Modified Titration Dosing Reduces ARIA-E Risk With Donanemab, A Discussion With John Sims, MD

John Sims, MD, discussed data presented on donanemab (Kisunla), an antiamyloid therapy for early symptomatic Alzheimer disease, highlighting a modified titration dosing strategy designed to reduce amyloid-related imaging abnormalities with edema/effusion (ARIA-E) while preserving amyloid-lowering efficacy. In the TRAILBLAZER-ALZ 6 study, modified titration dosing significantly lowered ARIA-E frequency and radiographic severity compared with standard dosing, including among apolipoprotein E (APOE) ε4 carriers, without compromising amyloid or plasma P-tau217 reduction.¹ Long-term extension data demonstrated that clinical benefit continued to grow over 3 years relative to an external cohort, with reductions in plasma P-tau217 and glial fibrillary acidic protein reflecting sustained amyloid clearance even after treatment completion.² Sims emphasized that these findings support limited-duration, treat-to-target dosing and reinforce the clinical importance of early intervention in patients with confirmed amyloid pathology.

Psychiatric Times: Could you share an overview and clinical highlights from the latest presentation on donanemab at AAIC?

John Sims, MD: Our symposia presentations focused on answering some of the most practical questions clinicians have as they begin incorporating donanemab into clinical practice. Rather than simply presenting individual datasets, they demonstrated how several complementary studies collectively strengthen our understanding of how to optimize treatment, improve monitoring, manage adverse events, and better characterize long-term outcomes. Together, these findings reinforced the established efficacy of donanemab while providing evidence that may inform clinicians as they incorporate treatment in everyday practice.

For example, modified titration dosing of donanemab significantly reduced the frequency and radiographic severity of ARIA-E without compromising amyloid reduction, with lower frequency of ARIA-E across APOE e4 carrier groups. We also saw that an abbreviated, ultra-rapid MRI protocol can reduce scan times without loss of diagnostic value. It may also increase access to MRI and reduce monitoring burden for patients and healthcare systems.

Also, steroid pretreatment did not compromise the amyloid lowering efficacy of the modified titration donanemab regimen and may be appropriate for management of IRRs when they occur. However, routine use is not recommended at this time.

Importantly, long-term extension (LTE) data demonstrated continued benefit of donanemab over 3 years with increasing clinical efficacy compared to an external ADNI cohort and reduction of plasma biomarkers P-tau217 and GFAP reflecting rapid amyloid clearance. Both clinical and biomarker outcomes from the LTE support limited duration, treat-to-target dosing with sustained benefits and reinforce the importance of early intervention in symptomatic patients with confirmed amyloid pathology.

This was reflected in the biomarker data as well: long-term changes in plasma biomarkers reinforce the rapid amyloid lowering of donanemab.

Moving forward, an ongoing study looking at a single donanemab dose one year after treatment completion will provide safety and biomarker data to inform shared clinical decision making.

PT: For the practicing clinicians in psychiatry, which aspects of the presentation would you highlight as most relevant?

Sims: For psychiatrists and other clinicians caring for patients with Alzheimer disease, the most relevant findings are those that help inform real-world treatment discussions. These data provide additional evidence to inform conversations about treatment benefits, safety, monitoring requirements, and what patients can expect over time.

Key aspects include:

• Improved benefit/risk conversations: A modified titration regimen significantly reduced ARIA-E frequency (15.6% vs. 24.2%) and severity versus standard dosing, without compromising amyloid or plasma P-tau217 reduction, which could be useful for patient conversations around holistic risk/benefit analysis.
• Durability after stopping treatment: In long-term extension data, clinical benefit continued to grow over 3 years compared to an external control cohort, including in patients who completed treatment by 52 weeks and remained off drug. This could relate to the "what happens after treatment ends?" question patients and families may ask.
• Manageable infusion reactions: Steroid pretreatment did not compromise amyloid reduction with donanemab. While these data do not support routine steroid pretreatment as standard practice, they may inform clinician decision-making around infusion-related reactions when they occur.

PT: Were there findings in these studies that were unexpected or surprising?

Sims: I would characterize the findings as reassuring. Many of the results confirmed what we hoped to see, mainly that the benefits observed in the original studies continue to hold up with additional follow-up and further analysis. Perhaps the most encouraging aspect overall is that the long-term extension data suggest treatment effects continue to separate (donanemab benefit continued to grow over 3 years compared to an external ADNI cohort, with delta, or changes in CDR-SB increasing from 0.6 at 18 months to 1.2 at 36 months) from the external comparison group over time, even after many participants had completed treatment, supporting the concept of limited-duration, treat-to-target therapy.

PT: What modifications were made to titration strategies in the study, and why was it important to address?

Sims: Optimizing titration is important because it directly addresses one of the primary concerns clinicians have when prescribing amyloid-targeting therapy: balancing efficacy with safety. The modified titration strategy was designed to reduce ARIA-E while preserving the amyloid-lowering effect of donanemab. These findings have also supported updates to recommended dosing in the labels of the majority of countries where donanemab is approved, including the United States.

Most notably, the initial TRAILBLAZER-ALZ 6 study showed that over 76 weeks, compared to standard dosing, donanemab modified titration dosing is associated with significantly lower frequency of ARIA-E (15.6% vs 24.2%), lower symptomatic ARIA-E (2.8% vs 4.8%), significantly lower frequency of ARIA-E across APOE ε4 carrier groups, and significantly lower ARIA-E radiographic severity. Following the modified titration phase, continued treatment with 1400mg administered monthly until they met amyloid-based treatment completion criteria.

As part of this presentation, Lilly shared trial design for an addendum to the TRAILBLAZER-ALZ 6 study which will deliver biomarker and safety data to help understand the ability of a single donanemab dose administered one year after treatment completion to maintain AD biomarkers, such as amyloid plaque, below clearance threshold levels.

Lilly also presented data on corticosteroid pretreatment with modified titration of donanemab which confirmed that corticosteroid pretreatment did not compromise the amyloid lowering efficacy of modified titration donanemab and may be appropriate for management of IRRs when they occur.

PT: What were the outcomes of the rapid MRI protocol? How might these results impact future clinical practice?

Sims: The rapid MRI findings have the potential to address an important practical barrier to treatment. Demonstrating that scan times can be substantially shortened without sacrificing diagnostic performance suggests MRI monitoring could become more efficient and accessible. If these findings are validated more broadly, they could reduce the burden on patients, caregivers, imaging centers, and health systems while maintaining the safety monitoring that remains essential for amyloid-targeting therapies.

PT: What do you hope the future of donanemab (titration strategies or general research) looks like?

Sims: Looking ahead, I hope we continue to generate evidence that makes Alzheimer treatment more effective, more accessible, and easier to integrate into routine clinical care.

We are at a pivotal moment in AD, but scientific innovation alone is not enough. We must ensure health systems are ready to diagnose symptomatic patients earlier and harness innovations so that scientific progress reaches patients.

Ultimately, I hope that in the future, Alzheimer disease care will be more comprehensive. Screening and diagnosis for symptomatic patients should start earlier and more proactively than it does now and engage a multidisciplinary team that involves not just the patient and the patient's physician but also loved ones and other individuals who can support the patient.

Dr Sims is senior medical director at Eli Lilly.

References

1. Wang H, Nery ESM, Ardayfio P, et al. The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6. J Prev Alzheimers Dis. 2025;12(8):100266.

2. Zimmer JA, Sims JR, Evans CD, et al. Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension. J Prev Alzheimers Dis. 2025;13(2):100446.