Results from Lilly's Landmark Phase 3 Trial of Donanemab Presented at Alzheimer's Association Conference and Published in JAMA

• Donanemab significantly slowed cognitive and functional decline for amyloid-positive early symptomatic Alzheimer's disease patients, lowering their risk of disease progression; nearly half of participants at earlier stage of disease on donanemab had no clinical progression at 1 year
• Additional subpopulation analyses presented live showed that those study participants at earliest stage of disease had even greater benefit, with 60 per cent slowing of decline compared to placebo
• Furthermore, treatment effect continued to increase relative to placebo over the course of the trial, even though many participants completed their course of therapy at 6 or 12 months, supporting limited duration dosing
• FDA submission completed in Q2; regulatory action expected by end of year

TORONTO, July 17, 2023 /CNW/ - Eli Lilly and Company presented full results from the Phase 3 TRAILBLAZER-ALZ 2 study showing that donanemab significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer's disease (AD). 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 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 per cent on iADRS and 36 per cent on CDR-SB. Among all amyloid-positive early symptomatic AD study participants (n=1736), treatment with donanemab significantly slowed decline by 22 per cent on iADRS and 29 per cent 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 per cent on iADRS and 46 per cent on CDR-SB (for those with mild dementia due to AD, n=534, donanemab slowed decline by 30 per cent on iADRS and 38 per cent 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=267), donanemab slowed decline by 48 per cent on iADRS and 45 per cent on CDR-SB.
• In participants aged 75 or greater (n=266), donanemab slowed decline by 25 per cent on iADRS and 29 per cent 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.

"The data presented here at AAIC gives us a full picture, reinforcing the preliminary results from earlier this spring that showed donanemab significantly slowed cognitive and functional decline in patients with early Alzheimer's disease," says Dr. Ziad Nasreddine, Cognitive Neurologist, Principal Investigator and Director of the MoCA Clinic, Montreal. "This is great news for Canadian patients and their families who now have hope that treatment can slow the progression of this devastating disease when diagnosed and treated early, this is such an important step forward."

"This is a very exciting time in Alzheimer's disease, following years of disappointment as promising molecules failed to reach their endpoints in clinical studies," says Dr. Sharon Cohen, Neurologist and Medical Director of Toronto Memory Program. "Today's donanemab presentation at AAIC is what we have been striving for. Slowing decline of cognition and function at an early stage of disease allows patients to remain mild and to preserve their quality of life."

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 per cent at 18 months, compared with a 1 per cent 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 per cent of participants with no progression at one year on the CDR-SB assessment, versus 29 per cent on placebo. Those participants treated with donanemab also had a 39 per cent 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.    

Adverse Events	Donanemab Group (n=853)	Placebo Group  (n=874)
Any serious adverse event	17.4 %	15.8 %
Overall death	1.9 %	1.1 %
Death related to treatment	0.4 %	0.1 %
Infusion-related reaction (IRR)	8.7 %	0.5 %
Any ARIA (-E or -H)	36.8 %	14.9 %
ARIA-E (asymptomatic)	17.9 %	1.9 %
ARIA-E (symptomatic)	6.1 %	0.1 %
ARIA-H	31.4 %	13.6 %

For full TRAILBLAZER-ALZ 2 results, see the JAMA publication.  

About TRAILBLAZER-ALZ 2 Study and the TRAILBLAZER-ALZ program

TRAILBLAZER-ALZ 2 (NCT04437511) is a Phase 3, 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) results from the Phase 2 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.

About Lilly Canada

Eli Lilly and Company is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by Colonel Eli Lilly, who was committed to creating high quality medicines that meet people's needs, and today we remain true to that mission in all our work. Lilly employees work to discover and bring life-changing medicines to people who need them, improve the understanding and management of disease, and contribute to our communities through philanthropy and volunteerism.

Eli Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto which eventually produced the world's first commercially available insulin. Our work focuses on oncology, diabetes, autoimmunity, neurodegeneration, and pain. To learn more about Lilly Canada, please visit us at www.lilly.ca.

* Participants completed their course of treatment with donanemab once they reached a pre-defined level of plaque clearance (<24.1 Centiloids). Average baseline amyloid levels were ~100 Centiloids for participants with early symptomatic Alzheimer's disease. 

SOURCE Eli Lilly Canada Inc.

Media Contact: Ethan Pigott, [email protected], 416-770-5843