Warren Greth

Sifalimumab, a Human Anti–Interferon‐α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose‐Escalation Study

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.

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study

Objectives The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physicians Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (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 on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. Trial registration number NCT01283139; Results.

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Objective To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. Methods A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. Results The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. Conclusions Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecules mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

Incidence and prevalence of adult systemic lupus erythematosus in a large US managed-care population

Objective The objective of this paper is to determine the incidence and prevalence of adult systemic lupus erythematosus (SLE) in a large US managed-care population. Methods Subject inclusion in the incidence cohort required a medical claim with an SLE diagnosis and a service date from 2003 to 2008 that satisfied the following criteria: 1) ≥18 years on service date; 2) continuously enrolled for 24 months before and 12 months after service date; 3) in the 12 months after service date, ≥ one inpatient claim or ≥ two office or ER visits with an SLE diagnosis; 4) no SLE diagnosis 24 months prior to service date; and 5) no SLE medications 12 months prior to service date. Prevalence cohort subjects were identified using a similar algorithm and were not required to satisfy criteria 4) and 5). Results A total of 1,557 subjects were included in the incidence cohort, and 15,396 were included in the prevalence cohort. The overall age- and gender-adjusted SLE incidence rate (2003–2008) was 7.22 cases per 100,000 person-years. The annual prevalence of SLE (per 100,000 individuals) varied from 81.07 in 2003 to 102.94 in 2008. Conclusion The SLE incidence in this large managed-care plan with geographic diversity was slightly higher than previous estimates, and the prevalence was within the range of previous estimates.

Resource utilization and direct medical costs in adult systemic lupus erythematosus patients from a commercially insured population

Objective Our aim was to estimate annual health care resource use and medical costs associated with systemic lupus erythematosus (SLE) in a large US managed care health plan. Methods Subjects at least 18 years of age and with claims-based evidence of SLE (ICD-9-CM 710.0x) were identified from a health plan database. Subjects were matched on the basis of demographic and clinical characteristics to unaffected controls. Resource use and costs were determined during a fixed 12-month period. A generalized linear model (GLM) was used to adjust costs for demographic and clinical characteristics. Results In total, 1278 newly diagnosed SLE subjects were matched to 3834 controls, and 10,152 subjects with existing SLE were matched to 30,456 controls. Health care resource use was significantly higher among SLE subjects than matched controls, including average annual numbers of ambulatory visits, specialist visits, and inpatient hospital stays (all p < 0.001). SLE subjects had significantly higher overall mean annual medical costs than matched controls (newly diagnosed:

Suppression of soluble T cell-associated proteins by an anti-interferon-α monoclonal antibody in adult patients with dermatomyositis or polymyositis

19,178 vs.

Impaired Health Status and the Effect of Pain and Fatigue on Functioning in Clinical Trial Patients with Systemic Lupus Erythematosus

4909; existing:

Epidemiology of Systemic Sclerosis in a Large US Managed Care Population

15,487 vs.

Medical costs and healthcare resource use in patients with lupus nephritis and neuropsychiatric lupus in an insured population

5156; both p < 0.001). Evidence of specific organ involvement including renal failure and central nervous system complications, were each associated with increased costs (both p < 0.001). Conclusions Subjects with SLE have high resource use and medical costs relative to controls.

Annual Medical Costs and Healthcare Resource Use in Patients with Systemic Sclerosis in an Insured Population

Objective. The aim of this study was to identify serum markers that are modulated by an investigational anti-IFN-α mAb, sifalimumab, in adult DM or PM patients. Methods. In a phase 1b clinical trial, sera were collected from a total of 48 DM or PM adult patients receiving either placebo for 3 months or sifalimumab for 6 months. Samples were tested for 128 selected proteins using a multiplex luminex immunoassay. Muscle biopsies from selected patients were stained for T cell infiltration using an anti-CD3 antibody. Results. A robust overexpression of multiple serum proteins in DM or PM patients was observed, particularly in patients with an elevated baseline type I IFN gene signature in the blood or muscle. Neutralization of the type I IFN gene signature by sifalimumab resulted in coordinated suppression of T cell-related proteins such as soluble IL-2RA, TNF receptor 2 (TNFR2) and IL-18. Muscle biopsies from two patients with the highest serum protein suppression were selected and found to have a pronounced reduction of muscle T cell infiltration. Down-regulation of IL-2RA correlated with favourable manual muscle test 8 (MMT-8) alterations in sifalimumab-dosed patients. Conclusion. A reduced level of multiple T cell-associated proteins after sifalimumab but not placebo administration suggests a suppressive effect of blocking type I IFN signalling on T cell activation and chemoattraction that may lead to a reduction of T cell infiltration in the muscle of myositis patients. Further, soluble IL-2RA changes from baseline may serve as a responsive and/or predictive marker for type I IFN-targeted therapy in adult DM or PM patients.