Background: The aim of this analysis was to explore the impact of rapid amyloid clearance (rAC) on downstream biomarkers and clinical efficacy.
Methods: In TRAILBLAZER-ALZ 2, participants were randomized to receive (1:1) donanemab (n=860) or placebo (n=876) intravenously every 4 weeks (w) for 72w. Donanemab-treated participants were determined as achieving rAC during the trial if the brain amyloid level was below 24.1 Centiloids at either 24w or 52w as measured by amyloid PET (positron emission tomography). Propensity score matching method was used to select matched placebo-treated participants comparable with donanemab-treated participants with rAC in terms of baseline age, amyloid level, global tau level, and number of APOLIPOPROTEIN ε4 alleles (mPlacebo). At 76w, the biomarker and clinical measurements were compared between the two matched groups.
Results: The rAC group had significantly less accumulation of tau (AD-signature-weighted neocortical SUVr as determined by PET) at 76w compared to mPlacebo [adjusted mean (SE) change from baseline: 0.0684 (0.006) for mPlacebo, and 0.0461 (0.006) for rAC, difference (SE): -0.0223 (0.008), P=0.007]. The adjusted mean change from baseline of plasma P-tau217 and plasma glial fibrillary acidic protein were both significantly different from mPlacebo (<0.001). Adjusted mean change in integrated AD Rating Scale score (SE) at 76w was -11.5 (0.62) in the mPlacebo group, and -7.6 (0.62) in the rAC group [adjusted mean difference from mPlacebo, 3.86 (0.89) P<0.001], representing a 33.6% slowing of disease progression.
Conclusion: These results demonstrate the downstream effect of donanemab-induced rAC on biomarker and clinical efficacy measurements.