Donanemab Shows Promising Results in Slowing Cognitive Decline in Alzheimer’s Disease

Introduction

Eli Lilly recently presented the full results from their Phase 3 TRAILBLAZER-ALZ 2 study at the Alzheimer’s Association International Conference (AAIC). The study focused on evaluating the effectiveness of donanemab, a potential treatment for early symptomatic Alzheimer’s disease (AD). The results, also published in the Journal of the American Medical Association (JAMA), demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid-positive AD patients. These findings bring hope to individuals living with Alzheimer’s disease, indicating a potential breakthrough in disease-modifying therapies.

Positive Results from Phase 3 Trial: The Phase 3 study, TRAILBLAZER-ALZ 2, examined the impact of donanemab on cognitive and functional decline in early symptomatic AD patients. The study involved a diverse group of participants, encompassing a broader range of cognitive scores and amyloid levels compared to previous trials of amyloid plaque-targeting therapies. The participants were stratified based on their level of tau, a biomarker associated with disease progression.

The study’s primary and secondary endpoints were met, indicating that donanemab successfully slowed cognitive decline. Among all participants with amyloid-positive early symptomatic AD, donanemab treatment led to a 22% reduction in decline on the integrated Alzheimer’s Disease Rating Scale (iADRS) and a 29% reduction on the Clinical Dementia Rating-Sum of Boxes (CDR-SB). These results were even more pronounced in participants at the earliest stage of the disease, with a 60% slowing of decline compared to the placebo group.

Significance for Early Treatment

The study’s findings highlight the importance of early detection and treatment for Alzheimer’s disease. At an earlier stage of the disease, participants experienced greater benefits from donanemab, emphasizing the potential of diagnosing and treating individuals sooner in the disease course. The delay in disease progression observed in the trial gives patients more time to engage in meaningful activities and maintain their quality of life.

Limited Duration Dosing and Treatment Effect

Another noteworthy finding from the trial is that the treatment effect of donanemab continued to increase relative to the placebo over the course of the study, even after participants completed their 6- or 12-month therapy. This observation supports the concept of limited duration dosing, indicating that donanemab may offer long-lasting benefits with a shorter treatment duration. The progressive increase in treatment effect suggests the potential for sustained improvement in cognitive and functional outcomes for patients.

Amyloid Plaque Clearance and Safety Profile: Donanemab specifically targets deposited amyloid plaque, and the study demonstrated that treatment with the drug significantly reduced plaque levels. Participants receiving donanemab experienced an average reduction of 84% in amyloid plaque at 18 months, compared to a 1% decrease in the placebo group. Importantly, participants who achieved pre-defined criteria for plaque clearance could discontinue donanemab.

Regarding safety, the trial reported adverse events consistent with previous studies. The occurrence of amyloid-related imaging abnormalities (ARIA) and infusion-related reactions was observed, as seen with other amyloid plaque-clearing antibody therapies. ARIA, which can manifest as temporary brain swelling or microhemorrhages, was managed through careful monitoring and appropriate actions. Infusion-related reactions were also observed but were generally manageable.

Regulatory Status and Future Outlook

Eli Lilly completed the submission to the U.S. Food and Drug Administration (FDA) for traditional approval of donanemab in Q2. Regulatory action is expected by the end of the year. Simultaneous submissions to other global regulators are currently underway, with the majority anticipated to be completed by year-end. If approved, donanemab has the potential to provide a much-needed treatment option for people with early symptomatic Alzheimer’s disease.

Conclusion

The Phase 3 TRAILBLAZER-ALZ 2 study demonstrated that donanemab significantly slowed cognitive and functional decline in early symptomatic Alzheimer’s disease patients. The findings offer hope to individuals living with this devastating disease and represent a significant advancement in developing disease-modifying therapies. Early treatment with donanemab resulted in even greater benefits, emphasizing the importance of timely diagnosis and intervention. The results also support the potential for limited duration dosing and sustained treatment effects. As regulatory submissions are underway, the approval of donanemab may pave the way for improved outcomes and a better quality of life for individuals affected by Alzheimer’s disease.