Merck Launches Alzheimer’s Trial | December 10, 2012 Issue - Vol. 90 Issue 50 | Chemical & Engineering News
Volume 90 Issue 50 | p. 11 | News of The Week
Issue Date: December 10, 2012 | Web Date: December 7, 2012

Merck Launches Alzheimer’s Trial

Pharmaceuticals: Late-stage studies begin but Bristol-Myers Squibb pulls its own candidate
Department: Business, Science & Technology
News Channels: Biological SCENE
Keywords: Alzheimer’s, amyloid hypothesis, pharmaceuticals, BACE
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Credit: Elan
This is an image of a drug Merck is in trying to target beta-secretase in those with Alzheimers disease.
 
Credit: Elan

BMS halts development of its γ-secretase inhibitor avagacestat (top), as Merck starts a trial of a drug targeting β-secretase (bottom).

Amid a string of failures for drugs targeting amyloid-β as a way to slow down the progression of Alzheimer’s disease, Merck & Co. is forging ahead with a late-stage study of its lead Alzheimer’s treatment. The news comes just days after Bristol-Myers Squibb announced that it will end development of its entry in the race.

Merck’s Phase II/III study will start with 200 patients with mild to moderate Alzheimer’s. After three months, the company will take a close look at whether its drug MK-8931, which inhibits β-secretase, an enzyme involved in the release of amyloid, is safe and shows signs of efficacy. If so, the trial will evolve into a multiyear study with roughly 1,700 patients.

Big pharma companies have spent hundreds of millions of dollars developing drugs aimed at lowering levels of amyloid-β, a protein that forms the hallmark plaques on the brains of those with Alzheimer’s disease. Scientists have tried sequestering it with antibodies and preventing it from forming by inhibiting key enzymes, but to date no drugs have shown clear signals of efficacy.

Among the most recent flops is the antibody bapineuzumab, which Pfizer and Johnson & Johnson pulled in August after it failed in multiple Phase III studies. Eli Lilly & Co. stopped work on semagacestat, an inhibitor of the enzyme γ-secretase, after data from two Phase III studies showed it caused cognition to worsen. BMS says its drug, a γ-secretase inhibitor called avagacestat, had no safety problems but that the data suggested it wasn’t working.

Merck argues that its competitors had flawed molecules or clinical trial designs. β-Secretase, also called BACE, is a different enzyme, and blocking it may be a more effective approach, the company contends. Merck’s head of neuroscience clinical development, David Michelson, says the various drug candidates aren’t comparable to one another in any meaningful way. “I don’t think we should be drawing conclusions about the likely effect of BACE inhibition in this disorder,” he says.

As evidence of the potential of β-secretase inhibitors, Michelson points to a recent study in which scientists from deCode Genetics searched through whole-genome data from 1,795 Icelanders for genetic variations in APP, the amyloid protein precursor gene. They discovered that a mutation near the location where β-secretase cuts APP to expose amyloid-β offers protection against Alzheimer’s disease (Nature, DOI: 10.1038/nature11283).

That study, along with other genetic evidence, makes a compelling case for testing drugs that target amyloid, says Steven M. Paul, director of the Appel Institute for Alzheimer’s Research at Weill Cornell Medical College. “This is still a very viable hypothesis,” says Paul, who previously headed R&D at Lilly. “It really hasn’t adequately been tested because nobody has tested it early enough with the right drug.”

Lilly, meanwhile, last week unveiled a study of a murine antibody that safely removes only amyloid-β that has been deposited on the brain, and not free-floating amyloid. Bapineuzumab targeted both soluble and insoluble protein. Lilly plans to take a humanized version of the antibody into Phase I studies.

 
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