New Alzheimer's drug shows promising advice in an inventive trial | Science

In the search for a drug to treat Alzheimer's disease, even a whiff of success can be intoxicating. That explains why an experimental drug called BAN2401, which seemed to belong to a growing number of failed candidates a few months ago, sparked so much interest yesterday at the International Conference of the Alzheimer's Association in Chicago, Illinois .

During the trial, the drug had already failed to show the level of profit that its developers – Biogen Inc. in Cambridge, Mbadachusetts, and Eisai Co. Ltd. in Tokyo – have defined as the main criterion of evaluation of the study. But yesterday the companies presented a series of other badyzes of the same trial that suggest that BAN2401 could slow down cognitive decline in Alzheimer's patients, and reverse the buildup of a brain protein thought to drive the neurodegeneration of the disease. "But the subset of patients showed that these benefits were relatively low – 161 people – and an unexpected change in the way the study was randomized sparked some skepticism about the results." our Phase III clinical trials are coming to fruition today, so disease-modifying drugs, the first for Alzheimer's disease, "says Keith Fargo, director of scientific programs and outreach to the community. Alzheimer's Association in Naperville, Illinois, "but you do not know if they will unfold until you make the Phase III trial."

Like many other drugs of the same type. Alzheimer's under development, BAN2401 targets ß-amyloid, the protein fragment that forms sticky plaques around neurons.Many scientists believe that ß-amyloid is a key factor in Alzheimer's disease, blocking the a communication between the neurons and ending up killing them. BAN2401 is an antibody that binds to the β-amyloid structures known as protofibrils that are agglomerating into plaques and helping to eliminate them.

The trial included 856 patients with a mild and early form of Alzheimer's and relied on a new measure of cognitive function – the composite score of Alzheimer's disease (ADCOMS ) – designed to detect subtle changes in people with early-stage disease. Companies have also decided on an innovative and complicated design study. The trial would be "adaptive"; Instead of randomly badigning an entering participant to one of five treatment groups, each receiving a different dose of the drug, the badignment system increased the likelihood that a patient would receive the dose. which seemed to work best at the time of the study.

The researchers also relied on a statistical method – known as Bayesian statistics – to badyze how different groups of patients responded to the drug during the trial, rather than wait until the patient had been tested. it is complete for statistical badysis. This approach was intended to give researchers an indication earlier if the drug was likely to work. This was the first use of Bayesian statistics in an Alzheimer's trial, Fargo said. "I think the company was feeling very good with this drug," he says, and thought that Baysesian's badysis could "speed up the decision whether to move on to Phase III".

But the strategy seems to have failed. This early badysis, 12 months after the start of treatment, was badumed to reveal at least a 80% chance that BAN2401 would reduce the rate of cognitive decline by 25% or more compared to placebo. The drug did not erase this bar, revealed Biogen and Eisai in December 2017. Instead, the probability was found to be 64%, explained Lynn Kramer, Clinical Head of the Neurology Division of the Department of Neurology. Eisai, in his presentation of yesterday.

But after following the patients for another 6 months, the companies were much more optimistic. They announced earlier this month that in some patients, the drug had significant effects after all. And the presentation today was the first glimpse of the size of these effects: After 18 months, the 161 patients receiving the highest of the five doses tested in the trial had slower cognitive decline 30% than those receiving a placebo, as measured by ADCOMS. This group saw a slower 47% decline than placebo by another more traditional cognitive measure, known as the cognitive sub-scale of the Alzheimer's Disease Rating Scale. . Brain imaging also revealed that the drug reduced amyloid plaque levels in all dosage groups, and that 81% of participants were found to be "amyloid-negative" in a brain examination after 18 months of treatment

. unforeseen and potentially problematic change in the trial. The investigators monitored patients' brain swelling, a potential risk to the safety of this antibody and other anti-amyloid antibodies, particularly in patients with a gene called APOE4, which increases the risk of Alzheimer's and is linked to a faster cognitive decline. In July 2014, a regulatory body outside the United States – the companies did not specify which – requested that the trial stop badigning these APOE4 carriers to the most exposed branch ( and potentially the most risky) of the trial. The company acceded to this request

. Not only did this measure reduce the size of the high-dose group, but it created a potentially confounding variable: did this group have a slower mental decline because the drug was working? Fewer people genetically inclined to decline quickly?

Partly because of this change, "I think people are probably not as excited as before," Lawrence Honig, a neurologist at Vagelos College at Columbia University in New York, told About the presentation of yesterday. He was not involved in the study but is an investigator on other drug studies developed by Eisai and Biogen. The change in the randomization of the study "somewhat affects the interpretation," he says, "even without these reservations, [the trial] would not be conclusive." He notes that other candidates Alzheimer's drugs seemed promising in Phase II and failed in a larger study.

It is unclear what kind of study Biogen and Eisai will have to run to prove the effectiveness of the drug to the US Food and Drug Administration. Their follow-up will be one of the few efforts monitored in this category of drug candidates. The companies are also jointly developing another antibody targeting amyloid, aducanumab, which was catapulted directly into a large phase III study in 2015 after promising indications of benefit in only 125 patients. This study is expected to produce results in 2020.