Good read Alzheimers Association on Aducanumab: Chance for More Time Merits Approval Marisa Wexler MS avatar by Marisa Wexler MS | June 3, 2021 aducanumab interview In a few days, the U.S. Food and Drug Administration (FDA) is expected to announce whether or not it decided that aducanumab, an investigational treatment for Alzheimers disease developed by Biogen, merits approval and wide clinical use. The medications review marks the first time in nearly two decades that the FDA has considered approving a potential Alzheimers treatment. If aducanumab is given a green light, it would become the first disease-modifying therapy for Alzheimers in history meaning, the first with the potential to alter this diseases course, rather than just easing its symptoms. Regardless of whether it [aducanumab] is approved or not, it is a moment of hope because it is the first drug that has made it [to the point of being considered by the FDA] in 17 years, Maria Carrillo, PhD, said in a phone interview with Alzheimers News Today. Carrillo is the chief science officer for the Alzheimers Association, which recently launched the More Time initiative calling on the FDA to approve aducanumab. We think that research is actually paying off, and that this is a time where it should be a message of hope, Carrillo said. We know that, for those individuals that could be eligible for this treatment would be eligible, lets say, if there is approval the drug could mean more time with family, she added. One of the most important things we wanted to do was to make sure that people understood what this means. To Carrillo, a slowing of Alzheimers decline itself would be priceless, because it allows patients more time in earlier disease stages, more time before more advanced stages of dementia drastically affect the quality of their lives and the lives of those closest to them. Hence, the associations campaign. Rough start in trying for more time Aducanumabs path toward FDA review, and possible approval, has been rather unique and quite tumultuous. After early trial data indicated that aducanumab had an acceptable safety profile and could reduce levels of amyloid plaques, the abnormal protein clumps that are a hallmark of Alzheimers, in patients brains, Biogen working with Eisai launched two Phase 3 trials. Those studies, ENGAGE (NCT02477800) and EMERGE (NCT02484547), aimed to evaluate the investigational therapys efficacy over 78 weeks (about 20 months) of monthly intravenous infusion treatments. Each trials main goal was to determine the effect of treatment on the rate of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB), a composite measure of functional and cognitive abilities that assesses skills like engaging in home activities, solving problems, and being active in a community. Collectively, the studies enrolled nearly 3,300 people with either mild cognitive impairment due to Alzheimers, or mild Alzheimers. A planned independent advisory committee assessment of interim data from these Phase 3 trials, however, determined that aducanumab was unlikely to benefit patients, and Biogen announced in 2019 a halt to its clinical development. Then, additional trial data were collected that revealed inaccuracies in the original interim analysis assumptions. One of the trials, EMERGE, met its primary endpoint: compared to participants given placebo, those assigned to aducanumab at high dose (up to 10 mg/kg) experienced a statistically significant 22% slowing of decline in CDR-SB. Based on these data, Biogen announced it was reversing course, and would request approval in the U.S., as well as in Europe and Japan. Those later findings, Carillo said, are crucial to the Alzheimers community, because no current treatment offers any such hope. Think about having months longer in that stage [mild cognitive impairment] before you go into the dementia diagnosis. Thats a pretty big deal. The longer you stay in this independent, mild cognitive impairment stage the longer you stay in mild dementia before you move into moderate dementia, which we know is much more debilitating, much more of a loss of independence, much more dependent on caregiving and longer hours of caregiving, Carillo said. So thats why we think that even a 22% [reduction] its still worth that time for individuals that are in that stage, she added. As part of its More Time campaign, the association called on people affected by Alzheimers to speak up on social media. There were over a million responses including those of celebrity activists like Samuel L. Jackson and Kimberly Williams-Paisley and the association sent a letter to the FDA detailing the groundswell of support for aducanumabs approval. People facing Alzheimers are facing a progressive and fatal disease, and would give anything to have More Time,' the association stated in an email. To deny millions of people days, weeks, months or even years of active life, particularly with early diagnosis, is inhumane. Impossible to wait five more years While the EMERGE trial met its primary goal, ENGAGE did not in the overall trial, no significant difference in the rate of decline in CDR-SB was seen between those given aducanumab or a placebo. Based in large part on these ambiguous results, an FDA advisory committee decided late last year that sufficient evidence is lacking to support the therapys effectiveness. The FDA considers, but is not bound to, recommendations by a committee. More recently, a recent interim report by the independent Institute for Clinical and Economic Review (ICER) reached a similar conclusion. Biogen, meanwhile, points out that treatment effect was seen in ENGAGE, though only in the relatively small subset of patients on its high dose. According to Carrillo, differences in dosing are key to understanding the outcomes of the two trials. Probably a bit into the Biogen launch of EMERGE and ENGAGE, science emerged from a few trials that demonstrated that there was less bioavailability of these monoclonal antibodies than we originally thought, Carrillo said. In other words, data indicated that, for aducanumab and medications like it, less of the active medication was getting into the brain than expected. Based on these findings, an increase in dose was not only recommended but actually safe, Carrillo added. A decision was made to increase the dosage of aducanumab used in both EMERGE and ENGAGE. However, due to logistical and bureaucratic differences between the trials, more people managed to get on that higher dose in the EMERGE trial that found positive results, Carrillo said. Biogen recently launched an open-label Phase 3b study, called EMBARK, which will continue to evaluate aducanumab in patients who took part in ENGAGE, EMERGE, or earlier trials. Both Carrillo and the Alzheimers Association, however, consider the clinical data gathered to date sufficient to support FDA approval. We have seen enough evidence to say we dont want to wait five more years for [another] trial, Carrillo said, because such a delay cuts out those who might benefit, but cant access the treatment until its too late to help them. Current trial data, in Carrillos opinion, also support aducanumabs safety. While she acknowledged that all drugs do have side effects especially those for serious conditions like Alzheimers she believes that side effects so far associated with aducanumab can be effectively managed in the clinic. For example, one of the most common adverse events in EMERGE and ENGAGE reported in about a third of trial participants given aducanumab was cerebral edema, or abnormal fluid accumulation in the brain, also called ARIA-E. Most of those experiencing an ARIA-E during the trials had no overt symptoms, Carrillo said, with ARIA-E detected on MRI scans. In a clinical setting, she added, ARIA-E can be managed simply by interrupting treatment, then resuming the medications use once the edema has abated. Even people who had symptomatic ARIA, [which includes] dizziness, maybe some even confusion and cognitive issues, weve [stopped treatment] and then reintroduced [it] later again safely, she said. Only the beginning Aducanumab, a monoclonal antibody, is designed to remove clumps of the misshapen beta-amyloid proteins that are characteristic of Alzheimers and thought to drive disease progression. But while aducanumab is the first potential Alzheimers treatment to be considered by the FDA in almost two decades, it is far from the only medication in development. This is such an exciting time in Alzheimers research, Carrillo said. The pipeline [of potential treatments] is rich and it is very diverse, overall. The association is closely following several other antibody therapies designed to target beta-amyloid, she said, such as gantenerumab, lecanemab, donanemab, and solanezumab. Recent results of a Phase 2 clinical trial (NCT03367403) indicated that donanemab, by Eli Lilly, can slow the decline in cognitive and daily life abilities. Other investigational medications are targeting tau, another disease-related protein that forms abnormal clumps in patients brains. The Alzheimers Association recently invested $14 million in research into tau-targeting therapies. Were excited that tau is coming into its own and moving into the clinical trial pipeline, Carrillo said, and expect to see probably tau treatments in Phase 3 [clinical trials] very soon. Other treatment strategies being explored range from lifestyle changes and inflammation-targeting treatments, to those aiming to modulate bacteria living in the body. Through its Part The Cloud initiative, the association is helping to fund 59 different Alzheimers clinical trials. This is the start of being able to address the underlying biology of Alzheimers. And thats so hopeful because its just the start, Carrillo said. She stressed that aducanumab and other treatments are not the silver bullet of a cure, but additional tools of help to patients. It is a slowing of decline, not even a stop, she said of aducanumab. But with better treatment that will really give us, I think, that combination therapy approach we know we will need. And thats our best chance. This is only the beginning. Print This Page About the Author Marisa Wexler MS avatar Marisa Wexler MS Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club. 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