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After a series of major failures, there is reason to hope in the search for a drug to slow the progression of Alzheimer's disease. The results of an early trial of an experimental drug showed that it improves cognition and reduces the clinical signs of Alzheimer's in the brain of study participants, and the Experts are "cautiously optimistic" that the results will be replicated in future clinical trials.
The drug, an antibody called BAN2401, not only reduces the formation of new beta-amyloid clusters in the brain, but reduces existing clusters by an average of 70%, US biogenetic company Biogen and Japanese Eisai said on Wednesday . The accumulation of beta-amyloid in the brain is a hallmark of Alzheimer's disease.
BAN2401 also provided a 26% to 30% advantage over a placebo in improving cognition in study subjects, the researchers said. Details on immunotherapy were presented at a press conference during the International Conference of the Alzheimer's Association of 2018 in Chicago.
"These were people with very mild impairments, some confusion, forgetting someone's name on occasion," said Dr. Lynn Kramer, Clinic Leader and Physician for Eisai. "It's the goal: to stop Alzheimer's disease when it's in the sweetest presentation."
The reaction of the experts was mixed. "I would not say shock and admiration," said Dr. Julie Schneider, professor of pathology at Rush Medical College. "It's encouraging to see cognitive effects and slowing the progression of the disease, but I personally think that there is still a lot of work to be done."
Maria Carrillo, scientific director of the non-profit Alzheimer's Association, said that a "combination of drugs" is the future, and there will be no ball for to defeat the Alzheimer's disease, to delay the progression of the disease for a few years would be enormous. "
Dr. Richard Isaacson, who heads the Alzheimer's Disease Prevention Clinic at the New York-Presbyterian Medical Center / Weill Cornell, said the research is "awesome on the surface, but we need to be cautiously optimistic." These data may to be encouraging, but it is impossible to say I do not want us to be wrong again, "as in previous failed trials.
BAN2401 is administered intravenously and has been tested in five doses in 856 patients with mild cognitive impairment or early-onset Alzheimer's disease in a phase 2 trial, which evaluates the dosage of BAN2401. a drug.
Hoping that the drug would be a viable treatment had declined in December when participants failed to show a significant improvement by the first goal of the 12-month study. However, Biogen recently stated that the highest dose of 10 milligrams per kilogram of a patient 's body weight, administered every two weeks, showed a statistically significant success at the completion of the treatment. 18 months study.
Kramer said Eisai and Biogen had reached out to regulators in the United States, Europe and Japan to discuss the results and next steps. The company said it hoped to obtain accelerated approval.
"This was only a phase two trial, and it will not be approved by the Food and Drug Administration until the results of the next largest trial are over," said Keith Fargo, director of programs scientists at the Alzheimer's Association. "Accelerated approval simply means that you are going to the front instead of the back of the line."
For patients who are anxiously waiting for help, Fargo warns that several years will pass before the drug is available, assuming it succeeds in the live test III, which will involve a larger group of patients.
"You will not be able to go to the doctor and get it anytime soon," Fargo said.
Safety and Side Effects
Previous safety tests showed that BAN2401 was well tolerated at all levels, including much lower rates of a side effect well-known anti-amyloid therapy: microblocking and 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 an ARIA, which can create headaches, confusion and visual disturbances that disappear once the stopped medication. "Of the 48 cases of ARIA-E, only five were symptomatic," said Kramer, "and could only be identified with an MRI. Of that number, only one couple showed external symptoms."
Patients with an ApoE -4 gene, the leading genetic risk factor for Alzheimer's disease, are more susceptible to ARIA-E problems. For safety reasons, said Kramer, a regulatory body outside the United States asked researchers to remove most of the patients with the high-dose benefit group gene that received twice-injected injections. month. However, they left patients with ApoE -4 in the placebo arm of the study.
According to Isaacson, this may have created a major flaw in the research.
"ApoE -4 patients decline faster," he said. "Was the study so good because it placed all people who received ApoE -4 in the placebo arm, or did the study have it? been good because lowering of amlyoid improves cognitive function?
Isaacson says that clinical doctors who see patients with ARIA-E who are also ApoE -4-positive recommend that they stay in a high-dose group, because the side effects are often manageable.
"Regulators must enter the same room as researchers and agree on things, so that these Confused changes do not happen mid-way through, "he said." In my opinion, there is no reason to do that. "
L & # 39; Amyloid Hypothesis
BAN2401 is one of many potential drugs using the "amyloid hypothesis", a belief that amyloid beta deletion should improve. improve memory loss and other cognitive changes seen in Alzheimer's disease. Various drug companies have targeted beta amyloid by trying to stop its formation, train the immune system to kill it or remove it from the blood and brain.
Results to date have been poor. By the end of 2016, Eli Lilly's solanezumab failed to outweigh the benefits of placebo in a Phase III trial of 2100 patients. In 2013, Pfizer discarded another antibody, bapineuzumab, when it did not outperform placebo effects in another phase III trial. Experts suggest that advanced stages of Alzheimer's disease among study participants in both trials might have contributed to the failures.
Pharmaceutical giant Merck used a different approach to fight against beta-amyloid in people with advanced Alzheimer's disease with its inhibitor of BACE, the verubecestat, but acknowledged its defeat in early 2017 after a independent study. A second attempt to treat the early stages of Alzehimer was also dropped in February.
The atabecestat, a Johnson & Johnson BACE inhibitor, designed to slow cognitive decline in people at risk for Alzheimer's, was also discontinued in May when hepatic enzymes increased in men. participants in the study. According to Kramer, one of the possible reasons for the success of BAN2401 is that the study was among the first to use PET scanners to verify that each participant in the study had definitive signs of beta-1. amyloid in the brain. Older studies have finally revealed that a number of patients tested did not actually have the aggregates and plaques targeted by the drug, which could account for failure rates.
The other Biogen amyloid antibody, aducanumab, also uses the PET scan model in its tests. Aducanumab binds to a different type of amyloid protein in the brain than BAN2401.
Biogen announced the updated results of a 24-month trial on aducanumab Sunday at the conference. The latest data has shown a "beneficial effect" in cognition for patients with pre-Alzheimer's disease. It has also shown a decrease in beta-amyloid plaque levels in a subgroup of ApoE -4 gene transporters, the leading genetic risk factor for Alzheimer's disease. However, complete results on the study are not expected for another year or two.
The results of these two studies are intriguing, said the Alzheimer's Association.
"This is the second test to show a reduction in amyloid and some improvement in cognition," said Carrillo. "The amyloid hypothesis remains an important therapeutic target to pursue in Alzheimer's disease."
The last drug against Alzheimer's disease approved by the Food and Drug Administration was in December 2014, and it was a combination of two existing drugs. Prior to that, a new drug for Alzheimer's disease had not entered the market since 2003. Of the five FDA-approved drugs to treat Alzheimer's disease, none is slowing down its progression .
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