BARCELONA, Spain – Presenters and panelists alike tried to make the best of a bad situation at the opening session of the 2018 Clinical Trials in Alzheimer's Disease (CTAD) meeting, lauding the open discussion, collaboration and potential scientific gains to be had from the continued analysis of the discontinued Alzheimer's disease (AD) trials APECS, EARLY and NAVIGATE-AD.

Still, the distressing bottom line was that all three beta-secretase 1 (BACE-1) inhibitors tested in those trials – verubecestat (Merck & Co Inc.), atabecestat (Janssen Biotech Inc.) and LY-3202626 (Eli Lilly and Co.) – appear to potentially have made things worse for the patients taking them.

It is important to note that because all three trials were halted early, either due to futility or, in the case of NAVIGATE-AD, due to concerns about liver toxicity, the data are incomplete. Trial groups are small, of different sizes and, in some cases, with differing exposure durations to the tested drug.

But even those imperfect data allow some disturbing conclusions.

In all three trials, patients in the groups receiving BACE-1 inhibitors were at higher risk of neuropsychiatric adverse effects.

One or more trials each also showed accelerated cognitive decline, higher rates of cognitive adverse events, and worse volumetric measurements, suggesting that BACE-1 inhibitors increased brain shrinkage.

Moreover, in the analyses, "p" values were not corrected for multiple measurements and "should be taken with a grain of salt," Michael Egan, vice president of neuroscience research at Merck & Co Inc., told the audience.

Still, that company's analysis of the APECS trial, which tested verubecestat in patients with prodromal AD, suggested that "verubecestat treatment is associated with worsening on essentially all of our clinical measures."

And in the analysis, hints of that worsening could be seen at the earliest time points.

"It's surprising, it's disappointing, it's upsetting," he said.

AD researchers are nothing if not persistent, and so in both audience questions and panelist comments, the point was repeatedly made that these results do not necessarily doom the BACE-1 approach.

Panelist Paul Aisen, director of the Alzheimer's Therapeutic Research Institute at the University of Southern California's Keck School of Medicine, reiterated the central mystery of the relationship of AD research: All the science suggests that amyloid precursor protein processing, which is the role of a pathway that includes BACE-1, is central to the disease.

"The evidence that this approach should be helpful remains compelling," Aisen said, though he also acknowledged that "we clearly need to learn more about how to best pursue" BACE-1, and perhaps the amyloid processing pathway overall.

And audience member Robert Vassar, professor of neurology and molecular and cell biology at Northwestern University and a preclinical BACE-1 researcher, said during the question-and-answer session that the drugs may work too well.

"Overinhibiting BACE may have deleterious effects," he said, adding the opinion that weaker inhibition starting at a very early stage would work better.

"I think there is a safe dose," he said.

Others will almost certainly beg to differ.