Results from landmark phase III trial of donanemab are presented at Alzheimer's Association conference and published in JAMA

The data were shared at the 2023 Alzheimer's Association International Conference (AAIC) as a featured symposium and simultaneously published in the Journal of the American Medical Association (JAMA).

"The positive TRAILBLAZER-ALZ 2 data bring hope to people with Alzheimer's disease who urgently need new treatment options. This is the first Phase III study of a disease-modifying therapy to replicate the positive clinical results observed in a previous study," said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience. "If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared. We must continue to remove any barriers in access to amyloid-targeting therapies and diagnostics in an already complex healthcare ecosystem for Alzheimer's disease."

Lilly previously announced that donanemab met the primary and all cognitive and functional secondary endpoints in the Phase III study. Submission to the FDA for traditional approval was completed last quarter with regulatory action expected by the end of the year. Submissions to other global regulators are currently underway, and the majority will be completed by year end.

The TRAILBLAZER-ALZ 2 results support Lilly's application for regulatory approval to treat people with amyloid-positive early symptomatic Alzheimer's disease (either mild cognitive impairment or mild dementia) , regardless of their baseline level of tau. TRAILBLAZER-ALZ 2 enrolled participants with a broader range of cognitive scores and amyloid levels than other recent trials of amyloid plaque-targeting therapies. Participants in TRAILBLAZER-ALZ 2 were stratified by their level of tau, a predictive biomarker for disease progression, into either a low-medium tau group (sometimes referred to as intermediate tau) or a high tau group, which represented a later pathological stage of disease progression. All participants were then assessed over 18 months using scales that measure both cognition and function, including the integrated Alzheimer's Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

As previously reported, among participants with low-medium levels of tau (n=1182), donanemab treatment significantly slowed decline by 35% on iADRS and 36% on CDR-SB. Among all amyloid-positive early symptomatic AD study participants (n=1736), treatment with donanemab significantly slowed decline by 22% on iADRS and 29% on CDR-SB.

Additional data presented at AAIC reinforced that regardless of baseline clinical or pathological stage of disease, treatment with donanemab resulted in cognitive and functional benefits relative to placebo: i. A pre-specified subpopulation analysis of low-medium tau participants based on clinical stage showed greater benefit of donanemab in those at earlier stage of disease: a. In participants with mild cognitive impairment (n=214), donanemab slowed decline by 60% on iADRS and 46% on CDR-SB (for those with mild dementia due to AD, n=534, donanemab slowed decline by 30% on iADRS and 38% on CDR-SB, respectively).ii. Similarly, a post-hoc subgroup analysis of low-medium tau participants based on age showed greater benefit of donanemab in patients under the age of 75: a. In participants under the age of 75 (n=542), donanemab slowed decline by 48% on iADRS and 45% on CDR-SB. b. In participants aged 75 or greater (n=551), donanemab slowed decline by 25% on iADRS and 29% on CDR-SB. iii. Results were similar across other subgroups, including participants who carried or did not carry an ApoE4 allele. iv. The overall treatment effect of donanemab continued to grow throughout the trial, with the largest differences versus placebo seen at 18 months.

"These results demonstrate that diagnosing and treating people earlier in the course of Alzheimer's disease may lead to greater clinical benefit," said Liana Apostolova, M.D., distinguished professor in Alzheimer's Disease research and professor in neurology, radiology, medical and molecular genetics at Indiana University School of Medicine, where she is associate dean for Alzheimer's disease research and directs the clinical core of the Alzheimer's Disease Center. "The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them."

Donanemab specifically targets deposited amyloid plaque and has been shown to lead to plaque clearance in treated patients. Treatment with donanemab significantly reduced amyloid plaque levels regardless of baseline pathological stage of disease. Among all participants, treatment with donanemab reduced amyloid plaque on average by 84% at 18 months, compared with a 1% decrease for participants on placebo. Participants were able to stop taking donanemab once they achieved pre-defined criteria of amyloid plaque clearance. Approximately half of participants met this threshold at 12 months and approximately seven of every ten participants reached it at 18 months.

In the earlier pathological stage of disease in participants with low-medium tau, treatment with donanemab resulted in 47% of participants with no progression at one year on the CDR-SB assessment, versus 29% on placebo. Those participants treated with donanemab also had a 39% lower risk of progressing to the next clinical stage of disease over the 18-month trial. This delay in progression meant that, on average, participants treated with donanemab had an additional 7.5 months before they reached the same level of cognitive and functional decline on CDR-SB compared to those on placebo.

The incidence of amyloid-related imaging abnormalities (ARIA) and infusion-related reactions was consistent with the previous TRAILBLAZER-ALZ study. ARIA occurs across the class of amyloid plaque clearing antibody therapies. It is most commonly observed as temporary swelling in an area or areas of the brain (ARIA-E) or as microhemorrhages or superficial siderosis (ARIA-H), in either case detected by MRI, and these may be serious and even fatal in some cases. This risk should be managed with careful observation, monitoring with MRIs, and appropriate actions if ARIA is detected. Serious infusion-related reactions and anaphylaxis were also observed.

About TRAILBLAZER-ALZ 2 Study and the TRAILBLAZER-ALZ program: TRAILBLAZER-ALZ 2 (NCT04437511) is a Phase III , double-blind, placebo-controlled study to evaluate the safety and efficacy of donanemab in participants ages 60-85 years with early symptomatic Alzheimer's disease (MCI or mild dementia due to Alzheimer's disease) with the presence of confirmed Alzheimer's disease neuropathology. The trial enrolled 1736 participants, across 8 countries, selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by PET imaging. Lilly previously announced and published in the New England Journal of Medicine (NEJM)( previously cited) results from the Phase II TRAILBLAZER-ALZ study in 2021. In addition, Lilly shared data from TRAILBLAZER-ALZ 4, the first active comparator study in early symptomatic Alzheimer's disease, at the 15th Clinical Trials on Alzheimer's Disease (CTAD) conference in 2022.

Lilly continues to study donanemab in multiple clinical trials, including TRAILBLAZER-ALZ 3, which is focused on preventing symptomatic Alzheimer's disease in participants with preclinical AD; TRAILBLAZER-ALZ 5, a registration trial for early symptomatic Alzheimer's disease currently enrolling in China; and TRAILBLAZER-ALZ 6, which is focused on expanding our understanding of ARIA through novel MRI sequences, blood-based biomarkers, and different dosing regimens of donanemab.

See- "Donanemab in Early Symptomatic Alzheimer Disease ; The TRAILBLAZER-ALZ 2 Randomized Clinical Trial."; John R. Sims, MD; Jennifer A. Zimmer, MD; Cynthia D. Evans, PhD; et al. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239.