Merck ignores red flags and throws dice on PhII/III Alzheimer's gamble

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Late last week Bristol-Myers Squibb delivered a brief obituary on its mid-stage Alzheimer's drug, avagacestat. The drug, the company said unceremoniously, just didn't fit the profile of a successful drug candidate. And like a string of Bristol-Myers ($BMY) drugs in recent months, the γ-secretase inhibitor was tossed into the scrap heap, one more fatally flawed pearl.

But while Bristol was executing one Alzheimer's drug candidate, Merck ($MRK) was shifting its megablockbuster hopeful--MK-8931--into a Phase II/III study. Investigators will first look for a clean safety profile in a 200-patient study and then--if it clears that hurdle--plan to expand enrollment to 1,700 as they look for pivotal data on a new approach to patients with a mild-to-moderate case of the disease.

MK-8931 is a BACE inhibitor, designed to blunt an enzyme believed critical to the development of amyloid beta peptide, which in turn should reduce levels of amyloid. So it's a new approach in late-stage circles to tackle the amyloid beta hypothesis, which has come under considerable debate since the late-stage failure of bapineuzumab and solanezumab. Merck says its Phase I study sent a clear biomarker signal that the therapeutic should reduce amyloid as planned.

"As the global health and financial burden of Alzheimer's disease grows, innovative research is critically needed, and we need to accelerate this research wherever possible," said Darryle D. Schoepp, Ph.D., senior vice president and head of Neuroscience and Ophthalmology, Merck Research Laboratories. "This new study is an important step in our overall strategy to understand the potential of the BACE inhibitor mechanism and MK-8931, our lead compound, in multiple stages of Alzheimer's disease."

It's interesting, though, that Merck is testing this approach in a patient population that includes patients with moderate cases. After solanezumab and bapineuzumab appeared to have hit that target without any clear signal that they had improved symptoms for patients with more fully developed cases, there has been a growing move to shift R&D into earlier-stage patients, whose brains have not already been seriously damaged by the disease. Merck is likely to face growing skepticism that it can succeed with the amyloid hypothesis when tackling the same population that hasn't delivered positive data. 

Also, as Reuters reported last July, BACE inhibitors raise the prospect of threatening patients, much like gamma-secretase inhibitors, because beta-secretase also is responsible for multiple physiological functions, raising the prospect of unintended consequences. Gamma-secretase inhibition, you might recall, was semagacestat's claim to fame, before Eli Lilly ($LLY) found that it harmed patients.

- here's the Merck release
- get the BMS release

Special Reports: The Alzheimer's pipeline: What's next? | The Top Phase III Disasters of 2012

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