Merck & Co.'s Alzheimer's Contender Wows in Human Clinical Trial

November 3, 2016
By Mark Terry, BioSpace.com Breaking News Staff

Merck & Co published results from its Phase I clinical trial of verubecestat for Alzheimer’s disease (AD) in the journal Science Translational Medicine. What investors and the public are probably hoping for are positive results from two pivotal Phase III trials of the drug. At the moment, the Phase I data provides information related mostly to the safety and activity of the drug, rather than whether it will provide clinical improvement in AD patients.

The Phase I trial was a randomized, double-blind, placebo-controlled multiple dose study. It was conducted in 32 patients with mild-to-moderate forms of AD. The doses were 12mg, 40mg and 60mg. The evaluation endpoint was a reduction of the levels of amyloid beta 42 in cerebral spinal fluid, which is a measure of BACE1 activity, an enzyme that is key to the production of amyloid beta in the brain. Amyloid beta is believed to be one of the primary causes of brain deterioration in AD patients. For each dose, respectively, a reduction of amyloid beta 42 was found of 57, 79 and 84 percent.

No patients left the study because of side effects, and lab tests, including liver function evaluations, did not show statistically significant changes related to administering the drug.

“The development of a potential disease modifying therapy for treatment of Alzheimer’s disease has long been a focus of biomedical research,” said Michael Egan, vice president, clinical development neurosciences, Merck Research Laboratories , in a statement. “We believe this research has the potential to contribute important evidence regarding the amyloid hypothesis, a leading scientific theory for what causes Alzheimer’s disease, and we look forward to seeing the data from our ongoing Phase III clinical trials.”

BACE1 stands for Beta-site Amyloid precursor protein Cleaving Enzyme 1, also known as beta-secretase 1. Although researchers don’t have a complete understanding of Alzheimer’s disease, the leading theory is that an accumulation of amyloid beta causes a “cascade of biological events leading to neurodegeneration. By blocking BACE1, the hope is this approach could prevent the buildup of these clumps in the first place. But until now,” writes Scientific American, “development of these drugs has been hindered by problems finding molecules with the right characteristics, and concerns over theoretical and actual side effects.”

So although the study doesn’t say the drug will cure Alzheimer’s, or even treat its symptoms—that’s being evaluated in the Phase III trials—it does support the theory of BACE1 inhibition. “This is the first detailed report of what a BACE inhibitor does in humans,” said Dennis Selkoe of Harvard University, who was not involved in the study, to Scientific American. “The good news is they didn’t see evidence so far of any of the side effects we’re concerned about with BACE inhibition.”

Biogen ’s aducanumab also focuses on beta amyloid, although with a different mechanism. That drug is also in two Phase III trials for Alzheimer’s disease. Instead of preventing the production of beta amyloid, however, it attempts to clean it out after it’s produced.

“With us,” said Ian McConnell, a spokesman for Merck to Scientific American, “it’s a question of switching off the tap. With them it’s mopping up the water.”

Eli Lilly ’s solanezumab is also focused on clearing beta amyloid plaques, but has a different mechanism than Biogen’s aducanumab. Although solanezumab failed a clinical trial in 2012, the company shifted its focus to patients with a milder form of the disease. In July, the company released interim data that showed patients receiving the drug had about a 35 percent improvement in cognition. That’s not a cure, and it’s only effective in about a third of patients with a milder form of the disease, but it’s better than what little else is on the market.

If the three drugs were all approved, it’s theoretically possible that the Merck drug would be effective in halting the disease, while the Lilly and Biogen drugs would help clear up the plaques already in existence. But those are big “ifs,” and well over 125 Alzheimer’s drugs have failed in late-stage clinical trials.