Brighter Tomorrows: Donanemab’s Role in Elevating Patient and Clinician Outcomes

• Donanemab, with improved safety, efficacy, convenient dosing regime, and most importantly its ability to not only prevent but also clear plaques has the potential to redefine the treatment regime for Alzheimer’s patients.
• With a comparable safety profile, Eli Lilly delivers on even the most basic outcomes essential for individuals with Alzheimer’s disease, offering hope for improved quality of life and independence.

Eli Lilly’s donanemab, a frontrunner applicant for Alzheimer’s disease, recognizes and eliminates excess aberrant Amyloid-β (Aβ) proteins thus not only preventing the deposition of new plaques but also clearing the existing plaques, unlike any approved anti-amyloid therapies, by targeting pyroglutamate forms of Aβ.

At the ongoing, American Academy of Neurology Annual Meeting (2024), in Denver, Eli Lilly presented analysis from the TRAILBLAZER-ALZ 2 (NCT04437511) Phase III study, to understand the clinical relevance of donanemab treatment, and to characterize amyloid-related imaging abnormalities (ARIA) risks associated with donanemab. The objective was to understand the impact of donanemab on readily interpretable outcomes that matter to patients, loved ones, and clinicians, and understand the risks associated, thereby understanding donanemab’s strong efficacy in the context of safety.

TRAILBLAZER-ALZ2 is a randomized, placebo-controlled, phase III study that evaluated donanemab for mild cognitive impairment or mild dementia due to Alzheimer’s. The study enrolled 1736 participants, of which 1182 had low/medium tau pathology and 552 had high tau pathology. Mixed model repeated measures and Cox proportional hazard modeling methodology, assessed treatment effects on an individual’s iADRS cognition and function items, CDR domains, and risk of advancing to greater disease severity.  

The treatment was associated with significant beneficial effects on iADRS cognitive items related to episodic memory, executive function, and instrumental activities of daily living related to communication, etc. Donanemab slowed cognitive and functional decline, in the low/medium tau population by 35% as measured by the iADRS score, and by 36% on the CDR-SB, at 18 months. Nearly 39% experienced a lower risk of progressing to the next clinical stage of disease as measured by Clinical Dementia Rating-Global Score (CDR-GS) compared to placebo. The cognitive and functional decline for the combined (low/medium and high) tau population, compared to placebo, based on iADRS and CDR-SB, was 22% and 29%, respectively, with a 37.4% lower risk of progression to the next stage.

Further, at 18 months, participants in the low or medium tau population experienced a 40% less decline in the ability to perform activities of daily living as measured by Alzheimer’s Disease Cooperative Study—Instrumental Activities of Daily Living (ADCS-iADL and 32% less decline in cognitive abilities measured by Alzheimer’s Disease Assessment Scale-Cognitive 13 (ADAS-Cog₁₃). The results demonstrated a slowing decline of memory, orientation, judgment, and problem-solving parameters, including word recall, recognition, orientation, etc. Essential activities like writing, speaking, making a meal, and other everyday communication were all significantly improved.  

As per these results, Donanemab not only slowed cognitive and functional decline and lowered the risk of progression to more severe stages in early symptomatic Alzheimer’s disease, but also delivered outcomes valued by patients and their care partners, thus corroborating the idea that donanemab slows decline and yields significant improvements for patients.

ARIA Insights from the Donanemab Trials

Amyloid-related imaging abnormalities (ARIA) are an important safety concern associated with the novel amyloid-targeting therapies. Identifying patient characteristics, comorbidities, concomitant medications, and modifiable factors potentially contributing to ARIA risk is paramount. In a posthoc exploratory analysis, using hypothesis-generating penalized regression and decision tree-based models, Eli Lilly identified variables associated with ARIA−edema and effusions (ARIA-E).

As per the assessment, in the TRAILBLAZER trials (NCT03367403 and NCT04437511), ARIA-E occurred in 27.5% and 24.0%, respectively. These events were transient and asymptomatic. Various factors like APOE ε4/ε4 genetic presence, number of microhemorrhages, presence of cortical superficial siderosis, mean arterial pressure and amyloid burden were directly associated with ARIA-E frequency, while antihypertensive medication use dampened the frequency.

All was sunshine and rainbows for Donanemab, but recently, the US FDA delayed its regulatory decision on Eli Lilly’s donanemab, citing the need for further review to establish its safety and efficacy. This FDA’s delay though raises concerns, but there remains optimism about donanemab’s potential to offer meaningful benefits to people with early symptomatic Alzheimer’s disease, hopes are high and it’s just a matter of time.