Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study

Abstract

Objective: To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).

Methods: In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results: Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n=4) versus 2.5% (n=1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion: The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

Trial registration: ClinicalTrials.gov NCT00482989.

Figure 1

Disposition of the patients. The asterisk indicates a patient who did not meet the inclusion criteria but was inadvertently randomized without receiving the study drug. This patient was excluded from the intent-to-treat (ITT) population.

Figure 2

Pharmacokinetics (PK) and pharmacodynamics of sifalimumab over time in patients with systemic lupus erythematosus (PK population). A, Serum concentrations of sifalimumab. Patients who missed the last 3 doses were excluded from the analysis. Values are the mean ± SD. B, Type I interferon (IFN)–inducible gene signature in whole blood. The type I IFN signature was inhibited by sifalimumab during the treatment phase. Values are the mean fraction of remaining type I IFN signature, using a 21-gene panel, in patients with an increased type I IFN signature at baseline.

Figure 3

Change from baseline in disease activity, as determined by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in patients with SLE (modified intent-to-treat population). A, Combined sifalimumab group (n = 121) and placebo group (n = 40). B, Combined sifalimumab group (n = 121) and placebo group (n = 40) adjusted for burst steroids in excess of that permitted in the protocol. Patients' baseline values were imputed for the value after excess steroid use (dose and duration). C, Subgroup of patients with a high type I interferon (IFN)–inducible gene signature (using a 4-gene panel) at baseline (n = 92 in the sifalimumab group and n = 30 in the placebo group). D, Subgroup of patients with a high type I IFN–inducible gene signature at baseline adjusted for burst steroids in excess (dose or duration) of that permitted in the protocol (and as described in B) (n = 92 in the sifalimumab group and n = 30 in the placebo group). Values are the mean.