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Phase III TRAILBLAZER-ALZ 2 trial: donanemab slows cognitive and functional decline in patients with early Alzheimer’s disease

Topline data has been released from Eli Lilly and Company showing that donanemab significantly slowed cognitive decline by 35% and improved all secondary endpoints, successfully clearing amyloid plaque deposits. The randomized, double-blind, Phase III TRAILBLAZER-ALZ 2 trial enrolled almost 1740 participants with early symptomatic Alzheimer’s disease, with brain tau pathology. This is the strongest Alzheimer’s disease Phase III data to date and underscores the benefit of amyloid-beta monoclonal antibodies for patients...

Alzheimer’s disease (AD) is the most common form of dementia. It is a progressive, neurodegenerative disease characterized by the amyloid-beta (Aβ) plaque deposits and tau tangles that destroy neural connections in the brain.

There is currently no cure for AD, but recent years have seen unprecedented success in tackling disease progression by targeting amyloid pathology. Aducanumab and lecanemab are monoclonal antibodies (mAbs) against Aβ that have been approved for the treatment of AD in the United States in June 2021 and January 2023, respectively. Similarly, donanemab is another investigational mAb that targets the N-terminal of pyroglutamate Aβ, only found in aggregated amyloid plaques of AD.1 Following binding, donanemab induces microglial-mediated clearance of these plaques. New data published on 3rd May 2023 has shown donanemab to produce the strongest cognitive benefit seen with any antibody AD drug to date, achieving a significant reduction in rates of cognitive and functional decline over 18 months.

Results from the Phase II randomized, placebo-controlled TRAILBLAZER-ALZ study (NCT03367403) published in 2021 showed that donanemab reached its primary endpoint by significantly slowing decline until 18 months on the composite Integrated Alzheimer’s Disease Rating Scale (iADRS; p=0.04), which combines measures of cognition and daily function.1 Consequently, the Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511) was conducted by Lilly over 18 months to evaluate the clinical profile of donanemab in 1736 patients with early symptomatic AD (prodromal Alzheimer’s disease and mild dementia due to Alzheimer’s disease), aged 60-85 years.2 Treatment course ran until a prescribed level of amyloid plaque clearance was reached.

Rebecca Edelmayer, PhD, Alzheimer’s Association, discusses the recent announcement of the topline data from the Phase III TRAILBLAZER-ALZ 2 study (NCT04437511) of donanemab in patients with early Alzheimer’s disease.

The patient cohort was stratified by their level of brain tau protein, as confirmed by PET imaging. A primary analysis population of patients with intermediate tau (n=1182; average MMSE 22.9) showed a slowing of decline of 35% at 18 months, relative to placebo (iADRS; p<0.0001).2 A key secondary endpoint, change in Clinical Dementia Rating-Sum of Boxes [CDR-SB] score from baseline, showed that nearly half (47%) of treated participants had no clinical progression at 12 months (defined as no decline on CDR-SOB), compared to 29% on placebo.2 Additionally, Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iAD) measured a 40% reduction decline in ability to perform daily activities at 18 months (p<0.0001).2 Aside from slowing decline, donanemab was found to significantly reduce amyloid plaque levels following only 6 months of treatment.

“We are extremely pleased that donanemab yielded positive clinical results with compelling statistical significance…this is the first Phase III trial of any investigational medicine for Alzheimer’s disease to deliver 35% slowing of clinical and functional decline.”, said Daniel Skovronsky, MD, PhD, Lilly’s Chief Scientific and Medical Officer, and President of Lilly Research Laboratories.

Over half of the participants completed their treatment of donanemab by 12 months (52%). Aside from the primary analysis population (n=1182), a sub-population of patients with high tau levels was enrolled (n=552) as a way to represent a later stage of AD progression. Findings from the combined population (n=1736) show less relative slowing compared to the intermediate tau group, with iARDS and CDR-SB scores in the donanemab arm showing a 22% (p<0.001) and 29% (p<0.001) slowing of decline, respectively.2

The occurrence of amyloid-related imaging abnormalities (ARIA) was similar to that reported in Phase II, with ARIA-E occurring in 24% of donanemab arm and ARIA-H in 31%. Incidences of ARIA were predominantly mild-moderate cases, however, serious events did occur. In Phase III, three participant deaths were ARIA-related.2

Full results and discussion of the trial will be presented at AAIC in July 2023 and submitted for publication in a peer-reviewed journal.

The clinical effects of donanemab appear to be better than what’s been achieved in aducanumab. Results from the TRAILBLAZER-ALZ 4 trial (NCT05108922), the first comparator study in early AD to date, showed a 36.3% difference in the number of patients who achieved amyloid clearance at 6 months.3 The long-term cognitive benefit of this substantial early clearance is not yet clear, and more data is expected at 12- and 18-months which will shed more light on their comparative performance.

In addition to the TRAILBLAZER-ALZ 4 trial, several other trials of donanemab are ongoing to investigate the different stages of AD. Following the 18-month treatment period, TRAILBLAZER-ALZ 2 participants can enter a double-blind 78-week long-term extension trial which will provide more data on the effects of donanemab over time. Additionally, the TRAILBLAZER-ALZ 3 trial (NCT05026866) is a novel study assessing the safety and efficacy of donanemab in over 3000 participants with preclinical AD, aimed at preventative options for early AD.4

“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.”, said Anne White, Executive Vice President of Eli Lilly and Company and President of Lilly Neuroscience.

The Centers for Medicare and Medicaid Services (CMS) have implemented a policy that is currently hindering Medicare access to FDA-approved AD treatments, which would include donanemab. Rebecca Edelmayer, PhD, Alzheimer’s Association, highlights the access issues surrounding anti-amyloid therapies for Alzheimer’s disease as a matter of concern.

Based on the encouraging results presented by Lilly, submission to the FDA and work with global regulators for approval is expected. Results from ongoing TRAILBLAZER-ALZ trials will provide a further insight into donanemab as a treatment over time and at different disease stages.

Written by Kate Antoni

Reviewed by Juliet Lawrence

Refererences

  1. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. May 2021;384(18):1691-1704.
  2. Eli Lilly and Company. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease [Press Release]. May 2023.
  3. Salloway S, Lee E, Papka M, et al. TRAILBLAZER-ALZ 4: Topline study results directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease (S26.009). Neurology. Apr 2023;100(17 Supplement 2).
  4. ClinicalTrials.gov. A Donanemab (LY3002813) Prevention Study in Participants With Alzheimer’s Disease (TRAILBLAZER-ALZ 3). Accessed Jun 2023.