Protein-targeting drug shows promise for Alzheimer's treatment

Researchers working to target the protein plaques associated with Alzheimer’s disease say their latest approach has shown promise in animal and early human trials. In a study published Wednesday in Science Transitional Medicine, Merck Research Laboratories researchers aimed to block an enzyme involved in producing amyloid beta, a protein that clumps together to form the plaques typically known as a hallmark of Alzheimer’s disease.

The drug, called verubecestat, is a BACE1 inhibitor. The drug works by attaching to the enzyme BACE1 and preventing it from cleaving amyloid precursor protein (APP), which decreases the production of amyloid, The Scientific American reported. While previous studies have taken a similar approach, researchers have not been able to find the right combination of molecules without concern over potential side effects.

Current trials involving verubecestat appear to have averted these challenges, as tests on animals found the therapy significantly reduced levels of amyloid and another protein called sAPP beta in the blood, cerebrospinal fluid and brain, The Scientific American reported. Researchers also said there were no signs of toxicity after six months of treatment in rats, and none after nine months of treatment in monkeys. One researcher hypothesized to the news outlet it’s possible no side effects have been reported because the dosage does not fully inhibit BACE1 activity. Researchers noted a loss of fur pigmentation in mice and rabbits, but not in monkeys. However, in humans, they successfully began early-stage trials to assess safety and tolerability.

After one week, the therapy reduced amyloid and sAPP beta in the cerebrospinal fluid of human adults with mild to moderate Alzheimer’s, researchers reported. They saw the same effect in healthy adults who underwent two weeks of treatment.

Experts not involved in the current study say these early results may offer promise.

“This is the first detailed report of what a BACE inhibitor does in humans,” Dennis Selkoe, The Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School, and co-director for the Center for Neurologic Diseases at Brigham and Women’s Hospital, who was involved in the study, told The Scientific American. “The good news is they didn’t see any evidence so far of any of the side effects we’re concerned about with BACE inhibition.”

The drug has entered phase III trials, which is the first BACE1 inhibitor to reach this stage. Researchers are currently conducting two trials to determine dosage safety and the effects of long-term usage. The first trial involves about 2,000 patients with mild to moderate Alzheimer’s, and will last 18 months. The second study involves 1,500 patients with early signs of Alzheimer’s and will last two years, The Scientific American reported.

“The big issue is: What will the long-term safety of these drugs be?” Robert Vasser, a molecular biologist who discovered BACE1 in 1999 and also was not involved in the current study, told the news outlet. “People may have to take these drugs for the rest of their lives, the trials are two years at most; what happens beyond that, as people get older, we have no idea.”

Researchers expect to have results in 2017 and 2019, respectively.