Innovative Therapies Show Promise Improving MG Symptoms

A new review of the latest therapies for myasthenia gravis (MG), including investigational ones, suggests that both complement inhibitors and neonatal Fc receptor (FcRn) blockers are effective at improving symptoms, though the study found no significant improvement among patients taking rituximab (Rituxan).

The authors cautioned, however, that the results were based on a meta-analysis of heterogeneous studies. They said longer-term, real-world evidence would be needed to validate the results. The findings were published in the European Journal of Neurology.

Treatment for the rare autoimmune disease has historically relied on treatment of symptoms, immunomodulating therapies, and thymectomy, noted corresponding author Francesco Saccà, MD, of Federico II University, in Italy. Still, many patients continue to experience symptoms, leading drug developers to devise several new strategies. Those new tactics include the anti-CD20 monoclonal antibody rituximab, along with complement inhibitors and FcRn blockers.

“The rationale for complement blockade consists in counteracting the effects of complement activation that result in neuromuscular junction membrane damage and morphology disruption,” Saccà and colleagues explained. Three complement blockers—all targeting complement factor 5—have so far been tested in phase 3, randomized, placebo-controlled trials of patients with generalized MG (gMG), the authors said. They are the monoclonal antibody eculizumab (Soliris), the monoclonal antibody ravulizumab (Ultomiris), and the subcutaneous peptide zilucoplan. The first 2 require intravenous administration, while the latter is a self-injection.

FcRn blockers reduce circulating levels of immunoglobulin G (IgG) on the FcRN receptor, Saccà and colleagues said.

“This reduction is thought to counteract all three proposed pathological mechanisms present in Ab-AChR (acetylcholine receptor)-positive gMG,” the authors said, “namely blockade of the neuromuscular junction, internalization and destruction of the AChR, and complement activation.”

About 85% of patients with MG are positive for AChR antibodies. The 2 anti-FcRn therapies to be subjected to phase 3 placebo-controlled randomized trials are the intravenously infused engineered human Fc-fragment efgartigimod (Vyvgart), and the subcutaneously infused monoclonal antibody rozanolixizumab.

All 5 therapies have had varying degrees of success in their clinical trials, but in general they showed success in reducing MG Activities of Daily Living scores (MG-ADL), an indication that patients were better able to go about daily activities such as talking, rising from a chair, and performing grooming tasks like brushing their teeth.

Still, with all of the new data—and more slated to come in the coming years—Saccà and colleagues decided to compile the most recent findings in hope of bringing clarity to the current MG treatment landscape.

The investigators searched for scientific literature related to MG therapies, specifically seeking studies that were double-blind, randomized, and placebo-controlled, and which reported MG-ADL scores and other key metrics. The 7 studies eventually included in the meta-analysis were all published between 2017 and 2022.

Overall, the studies showed the therapies led to a mean overall change in MG-ADL scores of –2.17 points (95% CI, –2.67, –1.67; P <.001). Complement inhibitors and FcRn blockers performed equally well, with no significant difference noted. On another scale, the Quantitative Myasthenia Gravis (QMG) scale, the mean change in score was –3.46 points (95% CI –4.53, 2.39; P <.001). On that scale, FcRn blockers (–4.78 change) outperformed complement inhibitors (–2.60 change). Rituximab lowered patients’ scores on both the MG-ADL and QMG scales, but neither reduction was statistically significant, the authors said.

“In the network meta-analysis, efgartigimod had the highest probability of being the best treatment, followed by rozanolixizumab,” the authors concluded.

The authors reiterated that a meta-analysis such as this comes with significant limitations, including different time frames due to the different dosing patterns of the various therapies. Still, they said these early data suggest anti-complement and FcRn therapies both have significant potential to improve the lives of patients with MG.

Reference

Saccà F, Pane C, Espinosa PE, Sormani MP, Signori A. Efficacy of innovative therapies in myasthenia gravis: A systematic review, meta-analysis and network meta-analysis. Eur J Neurol. Published online May 19, 2023. doi:10.1111/ene.15872