Merck dropped a Valentine’s Day downer announcing they will stop the EPOCH trial of verubecestat in mild to moderate Alzheimer’s disease. A prespecified interim analysis by an external data-monitoring committee gave the trial “virtually no chance of finding a positive effect,” according to a Merck press release. The trial had been slated to run until July of this year. Merck’s APECS trial, which uses the same doses of verubecestat to treat people with prodromal AD, will continue. APECS results are expected by 2019.
Researchers were disappointed but not that surprised by the news. Scientists had questioned the rationale for using a BACE inhibitor in people who had accumulated enough Aβ deposition in the brain to have frank dementia (see Alzforum’s 2012 interview with Merck’s Johan Luthman). “The field needs some success, especially after the solanezumab results, but I was not holding my breath for this particular trial,” noted Robert Vassar, Northwestern University, Chicago, who co-discovered BACE. “It was conducted in people with mild to moderate AD, and since many cross-sectional studies have shown that amyloid has plateaued and there is substantial synaptic and neuron loss [in these patients], it seems highly unlikely that stopping or slowing production of Aβ at that stage would have a clinical benefit,” he told Alzforum. Verubecestat blocks BACE cleavage of the amyloid precursor protein, which is the first step in production of Aβ. Vassar also noted that because EPOCH, like early solanezumab and bapinezumab trials, did not require patients have a positive amyloid test, 25 to 30 percent of them likely had dementia other than Alzheimer’s. “That could kill any positive signal,” said Vassar.
Others agreed that trial may have started too late. “This is sad news for Alzheimer patients and their families,” wrote Stefan Lichtenthaler, German Center for Neurodegenerative Diseases in Munich, adding “the lack of a positive effect strengthens the need to test BACE inhibitors as early as possible” (see full comment below). Paul Aisen, University of Southern California, San Diego, agreed. “I remain optimistic that very early treatment with these drugs may by quite effective,” he wrote (see full comment below). Bart DeStrooper, KU Leuven, Belgium, noted that it may be tricky to determine when to start treating people with a BACE inhibitor because scientists still don’t know exactly how Aβ causes AD. It may be a trigger only very early in disease, becoming irrelevant later on, he wrote (see full comment below).
New trials may tell. In addition to Merck’s prodromal trial of verubecestat, other BACE inhibitors are being put to the test at various stages of the disease. The EARLY trial being run by Reisa Sperling, Brigham and Women’s Hospital, Boston, will test Johnson & Johnson’s BACE inhibitor JNJ-54861911 in people who test positive for amyloid but have no signs of dementia, while the DIAN trials unit will test this inhibitor in asymptomatic people who carry familial Alzheimer’s disease mutations. The Generation trial, run by Novartis, Amgen, and The Banner Alzheimer’s Institute in Phoenix, will test Novartis’ CNP520 in people who have two copies of the ApoE4 variant, a major genetic risk factor for AD (see Aug 2016 news).
“The bottom line is we need prevention trials in asymptomatic individuals,” said Vassar. The paradigm for BACE inhibitors is statins, he noted. These drugs are given in early middle age, often for life, and they are successful for secondary prevention of heart disease by lowering cholesterol. Likewise, researchers hope that by lowering Aβ production, BACE inhibitors might prevent AD, he said. “Giving a statin to someone in heart failure will not keep them alive, and in AD at the time of diagnosis we basically have [brain] organ failure,” Vassar said.
Matt Kennedy from Merck told Alzforum that the company hopes to at least learn enough from this trial to inform other trials going forward. Kennedy said that a large number of the patients enrolled in the trial, which started in 2012, already have completed the 18-month dosing regimen. In previous trials Kennedy and colleagues had extensively tested target engagement, showing that verubecestat lowered production of Aβ by as much as 85 percent at the doses used in the EPOCH trial—12 and 40 mg daily (see Nov 2016 news). “We don’t have the data yet, but we’ll comb through [it] carefully and hope we can use it to inform about the prodromal trial and what other new ways we can use the molecule in different patients,” he told Alzforum. Kennedy noted that without seeing the full data, it is too soon to draw any formal conclusions about BACE inhibition in patients with mild to moderate AD. “But for BACE inhibition, we still feel that this molecule is appropriate to interrogate that mechanism,” he said.
On the plus side, the data monitoring committee noted no safety signals that warranted stopping EPOCH. Kennedy confirmed that with Alzforum. “It is heartening to know that the safety signal was not an issue,” he said. That also bodes well for other BACE inhibitors under evaluation.—Tom Fagan
- Q&A With Merck’s Johan Luthman
- New Ways to Target Aβ and BACE Show Promising Phase 1 Data
- Paper Alert: Verubecestat Preclinical and Phase 1 Data Published