get 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.”
