Rozanolixizumab shows limited efficacy in phase 2a trial of severe fibromyalgia

Rozanolixizumab, a neonatal Fc receptor (FcRn) inhibitor, did not demonstrate broad clinical efficacy in patients with severe fibromyalgia in a phase 2A clinical trial published in The Lancet Rheumatology. Although the treatment produced a greater improvement in pain-related interference scores than placebo, the difference was not statistically significant at the conventional 5% significance level and was not considered clinically meaningful at the group level. The findings suggest that reducing circulating immunoglobulin G (IgG) concentrations through FcRn inhibition may not provide substantial benefits across an unselected population of patients with severe fibromyalgia.

Rozanolixizumab is a humanized IgG4 monoclonal antibody that selectively targets FcRn, a receptor involved in protecting IgG from intracellular degradation and regulating its circulating half-life. By blocking the interaction between FcRn and IgG, rozanolixizumab accelerates IgG catabolism and reduces circulating IgG concentrations, including potentially pathogenic autoantibodies. The drug has been approved in several countries for the treatment of generalized myasthenia gravis. Its investigation in fibromyalgia was based on the possibility that IgG-mediated mechanisms contribute to disease manifestations in a subset of patients.

The multicenter, randomized, double-blind, placebo-controlled phase 2A trial enrolled adults aged 18–70 years with severe fibromyalgia at seven sites in northwest England. Participants were required to have a Brief Pain Inventory-Short Form (BPI-SF) interference score of 6 or higher and a 10-day mean daily Pain Numeric Rating Scale score of 6 or higher but below 10. The study aimed to evaluate whether reducing circulating IgG concentrations could improve pain-related interference and other clinical manifestations of fibromyalgia.

Participants were assigned to one of three treatment groups: once-weekly subcutaneous rozanolixizumab 560 mg for 24 weeks (n=22), placebo for 12 weeks followed by rozanolixizumab for 12 weeks (n=20), or placebo for 24 weeks (n=21). The primary endpoint was the mean change from baseline in the BPI-SF interference score at 12 weeks.

Rozanolixizumab was associated with a greater improvement in the primary outcome than placebo, with a least-squares mean difference of −0.5 (80% CI −1.0 to −0.1; p=0.065). This result met the prespecified one-sided 10% significance threshold. However, the difference did not reach statistical significance using the conventional two-sided 5% threshold (95% CI −1.2 to 0.2; p=0.13). Thus, the observed improvement did not establish a meaningful treatment benefit at the group level.

The safety profile was generally reassuring, with no serious treatment-emergent adverse events reported among participants receiving rozanolixizumab. Headache was the most frequently reported treatment-emergent adverse event. During the first 12-week double-blind treatment period, headache occurred in nine (41%) of 22 participants receiving rozanolixizumab and 17 (41%) of 41 receiving placebo. During the second 12-week period, it was reported in 11 (30%) of 37 participants receiving rozanolixizumab and three (15%) of 20 receiving placebo.

According to the investigators, this was the first prospective, randomized study to evaluate serum IgG reduction as a therapeutic approach in fibromyalgia. However, treatment responses varied considerably among participants, suggesting that the underlying disease mechanisms may differ across the study population. One important limitation was the absence of a validated assay to identify patients with pathogenic autoantibodies. Moreover, the investigators could not select participants based on a specific IgG-mediated disease mechanism, which may have contributed to the heterogeneity in treatment response.

The differences observed across treatment-related outcome measures also highlighted the challenges of assessing clinical responses to IgG reduction in fibromyalgia. Further research is needed to clarify the mechanisms underlying any potential treatment effects and identify outcome measures that adequately capture changes in pain, functional interference, and other patient-reported manifestations.

Reference

Goebel A, Meisner P, Rydevik G, Vugler A, Ioannou Y, Tankisheva E, Ewen C, Lambert J, Shaw S, Matthews I. Efficacy and safety of rozanolixizumab in severe fibromyalgia: a phase 2A randomised, double-blind, placebo-controlled, multicentre trial. Lancet Rheumatol. 2026 Nov;8(11):e864-e875.