AB0445 Exposure–Efficacy Analysis of Mavrilimumab in Rheumatoid Arthritis: Modeling and Simulation of Phase II Clinical Data

Abstract

BackgroundMavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor (GM–CSFR) α, is in Phase IIb investigation for the treatment of rheumatoid arthritis (RA).ObjectivesWe characterized the exposure–efficacy relationship of mavrilimumab with data from two Phase II randomized controlled trials of patients with moderate to severe RA, via population modeling and clinical simulations.MethodsIn a Phase IIa study, adult patients with active RA received 7 subcutaneous administrations of mavrilimumab (10, 30, 50 or 100 mg every other week [eow]). Mavrilimumab pharmacokinetics and efficacy (DAS28–CRP, ACR20/50) were modeled using a population approach. Clinical simulations were performed to facilitate the design of a Phase IIb trial, in which RA patients received placebo or mavrilimumab (30, 100, or 150 mg eow) for 24 weeks. We developed a joint probability model to describe the risk of voluntary dropouts at each scheduled visit of the Phase IIb study. The exposure–response relationship for mavrilimumab was characterized by clinical simulations via the PK-efficacy dropout model.ResultsMavrilimumab and placebo treatment effects observed in the Phase IIa study were adequately described by mechanistic PK-efficacy model. Although mavrilimumab 150 mg eow was not evaluated in the Phase IIa study, improved efficacy was observed at this dosage in Phase IIb, as predicted by a priori clinical simulations. The hazard rate of patient dropout prior to next scheduled visits was significantly greater for non-responders, and substantially greater for lower dosage groups at Week 12, when patient rollover to an open-label extension study was permitted. Clinical simulations indicated that the maximum efficacy was reached at the 150-mg eow dosage.ConclusionsEfficacy outcomes of the Phase IIb study confirmed the rational selection of mavrilimumab 150 mg eow as the best dosage, through modeling of Phase IIa data. Joint modeling of placebo effect, treatment response, and informative dropout greatly facilitates interpretation of Phase IIb results, and will assist in the design of late-stage clinical trials for mavrilimumab.Disclosure of InterestD. Jin Shareholder of: AstraZeneca, Employee of: MedImmune, C.-Y. Wu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune

Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date

“…Although the study was not powered to demonstrate statistical significance between mavrilimumab and golimumab, in sDMARD-IR subgroup, 24-week ACR20, ACR50, and ACR70 response rates seem to be apparently lower in the mavrilimumab-treated patients compared with golimumab (53.8%, 35.9%, and 10.3% vs 69.4%, 44.4%, and 27.8%, respectively) 62. However, the authors argued that the dose adopted in this study might be suboptimal as compared to the one (150 mg eow) predicted as most effective by the previously described exposure–response relationship simulation58 and subsequently confirmed by the results of EARTH EXPLORER 1 study 61. This argument is reasonable because ACR20, ACR50, and ACR70 response rates in the 150 mg group of EARTH EXPLORER 1 study seem to be higher (73.4%, 40.5%, and 13.9%, respectively) compared with the 100 mg group of EARTH EXPLORER 2 study (53.8%, 35.9%, and 10.3%, respectively) and comparable with the golimumab group of EARTH EXPLORER 2 study (69.4%, 44.4%, and 27.8%, respectively).…”

“…This explorative analysis indicated a priori that the maximum efficacy may be reached at the 150 mg eow dosage, although this mavrilimumab regimen was not evaluated in EARTH studies 58. According to these findings, in the subsequent 24-week randomized, double-blind, placebo-controlled phase IIb EARTH EXPLORER 1 trial, 326 sDMARD-insufficient responder RA patients were randomized to receive three different mavrilimumab eow doses including 150 mg (30 mg, n=81; 100 mg, n=85; or 150 mg, n=79) or placebo (n=81) in association with MTX.…”

A Promising Target in Rheumatoid Arthritis Treatment: Granulocyte-Macrophage Colony-Stimulating Factor

“…Results of phase IIb study (EARTH EXPLORER 1) were presented recently as abstracts [46][47][48][49][50][51][52]. The aim of the study was to evaluate the efficacy and safety of mavrilimumab in moderate to severe (DAS28-CRP ≥3.2; ≥4 swollen joint) RA patients with an inadequate response to ≥1 DMARDs.…”