Alzheimer’s disease is one of the deadliest, costliest, and demanding diseases in the world. It’s the fastest-growing cause of death in the world. Unfortunately, no drugs have been developed to prevent or reverse the brain disease. A promising new medication known as BAN2401 might offer hope, while helping redirect future research on effective treatments for Alzheimer’s disease.
Drug makers Biogen and Eisai teamed up to develop an antibody that can remove deadly proteins from the brain. Yesterday, the companies released results from a clinical trial of the drug, which included 856 patients. All were diagnosed with either mild cognitive impairment or mild Alzheimer’s disease. All had significant accumulations of the amyloid protein that clumps into plaques within the brain.
They presented their findings at the Alzheimer’s Association International Conference in Chicago. The results have sparked cautious optimism.
“Millions of people have Alzheimer’s disease and right now it’s a death sentence. So any time we see positive results from a trial that appears to show disease modification, that gives us hope,” said Keith Fargo, director of scientific programs at the Alzheimer’s Association. “But it’s a cautious hope.”
Alzheimer’s disease is an extremely complex disease of the brain. It’s not caused by a single cell failure. Instead, the best scientific understanding of what’s likely going on with Alzheimer’s disease is called the amyloid hypothesis. Beta-amyloid is a protein in the brain, and when it’s metabolized abnormally, it sets off a cascade of events that eventually kills the nerve cells in the brain and causes the brain to shrink. After this neurodegenerative process begins, people start to experience the hallmark symptoms of Alzheimer’s disease, including memory and cognition.
Despite the fact that Alzheimer’s disease is the most common cause of dementia there is not a single drug available to treat the condition—not just symptoms. The path to finding a drug that would stop the progression of or reverse the disease has been littered with expensive failures.
“It’s a complex system failure — multiple areas of the brain that depend on each other fail,” said Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center. “So despite spending billions of dollars on research into a variety of therapeutic approaches, there have been no new drugs in 15 years. And while amyloid buildup is necessary to diagnose the disease, there are many potential contributors to amyloid collections and Alzheimer’s disease — including genetics, head injuries and nutrition.”
The new, experimental medicine, BAN2401, tests the amyloid hypothesis. When amyloid protein is misprocessed, it begins to accumulate in the brain, forming a sticky buildup outside the nerve cells called beta-amyloid plaques. The accumulation of amyloid also stimulates an immune response, which causes another set of proteins (the tau proteins) to form tangles inside the nerve cells. BAN2401, which is delivered intravenously, is an antibody that helps the immune system fight that disease process.
“The theory is if we can interrupt the plaque formation, and these toxic forms of amyloid, hopefully we can interrupt that whole process and slow down memory loss — and that’s why we’re excited about this finding,” said Stephen Salloway, the director of neurology and the memory and aging program at Butler Hospital in Providence, Rhode Island, and a professor of neurology at Brown University. (He wasn’t involved in the trial but also runs clinical trials for Biogen.)
In the placebo-controlled, double-blind, randomized study of 856 patients with early Alzheimer’s disease, the drug companies said brain scans showed that higher doses of the medication were able to reduce amyloid plaques after 18 months. They also used an Alzheimer’s scale (called ADCOMS) to measure clinical symptoms in the patients, and found that the reduction in plaques corresponded with a slowing of Alzheimer’s disease progression by 30 percent. The most common side effect was allergic reaction at the site of infusion, and some patients experienced brain swelling.
“We think this result is really the first of its kind,” Lynn Kramer, chief medical officer of Eisai’s neurology business group, said in a press briefing Wednesday, and “robust enough to approach regulatory authorities to discuss next steps.”
If the drug is approved for market, it could mean people with early-stage Alzheimer’s disease might be able to slow the disease pathology. It could mean that we finally have an actual treatment for the disease–not just its symptoms. The results are still preliminary and not yet peer-reviewed or published.
“We want to make sure the data are meaningful and reproducible, and I think doing another trial to be able to reproduce the results would make good sense,” Salloway said.
The researchers used a complicated study design that must be validated. The trial was initially designed to test people’s responses to five dosage levels of BAN2401, compared to placebo, for one year, using an “adaptive” approach, meaning they could shift people from one dose group to another depending on how they were responding to the drug. They then used Bayesian statistics to analyze their results, and found the medication didn’t work after running the trial for 12 months. The companies released those failed results in December 2017. But when researchers used more traditional statistical methods to reanalyze their data, and ran the trial out to 18 months, the drug appeared to work at the highest doses.
A treatment for Alzheimer’s disease continues to elude industry titans as many of the large biotech and pharmaceutical companies have halted development of Alzheimer’s disease medication. Pfizer Inc. stopped pursuing research into the neurodegenerative disease in January, while Merck & Co. ended its late-stage trial for an experimental drug in February after that drug failed. Most recently, Eli Lilly and Co. and AstraZeneca Plc’s collaborative effort ended in June after a third-party group recommended stopping development of their lanabecestat drug because it did nothing for people with early onset and mild dementia.
Confidence about Alzheimer’s disease treatments remains low among investors, but Biogen’s BAN2401differs slightly from how other tests have been conducted, which has stirred interest and controversy.
While no one will see revenue from BAN2401 for the foreseeable future, Wednesday’s presentation could inspire confidence in aducanumab, Biogen’s other Alzheimer’s disease drug. Aducanumab just finished enrollment in its Phase 3 trials for the drug and results are expected to come in 2020. BAN2401 and aducanumab are both antibodies that latch onto and reduce the amount of amyloid plaques that build up in the brain. Amyloid plaque buildup is the prevailing theory for the cause of Alzheimer’s disease and other forms of neurodegeneration.
“This trial shows that we can clear plaque and change cognition,” said Dr. Reisa Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston. “I don’t know that we’ve hit a home run yet, but as a proof of concept, I feel like this is very encouraging.”
Many other drugs have managed to reduce amyloid levels but they did not ease memory decline or other cognitive difficulties. In the data presented Wednesday, the highest of the five doses of the new drug — an injection every two weeks of 10 milligrams per kilogram of a patient’s weight — both reduced amyloid levels and slowed cognitive decline when compared to patients who received placebo.
Dr. Sperling, who briefly advised Eisai last year on a different drug, called the reductions in amyloid dramatic, but said the cognitive results were less impressive.
“If you could really slow decline by 30 percent for people who are still normal or very mildly impaired, that would be clinically important,” she said.
Dr. Samuel Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center, said that for the drug to really be effective, it would have to allow patients to function longer independently without needing caregivers to help them with basic daily activities. That kind of practical application was not reflected in the data presented Wednesday.
“I wouldn’t say this is a quantum leap,” Gandy said. “It is a convincing moving of the needle. But it’s not clear that the needle has moved far enough to make a difference in people’s lives.”
Dr. Gandy said the BAN2401 results were encouraging for the prospects of aducanumab because it suggests that there are at least two compounds that may be able to attack both amyloid buildup and cognitive decline.
Some potential Alzheimer’s treatments have resulted in serious side effects, including dangerous swelling or bleeding in the brain. Fewer than 10 percent of the patients taking the new drug experienced such complications.
The drug works by attacking the stringy amyloid tendrils that form before they begin sticking together into plaques. The results of the trial add evidence to the idea that treatment for Alzheimer’s is most likely to succeed if it starts early in the disease process, because the brain begins to deteriorate years or even decades before full-blown dementia occurs. Some other drugs have failed because they were tried on patients with more advanced Alzheimer’s disease. Other drugs targeted the amyloid at later points in the disease progression.
“The prospect of being able to offer meaningful disease-modifying therapies to individuals suffering from this terrible disease is both exciting and humbling,” said Alfred Sandrock, M.D., Ph.D., executive vice president and chief medical officer at Biogen. “These BAN2401 18-month data offer important insights in the investigation of potential treatment options for patients with Alzheimer’s disease and underscores that neurodegenerative diseases may not be as intractable as they once seemed.”
Eisai is the maker of Aricept, which is one of the few drugs that can help slow early memory decline, but which is effective for only about six to nine months.
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Gary Chandler is a prion expert. He is the CEO of Crossbow Communications, author of several books and producer of documentaries about health and environmental issues around the world. Chandler is connecting the dots to the global surge in neurodegenerative disease, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt-Jakob disease, chronic wasting disease and other forms of prion disease. The scientific name for prion disease is transmissible spongiform encephalopathy. The operative word is “transmissible.” Even the global surge in autism appears to be related.