Donanemab demonstrates mixed results for early Alzheimer’s disease, requires further study

Donanemab, an investigational antibody that targets a modified form of beta amyloid, yielded “modestly less” cognitive and functional decline than placebo among patients with early symptomatic Alzheimer’s disease in a phase 2 trial.

However, the agent failed to slow disease progression by half — “an assumption on which the power calculation was based,” according to the researchers — and the study results demonstrated that treatment with donanemab led to amyloid-related imaging abnormalities.

“Donanemab is a humanized IgG1 antibody directed at an N-terminal pyroglutamate [amyloid-beta] epitope that is present only in established plaques,” Mark A. Mintun, MD, and colleagues wrote. “We conducted a phase 2 trial to evaluate the safety and efficacy of donanemab in patients with early symptomatic Alzheimer’s disease.”

Mintun, the vice president of pain and neurodegeneration research and clinical development at Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly & Company, and colleagues enrolled patients with early symptomatic AD who had evidence of tau and amyloid deposition on PET scans in the TRAILBLAZER-ALZ trial. They randomly assigned patients 1:1 to treatment with donanemab (700 mg for the first 3 doses and 1,400 mg thereafter) or placebo IV every 4 weeks for up to 72 weeks.

Change from baseline to 76 weeks in the Integrated AD Rating Scale (iADRS) score, with a range of 0 to 144 where lower scores signify a higher degree of cognitive and functional impairment, served as the primary outcome. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog₁₃), the AD Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL) and the Mini–Mental State Examination (MMSE), as well as changes in amyloid and tau burden on PET scans.

The researchers enrolled 257 patients aged 60 to 85 years in the trial, with 131 assigned to the donanemab group and 126 to the placebo group. They reported similar baseline characteristics between groups regarding mean age (75 years in the donanemab group vs. 75.4 years in the placebo group), sex (women, 51.9% vs. 51.6%, respectively), race (white, 93.1% vs. 96%, respectively) and APOE e4 carrier status (72.5% vs. 74.2%, respectively), as well as a baseline iADRS score of 106 in both groups.

Mintun and colleagues observed a change from baseline in the iADRS score at 76 weeks of 6.86 among patients receiving donanemab and 10.06 among patients receiving placebo (difference, 3.2; 95% CI, 0.12 to 6.27), with a smaller reduction representing less cognitive and functional decline, according to the study results. An analysis with a mixed model for reported measures (MMRM) showed that, at 76 weeks, the estimated percent change in the iADRS score in the donanemab group, compared with the placebo group, was similar to the Bayesian disease progression ratio over the entire 18-month period. According to this ratio, the posterior probability of at least 25% slower disease progression in the donanemab group than in the placebo group, as measured by the iADRS score, was calculated as 0.78.

Results regarding secondary outcomes were “mixed,” according to the researchers. They observed no significant difference in CDR-SB scores between the two groups, which prevented them from making “definite conclusions” about the differences in ADAS-Cog₁₃ scores. Mintun and colleagues saw no significant differences between the groups regarding ADCS-iADL and MMSE.

The percentage of patients in the donanemab group who achieved amyloid-negative status — defined as an amyloid plaque level of less than 24.1 centiloids — at 24, 52 and 76 weeks was 40.0%, 59.8%, and 67.8%, respectively, according to the study results. Further, approximately 27.4% and 54.7% of participants in the donanemab group had sufficient lowering of the amyloid plaque level to switch to placebo at 28 and 56 weeks, respectively. The researchers did not observe a substantial difference between groups regarding the difference from baseline to 76 weeks in global tau load as determined by flortaucipir PET or the change in hippocampal volume according to volumetric MRI. At 52 and 76 weeks, volumetric MRI demonstrated a greater decline in whole-brain volume and a greater increase in ventricular volume in patients receiving donanemab compared with patients receiving placebo.

The researchers reported no significant differences in rates of serious adverse events or deaths between the two groups. The rate of amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E) was significantly higher in the donanemab group vs. the placebo group (26.7% vs. 0.8%) and symptomatic ARIA-E was reported by 6.1% of patients in the donanemab group (22% of those with ARIA-E) compared with 0.8% of patients in the placebo group. Most cases of ARIA-E happened at or by week 12, according to the study results. Serious symptomatic ARIA-E resulting in hospitalization occurred in two participants (1.5%) in the donanemab group; both participants experienced symptoms of confusion and one noted trouble expressing herself. However, ARIA-E and related symptoms resolved in both participants, with a mean resolution time of 18 weeks.

“This randomized phase 2 trial showed that, in patients with early symptomatic [AD], treatment with donanemab resulted in modestly less cognitive and functional decline than placebo; however, slowing disease progression by half (an assumption on which the power calculation was based) was not achieved, and treatment resulted in amyloid-related imaging abnormalities,” the researchers wrote. “Longer and larger trials are required to study the efficacy and safety of donanemab in early Alzheimer’s disease. TRAILBLAZER-EXT, a follow-on study for those who participated in TRAILBLAZER-ALZ, is currently enrolling participants.”