Putting Research Into Practice With Aducanumab for Alzheimer Disease

In this video, Douglas Scharre, MD, FAAN, Director, Division of Cognitive Neurology, Ohio State University Wexner Medical Center, Columbus, OH, discusses his presentation “Translating Research Into Practice -- Everything You Need To Know About Aducanumab But Were Afraid To Ask” which was given virtually at Neurology Week.

Read the Transcript:

Dr Scharre:  Hello, I'm Dr. Douglas Scharre from Ohio State University. Recapping a talk I gave in Neurology Week, entitled, "Translating Research Into Practice -- Everything You Need To Know About Aducanumab But Were Afraid To Ask."

The first thing to know about aducanumab is that it was labeled and approved just last month. The label was changed so that it includes people that have this mild cognitive impairment due to Alzheimer's disease and people with very mild dementia.

Individuals who have Alzheimer's that have deficits decline from previous and also have maybe some very mild impairments in activities of daily living, but nothing to the degree of mild to moderate Alzheimer's, moderate to severe Alzheimer's. It is not labeled for that.

Going way back, it's been over 100 years since Alois Alzheimer first described the plaques and tangles in Alzheimer's. Aducanumab is a monoclonal antibody to get rid of these amyloid plaques. It wasn't until like 1984 that we knew what amyloid was made out of, this amyloid-beta peptide.

Tau was discovered. We've discovered ways to measure both of these in the spinal fluid so we can measure these conditions. We've been able to measure amyloid, and now, tau as well in PET imaging, so neuroimaging.

The best thing about being able to image or do spinal fluid to test for amyloid is the fact that these proteins build up 10, 15, 20 years before you forget your keys for the first time. It gives us a window of opportunity. Just when someone is beginning to have mild cognitive impairment, that would be the perfect time to consider thinking of something like aducanumab.

The clinical trials basically use this monoclonal antibody. It's a human immunoglobulin. It's designed to bind to both soluble and insoluble forms of amyloid-beta protein so that you have the monomers, the little 42-amino acid.

They combine beta pleat, and they go into these oligomers, and then built into fibrils, and eventually to plaques. Aducanumab is designed to attach or bind to both the very small soluble forms and the fibrils and some of the insoluble forms.

There are two clinical trials done, EMERGE and ENGAGE, by Biogen, both 18-month randomized placebo-controlled trials, over 3,000 patients. They had three groups, placebo group, a low-dose group, 6 milligrams per kilogram, and high-dose group, 10 milligrams per kilogram. They measured their cognitive and biomarker endpoints.

Most of these individuals had mild cognitive impairment due to Alzheimer's disease. About 80% and about the other 20% had mild Alzheimer's dementia.

They all had to have a positive PET scan. They could be on symptomatic treatments. They were not allowed to have anticoagulants, except for aspirin, but no anticoagulants. They couldn't have any other severe medical conditions. That was the inclusion/exclusion criteria.

About 50% of the group were on symptomatic Alzheimer medications. These are like donepezil, rivastigmine, galantamine. Two-thirds were APOE genotype carriers. That is, they had the epsilon4 allele, which would be typical if you have Alzheimer's disease. As I said, 80% were the mild cognitive impairment due to Alzheimer's disease.

What they found was a 22% reduction in the decline of the CDR Sum of Boxes. This is a functional and cognitive score. These patients still got worse. They just did not get worse as quickly or as severely as the placebo group.

There was a 18% decline in the worsening of Mini-Mental-State, 27% decline in the worsening of the ADAS-Cog 13, and a 40% decline in an activity of daily living skill, called the ADCS-ADL for Mild Cognitive Impairment. 40% declined less than placebo in the EMERGE trial.

This was the one trial that was positive. The ENGAGE trial did not show significance on these findings. Just one of the two trials were significant. Most importantly, why the FDA approved this medication was the significant change and decrease in amyloid that was in the brain, based on amyloid PET imaging.

The high doses of both studies, EMERGE and ENGAGE, both were highly statistically significant, whereas the placebo group did not change their amyloid load at all.

In fact, there were even some changes in CSF phospho-tau in the high-dose group in both studies, suggesting that there may be, in addition to reduction of amyloid, this medication may also impact tau from building up in the brain.

Discontinuations were higher, of course, in the studies. Twenty-five percent in the high-dose had to discontinue versus 16% in the placebo. There were some potential adverse events.

The ones that come out the most were something called amyloid-related imaging abnormalities, or ARIA -- there's two types -- and edema, and micro hemorrhages, or superficial siderosis, also called ARIA-H.

Of those that had ARIA-E, the edema part found on their MRI scans, which are done periodically for safety purposes, 35% of those in the high-dose group had edema, while only 2 to 3% were pleasant in the placebo group. In the terms of microhemorrhages, 18% in the high-dose versus 6% in the placebo.

The hemosiderosis, 14% in the high-dose versus 2% in the placebo. Ninety-eight percent of the time, these MRI of the ARIA-E, the edema resolve 98% of the time. Those that were symptomatic had any symptoms related to this. Most patients are asymptomatic, but 24% were symptomatic. That is, they were out of sorts. Very, very rare cases of having significant confusion. Even seizures that would have to be hospitalized or treated otherwise. So, 86% had no symptoms with these ARIA-E and ARIA-H side effects. There was symptomatic area also noted on the placebo group in about 5.6%.

Most of those findings are treatable. You can stop the medication, halt it, and then restart it. As I said, 98% resolve completely. There's a very few cases that would have to be watched and treated separately.

In summary, FDA-approved aducanumab, it's an amyloid-beta-directed antibody indicated for the treatment of Alzheimer's, and it's now indicated just for mild cognitive impairment due to Alzheimer's. Plus, it may be very mild Alzheimer's disease, a narrow slice of people that it would be useful for.

It is not good to use it in people with mild to moderate disease or the people that don't have cognitive symptoms. It's been approved under this accelerated approval based on the reduction in the amyloid noticed in the PET amyloid scans.

Approval for the indication may be contingent upon verification of a clinical benefit in confirmatory trials. Thank you for allowing me to recap for you, and thank you for your attention.