Skip to main content
Premium Trial:

Request an Annual Quote

Eli Lilly's Anti-Amyloid Drug Donanemab Slows Decline for Early Alzheimer's in Phase III Trial

3D illustration showing amyloid plaques in Alzheimer's disease

NEW YORK – Eli Lilly's anti-amyloid candidate for Alzheimer's disease, donanemab, significantly slowed cognitive and functional decline for patients with mild cognitive impairment and mild dementia, according to full Phase III study results the company presented Monday at the Alzheimer's Association International Conference in Amsterdam.

Lilly on Monday also said it completed its regulatory submission to the US Food and Drug Administration, through which it is seeking traditional approval, in the second quarter. The FDA previously rejected Lilly's bid for accelerated approval, determining that the firm's Phase II trial didn't have enough data from patients who had been taking donanemab for at least 12 months.

Lilly expects the FDA to issue a decision on donanemab by year-end.

For the Phase III study, dubbed TRAILBLAZER-ALZ 2, investigators enrolled more than 1,700 patients in eight countries with early symptomatic Alzheimer's and evidence of amyloid pathology, a hallmark sign of disease in which amyloid-beta builds up in the brain and which many say kicks off a cascade of issues that leads to neurodegeneration.

Study participants were stratified by their level of tau, another protein that accumulates in the brain and has been linked with neurodegeneration, into either a low-medium tau group or high tau group and randomized to either a treatment arm that received the monoclonal antibody, which targets amyloid-beta, or a placebo arm. Participants were administered the drug or placebo intravenously every four weeks.

All participants were tracked for 18 months using the integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

For patients treated with donanemab, the drug significantly slowed decline by 22 percent on iADRS and 29 percent on CDR-SB compared to those on placebo, said John Sims, Lilly’s global brand development leader and senior medical director of neurodegeneration, during a presentation Monday. Sims was the first author on a paper detailing results of the study, which was simultaneously published in the Journal of the American Medical Association on Monday.

Donanemab also significantly reduced various biomarkers of disease with 76 percent of patients reaching amyloid-beta plaque clearance and a 35 percent decrease in plasma pTau-217 by the end of the trial.

Among patients in the low-medium tau group, treatment with donanemab significantly slowed decline by 35 percent on iADRS and 36 percent on CDR-SB, suggesting administering the drug earlier has a greater benefit. In a subgroup analysis of the low-medium tau group based on age, investigators found that participants under 75 years of age experienced a greater benefit.

For participants under the age of 75, donanemab slowed decline by 48 percent on iADRS and 45 percent on CDR-SB. In participants aged 75 or older, the treatment slowed decline by 25 percent on iADRS and 29 percent on CDR-SB.

"There's a general hint that moving earlier is favorable," Sims said. In an analysis of patients with low-medium tau with mild cognitive impairment, donanemab slowed decline by 60 percent on iADRS and 46 percent on CDR-SB compared to 30 percent on iADRS and 38 percent on CDR-SB for those with mild dementia, which is a slightly later stage of disease.

"Overall, this data holds some promise for studies in the preclinical stage of the disease," Sims added. Lilly is already in the midst of TRAILBLAZER-ALZ 3, a clinical trial studying donanemab in preventing symptomatic Alzheimer's in patients with preclinical signs of the disease based on evidence of amyloid and early tau pathology.

Within the TRAILBLAZER-ALZ 2 Phase III study, treatment effect for patients on donanemab compared to the placebo group also continued to grow through the trial's 18 months, despite roughly half of participants completing their course of therapy by 12 months. Patients ended donanemab therapy after achieving a predefined level of amyloid plaque clearance, at which point they switched to receiving placebo for the rest of the study.

Nearly 90 percent of patients in the donanemab group experienced a treatment-emergent adverse event compared to 82.2 percent of the placebo group. The treatment-emergent adverse events that occurred more frequently in the treatment group included amyloid-related imaging abnormalities (ARIA), infusion-related reactions, and headaches.

Roughly three-quarters of ARIA cases were asymptomatic, according to Stephen Salloway, a professor of neurology at the Warren Alpert Medical School of Brown University and a coauthor on the paper in JAMA. The rate of ARIA was higher in patients who carried two copies of the APOE ε4 allele, mirroring results of other anti-amyloid programs, he said.

Eisai and Biogen's Leqembi (lecanemab), the only anti-amyloid treatment for Alzheimer's that's received full FDA approval, carries a boxed warning about the risk of ARIA and recommends testing patients to assess if they carry two copies of the APOE ε4 allele before starting treatment, since homozygous carriers have a higher risk of ARIA.

"The most common side effect, ARIA-E, was typically transient and asymptomatic, but serious and even fatal cases can occur," Salloway said during the presentation Monday. There were three participant deaths determined to be related to the treatment, all of whom had serious ARIA. "Careful safety monitoring is required to limit serious outcomes."