Eli Lilly and Company have presented full results from the phase 3 TRAILBLAZER-ALZ 2 study showing that donanemab significantly slows cognitive and functional decline in people with early symptoms of Alzheimer’s disease (AD).
The data was shared at the Alzheimer’s Association International Conference (AAIC) 2023 as a flagship symposium and is simultaneously published in Journal of the American Medical Association (JAMA).
“The positive TRAILBLAZER-ALZ 2 data brings 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 outcomes observed in previous studies,” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience.
“If approved, we believe donanemab could provide clinically meaningful benefits for people with this disease and likely complete their treatment as soon as six months after their amyloid plaques have cleared. We must continue to remove any barriers to access to amyloid-targeting therapies and diagnostics in the already complex healthcare ecosystem for Alzheimer’s disease.”
Lilly previously announced that donanemab met the primary and all cognitive and functional secondary endpoints in a phase 3 study. Submissions to the US Food and Drug Administration (FDA) for traditional approval were completed in the last quarter with regulatory action expected by the end of the year. Submissions to other global regulators are currently underway, and most will be finalized by the end of the year.
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 wider range of cognitive scores and amyloid levels than recent trials of amyloid plaque-targeting therapy. Participants in TRAILBLAZER-ALZ 2 were grouped based on their levels of tau, a predictive biomarker for disease progression, into low-medium tau groups (sometimes referred to as intermediate tau) or high tau groups, which represent later pathological stages of disease progression. All participants were then assessed for 18 months using scales that measure cognition and function, including the integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Number of Boxes (CDR-SB).
As previously reported, among participants with low-medium levels of tau, donanema treatment significantly slowed the decline by 35% in iADRS and 36% in CDR-SB. Among all participants in the amyloid-positive early-asymptomatic AD study, treatment with donanemab significantly slowed the decline by 22% in iADRS and 29% in CDR-SB. The additional data presented at AAIC reinforce that regardless of the clinical or pathological initial stage of the disease, treatment with donanemab produces both cognitive and functional benefits compared to placebo:
- Predetermined subpopulation analysis of low-medium tau participants based on clinical stage showed greater benefit of donanemab in those in earlier stages of disease:
- In participants with mild cognitive impairment, donanemab slowed decline by 60% in iADRS and 46% in CDR-SB (for those with mild dementia due to AD, donanemab slowed decline by 30% in iADRS and 38%, respectively) .
- Similarly, a post-hoc subgroup analysis of low-medium tau participants by age, demonstrated a greater benefit of donanemab in patients under 75 years of age:
- In participants under the age of 75 years, donanemab slowed decline by 48% in iADRS and 45% in CDR-SB.
- In participants aged 75 years or older, donanemab slowed decline by 25% in iADRS and 29% in CDR-SB.
- The results were similar across the other subgroups, including participants carrying or not carrying the ApoE4 allele.
- The overall effect of donanemab treatment continued to improve over the course of the trial, with the greatest difference compared to placebo seen at 18 months.
“These results suggest that diagnosing and treating people earlier in the course of Alzheimer’s disease can yield greater clinical benefits,” said Liana Apostolova, distinguished professor of Alzheimer’s disease research and professor of neurology, radiology, medical and molecular genetics at Indiana University School. of Medicine, where he was dean for Alzheimer’s disease research and directs the clinical core of the Alzheimer’s Disease Center.
“The delay in disease progression during this trial is significant and will give people more time to do the things that matter to them.”
Donanemab specifically targets amyloid plaque deposits and has been shown to cause plaque clearance in treated patients. Treatment with donanemab significantly reduced amyloid plaque levels regardless of the pathological early stage of the disease. Among all participants, treatment with donanemab reduced amyloid plaques by an average of 84% at 18 months, compared with a 1% reduction in participants who took a placebo. Participants were able to stop taking donanemab once they achieved the predetermined amyloid plaque clearance criteria. Roughly half of the participants met this threshold at 12 months and about seven out of every ten participants met it at 18 months.
In early pathological stages of disease in participants with low-intermediate tau, treatment with donanemab resulted in 47% of participants without progression at one year on the CDR-SB assessment, compared to 29% on placebo. Participants treated with donanemab also had a 39% lower risk of progressing to the next clinical stage of the disease over the 18-month trial. This developmental delay 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 the CDR-SB compared with those on placebo.
The importance of early diagnosis
“People living with early symptoms of Alzheimer’s disease are still working, enjoying commuting, sharing quality time with family – they want to feel like themselves, for much longer,” said Mark Mintun, group vice president of Neuroscience Research & Development at Lilly, and president of Avid Radiopharmaceuticals.
“The results of this study reinforce the importance of diagnosing and treating disease much faster than we do today.”
The incidence of amyloid-associated imaging abnormalities (ARIA) and infusion-related reactions is consistent with previous TRAILBLAZER-ALZ studies. ARIA occurs in all classes of amyloid plaque-clearing antibody therapies. This is most often observed as transient swelling of the area or areas of the brain (ARIA-E) or as micro-hemorrhage or superficial siderosis (ARIA-H), in both cases detectable by MRI, and it may be serious and even fatal in some cases. case. This risk must be managed with careful observation, monitoring with MRI, and appropriate action if ARIA is detected. Serious infusion-related reactions and anaphylaxis were also observed.