Alzheimer's experimental drug raises hope after early trials

(CNN) – After a series of major failures, there are reasons to hope in the search for a drug for 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. , an antibody called BAN2401, not only reduces the formation of new amyloid beta clusters in the brain, but reduces existing clusters by an average of 70%, US biogenetic company Biogen and Japanese drug maker 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, according to the researchers. Details on immunotherapy were presented at a press conference at the International Conference of Alzheimer's in Chicago in 2018.

"These are people with mild disabilities, a some confusion, forgetting the name of someone on the occasion ". clinical and medical doctor 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 is encouraging to see cognitive effects and slow 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 nonprofit Alzheimer's Association "is the future, and there will be no warning shot to defeat Alzheimer's disease, so being able to delay the progression of the disease for a few years would be huge. "

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 Of course, I do not want us to be wrong, "as in past trials that failed.

BAN2401 is administered intravenously and has been tested in five doses in 856 patients with mild or early-stage cognitive impairment. Alzheimer's in a phase two trial, which evaluates the dosage of a drug.

Hoping that the drug would be a viable treatment had declined in December when participants failed to show 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 body weight, administered every two weeks, showed a statistically significant success at the end of the 18-month study.

Kramer said that Eisai and Biogen had contacted US regulators. States, Europe and Japan to discuss 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", explained Keith Fargo, director of scientific programs at the Alzheimer's Association. "Accelerated approval simply means that you go to the front instead of the back of the line."

For patients eagerly waiting for help, Fargo warned that it will take several years before the drug is available.

"You will not be able to go to the doctor and you will receive it anytime soon," Fargo said.

Safety and side effects

showed that BAN2401 was well tolerated at all levels, including much lower rates of a well-known side effect of amyloid therapy: microblocking 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 suffered from ARIA, which can create headaches, confusion and visual disturbances that disappear once the drug stopped. "Of the 48 cases of ARIA-E, only five were symptomatic," said Kramer, "and could not be identified with an MRI, among them, only one couple showed external symptoms."

Patients with an ApoE gene ε4, the leading genetic risk factor for Alzheimer's disease, are more susceptible to ARIA-E problems. For safety reasons, said Kramer, a regulatory agency outside the United States asked the researchers to remove all patients with the beneficial high-dose group gene that received injections twice a month. However, they left patients with ApoE ε4 in the placebo arm of the study.

According to Isaacson, this may have created a major loophole in research.

"ApoE ε4 patients decline more quickly," he said. "Was the study so good because it placed all ApoE ε4 people in the placebo arm, or did the study look good because it was not good?" lowering of amlyoid improves cognitive function? "

patients with ARIA-E who are also ApoE ε4-positive recommend that they stay in a high-dose group because the side effects are often manageable.

"Regulators must enter the same room as the researchers and agree on things so that these confused changes do not happen midway through", he declares. "In my opinion, there is no reason to do it."

The Amyloid Hypothesis

BAN2401 is one of the many potential drugs using "amyloid hypothesis", a belief that beta amyloid suppression is expected to improve memory loss and other Cognitive changes observed 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 participants in both trials might have contributed to the failures.

The pharmaceutical giant Merck has used a different approach to fight against beta-amyloid in people with advanced Alzheimer's with its BACE inhibitor. In early 2017, after an independent study, he concluded that he had "virtually no chance" of working. A second attempt to treat the early stages of Alzehimer was also dropped in February.

Johnson & Johnson's Atabecestat Inhibitor of BACE, designed to slow cognitive decline in people at risk for Alzheimer's, was also scrapped in May when liver enzymes spiked among participants in the community. One possible reason for the success of BAN2401, Kramer says, is that the trial was among the first to use PET scanners to verify that every participant in the study had definitive signs of beta. amyloid in their brain. Older studies eventually revealed that a number of patients tested did not actually have the aggregates and plaques targeted, which could explain 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. He also showed a decrease in beta-amyloid plaque levels in a subgroup of ApoE ε4 gene transporters, the leading genetic risk factor for Alzheimer's disease. However, the full results of the study are not expected for a year or two.

The results of these two studies are intriguing, said the Alzheimer's Association.

"This is the second test to show amyloid reduction and some improvement in cognition," said Carrillo. "The amyloid hypothesis remains an important therapeutic target to pursue in the disease. 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. 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 .