Sifalimumab, an anti-interferon-α (IFN-α) immunoglobulin G monoclonal antibody, is a promising treatment option for adults with moderate to severe systemic lupus erythematosus (SLE), according to data published in Annals of Rheumatic Diseases.
Clinical trials have established its safety profile and its suppression of IFN-α-induced genes. In the phase IIb dose-ranging trial (ClinicalTrials.gov Identifier NCT01283139), researchers sought to evaluate the efficacy and safety of 3 fixed intravenous doses of sifalimumab in adults with moderate to severe SLE with inadequate responses to standard-of-care treatments.
Eligible study participants fulfilled at least 4 of the American College of Rheumatology criteria for SLE, with a disease history ≥ 24 weeks at time of baseline screening, who were currently on stables doses of oral corticosteroids and/or immunosuppressants. Patients with neuropsychiatric SLE, severe SLE-driven renal disease, or evidence of clinically active infection were excluded from this study.
The researchers randomly assigned 431 patients to receive monthly intravenous infusions of sifalimumab at 200 mg, 600 mg, or 1200 mg, or placebo in addition to standard-of-care medications. They stratified patients by disease activity, interferon gene signature test, and geographical region. The primary outcome measure was defined as the percentage of patients achieving an SLE responder index (SRI) response at 52 weeks.
At all dosages, a greater percentage of patients who received sifalimumab achieved an SLE responder index response at week 52 as compared to placebo (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg: 59.8%).
Researchers also observed improvements with sifalimumab in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (CLASI; 200 mg and 1200 mg monthly), Physician’s Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA; 1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score, and reductions in counts of swollen joints and tender joints.
Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients taking sifalimumab. Researchers also observed more herpes zoster infections among the patients taking sifalimumab.
“The broad-based improvement measured in both SLE composite endpoints (SRI4, BICLA) and individual organ systems (CLASI, joint counts) supports preclinical and clinical evidence that IFN-α plays an important role in SLE pathogenesis,” the authors of the study wrote.
“Although the 1200 mg dosage provided the most consistent results, no clear sifalimumab dosage effect was observed in the study. These potentially promising results are important in early drug development, but are not definitive until prospectively replicated in larger studies with a more stringent statistical significance level.”
Summary and Clinical Applicability
The phase IIb study demonstrated greater efficacy with IFN-α therapy than with placebo in the treatment of patients with moderate to severe SLE. However, the authors note that modulation of the type I IFN pathway can potentially disrupt mechanisms of viral defense and therefore increase susceptibility to viral infections or malignancies. Further, larger studies are required to demonstrate those at highest risk for complications.
“The clinical effects of sifalimumab are supported by improvements in both global and organ-specific outcome measures, with an acceptable safety profile,” the authors noted. “Our observations demonstrate that blocking the type I IFN pathway is a promising approach for the treatment of moderate to severe active SLE.”
Limitations and Disclosures
Researchers observed a modest proportion of adverse effects in the overall patient population. The discrimination between the sifalimumab and placebo groups was greater in the low standard-of-care response regions, which may have caused geographical disparities in the data. Further investigation of these regional anomalies is required.
Additionally, the overall effect sizes observed in this population were modest, and the lack of a clear dose response curve to sifalimumab warrant further study.
Several authors disclosed financial ties to MedImmune, which funded the study.
Khamashta M, Merril JT, Werth VP, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study. Ann Rheum Dis. 2016; doi: 10.1136/annrheumdis-2015-208562.