Secondary Analysis of TRAILBLAZER-ALZ Highlights Donanemab’s Effect on Alzheimer-Related Plasma Biomarkers

Changes in plasma pTau217 and GFAP levels from donanemab significantly correlated with percent change in amyloid plaque level as measured by amyloid PET imaging.

Mark A. Mintun, MD, president, Avid Radiopharmaceuticals

Mark A. Mintun, MD

Recently published secondary findings from the phase 2 TRAILBLAZER-ALZ study (NCT03367403) showed that treatment with donanemab (Eli Lilly), an investigational therapy that targets a modified form of amyloid-ß called N3pG, resulted in significant reductions in plasma biomarkers phosphorylated tau217 (pTau217) and glial fibrillary acidic protein (GFAP) compared with placebo.1

In a cohort of 272 men and women aged 60 to 85 years with early symptomatic AD, the mean plasma pTau217 levels decreased by 23% from baseline to week 76 after treatment with donanemab, whereas levels continued to rise by 6% in those on placebo. Similarly, mean plasma GFAP levels decreased by 12% from baseline while levels continued to rise by 15% for those on placebo. No significant between-group differences were observed for neurofilament light (NfL) levels.

Senior investigator Mark A. Mintun, MD, president, Avid Radiopharmaceuticals, and colleagues concluded that the findings "add weight to the hypothesis that reduction of amyloid by anti-Aβ antibodies could have downstream effects consistent with disease modification and suggest that fluid biomarkers could have a role in monitoring response to treatments (at least as a group measure of target engagement/amyloid clearance) in future clinical trials."

Participants in the study were randomly assigned 1:1 to receive intravenous donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg. The effect of donanemab on brain amyloid and tau pathology was assessed using specific PET tracers: 18F-florbetapir, which detected amyloid plaque at baseline and weeks 24, 52, and 76; and 18F-flortaucipir, which detected tau neurofibrillary tangles at baseline and week 76. Plasma samples were collected at baseline and weeks 12, 24, 36, 52, 64, and 76.

All told, baseline plasma pTau217 levels were positively associated with both baseline amyloid plaque levels as measured by amyloid PET imaging (Spearman r = 0.148; 95% CI, 0.019-0.271; P = .02) and global tau deposition as measured by tau PET imaging (r = 0.378; 95% CI, 0.262-0.483; P <.001). Notably, baseline plasma levels of GFAP, NfL, and Aß42/40 were not significantly correlated with baseline amyloid or tau PET end points.

After 76 weeks of treatment, investigators noticed that plasma pTau217 was positively correlated with the percent change in amyloid plaque (r = 0.484; 95% CI, 0.359-0.592; P <.001). Additionally, the change in plasma GFAP was positively correlated with the percent change in amyloid plaque observed at the same time point (r = 0.453; 95% CI, 0.306-0.579; P <.001). Not only were plasma levels of pTau217 and GFAP significantly associated at baseline, but this positive correlation persisted through the end of the study period (r = 0.393; 95% CI, 0.254-0.517; P <.001).

Regardless of stopping or continuing treatment, plasma levels of pTau217 and GFAP were significantly lower in donanemab-treated patients at the end of the study. For those who stopped treatment at 24 weeks, the effects of donanemab on plasma levels of pTau217 and GFAP persisted up to 1 year after the end of treatment. Notably, the decrease in these levels were not significantly greater in those who continued treatment vs those who stopped at 24 weeks.

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Across the cohort, the reductions seen in these 2 plasma biomarkers were independent of amyloid-related imaging abnormalities-edema (ARIA-E), which have become a concern for anti-amyloid therapies in recent years. When looking at change in plasma biomarker vs change in volumetric MRI, only NfL showed a significant correlation with change in whole brain volume (R = –0.1710; 95% CI, –0.3205 to –0.0132; P = .03).

There were no significant correlations between pTau217, GFAP, NfL, or Aß42/40 and baseline Integrated Alzheimer’s Disease Rating Scale (iADRS), the original primary outcome of the study. Only change in plasma NfL showed a significant correlation with change in iADRS (r = –0.182; 95% CI, –0.322 to –0.035; P = .02). In a marginal logistical analysis, pTau217 change at 24 weeks was positively associated with the odds of exhibiting a meaningful worsening on iADRS (coefficient estimate, 0.704; 95% CI, 0.022-1.386; P = .04). Mintun et al wrote, "That is, the decline in pTau217 values is associated with lower odds of within-patient change in iADRS consistent with meaningful worsening. The analyses on GFAP did not show any association."

In March 2021, data from TRAILBLAZER-ALZ was published in the New England Journal of Medicine, which showed that patients with early AD treated with donanemab have improved composite scores for cognition and ability to perform activites of daily living. At baseline, iADRS score was 106 in both the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intent-to-treat population) groups. After 76 weeks, the treatment group’s scores changed by –6.86 points whereas the placebo group’s changed by −10.06 (difference, 3.20; 95% CI, 0.12-6.27; P = .04). This change was equivalent to a 32% difference in slowing decline for the donanemab group, a significant difference that was identifiable by month 9.2

Donanemab is also currently being assessed in a large-scale, confirmatory phase 3 trial called TRAILBLAZER-ALZ 2 (NCT04437511). The study is expected to reach approximately 1500 participants, aged 60 to 85 years, with early symptomatic AD. Change from baseline in iADRS will continue to serve as the primary end point, with secondary end points that include Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Clinical Dementia Rating Scale-Sub of Boxes scores, among others.

REFERENCES
1. Pontecorvo MJ, Lu M, Burnham SC, et al. Association of donanemab treatment with exploratory plasma biomarkers in early symptomatic Alzheimer disease: a secondary analysis of the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. Published online October 17, 2022. doi:10.1001/jamaneurol.2022.3392
2. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708.
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