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In Alzheimer's mystery, key biomarker will determine success of pivotal studies

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Diagnosing and treating Alzheimer's disease has been one of the big scientific mysteries of the past generation. But even without a full understanding, or even scientific consensus, on what causes the disease, the prospect of earning $9 billion to $10 billion a year for a drug that can even modestly ameliorate a terrible disease afflicting millions of people has kept investigators in the game. And while it may be an inexact tool, a key biomarker will play a big role in both patient selection as well as establishing the hoped-for efficacy of two of the most advanced drugs now in the clinic.

One of several big ideas in Alzheimer's research is that the toxic beta amyloid protein that spreads in the brains of patients is the right target. Reduce the level of plaque, adherents of the amyloid hypothesis believe, and you can improve the lives of patients. But two big late-stage tests for Eli Lilly's ($LLY) solanezumab and Johnson & Johnson's ($JNJ) and Pfizer's ($PFE) bapineuzumab--both operating on the amyloid hypothesis--didn't hit their primary endpoints in patients with mild to moderate cases. There was a signal seen in a secondary analysis of one solanezumab study--which used amyloid levels in the blood as a biomarker that could indicate whether the drug was working in flushing out the protein--that indicated that patients with a mild form of the disease could have responded. And that's helped accelerate a big shift in the field, as many investigators are now exploring whether the amyloid hypothesis can work in early-stage or prodromal patients, before the disease damages the brain.

Roche ($RHHBY) set out to create a companion diagnostic for its late-stage hopeful gantenerumab, which tests cerebral spinal fluid (CSF) in patients. Low levels of amyloid in CSF indicate that the protein has accumulated in the brain, Roche says, allowing investigators to find patients who should be in an early stage of the disease. The Alzheimer's Disease Neuroimaging Initiative, funded by the NIH, developed that biomarker, identifying a "threshold" for amyloid levels that should predict risk of developing Alzheimer's. But it's a challenge, as investigators say that at that stage only 20% of patients go on to full-blown dementia, so investigators will have to track hundreds of patients for a considerable amount of time to track the drug's impact on cognitive decline.

The CSF amyloid biomarker is also key to Merck's ($MRK) newly announced Phase II/III study of MK-8931, a new rival in one of the most expensive drug development races in the industry. The drug tries to address the amyloid hypothesis but uses a different--and rather controversial--method of action than either gantenerumab or solanezumab and bapi. But while Merck is using the same biomarker as Roche, they are looking for a different signal. In Merck's Phase I studies, investigators say that MK-8931 reduced the level of beta amyloid in CSF by 90% in healthy patients, providing evidence that the drug could do what it set out to do and flush out the toxic protein. But Merck is pushing ahead in the mild-to-moderate population, despite the growing belief that the amyloid hypothesis won't mean much for patients who have more advanced cases.

As long as Alzheimer's remains a big mystery in many ways, some of the world's biggest drug developers will be betting huge sums on their biomarker strategies. The winner will have one of the most important diagnostic tools in biopharma. The losers will be in good company, joining the ranks of other developers who have tried and failed on more than 100 different programs.

- here's a link to the Merck release

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

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