Merck Chemists Use High-Tech Science to Combat Alzheimer’s Disease Challenge

12/14/11Follow @arleneweintraub

At an R&D and business briefing meeting that Merck (NYSE: 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 orget beyond the membranes that cover neurons. That’s why many of the compounds that were tested against BACE in the early days failed.

So Merck’s structural chemistry group decided to try something different. Rather than testing millions of known compounds—a common technique known as “high throughput screening”—they sifted through a selection of about 10,000 small chemical fragments. They used an emerging method called screening by nuclear magnetic resonance (NMR), Parker says. “You can look for fragments that bind with one or two points of contact, then start thinking about putting them together into a molecule that will have multiple points of contact with the enzyme.”

Screening by NMR was a year-long process that generated an interesting but problematic lead compound, Parker says. It did inhibit BACE, but not in a very potent way. And it looked like it might react with other proteins in the body—presenting a potential side-effect risk, Parker says.

Enter Andrew Stamford, Merck’s a medicinal chemistry lead on the project. Stamford’s group took the compound and tweaked it to both enhance its good qualities and eliminate its shortcomings. “They redesigned the lead inhibitor to make it into something with more potency,” Parker says. “They got rid of a lot of the chemical liabilities and made it more drug-like.” That process took another three or so years, Parker says.

Parker says trials of MK-8931 in Alzheimer’s patients will help answer some key questions, such as how early in the disease the drug should be given. Experiments in animal models of Alzheimer’s suggest that inhibiting BACE in the earliest stages seems to prevent amyloid plaques from appearing, Parker says. New imaging techniques will help Merck determine exactly how the drug is working. “We now have tools to visualize amyloid plaques in the brains of Alzheimer’s patients, and we do intend to use those in the clinical trials,” Parker says.

He adds that Merck has studied the effect of the BACE inhibitor in animal models of more advanced Alzheimer’s disease. “We have some initial evidence that we can reverse the amyloid-plaque load below the baseline level,” Parker says. “It looks pretty promising.”

Although it’s too early to estimate the potential impact of MK-8931 on Merck’s bottom line, no one disputes that the market opportunity is vast. A 2010 report by research firm Decision Resources estimated that the market for Alzheimer’s treatments in the US, Europe, and Japan will more than triple to $13.3 billion in the next seven years.

In 2012, Merck plans to publish detailed results from its Phase 1 trial and start a Phase 2 trail in Alzheimer’s patients. The company has not estimated exactly how many patients it will include in later trials or how long they will take.

During a Q&A with journalists at Merck’s R&D briefing, Kim admitted Merck has a long way to go to get MK-8931 onto the market. “We’ve proven many times that mice are not humans,” he said. “We really don’t know whether this will work.” Still, his excitement was palpable. “If it pans out,” he said, ‘it’s going to have a dramatic impact on medicine.”

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  • timothy miles

    excellent research Dr. Parker== Dr. Tim Miles UNC