Details

Autor(en) / Beteiligte

• Gueorguieva, Ivelina
• Chua, Laiyi
• Chow, Kay Hoong
• Ernest, C Steven
• Willis, Brian A.
• Shcherbinin, Sergey
• Sims, John R.
• Chigutsa, Emmanuel

Titel

Donanemab exposure‐efficacy relationship in patients with early symptomatic Alzheimer’s disease

Ist Teil von

• Alzheimer's & dementia, 2023-06, Vol.19 (S7), p.n/a

Erscheinungsjahr

2023

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Background Donanemab is an IgG1 antibody targeting N3pG (a modified beta amyloid present solely in brain plaques). A population pharmacokinetic/amyloid positron emission tomography (PET) imaging model described donanemab’s effect on amyloid plaque measurements and associated treatment‐effect with maintaining median (95%CI) threshold concentration of 4.43 (0.96 to 10.4 mg/mL). The extent to which exposure exceeded this threshold did not influence degree of amyloid removal. The current analysis aimed to quantify treatment effect on change in clinical decline (integrated AD Rating Scale, iADRS); evaluate the relationship of donanemab‐mediated changes in amyloid plaque on iADRS; and evaluate patient factors potentially affecting response to donanemab treatment. Method Analyses included patients with early symptomatic Alzheimer’s disease (AD, including prodromal AD and mild AD dementia) randomized to donanemab monotherapy versus placebo in a phase 2 study (TRAILBLAZER‐ALZ; N = 256; NCT03367403). Exposure‐response modeling employed a non‐linear mixed effects modeling approach. The treatment‐efficacy model utilized a Richard’s logistic function to fit the time course of all available iADRS data and characterize clinical decline. The impact of absolute or relative change from baseline in amyloid PET measurements (centiloids) was evaluated as a predictor of clinical decline. Result Disease progression model‐based analyses showed donanemab significantly reduced rate of clinical decline by 28% in the overall population and 42% in APOE ε4 carriers (iADRS, p<.001 for both). No clear treatment‐effect was identified in the smaller APOE ε4 noncarrier population (27% of study participants). Overall, serum concentrations of donanemab were not correlated with clinical decline. Antidrug antibody titer did not affect donanemab’s efficacy. Model simulations showed patients would benefit from donanemab treatment regardless of baseline disease severity, and patients with worse iADRS score at baseline had a greater absolute drug effect (difference between donanemab and placebo at 76 weeks). APOE ε4 carriers who had a 100% decrease in amyloid level from baseline with donanemab treatment are predicted to achieve, on average, a 43.5% slowing of clinical decline rate versus placebo‐treated patients (Figure). Conclusion Findings show donanemab treatment would benefit patients regardless of baseline disease severity. Both exposure‐efficacy and amyloid plaque biomarker models showed donanemab reduces rate of clinical decline and produces better patient outcomes than placebo.