Faculty Bibliography

Background/Purpose: The efficacy and safety of anifrolumab (ANIFR), a type I IFN receptor antagonist, were assessed in a Phase II, randomized, double-blind, placebo-controlled study in SLE (NCT01438489). Methods: Three hundred and five adults with seropositive moderate to severe SLE despite standard of care medication were randomized and received intravenous (iv) ANIFR (300 mg, 1000 mg) or placebo (PBO) every 4 weeks for 48 weeks. Patients were stratified by SLEDAI score, oral corticosteroid (OCS) dose, and IFN gene signature (IFN high vs. IFN low) based on a 4-gene expression assay. Disease activity was assessed by SLEDAI-2K, BILAG 2004, Physician's Global Assessment, CLASI, BICLA, and 28-joint count. The primary endpoint was a composite of SRI(4) response at Day 169 with sustained reduction of OCS (<10 mg/day and 10 mg/day at baseline. Other efficacy measures of systemic and organ-specific disease activity and safety were also assessed at Day 365. Results: The primary endpoint at Day 169 was met by a greater proportion of ANIFR-treated patients vs. PBO (PBO: 17.6%; 300 mg: 34.3%, p=0.014; 1000 mg: 28.8%, p=0.063). At Day 365, the secondary SRI endpoint was met by 25.5% of PBO, 51.5% of 300 mg (p<0.001) and 38.5% of 1000 mg (p=0.048) patients. OCS reduction to <7.5 mg/day at Day 365 was achieved by 26.6% of PBO, 56.4% of 300 mg (p=0.001) and 31.7% of 1000 mg (p=0.595) patients. ANIFR demonstrated consistent benefit across multiple global and organ-specific measures at Day 365 (Table), as well as lower rates of BILAG moderate/severe flares/patient-year (PBO: 0.611; 300 mg: 0.266; 1000 mg: 0.391). 75% of patients were IFN high at baseline. The ANIFR efficacy observed in the entire cohort was similar or more pronounced in IFN high patients. Median suppression of 21 IFN-regulated genes was ~90% for both doses of ANIFR. Serious adverse events were reported in 18.8% of patients on PBO and 16.7% of patients in the pooled ANIFR groups. A higher frequency of influenza (most unconfirmed) (PBO: 1.0%; 300 mg: 6.1%; 1000 mg: 7.6%) and a dosage-dependent increase in Herpes zoster (PBO: 2.0%; 300 mg: 5.1%; 1000 mg: 9.5%) occurred in the ANIFR arms. Conclusion: Anifrolumab significantly reduced disease activity compared with PBO across multiple clinical endpoints. Enhanced effects in IFN high patients support the pathobiology of this treatment strategy. The lack of dose response can be explained by the nearly similar degrees of IFN gene signature inhibition achieved with the two anifrolumab doses. These data strongly support further development of anifrolumab. (Table Presented)

INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for >/= 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naive B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.