Background: Evidence from preclinical studies suggests that IL-6 signalling has the potential to modulate immunopathogenic mechanisms upstream of autoantibody effector mechanisms in patients with generalised myasthenia gravis. We aimed to assess the safety and efficacy of satralizumab, a humanised monoclonal antibody targeting the IL-6 receptor, in patients with generalised myasthenia gravis.

Methods: LUMINESCE was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study at 105 sites, including hospitals and clinics, globally. Eligible patients were aged 12 years and older, with seropositive generalised myasthenia gravis (autoantibodies to the acetylcholine receptor [AChR-IgG], muscle-specific kinase [MuSK-IgG], or low-density lipoprotein receptor-related protein 4 [LRP4-IgG]), a Myasthenia Gravis Foundation of America severity class II-IV, a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 5 or more (non-ocular contribution >50%), and use of stable background therapy. Patients were randomly assigned (1:1) with a permuted-block randomisation method to receive subcutaneous satralizumab (120 mg for bodyweight ≤100 kg; 180 mg for bodyweight >100 kg) or placebo at weeks 0, 2, 4, and every 4 weeks thereafter until week 24. Randomisation was stratified according to background therapy, autoantibody type, and geographical region. The primary efficacy endpoint was mean change from baseline in total MG-ADL score at week 24 in the modified intention-to-treat population (all randomised AChR-IgG-positive patients who completed at least one post-baseline MG-ADL assessment). Safety was assessed in all randomly assigned patients who received at least one dose of study drug. The open-label extension was terminated early because of the sponsor's decision to halt further development of satralizumab for treatment of generalised myasthenia gravis. This trial is registered with ClinicalTrials.gov, NCT04963270, and EudraCT, 2020-004436-21.

Findings: Between Oct 19, 2021, and Aug 15, 2023, 188 patients were randomly assigned to satralizumab (n=96) or placebo (n=92). 166 AChR-IgG-positive patients (80 in the placebo group and 86 in the satralizumab group) were included in the modified intention-to-treat population. At week 24, statistically significant yet small improvements in MG-ADL score were observed with satralizumab versus placebo (adjusted mean -3·59, 95% CI -4·15 to -3·02 vs -2·57, -3·25 to -1·88; difference -1·02, -1·88 to -0·16; p=0·0120). The proportion of patients with at least one adverse event during the double-blind period was slightly higher in patients treated with satralizumab compared with patients treated with placebo (86 [90%] patients vs 67 [73%] patients). Three serious adverse events (in three [3%] patients) were reported in the satralizumab group (pneumonia, pyelonephritis, and increased lipase) compared with nine (in six [7%] patients) serious adverse events in the placebo group (COVID-19, COVID-19 pneumonia, bacterial urinary tract infection, chest pain, back pain, and rosacea). There were no deaths or adverse events of special interest.

Interpretation: Satralizumab was well tolerated and resulted in small improvements in patient-reported and clinician-reported outcomes compared with placebo at week 24 in patients with AChR-IgG-positive generalised myasthenia gravis. Further research analysing the immunological underpinnings of the observed clinical response to IL-6 signalling inhibition in patients with generalised myasthenia gravis and exploring the role of IL-6 in autoantibody-mediated diseases is warranted.

Funding: F Hoffmann La Roche.

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(24)00514-3DOI Listing

Publication Analysis

Top Keywords

myasthenia gravis
32
generalised myasthenia
28
patients
18
patients generalised
16
mg-adl score
12
randomly assigned
12
adverse events
12
satralizumab
10
myasthenia
9
safety efficacy
8

Similar Publications

The role of IL-6 blockers in myasthenia gravis.

Lancet Neurol

February 2025

Department of Neurological Sciences, Robert Larner MD College of Medicine, University of Vermont and the University of Vermont Medical Center, Burlington, VT 05401, USA.

View Article and Find Full Text PDF

Background: Evidence from preclinical studies suggests that IL-6 signalling has the potential to modulate immunopathogenic mechanisms upstream of autoantibody effector mechanisms in patients with generalised myasthenia gravis. We aimed to assess the safety and efficacy of satralizumab, a humanised monoclonal antibody targeting the IL-6 receptor, in patients with generalised myasthenia gravis.

Methods: LUMINESCE was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study at 105 sites, including hospitals and clinics, globally.

View Article and Find Full Text PDF

Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study.

View Article and Find Full Text PDF

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated disorder strongly associated with antigen presentation by dendritic cells (DCs). In MG, mucosal tolerance is linked to increased expression of TGF-β mRNA in monocytes. Additionally, monocytic myeloid-derived suppressor cells (M-MDSCs) exhibit negative immunomodulatory effects by suppressing autoreactive T and B cells.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!