01. Can Donanemab Slow Alzheimer’s Progression?

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Donanemab: A New Medication for Alzheimer’s Disease

You’ve probably heard that there have been some new medications approved for Alzheimer’s disease that may slow the rate of progression in a meaningful way. Today, we’re looking at the most recent medication to gain approval, donanemab.

Is this something you should discuss with your patients as an option? Let’s take a look.

How Donanemab Works: Reducing Beta-Amyloid Plaque

Donanemab is a monoclonal antibody treatment similar to two other medications that have been approved in recent years:

• Aducanumab (later withdrawn from the market)
• Lecanemab (approved last year and still in use)

All of these medications work by reducing beta-amyloid plaque in the brain based on the theory that Alzheimer’s is driven by accumulation of this plaque and the subsequent accumulation of tau protein, though that causal theory is still unproven.

The TRAILBLAZER 2 Trial: Measuring Efficacy

The major placebo-controlled trial involving donanemab was known as the TRAILBLAZER 2 trial and was published in JAMA in 2023. The trial lasted 18 months and involved about 1700 participants.

The main outcome was the Integrated Alzheimer’s Disease Rating Scale which measures cognition and functional ability, with the treatment group showing an average decline of about 3 points less than that of the placebo group over the 18-month timeframe. This means that donanemab performed significantly better than had lecanemab in its main trial.

Patients younger than 75 years had the greatest benefit with donanemab. Overall though, the average change was probably too small to be detected by most patients and their families.

Tau Protein: A Key Difference in the Donanemab Trial

One interesting note about the donanemab trial that differed from the prior lecanemab trial is that participants had to have measurable tau buildup in order to enroll. Tau protein was not targeted by the therapy, but the investigators wanted to make sure that participants were either at a more advanced stage or that their disease was progressing more rapidly.

A lack of tau protein generally suggests either an earlier stage of the illness or slower disease progression. Narrowing the participants in this way may have predisposed the trial to show a larger difference.

In looking at subgroups:

• Patients with low to moderate tau had the most significant benefit
• Patients with more tau protein didn’t do as well

This suggests that the drug may have a sweet spot which could be useful to clinicians in choosing who would benefit most, though the technology to measure levels of tau is costly and not available at most hospitals.

ARIA: The Biggest Side Effect Concern

The biggest side effect that people worry about is brain swelling and bleeding risk, a phenomenon known collectively as ARIA (amyloid-related imaging abnormalities). Nearly a quarter of patients taking the medication in the trial experienced swelling and nearly a third showed evidence of bleeding.

Most of these cases were asymptomatic, resolving over several weeks, but three patients did die from brain swelling.

Patients carrying two copies of APOE4, now hypothesized to represent a genetic form of Alzheimer’s rather than simply a risk factor, seem to be at the greatest risk for ARIA, with up to 40% of them experiencing this side effect. Single gene carriers were in the middle at about 23%, and patients without any copies of APOE4 only had about a 16% risk, which was similar to the risk of 15% with placebo.

One theory is that patients with APOE4 may have increased permeability of the blood-brain barrier which could lead to a higher drug concentration of donanemab in the CSF. Despite the increased risk for ARIA, the FDA committee concluded that the benefits still outweighed the risks even for patients with two copies of APOE4.

Feasibility of Treatment: A Unique Aspect of Donanemab

One of the other major limitations of these medications is the feasibility of treatment. Donanemab requires monthly infusions, an improvement over lecanemab which requires twice monthly infusions. But patients still have to show up to an infusion center each month and require significant monitoring in between.

What is really unique about donanemab though is the fact that it can be discontinued once scans indicate that the amyloid plaque has been mostly cleared, whereas lecanemab at least initially was continued indefinitely. For over three-quarters of trial participants in the TRAILBLAZER 2 study, clearance of amyloid occurred by the end of the 18-month study period.

It’s currently believed that once the plaque is cleared it will take up to four years for it to begin to accumulate again. During that time, patients will need to be closely monitored for re-emergence of plaque but don’t need to receive monthly infusions. Slowing of disease progression meanwhile continues even after stopping the medication.

This could be a real game changer in terms of feasibility of treatment, making it time limited for many patients with lasting benefits beyond the course of treatment.

Discussing Donanemab with Your Patients

At the end of the day, if you have patients with mild to moderate Alzheimer’s or MCI, it’s worth discussing these options with them to see if they might be interested in learning more. While the benefits are modest so far, even slight delay of progression can be hugely important for quality of life and caregiver burden.

Abstract

Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial

John R. Sims, M.D.; Jennifer A. Zimmer, M.D.; Cynthia D. Evans, Ph.D.; Ming Lu, M.D, M.S, MPH; Paul Ardayfio, Ph.D.; JonDavid Sparks, Ph.D.; Alette M. Wessels, Ph.D.; Sergey Shcherbinin, Ph.D.; Hong Wang, Ph.D.; Emel Serap Monkul Nery, M.D.; Emily C. Collins, Ph.D.; Paul Solomon, Ph.D.; Stephen Salloway, M.D.; Liana G. Apostolova, M.D.; Oskar Hansson, M.D., Ph.D.; Craig Ritchie, M.D., Ph.D.; Dawn A. Brooks, Ph.D.; Mark Mintun, M.D.; Daniel M. Skovronsky, M.D., Ph.D.

Importance There are limited efficacious treatments for Alzheimer disease.

Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.

Design, Setting, and Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).

Interventions Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.

Main Outcomes and Measures The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.

Results Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.

Conclusions and Relevance Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.

Reference

Sims, J. M.D.; Zimmer, J. M.D.; Evans, C. Ph.D.; et al. (2023). Donanemab in Early Symptomatic Alzheimer Disease, The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527.