In July 2023, data on the results of the donanemab study (Trailblazer-Alz 2) were published. The study design differed slightly from the other antibody studies [10].

Donanemab is a monoclonal immunoglobulin G1 antibody directed against an N‑terminal pyroglutamate epitope present in mature Aβ plaques. Trailblazer-Alz 2 was a 76-week, multicenter, randomized, double-blind, placebo-controlled phase 3 study. The study was originally planned as a phase 2 study but was converted to a larger phase 3 study in February 2021 to confirm and expand on the results of the earlier Trailblazer-Alz study [11]. It included 1736 participants aged 60–85 years with early symptomatic Alzheimer’s disease (mild cognitive impairment or mild Alzheimer’s disease). Eligible participants were randomized in a 1:1 ratio to receive donanemab or placebo and the substance was administered intravenously every four weeks. Eligible participants had mini-mental state examination (MMSE) screening scores ranging from 20 to 28, amyloid pathology (≥ 37 centiloids) assessed by 18F-florbetapir13 or 18F-florbetaben14 positron emission tomography (PET), and tau pathology assessed through 18F-flortaucipir PET imaging with centralized image interpretation. Centiloids are a unit of measurement for the amyloid burden in the brain of Alzheimer’s patients, with a value below 30 considered negative or normal.

Before randomization patients were divided into groups with low/medium tau burden (68.1% of participants) or high tau burden (31.8%) based on baseline tau PET values. If the amyloid plaque concentration (measured after 24 and 52 weeks) on a single amyloid PET scan was less than 11 centiloids or less than 25 but greater than or equal to 11 centiloids on two consecutive PET scans, donanemab was switched blindly to placebo.

Unlike other studies, the primary endpoint was the integrated Alzheimer’s disease rating scale (iADRS). The iADRS is an integrated assessment of cognitive abilities and daily functioning based on the 13-item cognitive subscale of the Alzheimer disease assessment scale (ADAS-Cog13) and the Alzheimer disease cooperative study-instrumental activities of daily living (ADCS-iADL). It measures the severity of Alzheimer’s disease in a single summary score. Possible scores on the iADRS range from 0 to 144 (lower scores indicate greater impairment). In the low-medium tau population, the change in iADRS score from baseline after 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 1.88–4.62; P < 0.001), corresponding to a 35.1% slowing of disease progression. In the overall population (low-medium tau population + high tau population), the change in iADRS score from baseline after 76 weeks was −10.19 (95% CI −11.22 to −9.16) in the donanemab group and −13.11 (95% CI −14.10 to −12.13) in the placebo group (difference, 2.92, 95% CI 1.51–4.33; P < 0.001), corresponding to a 22.3% slowing of disease progression in the verum group versus placebo. For the CDR-SB in the low-medium tau population, the difference of the change between the treatment groups after 76 weeks was −0.67 (95% CI, −0.95 to −0.40), indicating 36.0% slowing of clinical progression. In the combined population, the differences in CDR-SB between the donanemab and placebo groups were −0.70 (95% CI −0.95 to −0.45), indicating a 28.9% slowing of clinical progression. Similar treatment benefits were seen for all secondary clinical endpoints, with low-middle tau patients generally showing larger effect sizes than those in the overall population. This result is in line with the view that treatment in earlier disease stages is more efficient as compared to treatment at more advanced stages of Alzheimer’s disease. After 76 weeks disease progression was delayed by 4.4 months on the iADRS and by 7.5 months on the CDR-SB in the low-moderate tau group under donanemab treatment. The percentages of participants treated with donanemab who achieved amyloid clearance to a normal level at 76 weeks was 80.1% in the low-medium tau population and 76.4% in the combined population. The effects of treatment on biomarkers of Alzheimer’s disease downstream of Aβ were variable. Donanemab led to a significant reduction in plasma P‑tau217 concentrations, a marker of Aβ-mediated tau phosphorylation and secretion; however, no effect was observed on longitudinal tau PET in the frontal cortex region.

During the Trailblazer-Alz 2 study, 3 participants in the donanemab group died with severe ARIA (2 heterozygous APOE ε4 carriers and one non-carrier; none were prescribed anticoagulants or antiplatelet agents; one participant resumed treatment after resolution of severe ARIA‑E and severe ARIA‑H, and one participant had superficial siderosis at baseline). The ARIA‑E occurred in 24.0% of the donanemab group, with most being mild to moderate; 6.1% experienced symptomatic ARIA‑E, a detailed description is shown in Table 1. Most cases of first ARIA‑E (57.9%) occurred after approximately 3 donanemab infusions. The ARIA‑E was numerically less frequent in APOE ε4 non-carriers compared to carriers, with a higher frequency in homozygotes (40.6%) than in heterozygotes (22.8%), compared to APOE ε4 non-carriers (15.7%). The occurrence of any serious adverse event due to ARIA (E or H) was 0.5–1.5%. Infusion-related reactions were reported in 8.7% of participants in the donanemab group.

The design of Trailblazer-Alz 2 included two innovative aspects that could impact patient care. Firstly, the amyloid plaque burden was assessed by PET at 24 and 52 weeks, and patients who met predefined discontinuation thresholds in PET were switched from donanemab to placebo, which occurred in 52% of patients in the treatment group. Considering the high patient burden and expected costs of Aβ-directed monoclonal antibodies, a limited treatment duration could significantly improve the feasibility of the treatment. Secondly, patients were stratified based on the baseline tau PET, with patients in the low-medium tau group benefiting more, while patients in the high tau group showed little to no clinical benefit compared to placebo. These results suggest that in addition to clinical criteria and Aβ biomarker positivity, the classification of tau may be critical in identifying patients who would benefit the most; however, the implementation of these techniques in clinical practice will be challenging given the limited access to Aβ-PET and especially tau-PET. Further research is needed to determine whether blood-based biomarkers could replace expensive PET scans in measuring biomarker treatment response and in predicting clinical response in the future.

In July 2024 donanemab received full FDA approval. An application for approval was also put forward to the EMA, the final decision is currently pending and is expected in 2025.