Background/Purpose:

Efficacy and safety of sifalimumab were assessed in a Phase 2b, randomized, double-blind, placebo (PBO)-controlled study in subjects with SLE (NCT01283139).

Methods:

Adults (n=431) with seropositive moderate to severe SLE, despite standard of care treatment, were randomized (1:1:1:1) to monthly IV sifalimumab 200, 600, 1200 mg, or PBO for 1 year. Minimum disease activity for entry: SLEDAI-2K ≥6 and 1 BILAG A or 2Bs and MDGA ≥1. Randomization was stratified by disease activity, IFN 4-gene signature, and geographic region. The primary efficacy endpoint was SLE Responder Index (4) response at Day 365. Other endpoints measured disease activity, using global and organ-specific measures, fatigue, safety, and tolerability.

Results:

Baseline characteristics were similar across all groups: (mean age 39.4 years; 92.3% female; 58.7% Caucasian, 15.1% Asian, 7.7% black). Subjects had a mean duration of SLE of 8.2 years; SLICC/ACR damage score 0.7; SLEDAI-2K, 11.3. 81.2% had a positive IFN gene signature. Low C3 was seen in 42.9%, low C4 in 26.7% and elevated dsDNA antibody in 26.5% of subjects at baseline. The percentage achieving SRI(4) response at Day 365 were significantly higher for sifalimumab 200, 600, and 1200 mg (58.3%, 56.5%, 59.8%, respectively) vs PBO (45.4%; effect size 1200 mg vs PBO 14.4 percentage points; p=0.031; Table). Analyses of more stringent SRI(6–8) endpoints demonstrated even greater discrimination between the 1200 mg dose and PBO. In subjects with moderate/severe baseline mucocutaneous involvement (CLASI≥10), significantly higher percentages had a ≥4 point decrease in CLASI on sifalimumab 200 mg (72.7%) and 1200 mg (73.1%) vs PBO (48.6%). Significant improvements in the sifalimumab vs PBO arms were seen in joint counts and numerical improvements were seen in FACIT-Fatigue scores. Baseline low complement levels and elevated dsDNA levels did not normalize over time. A direct comparison of IFN gene signature positive and negative subjects was not possible due to the low proportion of IFN negative subjects but the trend was in favor of signature status driving response. There were six deaths during the study; four deaths in the total sifalimumab group and two deaths in the PBO group. Most commonly reported adverse events (AEs) were similar across groups including worsening SLE (sifalimumab 30.0% vs PBO 34.3%), urinary tract infection (17.6% vs 13.9%), and headache (13.3% vs 13.9%). Serious AEs were reported in 18.3% (sifalimumab) vs 17.6% (PBO) of subjects. Herpes zoster occurred more frequently in sifalimumab groups (200 mg, 4.6%; 600 mg, 3.7%; 1200 mg, 8.4%) vs PBO (0.9%).

Conclusion:

In this study, the primary endpoint was achieved. Sifalimumab reduced SLE disease activity across multiple clinical measures, and had an acceptable safety profile in both IFN signature positive and negative subjects. These data support IFN-alpha as a promising therapeutic target in SLE.