by John Carroll

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The BACE theory in Alzheimer’s R&D is simple. Cut off the flow of amyloid beta to the brain and you can eliminate what is widely believed — though not proven — to be a cause of the disease. Do that, and you could bend the course of this devastating illness in millions of people with mild to moderate forms of the disease.

And Merck $MRK just spent a fortune to demonstrate that it may well be completely wrong.

To be sure, Merck ran a clean study for verubecestat, the leading BACE drug in the clinic, and displayed the data on 1,958 patients for all to see today in the New England Journal of Medicine. Investigators carefully tracked amyloid beta flows in cerebrospinal cords and found that the drug did what it was intended to do, with a dramatic reduction of the toxic protein. 

It had no effect, with patients in the two dosage groups tracking in parallel decline on both cognition and function, the two classic measures for Alzheimer’s. 

The conclusion they reached is that the damage already present in the brains of patients with Alzheimer’s may be too extensive to treat with any BACE drug. And they also concede that the amyloid theory itself may be just flat wrong.

This suggests that once dementia is present, disease progression may be independent of Aβ production or, alternatively, that the amyloid hypothesis of Alzheimer’s disease may not be correct. Because Aβ deposition takes place years before clinical symptoms become apparent, it has been proposed that treatments targeting amyloid should be implemented early in the disease process, before the onset of clinical symptoms.

Soon after this study failed, Merck also threw in the towel on their second pivotal trial, noting it too was a flop. Those data are still being evaluated, but it underscores the belief that all of the BACE studies — including those at Eli Lilly $LLY, partnered with AstraZeneca $AZN, or Biogen $BIIB, allied with Eisai — are headed straight to failure.

Biogen is also rolling the dice on aducanumab, which the company has touted as a leading amyloid beta therapy. But with investigators in the field openly wondering whether the amyloid theory has lured a long lineup into a clinical disaster zone, it’s likely to face growing skepticism that it can develop a safe, effective therapy with just one drug.

This doesn’t by any means eliminate work in the area. True, Pfizer recently pulled out after spending hundreds of millions of dollars on their programs. But startups like Denali believe that new and better technology can give them better odds at success, while Celgene is jumping in with its own new pipeline. Others want to see if combination approaches using tau and amyloid beta together could work. 

Merck’s suggestion about going even earlier in the disease process has also prompted a range of studies in pre-symptomatic patients, while the FDA has signaled its interest in coming up with biomarkers to help speed new studies.

After more than 200 R&D projects ended in disaster, though, Alzheimer’s is looking like an increasingly daunting challenge, with no clear path forward that would inspire confidence among patients with the disease.

Merck study may signal doom for a broad group of pivotal Alzheimer’s studies