Story highlights Eighteen-month results for a new Alzheimer's drug show promise BAN2401 removed plaque and improved cognition better than a placebo Other drug trials have failed, so caution is needed, scientists say (CNN) — After a series of prominent failures, there’s reason to be hopeful in the search for a drug to slow the progression of Alzheimer’s disease. Results of an early trial of an experimental drug showed that it improved cognition and reduced clinical signs of Alzheimer’s in the brains of study participants, and experts are “cautiously optimistic” that the results will be duplicated in future clinical trials. The drug, an antibody called BAN2401, not only reduced the formulation of new beta amyloid clusters in the brain, it reduced existing clusters by 70% on average, American biotechnology company Biogen and Japanese drugmaker Eisai announced Wednesday. The buildup of beta amyloid in the brain is a hallmark of Alzheimer’s disease. BAN2401 also provided a 26% to 30% benefit over a placebo in improving cognition in study subjects, researchers said. Details about the immunotherapy were presented at a news conference during the 2018 Alzheimer’s Association International Conference in Chicago. “These were people with very mild impairments, some confusion, forgetting someone’s name on occasion,” said Dr. Lynn Kramer, the chief clinical and medical officer for Eisai. “That’s the goal: to stop Alzheimer’s disease when it’s in the mildest presentation.” Reaction from experts was mixed. “I would not say shock and awe,” said Dr. Julie Schneider, a professor of pathology at Rush Medical College. “It’s encouraging to see some cognitive effect and slowing of disease progression, but I personally think there is a lot more work to be done.” Maria Carrillo, chief science officer for the nonprofit Alzheimer’s Association, said that a combination of drugs “is the future, and there won’t be a sliver bullet to defeat Alzheimer’s, so being able to delay the progression of the disease for a couple years would be huge.” Dr. Richard Isaacson, who directs the Alzheimer’s Prevention Clinic at NewYork-Presbyterian / Weill Cornell Medical Center, said that the research is “impressive on the surface, but we have to be cautiously optimistic. This data may be encouraging, but it’s not possible to say for sure. I don’t want us to be wrong again,” as with previous trials that have failed. BAN2401 is administered intravenously and was being tested in five dosage strengths in 856 patients with either mild cognitive impairment or early-stage Alzheimer’s in a phase two trial, which assesses a medication’s dosage. Hope that the drug would be a viable treatment had waned in December when participants failed to show significant improvement by the study’s first goal of 12 months. However, Biogen recently said the highest dose of 10 milligrams per kilogram of a patient’s body weight, given biweekly, showed statistically significant success at the study’s 18-month completion. Kramer said Eisai and Biogen had reached out to regulators in the United States, Europe and Japan to discuss results and next steps. The company has said it hoped to obtain accelerated approval. “This was only a phase two trial, and it’s not going to be approved by the Food and Drug Administration until results from the next larger trial are in,” explained Keith Fargo, director of scientific programs at the Alzheimer’s Association. “Accelerated approval just means you go to the front instead of the back of the line.” For patients anxiously waiting for help, Fargo warned that it will be several years before the drug is available, assuming it’s successful in the phase three trial, which will involve a larger group of patients. “You are not going to be able to go to the doctor and get this anytime soon,” Fargo said. Safety and side effects Earlier safety trials showed that BAN2401 was well-tolerated at all levels, including much lower rates of a well-known side effect of anti-amyloid therapy: microbleeding and minor swelling in the brain called amyloid related imaging abnormalities, or ARIA-E. Kramer said that less than 10% of patients in any of the five treatment arms experienced ARIA, which can create headaches, confusion and visual disturbances that resolve once the drug is stopped. “Of the 48 cases of ARIA-E, only five were symptomatic,” Kramer said, “and could only be identified with an MRI. Of those, only a couple showed any outward symptoms.” Patients who carry an ApoE ε4 gene, the major genetic risk factor for Alzheimer’s disease, are known to be more susceptible to ARIA-E problems. Due to safety concerns, Kramer said, a regulatory agency outside the United States asked the researchers to remove most patients with the gene from the beneficial high-dosage group that received twice-a-month injections. However, they left patients with ApoE ε4 in the placebo arm of the study. According Isaacson, that may have created a major flaw in the research. “ApoE ε4 patients decline quicker,” he said. “So did the study look so good because they put all of the ApoE ε4 people in the placebo arm, or did the study look good because lowering amlyoid improves cognitive function? That’s the confusing part.” Isaacson says clinical doctors who see patients with ARIA-E who are also ApoE ε4-positive would recommend that they remain in a high-dosage group, because the side effects are often manageable. “Regulatory agencies need to get in the same room with researchers and agree on things so these confusing changes don’t happen mid-study,” he said. “In my opinion, there’s no reason to do that.” The amyloid hypothesis BAN2401 is one of many potential drugs using “the amyloid hypothesis,” a belief that getting rid of beta amyloid should improve memory loss and other cognitive changes seen in Alzheimer’s. Various drug manufacturers have targeted beta amyloid by trying to stop its formation, train the immune system to kill it or remove it from the bloodstream and brain. Results to date had been poor. In late 2016, Eli Lilly’s solanezumab failed to surpass placebo benefits in a phase three trial of 2,100 patients. In 2013, Pfizer scrapped another antibody, bapineuzumab, when it didn’t surpass placebo effects in another phase three trial.<doc-sep>The long, discouraging quest for a medication that works to treat Alzheimer’s reached a potentially promising milestone on Wednesday. For the first time in a large clinical trial, a drug was able to both reduce the plaques in the brains of patients and slow the progression of dementia. More extensive trials will be needed to know if the new drug is truly effective, but if the results, presented Wednesday at the Alzheimer’s Association International Conference in Chicago, are borne out, the drug may be the first to successfully attack both the brain changes and the symptoms of Alzheimer’s. “This trial shows you can both 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, who was not involved in the study. “I don’t know that we’ve hit a home run yet. It’s important not to over-conclude on the data. But as a proof of concept, I feel like this is very encouraging.” Aside from a couple of medications that can slow memory decline for a few months, there is no effective treatment for Alzheimer’s, which affects about 44 million people worldwide, including 5.5 million Americans. It is estimated that those numbers will triple by 2050.<doc-sep>Today’s Headlines The most important news stories of the day, curated by Post editors and delivered every morning. By signing up you agree to our Terms of Use and Privacy Policy<doc-sep>Alzheimer’s is one of the deadliest, costliest, and most emotionally draining diseases in this country. Yet we have no drugs to reverse the condition, and the last medicine that came on the market to treat Alzheimer’s symptoms was approved some 15 years ago. So it’s no surprise that Alzheimer’s researchers, patients, and investors were eagerly anticipating the results of a phase 2 study on a potentially promising new medication, called BAN2401, from the drugmakers Biogen and Eisai. On July 5, the companies released a summary of the findings from a trial of the drug involving 856 patients with early Alzheimer’s, showing the medication could slow the progression of the brain-ravaging illness. On Wednesday afternoon, they presented more details about their findings at the Alzheimer’s Association International Conference in Chicago. The results have sparked cautious optimism. “Millions of people have Alzheimer’s, 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.” That’s because, while the experimental drug is potentially exciting, and may represent a step forward in the grinding, frustrating quest to treat Alzheimer’s, it’s far from being ready to prescribe to patients. First, the results haven’t been peer-reviewed, much less replicated by other researchers. Also, the way the drug companies ran and analyzed the data in their trial makes some experts suspicious. That’s why, with a huge market for an effective drug and massive potential profits at stake, we need to evaluate the new drug very, very carefully. The drug slowed Alzheimer’s progression by 30 percent, according to the drug company Before we explore why there’s reason to question the early results, let’s briefly touch on why they may potentially be significant. First off, Alzheimer’s 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 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. Years (or even decades) after this process begins, people start to experience the hallmark symptoms of Alzheimer’s, like forgetfulness and confusion. Despite the fact that Alzheimer’s is the most common cause of dementia in older people — and there are an estimated 5.7 million Americans living with the disease — there is not a single drug available to treat the condition. (The medications on offer only ameliorate Alzheimer’s symptoms — like anxiety, aggression, and depression — and only in some people.) The path to finding a drug that would stop the progression of or reverse the disease has been littered with failures. And that’s largely because of how complicated Alzheimer’s is. “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 Alzheimer’s — including genetics or a history of head injury or stroke. The new, experimental medicine, BAN2401, purports to test the aforementioned 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, 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 results are indeed solid, and the drug is approved for market, it could mean people with early-stage Alzheimer’s might be able to keep the disease at bay. It could also mean that we finally have an actual treatment for the disease, and not just its symptoms, available for patients. The drug still needs to pass a phase 3 clinical study and FDA scrutiny But again, there’s reason to be cautious with these findings. Today’s data, unfortunately, can’t definitively answer the question of whether this is truly an Alzheimer’s breakthrough. First, the trial was a phase 2 study, and the drug will likely need to pass a phase 3 trial, involving a larger group of people to confirm its effectiveness and monitor any side effects before it can be approved by the Food and Drug Administration. “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 results are still preliminary and not yet peer-reviewed or published.<doc-sep>
An experimental drug being tested to see if it can treat Alzheimer’s disease helped slow the inevitable loss of clear thinking and memory that comes with the condition, researchers reported Wednesday. It’s a rare success in a field littered with failures. No drug has yet been shown to reverse the symptoms of Alzheimer’s, which affects more than 5 million Americans and has no cure. And this one is no home run. Everyone who took the drug continued to get worse. But those who got the highest doses got worse more slowly. “We had a 47 percent reduction in decline at 18 months,” Dr. Lynn Kramer, chief medical officer of the neurology division of drug company Eisai, told reporters. It was the second piece of good news on the Alzheimer’s front. Earlier Wednesday, researchers reported that lowering blood pressure to recommended levels was safe and reduced the rate of mild cognitive impairment — a precursor of dementia — by 20 percent. Eisai and its U.S. partner Biogen presented results to an eager audience at the Alzheimer’s Association annual meeting in Chicago Wednesday. They’ve been treating more than 800 patients with early-stage Alzheimer’s with various doses of the drug, called BAN2401. It’s a monoclonal antibody, a lab-engineered immune system protein designed to remove amyloid plaques from the brain. One leading theory about Alzheimer’s is that these amyloid clogs cause the disease. “This is the first large trial to support the amyloid hypothesis,” Kramer said. The drug cleared the plaques from the brains of the patients, by 93 percent at the highest dose. Dr. James Hendrix, director of global science initiatives at the Alzheimer’s Association, says the findings are significant. “Not only do we see a slowing in the rate of cognitive decline, we also see that reduction of amyloid burden in the brain as measured by amyloid PET (imaging)", Hendrix told NBC News. “That biomarker confirmation really adds confidence that what you are seeing in the primary measure is real.” Still, the researchers had to tweak the results to be able to declare a success. When the trial was at the 12 month point, they said, they didn’t see a benefit. Now, after their patients have been infused with the drug for 18 months, they say they can see an effect. To find out more, Hendrix said, the companies will have to design an advanced trial called a Phase 3 clinical trial — the final stage before seeking full Food and Drug Administration approval. Dr. Howard Fillit, founding executive director of the Alzheimer’s Drug Discovery Foundation, supports the way Biogen and Eisai changed the study. "The Biogen studies are being done in a different way than all of the studies we have done for the past 40 years," Fillit, who was not involved in the research, told NBC News. "The Biogen study took advantage of everything that we have learned about doing modern, efficient clinical trials." He called the results "amazing" — especially the reduction of amyloid in the brain. It’s difficult to describe what a 47 percent decrease in in the worsening of symptoms looks like, researchers said. The patients all took a battery of tests used to diagnose and define Alzheimer’s. “When you are talking about early-stage Alzheimer’s disease, you are talking about people who are living pretty well and still able to live independently at home,” Hendrix said. “If you are able to slow that decline, that means they may be able to keep that quality of life for more time.” One problem is a side effect that causes the brain to swell, which has been seen in all the monoclonal antibodies tried against Alzheimer’s. This affected about 10 percent of the patients. “This is the second Alzheimer’s clinical trial that has demonstrated both clearance of amyloid from the brain and cognitive benefits — again, the studies were not large enough to definitely demonstrate cognitive efficacy and the BAN2401 study did not meet its primary endpoint," the Alzheimer’s Association said in a statement. When trials don't meet their primary endpoints — when they don't do what they were designed to do — that can shed doubt on any results. And depending on which test results were used, the improvement was either 30 percent or 47 percent - a discrepancy that troubles some experts. But anything that might help would be welcome. “The global urgency to better treat and prevent Alzheimer’s disease and other dementias is higher than ever, and growing," the Alzheimer's Association said.