NEWS OF THE W EEK
PHARMACEUTICALS: Late-stage studies begin but Bristol-Myers Squibb pulls its own candidate
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MID 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 BristolMyers 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 BMS halts development of its γ-secretase inhibitor it early enough with the right drug.” avagacestat (top), as Lilly, meanwhile, last week unveiled a study Merck starts a trial of a of a murine antibody that safely removes only drug targeting β-secretase amyloid-β that has been deposited on the brain, (bottom). 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.—LISA JARVIS EL AN
MERCK LAUNCHES ALZHEIMER’S TRIAL
VISA POLICY House bill would allow more science-educated workers to stay in U.S. More foreign-born students who graduate with degrees in science, technology, engineering, or mathematics (STEM) from U.S. universities would be allowed to stay and work in the country under a bill (H.R. 6429) passed last week by the House of Representatives. Sponsored by Rep. Lamar S. Smith (R-Texas), the bill would allow 55,000 immigrants with advanced STEM degrees to remain in the U.S. after graduation. In exchange, the bill would eliminate the long-standing diversity visa program, a lottery for people from countries generally underrepresented in the U.S. The bill would also allow some spouses
and minor children of permanent residents to get a green card after a one-year wait. “We could boost economic growth and spur job creation by allowing American employers to more easily hire some of the most qualified foreign graduates of U.S. universities,” says Smith. Although STEM visas have had bipartisan support, the bill passed largely along party lines because most Democrats do not want to eliminate the diversity visa. Rep. Zoe Lofgren (D-Calif.) and Sen. Charles E. Schumer (D-N.Y.) both proposed bills in the House and Senate that would create the same number
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of STEM visas as H.R. 6429 without eliminating other programs. The White House issued a statement opposing H.R. 6429. It supports STEM visa reform in general but wants the changes made through comprehensive immigration reform. Many high-tech companies support immigration reform because a lack of STEM workers, they say, is stifling innovation in the U.S. and forcing companies to take their research hubs overseas. The Senate blocked the bill from coming to a vote by unanimous consent, making its future uncertain.—ANDREA WIDENER
