Donanemab Shows Potential for Early Alzheimer’s in Phase 2 Trial

Donanemab showed an ability to slow cognitive decline and the loss of daily life abilities in people at earlier stages of Alzheimer’s disease relative to those given a placebo in the Phase 2 TRAILBLAZER-ALZ trial, researchers report.

A plaque-targeting therapy, donanemab also cleared substantial amounts of amyloid plaques in the brains of treated patients. But outcomes in secondary trial goals — measures of cognition, memory, and activities of daily living — were more mixed and further study recommended.

A global Phase 3 trial of donanemab, called TRAILBLAZER-ALZ-2 (NCT04437511) is underway in this same patient group, and starting or getting ready to enroll up to 1,500 diagnosed adults at 230 sites worldwide. More information is available here.

Eli Lilly, the investigative therapy’s developer, presented trial results at the 15th International Conference on Alzheimer’s & Parkinson Diseases held virtually March 9–14. They were simultaneously published in the New England Journal of Medicine, as an article titled “Donanemab in Early Alzheimer’s Disease.”

“This is the first late-stage study in Alzheimer’s disease to meet its primary endpoint at the primary analysis,” Daniel Skovronsky, MD, PhD, Lilly’s chief scientific officer and president of Lilly Research Laboratories, said in a press release.

It has “the potential to become a very important treatment for Alzheimer’s disease,” he added. “The constellation of clinical and biomarker results indicates the potential for long-term disease modification.”

Donanemab is an antibody designed to recognize a harmful form of the beta-amyloid protein that clumps into toxic plaques in Alzheimer’s patients. Antibodies trigger immune reactions by attaching themselves to their target molecules (toxic amyloid clumps, in this case), labeling them as harmful.

In this way, donanemab is designed to call the immune system’s attention, so to speak, to amyloid plaques it might otherwise overlook. Clearing such plaques from the brain is expected to slow Alzheimer’s progression.

The Phase 2 study (NCT03367403) evaluated donanemab’s safety, tolerability, and efficacy, as compared with a placebo, in adults with early stage and symptomatic Alzheimer’s.

The trial enrolled 257 people, ages 60 to 85, and randomly assigned 131 to donanemab and 126 to receive placebo. A third group of 15 patients given donanemab and a BACE1 inhibitor was discontinued early, and the data on this group was not included in the final analysis. (BACE1 is a gene which encodes for beta-secretase 1, an enzyme that helps amyloid plaques form.)

Changes from baseline — the study’s start — in the integrated Alzheimer’s Disease Rating Scale (iADRS) was the study’s primary goal. iADRS is a combined measure of cognitive and daily life abilities, used to track disease progression and detect treatment differences, such as those between patients on donanemab and on placebo.

Specifically, iADRS combines scores from the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study–instrumental Activities of Daily Living (ADCS-iADL). Scores on this scale range from 0 to 144, with lower scores indicating greater cognitive and functional decline.

At baseline, the mean iADRS score for patients assigned to donanemab was 106.2, and 105.9 for those randomized to placebo.

Over 76 weeks of treatment, iADRS scores of treated patients dropped by an average of 6.86 points, while those of the placebo group declined by 10.06 points — a difference of 3.2 points or 32%, which the press release noted as statistically significant.

Lilly also stated that significant differences in the rates of decline, as measured by the iADRS, began to appear at 36 weeks, or nine months, of treatment.

The trial “was powered to show a 6-point difference” in iADRS scores between the two patient groups, the researchers noted.

Secondary trial goals included measures of changes in cognitive skills and daily life activities (the ADAS-Cog and ADCS-iADL scales individually), as well as the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score and the Mini Mental State Examination (MMSE) score.

Differences from baseline to week 76 between the donanemab and placebo groups were less conclusive in these measures. A trend for consistently slower cognitive and functional decline was seen, but not all time points showed statistical significance.

Donanemab did, however, clear amyloid plaques more effectively than placebo.

The percentage of participants classified as amyloid negative grew from 40% to 67.8% between weeks 24 and 76, compared to no significant change among those receiving placebo. Additionally, plaque levels dropped enough in 54.7% of donanemab-treated participants to enable them to switch to placebo by week 56.

“A key insight of the results from the TRAILBLAZER-ALZ study is that donanemab not only significantly reduced the amount of amyloid deposition in these patients but also slowed the clinical progression of the disease,” said Liana Apostolova, MD, one of the trial investigators. This finding, she added, suggested that donanemab could be disease-modifying for Alzheimer’s.

Patients assigned to treatment also accumulated tau protein more slowly over 18 months than those on placebo, as measured by positron emission tomography (PET). This difference, however, was not considered “substantial.”

In healthy people, tau helps in the transport of essential nutrients and other molecules to brain cells. Tau grows misshapen in Alzheimer’s, however, tangling into structures that re incapable of transport and contribute to cell death in the brain.

Researchers suggest that global tau changes seen on PET may lag  changes in amyloid, and 18 months may be too short a time to detect them.

Changes in brain volume — a measure of brain atrophy that often precedes cognitive symptoms — showed that donanemab associated with a greater whole-brain volume loss and a greater increase in ventricular volume compared to placebo, while no substantial difference occurred in hippocampal volume between groups. The exact meaning of these findings are not clear.

“The observations of a greater decrease in whole brain volume and a greater increase in ventricular volume with donanemab than with placebo are paradoxical and need further investigation,” the scientists wrote.

Donanemab-treated patients experienced significantly more “amyloid-related imaging abnormalities — edema” (ARIA-E, a type of brain swelling) — than control-group patients, 26.7% vs 0.8%. Of these, 6.1% were symptomatic, with most cases occurring within 12 weeks of starting treatment.

ARIA-E was severe enough in two patients to require hospitalization. Both had symptoms of confusion and one reported experiencing difficulties with self-expression. Symptoms resolved for both people over a mean of 18 weeks.

Other common side effects in the donanemab group included evidence of small brain bleeds (7.6% of patients), a buildup of iron-storage complexes called siderosis in the brain and spinal cord (13.7%), nausea (10.7%), and infusion-related reactions, which were higher in the donanemab group (7.6%). All these reactions were more common among donanemab-treated patients than those given placebo.

Serious infusion-related reactions or hypersensitivity were found in three patients (2.3%), all on donanemab.

Seven (5.3%) in this group stopped treatment, including two (1.5%) patients due to ARIA-E  events. Individuals who discontinued donanemab use were allowed to stay in the study.

Overall, trial findings showed that donanemab “modestly” lessened cognitive and functional decline, the researchers concluded.  Longer trials in a larger patient groups are needed to evaluate the antibody’s safety and efficacy in people with early Alzheimer’s.

“I’m particularly encouraged by the significant plaque lowering and the slowing of clinical decline with donanemab,” said Stephen Salloway, MD, another trial investigator. “The donanemab results are a significant and encouraging milestone for people impacted by Alzheimer’s disease and we are eager to continue on in this fight.”