At an R&D and business briefing meeting that Merck (NYSE: [[ticker:MRK]]) held for Wall Street analysts at its Whitehouse Station, NJ, headquarters in November, the drug giant generated quite a bit of buzz for a drug that’s still several years away from market. That’s because the drug, called MK-8931, may offer a completely new way to attack Alzheimer’s disease—one of the hottest and most challenging targets in drug development. “We think this is the molecule that will provide the best option for Alzheimer’s patients,” declared Peter Kim, president of Merck Research Laboratories, during a Q&A with analysts towards the end of the meeting. It was a bold statement, considering the fact that the drug has so far only been tested in healthy volunteers.
But the results seen in that one small trial were enough to persuade Merck’s scientists to forge ahead and test MK-8931 in Alzheimer’s patients. The drug targets an enzyme known as BACE (beta-site APP cleaving enzyme), which generates proteins that in turn lead to the formation of amyloid plaques—the brain deposits thought to cause the cognitive impairments that are the hallmark of Alzheimer’s. In the trial, a once-daily dose of MK-8931 taken by mouth lowered levels of the amyloid-forming protein by more than 90 percent, with no significant side effects.
Scientists at universities and drug companies around the world have spent much of the last decade trying different methods for blocking BACE—to little avail. When Merck bought Schering-Plough in 2009, the two companies merged their BACE efforts, embarking on a multifaceted plan that resulted in MK-8931 and several back-up compounds. It was no small feat, Kim said during the R&D briefing. “If you look at what our chemists had to do, it’s an unbelievably impressive story,” he said.
During a recent phone interview with Xconomy, one of the scientists who managed Merck’s BACE program provided a taste of the hurdles the team faced, and the technology they used to come up with new approaches to targeting BACE. Eric Parker, senior director and neuroscience site lead for Merck, says the basic challenge lies in the very structure of BACE. The enzyme is so complex, he says, “you need a large molecule to make many different points of contact with it.” With any drug, he adds, “it’s difficult to make it stick—to make it bind with high affinity for the enzyme.”
One problem with large molecules, Parker says, is that it’s difficult to make them into pills that can travel through the stomach without getting destroyed. What’s more, large molecules can’t easily cross the blood-brain barrier or
