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Clinical Trials of the Anti-Amyloid Therapy, Aducanumab, Are Stopped After Disappointing Results
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The termination of the aducanumab trials was the latest setback in the field of Alzheimer's disease research. It also has renewed debate among researchers regarding the best approach to target the disease.

Hopes that a drug that targets amyloid-beta buildup might be the breakthrough that Alzheimer's disease (AD) patients and families have longed for were dashed in March when two phase 3 trials were halted because the drug wasn't showing effectiveness.

The monoclonal antibody aducanumab had been viewed as a promising development for Alzheimer's disease before Biogen and its Japanese partner Eisai, Co., Ltd. announced their decision March 21 to end global clinical trials of the drug through the ENGAGE and EMERGE trials because a futility analysis of data found that the studies were unlikely to meet the desired results.

The companies did not provide specifics on the trials, saying instead in a news statement that detailed data “will be presented at future medical meetings to inform ongoing research.” The companies said that considering the disappointing results, they were also discontinuing other studies of aducanumab, including the EVOLVE phase 2 safety study and the long-term extension of the PRIME phase 1b study.

The termination of the aducanumab trials was the latest setback in the field of AD research, which has not yet delivered a disease-modifying therapy. It also served to renew the debate among researchers regarding the best approach to target AD. Some researchers believe that targeting the build-up of amyloid-beta (Abeta) plaques could help reduce the disease's cognitive decline, while other researchers think it makes sense to focus on tau (tangles).

Aducanumab was being tested in patients with mild cognitive impairment due to AD and mild AD dementia. The phase 3 trials were assessing the effectiveness of monthly doses of aducanumab compared with placebo in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum Boxes (CDR-SB) score. The studies also included some secondary outcomes measures.

“Initiation of the aducanumab phase 3 secondary prevention trial will be assessed while the other data from ENGAGE and EMERGE are further evaluated,” the news release said.

Time to Reassess

AD experts interviewed by Neurology Today said they were disappointed by the news that the aducanumab trials apparently failed to show a clinical benefit and felt bad for patients and families who are desperate for treatments. But they said the setback also provides an opportunity for AD researchers to take stock of where research stands and where it should head, both in terms of developing therapeutics and more fully understanding at the cellular level the science behind the disease. While aducanumab may have fizzled in the trials, most of the experts interviewed were not ready to throw anti-amyloid pursuits to the curb.

“Clearly the amyloid hypothesis is not dead—far from it,” said Dennis J. Selkoe, MD, FAAN, the Vincent and Stella Coates Professor of Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School. “I fully support alternative approaches like tau, but since none of these have reached phase 2 (testing) we have no idea whether they deserve our optimism more than the next Abeta-lowering trials,” he said in an email to Neurology Today.

“Both Abeta and tau and other approaches need to be pursued vigorously,” he added. “It's never ‘us versus them,’ as some seem to feel.”

Dr. Selkoe said it is possible that further analysis of the trial data will show that aducanumab did slow the cognitive decline of certain individual patients. “It is unfortunate that our clinical trials lead to ‘all or nothing’ analyses of outcome—it either succeeds or fails,” he said.

Dr. Selkoe sent a message to his patients and research associates offering his thoughts on why the aducanumab trials disappointed. He said that the trials may have intervened too late in the course of AD, making it unlikely that the clearing of amyloid would lead to a clinical benefit.

He also said that while it is possible that the amyloid hypothesis is wrong, “the enormous amount of genetic, neuropathological, experimental, and preclinical and clinical biomarker data that we have gathered so far makes it scientifically very unlikely that amyloid-beta build-up has nothing to do with the development of AD symptoms.”

“We must avoid throwing up our hands and assuming it is impossible to treat Alzheimer's,” he said in the message.

Richard S. Isaacson, MD, FAAN, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian told Neurology Today, “I think we need to take a step back and catch our breath and re-evaluate what many people have been thinking for a long time.”

Dr. Isaacson said he doubts that a singular approach, whether aimed at amyloid or tau or something else, will provide a “magic pill.”

“I believe a person can take many roads to Alzheimer's and to have the greatest impact, we need to intervene before amyloid accumulates,” he said.

Dr. Isaacson said more attention needs to be paid to Alzheimer's risk reduction and prevention, including the management of other health conditions such as hypertension, hyperlipidemia, insulin resistance, elevated homocysteine, and physical inactivity.

He will present some results from his clinic's use of precision medicine for risk reduction at the Alzheimer's Association International Conference this summer in Los Angeles.

Return to the Basics

Gregory Petsko, DPhil, professor of neurology at Harvard Medical School and Brigham and Women's Hospital, said the message he takes away from the latest news on an anti-amyloid therapy is that research “has to get back to basic science,” and capitalize on what is going on at the cellular level, inside neurons, to set in motion the course of AD.

He does not believe that targeting extracellular amyloid or tau will be a fruitful therapeutic approach. Instead, he believes the focus should to be on developing drugs that could unlock the “endosomal traffic jams” inside neurons that ultimately lead to the disease's hallmark features.

Dr. Petsko said he was not surprised that the aducanumab trials fell short of expectations, but said the patients, companies, and investigators should be commended for doing the research.

“We have to try to understand what the failures are trying to teach us,” Dr. Petsko said. “The real catastrophe is if we fail to learn from them.”

Eric Reiman, MD, executive director of the Banner Alzheimer's Institute in Phoenix, said that trials of the right anti-amyloid treatments in cognitively unimpaired at-risk persons are “still needed to provide a more definitive test of the amyloid hypothesis and clarify whether the treatments work before the disease has ravaged the brain.” Some such studies are ongoing, and others are needed, Dr. Reiman said in an email to Neurology Today.

At the same time, he added, “We cannot exclude the possibility that combination therapies might work in the clinical stages of AD, such that treatments that target amyloid and other downstream effects might be able to extinguish both the kindling (possibly amyloid) and the fire (for example, neuroinflammation, tau pathology, and neurodegeneration).”

Ronald Petersen, MD, PhD, FAAN, director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, MN, was attending the Alzheimer's & Parkinson's Disease Congress in Lisbon just after the news on aducanumab broke, and he said it was one of the main topics of conversation. “It was a trial that many of us had high hopes for, but that didn't happen,” he said.

Dr. Petersen said he had heard reports on the aducanumab preliminary data at a conference several years ago and is now anxious to learn what transpired in the phase 3 testing. “The drug appeared to be doing what it was supposed to do (remove amyloid from the brain) but apparently it didn't have any clinical impact,” he said.

Dr. Petersen said, “maybe if we went earlier,” the results would turn out differently but that is still speculation. “We all in the field need to scrutinize these data closely and learn from them. These are very expensive trials and a lot of patients have put in their time and effort.”

Dr. Petersen directs the Mayo Clinic Study of Aging, a longitudinal community-based study that is gathering a wide range of data related to AD, including measuring various biomarkers in the participants to look for clues that may help guide future prevention and treatment.

Dr. Petersen said the setback on aducanumab is “discouraging but not the end of the line. We can't give up on this disease. It's too important and it has too great an impact on patients and families.”

Disclosures

Dr. Reiman disclosed no competing interests. Dr. Petsko is chair of the scientific advisory board of MeiraGTx, a gene therapy company developing treatments for several diseases, including AD. He receives a stipend for serving on the scientific advisory boards of QR Pharma, Amicus Therapeutics, and Proclara. Dr. Petersen has received consulting fees from Biogen, Eisai, Roche, Merck, Genentech, as well as GE Healthcare. Dr. Selkoe has received honoraria from Biogen, board of director fees and travel expenses from Prothena Biosciences, and consulting fees and travel expenses from E-Scape Bio.

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