A modified titration protocol for donanemab, an anti-amyloid antibody, significantly reduces the risk of ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) in patients with Alzheimer's disease, according to data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference. The adjusted dosing regimen involves a gradual increase in donanemab dosage over the first four months, leading to a 40% reduction in ARIA-E rates. This change is poised to enhance the safety profile of donanemab, particularly for individuals with the APOE4 gene, while sustaining its efficacy in amyloid plaque removal.
Stepwise Titration Results in Safety Gains
The Phase 3 Trailblazer-Alz2 trial revealed that approximately 25% of participants treated with donanemab experienced ARIA-E, with a subset exhibiting symptoms like headaches or confusion. APOE4 homozygotes faced the highest risk, with 40% developing edema. To mitigate these risks, Eli Lilly conducted the Trailblazer-Alz6 trial, randomizing 843 participants into four dosing arms to test different titration schemes.
The stepwise titration strategy, involving doses of 350, 700, and 1,050 mg in the first three months, reduced the overall ARIA-E rate to 14%, compared to 24% with the standard protocol. This rate is similar to the 12% ARIA-E rate reported for lecanemab. Notably, in APOE4 homozygotes, the stepwise protocol slashed the ARIA rate from 57% to 19%, aligning it with the risk levels observed in heterozygotes and noncarriers.
Impact on ARIA Severity and Other Adverse Events
Furthermore, the stepwise titration not only reduced the incidence of ARIA-E but also its severity. Symptomatic ARIA-E occurred in 3% of participants on the stepwise titration, compared to 5% on the standard protocol. The majority (over 85%) of ARIA-E cases were rated mild on MRI, with no severe cases reported. The rate of concurrent ARIA-E and -H (microhemorrhages) also decreased from 16% to 10%, and rates of superficial siderosis halved from 13% to 7%.
New Appropriate Use Recommendations for Donanemab
In conjunction with the modified titration data, updated appropriate use recommendations (AUR) for donanemab have been issued. These recommendations emphasize more stringent MRI criteria to exclude patients at higher risk for ARIA. Specifically, the AUR advise against treating patients with even one area of superficial siderosis at baseline, a stricter stance compared to the Phase 3 trial, which allowed one such area. The AUR also suggest caution in treating patients on anticoagulants, pending further data.
Balancing Safety and Efficacy
The donanemab AUR address two unique aspects of this drug: the use of baseline tau PET scans to determine eligibility in its Phase 3 trial, and stopping dosing after a given person’s brain amyloid load had dropped below a preset threshold. For clinical practice, the AUR do not recommend tau PET. They do note that, if a scan is available, it can be used to estimate the benefit a person might experience from treatment. Regarding how long to treat, the AUR suggest clinicians consider stopping donanemab based on a visually negative amyloid PET scan taken after 12 to 18 months of infusions.
While some experts advocate for strict adherence to the AUR to prioritize patient safety, others argue for more flexibility, emphasizing patient autonomy and individual risk assessment. As real-world data accumulates, the optimal balance between safety and efficacy will continue to be refined, guiding clinicians in the use of anti-amyloid antibodies like donanemab.
