Lilly Presents New Analyses Demonstrating Link Between Amyloid Plaque Reduction and Slowed Cognitive Decline with Donanemab in Early Alzheimer’s Disease

Recently, Eli Lilly and Company presented two latest exploratory analyses of its Alzheimer's disease (AD) antibody therapy donanemab from the Phase 2 TRAILBLAZER-ALZ clinical trial at the Alzheimer's Association International Conference (AAIC 2021). The first analysis demonstrated that the greater the reduction in amyloid deposition in patients following donanemab treatment, the slower the rate of cognitive decline. The second analysis revealed that donanemab also rapidly decreased plasma P-tau217 levels in patients, a biomarker reflecting AD pathology.

In AD drug development, amyloid-beta (Aβ) is one of the most extensively studied yet highly controversial targets. Although amyloid deposition in the brain is a hallmark feature of AD patients, the severity of deposition does not strongly correlate with the degree of cognitive decline. Moreover, numerous investigational therapies designed to clear amyloid deposits have failed to significantly improve cognitive decline across multiple clinical trials. This June, the U.S. FDA granted accelerated approval to Aduhelm (aducanumab), an antibody therapy developed by Biogen and Eisai, using the clearance of amyloid deposits as a surrogate endpoint. This decision has once again brought the relationship between amyloid levels and cognitive decline into sharp focus for researchers.

Eli Lilly's donanemab binds to specific Aβ subtypes within cerebral amyloid deposits, thereby accelerating the clearance of amyloid plaques. Previously announced Phase 2 clinical trial results showed that it can slow the rate of cognitive and activities of daily living decline in patients with early-stage Alzheimer's disease (AD).

▲ The rate of decline in the Integrated Alzheimer's Disease Rating Scale (iADRS) score was slower in AD patients treated with donanemab compared to the placebo group (Image source: Reference [2])

New data analysis presented by Eli Lilly at AAIC-2021 shows that in patients with early symptomatic Alzheimer's disease (AD), donanemab rapidly induces clearance of amyloid deposition, with the fastest clearance rate observed in patients with the highest baseline amyloid burden. This patient subgroup met the criteria for complete amyloid clearance by Week 24, enabling them to reduce their donanemab dose or discontinue donanemab earlier than other patients.

PET scans of these patients at week 76 revealed that tau spread across multiple brain regions was significantly lower than in the control group. Tau spread is a predictive biomarker for AD progression.

Furthermore, data analysis demonstrated that a greater reduction in amyloid levels at week 24 was associated with improvements in the iADRS score, which assesses cognitive and daily functioning. Pharmacokinetic and pharmacodynamic model analyses also indicated that a greater degree of relative amyloid clearance was associated with greater clinical benefit.

Another analysis focused on plasma P-tau217 levels, an investigational blood-based biomarker developed by Eli Lilly that is associated with amyloid and tau pathology, as well as AD diagnosis. A prespecified analysis found that treatment with donanemab led to a significant reduction in P-tau217 levels as early as 3 months (p < 0.01). P-tau217 levels were significantly correlated with changes in amyloid at all timepoints (R = 0.394, p < 0.0001 at 24 weeks; R = 0.492, p < 0.0001 at 76 weeks).

“Notably, these data support the amyloid cascade hypothesis, demonstrating that amyloid-related tau pathology can be modified by donanemab clearance of amyloid deposits. Furthermore, the data support that early and profound amyloid clearance may translate into clinical benefit for patients,” said John Sims, Senior Medical Director of Neurodegeneration at Eli Lilly and co-author of this analysis.

The Phase 3 TRAILBLAZER-ALZ3 clinical trial of donanemab for the treatment of patients with early AD will be initiated later this year.

References:

[1] Lilly releases donanemab data that demonstrated relationship between reduction of amyloid plaque and slowing of cognitive decline. Retrieved July 30, 2021, from https://investor.lilly.com/news-releases/news-release-details/lilly-releases-donanemab-data-demonstrated-relationship-between

[2] Mintun et al., (2021). Donanemab in Early Alzheimer’s Disease. NEJM, DOI: 10.1056/NEJMoa2100708

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