Has research into Alzheimer’s disease reached a crisis point?
After two major drugs trials fail, time to change thinking on dementia: scientists
When scientists at U.S. drug giant Merck announced recently they were putting an end to late-stage trials of their latest Alzheimer’s drug, it wasn’t just patients and families who were devastated.
With verubecestat, a oncepromising therapy, declared as having no positive effect, its failure set alarm bells ringing across the entire drug-research community.
This was the second Alzheimer’s treatment trial to be cancelled in short order. In November, solanezumab, an injectable therapy from American pharma giant Eli Lilly — also aimed at mild to moderate forms of Alzheimer’s — had been halted in late-stage trials.
Bart De Strooper, director of the new $411-million Dementia Research Institute at University College London, has warned that researchers must change the way they think about the disease.
“Researchers have had too simplistic an approach to dementia,” he said. “What is emerging is that these brain diseases are highly complex, with many processes, not just one. We need to make our research more nuanced.”
Solanezumab and verubecestat both affect the buildup of amyloid proteins, which turn into sticky clumps of plaque in the brains of people with Alzheimer’s disease. Verubecestat belongs to a class of drugs called BACE inhibitors, which interfere with the production of Beta-secretase 1, an enzyme known as BACE1, while solanezumab is a monoclonal antibody designed to clear away amyloid.
For years, these proteins have been the focus of researchers desperate to find a way to stop the progression of the illness. Indeed, there is still an ongoing trial into a drug called AZD3293, a collaboration between AstraZeneca and Eli Lilly, not due to end until May 2019.
But do these public failures mean that scientists have been looking in the wrong place all along? Are we at crisis point for research into Alzheimer’s?
The news about Merck’s failed therapy is certainly disappointing, said Dr. Rosa Sancho, head of research at Alzheimer’s Research U.K. — especially, she pointed out, for those affected by dementia involved in the trial itself. “We’re waiting to hear from Merck once they have analyzed their data fully to see what we can learn from this setback.”
But she insisted the situation is not without its positives, the principal lesson from the trials being that amyloid plaques are building up many years before the symptoms of dementia start to show. “Probably what has happened is that by the time patients got the Merck drug, it was already too late,” she said.
Rudolph Tanzi, vice-chair of neurology and director of the Genetics and Aging Research Unit at Massachusetts General Hospital in the United States, agreed. “The failure of the BACE inhibitor at Merck is further proof that targeting amyloid plaques after clinical symptoms arise is too late,” he said.
“Amyloid plaques trigger the disease a decade or so before symptoms. Successfully treating this disease will require early detection of plaque in the brain by imaging, followed by amyloid-lowering drugs, long before symptoms arise.”
He offered a familiar analogy: “It would be like using cholesterollowering drugs long before symptoms of congestive heart failure, back when the earliest signs of coronary artery disease or even high cholesterol levels are detected.”
Sancho added: “We have to change our thinking — we have to start treatment earlier.” She pointed out that verubecestat may yet be useful. Another trial is under way on people without dementia but who are experiencing memory loss and thinking problems. “There is a chance those people will benefit more.”
Consultant neuroradiologist Dr. Emer MacSweeney, chief executive and medical director at Re: Cognition Health, a consultancy, isn’t writing off BACE inhibitors just yet, either.
“For the Merck study, patients were not pre-screened for amyloid positivity before entering the trial.
“Positive amyloid status can be demonstrated using a new brainimaging technique or spinal fluid analysis and is now the recognized hallmark for Alzheimer’s disease. New clinical trials for similar medications have been able to use the new diagnostic test for amyloid protein and select only those individuals proved to be amyloid positive. These studies are ongoing and there is cautious optimism, although results are not available yet.”
And there are other promising drugs coming through, including agents that target inflammation and other changes in the brain, said MacSweeney. “There is no reason to believe we are in a crisis. More time, energy and funding are being directed into new drug development for Alzheimer’s than ever before.
One last but significant positive to emerge from Eli Lilly’s trial is attitudinal — and could be influential.
Not only was the company open about its test failures, but representatives agreed to speak at a symposium called by Alzheimer’s Research U.K., where they showed all their data and allowed discussion about the next steps. Sancho hopes other drug developers will follow Eli Lilly’s lead, and share results with the dementia research community.