Donanemab TRAILBLAZER-ALZ-2-Phase-3 Trial Results

Pat & Dennis Bender Early Dementia Diagnosis & Prognosis Fund

 

J. Dennis Bender

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We support the development of improved diagnostic methods for the early detection and diagnosis of MCI, Alzheimer’s, vascular and other dementias, their likely prognosis, and best treatment. We focus on the development of Bayesian-based medical-decision-support systems, comparative-effectiveness research, and the better utilization of these for the above. (After incorporating in KY as a 501(c)(3) in 2002, we dissolved that entity for a simplified form of two entirely self-financed, private philanthropies utilizing a Vanguard Charitable Trust for making annual-research-grants for early-dementia-detection and its correct differential-diagnosis and likely-prognosis. They will continue on, after I am gone, either mentally or physically. Prof. Randall Bateman is the first of our fund’s research advisors.

See: https://www.alz.org/alzheimers-dementia/research_progress/earlier-diagnosis )

 

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www.JDBender.com – EMS/eVTOL Experimental Aviation Fund (Vanguard Charitable Trust)

www.JDBender.org – Dementia Diagnosis Fund (Vanguard Charitable Trust)

 

May 4, 2023

Good news and a night for celebration at Bistro du Marche! Donanemab’s amyloid-plaque-targeting-therapy is apparently not a dead-end and seems to be working well enough to proceed with FDA-approval efforts.

 

 

Celebration at Bistro du Marche! [Morel-mushroom-month, just like those we picked wild in Ohio every Spring.]

 

“Donanemab significantly slowed cognitive and functional decline in people with early-symptomatic-Alzheimer's-disease. Donanemab met the primary-endpoint of change-from-baseline at 18-months on the integrated Alzheimer's Disease Rating Scale (iADRS). . . All secondary-endpoints of cognitive and functional-decline were also met and showed highly-statistically-significant-clinical-benefits with similar-magnitude. . . People in the early-pathological-stage-of-disease could be the most-responsive-to-therapeutics-targeting-amyloid. . . Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the U.S. Food and Drug Administration (FDA) yet this quarter. It will work with the FDA and other global regulators to achieve the fastest-path-to-traditional-approvals.”

• Nearly-half (47%) of the participants on donanemab (compared to 29% on placebo) had no-clinical-progression at 1 -year (defined as no-decline-in-CDR-SB.)
• Phase-3-trial met primary-endpoint and all-secondary-endpoints measuring cognitive and functional decline.
• Donanemab treatment slowed-clinical-decline-by-35% compared to placebo, and resulted in 40%-less-decline on the ability to perform-activities-of-daily-living.
• Over half of all participants completed their course-of-treatment by 12-months. 

Participants in TRAILBLAZER-ALZ-2 were stratified by their level-of-the-brain-protein-tau, as I have been advocating for a very-long-time now. Both amyloid-beta and tau blood-plasma-levels need to be measured and adjusted for gender and APOE-status, as C₂N and others are currently doing and now finally providing FDA-approved test-kits in the U.S., key to our approach.

The “CDR-SB” measure is admittingly a crude-and-rather-insensitive-measure, [CDR-SB levels of 0, 0.5, 1.0–2.5, 2.5–4.0, and ≥4.5 were defined as NC, SCD, MCI, very-mild-dementia (VMD), and dementia, respectively,] but it is the one commonly-used in dementia-research. MMSE is the oldest measure commonly reported in medical-research reports so unfortunately became a standard-of-comparison for publications. (The maximum score for the MMSE is 30, a simple check-list with just an unweighted-total-count. A score of 25-or-higher is classed as normal. If the score is below-24, the result is usually considered to be abnormal, indicating possible-cognitive-impairment. There are many better measures, such as iADRS. The iADRS is a linear-combination of its two components: the ADAS-Cog13 (range: 0–85; higher-scores indicating greater deficit of global cognition)21 and the ADCS-iADL (range: 0–59; lower-scores indicating greater-impairment.)

News Release

Lilly's Donanemab Significantly Slowed Cognitive and Functional Decline in Phase-3 Study of Early-Alzheimer's-Disease

May 3, 2023

Indianapolis, May 3, 2023 /PRNewswire/ Download PDF

Eli Lilly and Company (NYSE: LLY) announced today positive-results of the TRAILBLAZER-ALZ-2-Phase-3 study showing that donanemab significantly slowed cognitive and functional decline in people with early-symptomatic-Alzheimer's-disease. Donanemab met the primary-endpoint of change from baseline until 18-months on the integrated-Alzheimer's-Disease-Rating-Scale (iADRS).

The primary-endpoint-of-iADRS measures cognition and activities-of-daily-living such as managing finances, driving, engaging in hobbies, and conversing about current events. All secondary-endpoints of cognitive and functional-decline were also met and showed highly-statistically-significant-clinical-benefits with similar-magnitude. Based on these results, Lilly will proceed with global regulatory submissions as quickly as possible and anticipates making a submission to the U.S. Food and Drug Administration (FDA) yet this quarter. Lilly will work with the FDA and other global regulators to achieve the fastest-path-to-traditional-approvals.

TRAILBLAZER-ALZ-2, a randomized, double-blind, placebo-controlled study, evaluated the safety-and-efficacy of donanemab, an investigational amyloid-plaque-targeting-therapy. The study enrolled people with early-symptomatic-Alzheimer's-disease (AD), which includes mild-cognitive-impairment (MCI) and the mild-dementia stage-of-disease, with the confirmed-presence-of-AD-neuropathology, and participants completed their course-of-treatment with donanemab once they reached a prespecified-level-of-amyloid-plaque-clearance.

Participants in TRAILBLAZER-ALZ-2 were stratified by their level-of-the-brain-protein-tau, a predictive-biomarker-for-Alzheimer's-disease-progression. The primary-analysis-population (n=1,182) for which the study was powered was comprised of people with an intermediate-level-of-tau and clinical-symptoms-of-Alzheimer's-disease. In this population, the primary-endpoint (iADRS) showed 35%-slowing-of-decline (p<0.0001), and an important key-secondary-endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36%-slowing-of-decline (p<0.0001) over-18-months. Additional prespecified-secondary-analyses showed:

• 47% of participants on donanemab showed no-decline-on-CDR-SB, a key measure of disease severity at 1 year (compared to 29% of participants on placebo, p<0.001).
• 52% of participants completed their course-of-treatment by-1-year and 72% completed by 18-months as a result of achieving-plaque-clearance.
• Participants on donanemab had 40% less decline in ability to perform activities of daily living at 18 months [as measured by Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL), p<0.0001].
• Participants on donanemab experienced a 39%-lower-risk-of-progressing-to-the-next-stage-of-disease compared to placebo (CDR-Global Score, HR=0.61; p<0.001).

"Over the last-20-years, Lilly scientists have blazed new trails in the fight against Alzheimer's-disease by elucidating-basic-mechanisms-of-AD-pathology and discovering-imaging-and-blood-biomarker-tools-to-track-the-pathology," said Daniel Skovronsky, M.D., Ph.D., Lilly's Chief Scientific and Medical Officer, and President of Lilly Research Laboratories. "We are extremely pleased that donanemab yielded-positive-clinical-results with compelling statistical-significance for people with Alzheimer's-disease in this trial. This is the first Phase-3-trial of any investigational medicine for Alzheimer's-disease to deliver 35%-slowing-of-clinical-and-functional-decline." [But how important for the typical dementia-patient?]

The study also enrolled a smaller-number-of-people with high-levels-of-tau-at-baseline (n=552), representing a later-stage-of-disease-progression. Because these participants were predicted to progress-more-quickly and be-less-responsive-to-therapy, the target-population for the study was the intermediate-tau-population. The high-tau-participants were combined-with-the-intermediate-tau-population in an additional primary-analysis of all participants enrolled (n=1,736). In this combined-population, donanemab also demonstrated meaningful-positive-results across all clinical endpoints (p<0.001), with CDR-SB and iADRS showing 29% and 22% slowing-of-decline, respectively.

The incidence of amyloid-related-imaging-abnormalities (ARIA) was consistent with the TRAILBLAZER-ALZ-Phase-2 study. ARIA is observed with the amyloid-plaque-clearing-antibody-class-of-therapies and 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. In the overall-donanemab-treatment-group, ARIA-E occurred in 24.0% of treated participants, with 6.1% experiencing symptomatic ARIA-E. ARIA-H occurred in 31.4% in the donanemab- group and 13.6% in the placebo-group. The majority-of-ARIA-cases were mild-to-moderate and resolved-or-stabilized-with-appropriate-management. ARIA is usually-asymptomatic, although serious and life-threatening events can occur. In this study, the incidence-of-serious-ARIA was 1.6%, including 2 participants whose death was attributed-to-ARIA and a third participant who died-after-an-incident-of-serious-ARIA. Infusion-related-reactions occurred in 8.7%-of-participants with most-cases-mild-to-moderate-in-severity.

"We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated-risks that may be serious-and-life-threatening," said Mark Mintun, M.D., Group Vice President Neuroscience Research & Development at Lilly, and President of Avid Radiopharmaceuticals. "We note that these results suggest that people in the early-pathological-stage-of-disease could be the most-responsive-to-therapeutics-targeting-amyloid. We thank the participants in the clinical trial and their loved ones for their time and commitment to finding solutions for this disease."

In addition to slowing-cognitive-and-functional-decline in TRAILBLAZER-ALZ-2, donanemab produced significant-reductions in brain-amyloid-plaque-levels as-early-as-6-months-after-initiating-treatment, as observed using amyloid-positron-emission-tomography (PET) brain-scan, [that we helped to develop at the U. of Pittsburgh,] with many patients reaching amyloid levels considered negative for pathology¹ (34% of participants in the intermediate-tau-population achieved amyloid-clearance-at-6-months and 71%-achieved-clearance-at-12-months).

"Amyloid-plaque is a defining-pathophysiological-feature of Alzheimer's-disease." said Dr. Eric Reiman, CEO of Banner Research, one of the research sites for the TRAILBLAZER-ALZ-2 trial. "This study's topline-results provide compelling support for the relationship between amyloid-plaque-removal and a clinical-benefit in people with this disease." [Yes, but still remains controversial.]

"These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them," said Anne White, Executive Vice President of Eli Lilly and Company and President of Lilly Neuroscience. "We believe our data meets the 'high level of evidence' the Centers for Medicare & Medicaid Services (CMS) has described as the trigger-for-reconsideration-of-its-National-Coverage-Determination. People with early-Alzheimer's-disease need and deserve full-coverage-and-access for approved therapies."

Topline study results: In the intermediate-tau-population, the baseline-characteristics were similar to other contemporary-early-symptomatic-AD-studies (e.g., MMSE-score was 23). Accordingly, the placebo-arm progressed-as-expected (decline on iADRS and CDR-SB of 9.3 and 1.9-points respectively over-18-months). Prespecified analyses used standard statistical methods including the mixed-model-for-repeated-measures (MMRM) and natural-cubic-spline (NCS) analyses, with similar results across both methods, [just as I would have both used.] The following efficacy-measures were obtained at-18-months comparing decline-in-donanemab-to-placebo-treated-participants:

Intermediate tau population	MMRM statistical analysis		NCS statistical analysis
	Relative % slowing	p-value	Relative % slowing	p-value
iADRS	40 %	p<0.0000004	35 %	p<0.000004*
CDR-SB	36 %	p<0.000002*	37 %	p<0.0000005
ADCS-iADL	43 %	p<0.00005	40 %	p<0.0001*
ADAS-Cog13	35 %	p<0.00003	32 %	p<0.00005*
*indicates alpha-controlled analyses; iADRS= Alzheimer's Disease Rating Scale; CDR-SB= Clinical Dementia Rating-Sum of Boxes; ADCS-iADL = Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (iADL); ADAS-Cog13 = the 13-item Alzheimer's Disease Assessment Scale – Cognitive

In the combined-intermediate-and-high-tau-population the baseline-MMSE-score was 22.3 and the placebo-arm showed a greater-decline compared to the intermediate-tau-population (worsening on iADRS and CDR-SB of 13.1 and 2.4 points respectively over-18-months). Study results at 18-months showed:

Combined intermediate and high-tau population	MMRM statistical analysis		NCS statistical analysis
	Relative % slowing	p-value	Relative % slowing	p-value
iADRS	23 %	p<0.00004	22 %	p<0.00006*
CDR-SB	29 %	p<0.00000005*	29 %	p<0.00000007
ADCS-iADL	28 %	p<0.0002	28 %	p<0.0002*
ADAS-Cog13	19 %	p<0.0008	20 %	p<0.0007*
*indicates alpha-controlled analyses

Full results of the TRAILBLAZER-ALZ-2 study will be presented at the Alzheimer's Association International Conference in July and submitted for publication in a peer-reviewed-clinical-journal.

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 1,736 participants 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.

Refer to:  J.K. Wall; This email address is being protected from spambots. You need JavaScript enabled to view it.; 317-433-5328 (Media), Joe Fletcher; This email address is being protected from spambots. You need JavaScript enabled to view it.; 317-296-2884 (Investors)

© Lilly USA, LLC 2023. All Rights Reserved.

1. JAMA. 2011;305(3):275-283

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