Targeting the interferon pathway with sifalimumab for the treatment of systemic lupus erythematosus.

Dysregulation of the type I interferon (IFN) system is associated with various immunologic diseases, such as systemic lupus erythematosus (SLE). Targeting this dysregulation presents an attractive approach for SLE therapy. Sifalimumab, a fully human immunoglobulin G1 κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes, has been recently evaluated in a Phase IIb study in patients with moderate to severe SLE. Insights gained from earlier studies were used to inform design of the Phase IIb study, to provide a more comprehensive evaluation of sifalimumab. Sifalimumab demonstrated broad efficacy across composite and organ-specific end points, suggesting that targeting of IFN-α is a promising treatment option for SLE, particularly for those patients whose disease is refractory to current standard of care.

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), Physician's 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.

Population pharmacokinetic analysis of sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients.

AIMS: Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients. METHODS: PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200-1200 mg) of sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap. RESULTS: A two compartment model with first order elimination adequately described sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1 ) were 184 ml day(-1) and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for <10% of PK variability in the final model. Typical values and BSV of PK parameters from the current analysis with fixed dosing were similar to previous population PK results with body weight normalized dosing. CONCLUSIONS: The transition from body weight normalized dosing to fixed dosing did not impact sifalimumab PK. These findings support the use of fixed dosing for sifalimumab in future clinical studies evaluating it as a potential treatment for SLE.

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 molecule's 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.

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

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.

Impaired health status and the effect of pain and fatigue on functioning in clinical trial patients with systemic lupus erythematosus.

OBJECTIVE: Our study evaluated the impaired health status of clinical trial patients with systemic lupus erythematosus (SLE) and explored the relationship between changes in fatigue and pain and their effect on overall health status. METHODS: Pooled treatment and placebo data from a phase Ib clinical trial of adults with moderate/severe SLE were analyzed. Measures included patient-reported Medical Outcome Study Short Form-36 Survey, Version 2 (SF-36v2), Fatigue Severity Scale, and numeric rating scales (NRS) for pain and global health assessment and clinician-reported global assessment of disease activity (MDGA). Disease burden was compared to the US general population. Health status of responders and nonresponders on pain or fatigue were compared. RESULTS: The sample included 161 patients with SLE, predominantly female (96%) and white (72%), with average age of 43 ± 11 years. Mean SF-36v2 component summary scores reflected overall problems with physical [physical component summary (PCS); 35.2 ± 9.7] and mental health (mental component summary; 40.9 ± 12.9). Patients with SLE had worse health status on all SF-36v2 subscales than the US general population and comparable age and sex norms (effect size -0.51 to -2.15). Pain and fatigue responders had greater improvements on SF-36v2 scores (bodily pain, physical functioning, social functioning, PCS), patient global health assessment NRS, and MDGA than nonresponders. There was moderate agreement in responder status, based on global assessments by patients and clinicians (68.1%), with some discrepancy between patients who were MDGA responders but patient assessment nonresponders (27.7%). CONCLUSION: Improvements in patient-reported pain or fatigue correlated with improvements in overall health. Patient assessments offer a unique perspective on treatment outcomes. Patient-reported outcomes add value in understanding clinical trial treatment benefits.

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.

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

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organ systems, including the kidneys (lupus nephritis) and the central nervous system (neuropsychiatric lupus, or NPSLE). The healthcare costs and resource utilization associated with treating lupus nephritis and NPSLE in a large US managed care plan were studied. METHODS: SLE subjects ≥18 years of age and with claims-based evidence of nephritis or neuropsychiatric conditions were identified from a health plan database. An index date was set as a randomly drawn date from all qualifying claims during 2003-2008 for study subjects. Subjects were matched on the basis of demographic and clinical characteristics to unaffected controls. Costs and resource use were determined during a fixed 12-month post-index period. RESULTS: Nine hundred and seven lupus nephritis subjects were matched to controls, and 1062 subjects with NPSLE were matched to controls. Mean overall post-index healthcare costs were significantly higher among subjects with lupus nephritis in comparison to matched controls ($33,472 vs $5347, p < 0.001). Similarly, mean overall post-index healthcare costs were significantly higher among subjects with NPSLE compared to controls ($30,341 vs $4646, p < 0.001). Subjects with lupus nephritis or NPSLE had higher mean post-index numbers of ambulatory visits, specialist visits, emergency department visits and inpatient hospital stays, compared to controls (all p < 0.001). LIMITATIONS: Additional research, such as medical chart review, could provide validation for the claims-based identification of lupus nephritis and NPSLE subjects. Also, indirect costs were not evaluated in this study. CONCLUSION: Subjects with lupus nephritis or NPSLE have high costs and resource use, compared to unaffected controls.

Annual medical costs and healthcare resource use in patients with systemic sclerosis in an insured population.

OBJECTIVE: Systemic sclerosis (SSc) is a chronic autoimmune disease. The objective of our study was to estimate the medical costs and healthcare resource use of subjects with SSc in a large US managed care plan. METHODS: Subjects at least 18 years of age and with claims-based evidence of SSc (ICD-9-CM code 710.1x) were identified from a health plan database from 2003 through 2008. Subjects were matched to unaffected controls, based on index date, age, sex, geographic region, time on insurance, and comorbidity score. Costs and resource use were identified during the 12-month postindex period. A generalized linear model (GLM) was used to estimate costs, controlling for demographic and clinical characteristics. RESULTS: In this study, 1648 subjects with SSc were matched to 4944 controls. Mean overall annual medical costs were higher among SSc subjects than controls ($17,365 vs $5,508; p < 0.001). A GLM model supported these results. Evidence of lung disease, gastrointestinal bleeding, or renal disease increased costs (all p < 0.001). Compared to controls, significantly higher proportions of SSc subjects had postindex ambulatory visits, emergency department visits, and inpatient hospital stays (all p < 0.001). CONCLUSION: Our findings suggest that the medical costs and resource use associated with treating SSc are high (compared to matched controls), and as expected, subjects with serious disease complications experience the highest costs.

Epidemiology of systemic sclerosis in a large US managed care population.

OBJECTIVE: To estimate the incidence and prevalence of systemic sclerosis (SSc) in a large US managed care organization (MCO) database. METHODS: Subjects with claims-based evidence of SSc (ICD-9-CM code 710.1x) were identified from a health plan database. Incidence and prevalence for the period 2003-2008 were calculated. RESULTS: The overall age- and sex-adjusted incidence rate (2003-2008) for SSc was 5.6 cases per 100,000 person-years. The annual prevalence of SSc ranged from 13.5 in 2003 to 18.4 (per 100,000) in 2008. CONCLUSION: This analysis suggests a higher incidence and lower prevalence of SSc in this MCO than those previously reported for the United States.