AAN 2023: Donanemab works better than Aduhelm in biomarker study
Therapy more effective in removing toxic clumps in brain in trial
Eli Lilly’s donanemab was found to work better than Aduhelm (aducanumab) in a biomarker study of people with early Alzheimer’s in removing disease-associated toxic protein clumps in the brain.
The experimental therapy outperformed the approved treatment, from Eisai and Biogen, in a Phase 3 clinical trial, according to new top-line results.
“This was the first study directly comparing two disease-modifying medications [for Alzheimer’s],” said Stephen Salloway, MD, of the Alpert Medical School of Brown University, who discussed the findings at last week’s American Academy of Neurology (AAN) Annual Meeting, held in Boston and virtually.
His presentation was titled, “TRAILBLAZER-ALZ 4: Topline study results directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease.” The work was funded by Eli Lilly.
First head-to-head testing of disease-modifying therapies
Alzheimer’s is marked by the formation of aggregates, or clumps, of amyloid-beta protein in the brain. Donanemab and Aduhelm are both antibody-based therapies designed to slow disease progression by breaking down these toxic protein clumps.
Based on early clinical data showing Aduhelm could clear amyloid plaques as designed, the U.S. Food and Drug Administration (FDA) in 2021 granted accelerated approval of the therapy for Alzheimer’s patients. Accelerated approval allows a treatment to be approved based on early clinical evidence that it’s likely to be effective, with a requirement that developers conduct additional testing to confirm its efficacy.
Another amyloid-targeting therapy, Leqembi (lecanemab), was granted accelerated approval by the FDA earlier this year, and is now up for traditional approval. Like Aduhelm, Leqembi was developed by Eisai and Biogen.
Shortly after granting accelerated approval to Leqembi, the FDA rejected an application that sought accelerated approval for donanemab. The regulatory agency said in that decision that available long-term clinical trial data for the therapy covered too few patients.
Lilly is now sponsoring a Phase 3 trial called TRAILBLAZER-ALZ 2 (NCT04437511) to further assess the efficacy and safety of donanemab against a placebo in Alzheimer’s patients.
The company also is conducting another Phase 3 trial called TRAILBLAZER-ALZ 4 (NCT05108922) that is comparing the effects of donanemab against Aduhelm in patients with early Alzheimer’s. The AAN presentation by Salloway covered the top-line results from this trial.
In the study, 71 people with early Alzheimer’s were treated with donanemab, given via into-the-vein (intravenous) infusion every four weeks, or about once per month. The initial dose was 700 mg for the first three infusions and 1,400 mg thereafter. Another 69 patients were treated with Aduhelm, given according to the therapy’s approved dosing schedule.
Salloway highlighted that, with the approved dosing schedule, patients on Aduhelm don’t start receiving the highest dose of the therapy until after about six months of treatment. In this analysis, results were compared between the donanemab and Aduhelm groups after 24 weeks, which is about six months — so by definition, patients on Aduhelm were not on the highest dose for most of the studied period.
The results showed that, after six months of treatment, the percentage of amyloid clearance was significantly higher in patients given donanemab compared with those on Aduhelm (65.2% vs. 17%).
There’s some important questions, I think, for the field to answer, and this provides some initial information.
More than 1 in 3 patients (37.9%) on donanemab had such a substantial decrease in amyloid levels on imaging tests that they no longer met the diagnostic cutoff to be considered positive for these disease-associated plaques. By contrast, just 1.6% of those on Aduhelm reached this cutoff.
Donanemab also outperformed Aduhelm at lowering the levels of the disease biomarker P-tau 217 in patients’ blood. Results were comparable in a subset of patients who had lower levels of the Alzheimer’s-related protein tau on imaging tests.
Safety data comparable for donanemab, Aduhelm
Amyloid-targeting therapies like Aduhelm and donanemab are known to cause a form of brain swelling, known as ARIA-E. Safety data showed that ARIA-E rates were comparable between the two therapies, with the events occurring in about one out of every five patients in both groups.
“Even though the amyloid lowering is greater for donanemab, there wasn’t a difference in the ARIA rate,” Salloway said.
With both therapies, ARIA was more common in patients carrying an Alzheimer’s-associated genetic risk variant called APOE4. ARIA also tended to be more common among donanemab patients early on, whereas patients on Aduhelm usually didn’t develop this side effect until much later on. Salloway said this likely was attributable to the difference in dosing schedules.
Infusion reactions were rare in both groups, but were more common with donanemab (7% vs. 2.9%). None of these infusion reactions were serious, and there were no deaths due to treatment side effects reported in the study.
The TRAILBLAZER-ALZ 4 trial is ongoing, and future data from the study may provide more insight about the effect of donanemab versus Aduhelm after longer periods of treatment.
“There’s some important questions, I think, for the field to answer, and this provides some initial information,” Salloway said.
“I don’t think this is a definitive study, but it’s certainly informative about how much amyloid lowering is needed to produce a clinical benefit. How quickly should that amyloid lowering take place? Does it matter? Obviously time matters in Alzheimer’s disease as with any chronic disease — but how important is it for the clinical benefit? How safe is it to lower the amyloid quickly versus more slowly?” Salloway said.