Maintenance of zilucoplan efficacy in patients with generalised myasthenia gravis up to 24 weeks: a model-informed analysis

Abstract

Background: Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available.

Objectives: Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks.

Design: A model-informed analysis (MIA) within a Bayesian framework.

Methods: Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed.

Results: At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG.

Conclusion: This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.

Keywords: Bayesian; C5; complement inhibitor; external comparator; meta-regression analysis; model-informed analysis; myasthenia gravis; zilucoplan.

Figure 1.

Evolution of predicted mean change from baseline (and associated 95% CrI) in MG-ADL score through week 24. Primary analysis: Data from the double-blind studies, including RAISE-XT data for patients randomised to zilucoplan in the double-blind studies, were included in Part 2. A linear model with log time using the historical prior. Sensitivity analysis 1: Placebo data from the phase II study were included in Part 1. Data from RAISE only were included in Part 2. A linear model with log time using the historical prior. CrI, credible interval; MG-ADL, myasthenia gravis activities of daily living.

Figure 2.

Distribution of the difference between zilucoplan and control in predicted mean changes from baseline to week 24 in MG-ADL score. A negative value in the difference (zilucoplan minus control) corresponds to an improvement in MG-ADL score. Primary analysis: Data from the double-blind studies, including RAISE-XT data for patients randomised to zilucoplan in the double-blind studies, were included in Part 2. A linear model with log time using the historical prior. CrI, credible interval; MG-ADL, myasthenia gravis activities of daily living.

Figure 3.

Evolution of predicted mean change from baseline (and associated 95% CrI) in QMG score through week 24. Primary analysis: Data from the double-blind studies, including RAISE-XT data for patients randomised to zilucoplan in the double-blind studies, were included in Part 2. A linear model with log time using the historical prior. Sensitivity analysis 1: Placebo data from the phase II study were included in Part 1. Data from RAISE only were included in Part 2. A linear model with log time using the historical prior. CrI, credible interval; QMG, quantitative myasthenia gravis.