Phase 3 trial shows efficacy of donanemab for Alzheimer disease
In an industry-funded, placebo-controlled trial of patients with early symptomatic Alzheimer disease and amyloid and tau pathology, patients on the investigational drug donanemab showed significant slowing in worsening on the integrated Alzheimer Disease Rating Scale score.
Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab treatment significantly slowed clinical progression at 76 weeks, an industry-funded study found.
To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque, researchers conducted a phase 3 trial at 277 medical research centers/hospitals in eight countries over 18 months. The trial enrolled 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. The drugmaker funded and conducted the study.
The researchers randomized patients to receive donanemab (n=860) or placebo (n=876) by IV every four weeks for 72 weeks. Participants in the donanemab group were switched to placebo if dose completion criteria were met. The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0 to 144, with lower scores indicating greater impairment). There were 24 gated outcomes including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0 to 18, with higher scores indicating greater impairment). Results were published July 17 by JAMA.
Of 1,736 patients (68.1% with low/medium tau pathology and 31.8% with high tau pathology), 76% completed the trial. In the low/medium tau group, 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 to 4.62]; P<0.001). In the patient population overall, it was −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 to 4.33]; P<0.001).
LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00 to 1.41) with donanemab and 1.88 (95% CI, 1.68 to 2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P<0.001) in the low/medium tau group and 1.72 (95% CI, 1.53 to 1.91) with donanemab and 2.42 (95% CI, 2.24 to 2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P<0.001) in the overall 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 the study) in the placebo group. Seventy-four participants in the donanemab group and four in the placebo group had infusion-related reactions (8.7% vs.0.5%). Three deaths in the donanemab group and one in the placebo group were considered to be related to treatment.
The study authors concluded that donanemab significantly slowed clinical progression at 76 weeks in patients with low/medium tau and in the combined low/medium and high tau population.
A series of four editorials accompanied the study. The first noted a lack of racial diversity in participants despite recruitment efforts, as well as the fact that minority patients are typically diagnosed later in their Alzheimer disease progression. The second editorial stated that the benefits and limitations of treating early-stage Alzheimer disease with Aβ-targeting monoclonal antibodies are coming into focus and that a combination of drugs targeting additional molecular pathways involved in Alzheimer disease pathophysiology will be needed.
A third editorial stated that donanemab's treatment protocol, in which therapy was stopped once amyloid plaques were cleared, improved its cost profile in clinical trials and could be key to making treatments for Alzheimer disease more affordable. The fourth editorial expanded on the issue of cost, noting that the modest benefits seen in the study would likely not be questioned by patients, clinicians, or payers if amyloid antibodies were low risk, inexpensive, and simple to administer. “Ultimately, new treatments such as donanemab will not only change the Alzheimer research landscape but also the clinical one. Accurate and timely diagnosis, thoughtful discussion on individualized risks and benefits, and an emphasis on chronic care management have never been more important,” it said.
Donanemab is on an accelerated FDA approval pathway and is expected to be considered sometime this year.