Quantitative systems pharmacology-based exploration of relevant anti-amyloid therapy challenges in clinical practice

Abstract

Introduction: Addressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real-world evidence is not practical, nor feasible.

Methods: Here we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid-related imaging abnormality-edema (ARIA-E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges.

Results: Treatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio-fluid biomarkers to detect central amyloid negativity-is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24-month, 48-month and 64-month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA-E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA-E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA-E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period.

Discussion: This QSP platform could support clinical practice challenges to optimize real-world treatment paradigms for new and existing amyloid drugs.

FIGURE 1

When introducing the pharmacology and PK profile of donanemab and gantenerumab, the model reproduces the biomarker dynamics observed in donanemab's TRAILBLAZER trials (A,B) and gantenerumab's GRADUATE trials (C,D), both for central amyloid readouts (A,C) and ARIA‐E liability (B,D). Circles are clinically reported data (Clin Data). Data were compared to placebo. ARIA‐E, amyloid‐related imaging abnormality–edema; CL, centiloids; SUVR, standardized uptake value ratio.

FIGURE 2

Outcomes simulated for donanemab, lecanemab, aducanumab, and gantenerumab to reach amyloid negativity for a range of baseline central amyloid values using the reported titration schedules from the Phase 3 studies. All outcomes are for an APOE4+ subject. (A) Duration to reach amyloid negativity ranges from 4 to 23 months for donanemab, 5 to 48 months for lecanemab, 10 to 44 months for aducanumab, and 10 to 70 months for gantenerumab. (B) Final protofibril levels normalized to baseline at time of reaching amyloid negativity. Lecanemab has the greatest reduction, followed by aducanumab, gantenerumab, and donanemab. (C) Increase in CSF Aβ42 normalized against baseline at the time of reaching amyloid negativity as a function of baseline amyloid load is greatest for lecanemab, followed by aducanumab, and much smaller for donanemab and gantenerumab. (D) Difference from baseline in plasma Aβ42/Aβ40 ratio at the time of reaching amyloid negativity for different baseline amyloid central amyloid levels. The difference is greatest for lecanemab. Aβ, amyloid beta; Adu, aducanumab; APOE4, apolipoprotein E ε4 allele; CL, centiloids; CSF, cerebrospinal fluid; Dona, donanemab; Gan, gantenerumab; Leca, lecanemab; SUVR, standardized uptake value ratio.

FIGURE 3

SUVR AMYLOID dynamics in maintenance treatment for a 75‐year‐old APOE4+ subject after reaching amyloid negativity and switching to increasing intervals (in months) at the last dose for (A) donanemab, (B) lecanemab, and (C) aducanumab. (D) Central amyloid levels attained 10 years after regular treatment until amyloid negativity, followed by maintenance treatment at different intervals for the different antibodies. Time at which dosing is switched to maintenance is indicated with the arrow. In order to keep amyloid levels below the positivity threshold (25 CL) for this period, aducanumab and donanemab can be given every 48 and >60 months respectively, while lecanemab needs to be applied every 24 months. Adu, aducanumab; CL, centiloids; Dona, donanemab; Leca, lecanemab; SUVR, standardized uptake value ratio.

FIGURE 4

(A) Additional delay for reaching amyloid negativity after interrupting treatment for 12 weeks after an ARIA‐E incident at a specific time after treatment start. After the incident treatment is restarted using a conservative titration schedule of single 1 mpk, 3 mpk, 6 mpk (and 10 mpk for donanemab) doses Q4W before reaching the original dosing before the ARIA‐E. The delay ranges from 3 to 7 months and is smallest for donanemab. While the delay for lecanemab (between 4 and 5 months) is independent of the timing, for both donanemab and aducanumab the delay increases as the incident happens later, likely due to interference with the titration schedule. (B). Introduction of a 3‐month drug holiday in the titration schedule in the absence of ARIA‐E at any time during the first 12 months can maximally reduce ARIA‐E liability with 8% for lecanemab, 12% for donanemab, and 18% for aducanumab. ARIA‐E at time t = 0 months reflects the maximal liability using the titration schedules of the Phase 3 studies. The greatest impact is for an early drug holiday (first two months) for lecanemab and donanemab, while the window between 4 and 10 months is optimal for aducanumab. Adu, aducanumab; ARIA‐E, amyloid‐related imaging abnormality–edema; Dona, donanemab; Leca, lecanemab.

FIGURE 5

Virtual patient trial of 200 APOE4+ subjects (50% female) with an average age of 75 ± 13 years and a baseline central amyloid of 124 ± 45 CL and each patient treated with the three different antibodies with their appropriate titration schedules. (A) Titration schedules for the three antibodies. (B) The fraction of amyloid negative patients at any time is greatest for donanemab, while aducanumab catches up with lecanemab only at 18 months. (C) Box‐and whisker plots (median, upper and lower quartile) for central amyloid reduction showing the greatest effect for donanemab. (D) By defining a therapeutic index as fractional central amyloid reduction normalized to baseline divided by ARIA‐E liability, lecanemab has on average the greatest impact compared to aducanumab and donanemab on the same patient population. (E) Diagram showing the fraction of patients for which the therapeutic index is the highest, demonstrating that the majority has the greatest benefit with lecanemab, although sizeable minorities have better outcome with aducanumab and donanemab. ADU, aducanumab; APOE4, apolipoprotein E ε4 allele; CL, centiloids; DONA, donanemab; LECA, lecanemab; mpk, mg/kg; SUVR, standardized uptake value ratio.

FIGURE 6

Simulation of biomarkers in Down syndrome patients when treated at 47 years using the titration schedule for the Phase 3 studies in AD with 25% non‐APOE4 and 75% APOE4+ carrier. (A) Central amyloid decrease is much greater for donanemab compared to aducanumab and lecanemab. (B) For APOE4+ patients, the same order is observed for ARIA‐E side effects with donanemab a much greater liability. (C) Despite having a relatively modest central amyloid reduction, lecanemab has the greatest effect on protofibril clearance. (D) Lecanemab is superior with regard to the therapeutic index, defined as the ratio of normalized central amyloid decline divided by ARIA‐liability. These outcomes are qualitatively similar for different trial start dates. AD, Alzheimer's disease; ADU, aducanumab; APOE4, apolipoprotein E ε4 allele; ARIA‐E, amyloid‐related imaging abnormality–edema; CL, centiloids; DONA, donanemab; LECA, lecanemab; mpk, mg/kg; PLA, placebo; SUVR, standardized uptake value ratio.