Alzheimer’s Association on Aducanumab: Chance for ‘More Time’ Merits Approval
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 Alzheimer’s disease developed by Biogen, merits approval and wide clinical use.
The medication’s review marks the first time in nearly two decades that the FDA has considered approving a potential Alzheimer’s treatment. If aducanumab is given a green light, it would become the first disease-modifying therapy for Alzheimer’s in history — meaning, the first with the potential to alter this disease’s 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 Alzheimer’s News Today.
“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, let’s 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 Alzheimer’s 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 association’s campaign.
Rough start in trying for ‘more time’
Aducanumab’s 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 Alzheimer’s, in patients’ brains, Biogen — working with Eisai – launched two Phase 3 trials. Those studies, ENGAGE (NCT02477800) and EMERGE (NCT02484547), aimed to evaluate the investigational therapy’s efficacy over 78 weeks (about 20 months) of monthly intravenous infusion treatments.
Each trial’s 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 Alzheimer’s, or mild Alzheimer’s.
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.
Those later findings, Carillo said, are crucial to the Alzheimer’s 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. That’s 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 that’s why we think that even a 22% [reduction] … it’s 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 Alzheimer’s 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 aducanumab’s approval.
“People facing Alzheimer’s 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 therapy’s 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 Alzheimer’s Association, however, consider the clinical data gathered to date sufficient to support FDA approval.
“We have seen enough evidence to say we don’t want to wait five more years for [another] trial,” Carrillo said, because such a delay cuts out those who might benefit, but can’t access the treatment until it’s too late to help them.
Current trial data, in Carrillo’s opinion, also support aducanumab’s safety. While she acknowledged that “all drugs do have side effects” — especially those for serious conditions like Alzheimer’s — 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 medication’s use once the edema has abated.
“Even people who had symptomatic ARIA, [which includes] dizziness, maybe some even confusion and cognitive issues, we’ve [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 Alzheimer’s and thought to drive disease progression. But while aducanumab is the first potential Alzheimer’s 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 Alzheimer’s research, Carrillo said. “The pipeline [of potential treatments] is rich and it is very diverse, overall.”
Other investigational medications are targeting tau, another disease-related protein that forms abnormal clumps in patients’ brains. The Alzheimer’s Association recently invested $14 million in research into tau-targeting therapies.
“We’re 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 Alzheimer’s clinical trials.
“This is the start of being able to address the underlying biology of Alzheimer’s. And that’s so hopeful because it’s 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 that’s our best chance.
“This is only the beginning.”