see comment below). The Merck trial enrolled participants as old as 85.
Other ongoing trials are already testing BACE inhibition in younger, presymptomatic populations. The A5 EARLY trial administers Janssen’s JNJ-54861911 to amyloid-positive people age 60 or older, and the Alzheimer’s Prevention Initiative tests Novartis’ CNP520 in a similar population (Dec 2017 conference news). Meanwhile, DIAN researchers are planning to give BACE inhibitors to young adults with a familial AD mutation but no detectable amyloid deposition (Aug 2017 conference news). “Primary prevention is the ideal stage for an [Aβ] production inhibitor,” Randall Bateman at Washington University in St. Louis explained (see comment below).
Despite this latest setback, Paul Aisen at the University of Southern California ATRI Institute in La Jolla, California, remains optimistic about the future of this class of drugs. “This discontinued trial does not really dampen our enthusiasm for BACE inhibitors … it remains very likely that they will be a mainstay of AD therapy, particularly in primary prevention,” he wrote (see comment below).
The APECS findings also renewed calls by some to pair BACE inhibition with plaque removal at later disease stages. “I would like to see this outcome encourage consideration of combination strategies, which may limit risk and allow treatment at ever-so-slightly later stages of disease where success may be easier to measure, if admittedly harder to achieve,” Joanna Jankowsky at Baylor College of Medicine, Houston, wrote to Alzforum (see comment below).—Madolyn Bowman Rogers
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