Eli Lilly presents results from Phase 3 trial of Donanemab at Alzheimer's Association Conference

"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 3 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 3 study. Submission to the U.S. 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:

• 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:
  • 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).
• 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:
  • In participants under the age of 75 (n=542), donanemab slowed decline by 48% on iADRS and 45% on CDR-SB.
  • In participants aged 75 or greater (n=551), donanemab slowed decline by 25% on iADRS and 29% on CDR-SB.
• Results were similar across other subgroups, including participants who carried or did not carry an ApoE4 allele.
• 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.

"People living with early, symptomatic Alzheimer's disease are still working, enjoying trips, sharing quality time with family – they want to feel like themselves, for longer," said Mark Mintun, M.D., group vice president Neuroscience Research & Development at Lilly, and president of Avid Radiopharmaceuticals. "The results of this study reinforce the importance of diagnosing and treating disease sooner than we do today."

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.