(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. Experts suggest that the advanced stages of Alzheimer's among study participants in both trials might have contributed to the failures.
Drug giant Merck used a different approach to fight beta amyloid in people with late-stage Alzheimer's with its BACE inhibitor verubecestat but admitted defeat in early 2017 after an independent study found that it had "virtually no chance" of working. A second attempt to treat earlier stages of Alzehimer's was also scrapped in February.
Johnson & Johnson's BACE inhibitor atabecestat, designed to slow cognitive decline in people at risk for Alzheimer's, was also shelved in May when liver enzymes spiked in study participants.
One possible reason for the success of BAN2401, Kramer said, is that the trial was among the first to use PET scans to verify that each study participant had definitive signs of beta amyloid in their brains. Older studies ultimately found that a number of patients tested did not actually have the clumps and plaques the drug was targeting, which might help explain failure rates.
Biogen's other amyloid antibody, aducanumab, is also using the PET scan model in its trials. Aducanumab binds to a different type of amyloid protein in the brain than BAN2401.
Biogen announced updated results from a 24-month trial on aducanumab on Sunday at the conference. The latest data showed a "beneficial effect" in cognition for patients with pre-Alzheimer's disease. It also showed a decrease in beta amyloid plaque levels in a subgroup of ApoE ε4 gene carriers, the major genetic risk factor for Alzheimer's disease. However, full results on the study aren't expected for another year or two.
The results of both of these studies are intriguing, the Alzheimer's Association said.
"This is the second trial to show reduction in amyloid and some improvement in cognition," Carrillo said. "The amyloid hypothesis remains an important therapeutic target to pursue in Alzheimer's disease."
The last Alzheimer's drug approved by the Food and Drug Administration was in December 2014, and it was a combination of two existing drugs. Before that, a new medicine for Alzheimer's hadn't entered the market since 2003. Of the five drugs approved by the FDA to treat Alzheimer's, none slows its progression.