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Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

ABSTRACT: BACKGROUND:Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in healthy volunteers (HV) and patients with SLE with active cutaneous disease as well as proof of biological activity and preliminary clinical response in the SLE cohort. METHODS:A randomized, double-blind, placebo-controlled clinical trial was conducted in HV (n = 54) and patients with SLE (n = 12). All subjects were monitored for adverse events. Serum BIIB059 concentrations, BDCA2 levels on pDCs, and IFN-responsive biomarkers in whole blood and skin biopsies were measured. Skin disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A). RESULTS:Single doses of BIIB059 were associated with favorable safety and PK profiles. BIIB059 administration led to BDCA2 internalization on pDCs, which correlated with circulating BIIB059 levels. BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score. CONCLUSIONS:Single doses of BIIB059 were associated with favorable safety and PK/PD profiles and robust target engagement and biological activity, supporting further development of BIIB059 in SLE. The data suggest that targeting pDCs may be beneficial for patients with SLE, especially those with cutaneous manifestations. TRIAL REGISTRATION:ClinicalTrials.gov NCT02106897. FUNDING:Biogen Inc.

SUBMITTER: Furie R

PROVIDER: S-EPMC6391094 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

Furie Richard R Werth Victoria P VP Merola Joseph F JF Stevenson Lauren L Reynolds Taylor L TL Naik Himanshu H Wang Wenting W Christmann Romy R Gardet Agnes A Pellerin Alex A Hamann Stefan S Auluck Pavan P Barbey Catherine C Gulati Parul P Rabah Dania D Franchimont Nathalie N

The Journal of clinical investigation 20190218 3

<h4>Background</h4>Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in he ...[more]

PMID: 30645203

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Project description:Sifalimumab is a fully human immunoglobulin G1? monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-?. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT)-based dosing regimens.Sifalimumab serum concentration-time data were collected from a phase Ib study (MI-CP152) designed to evaluate the safety and tolerability of sifalimumab in adult patients with SLE. Sifalimumab was administered every 14 days as a 30- to 60-minute intravenous infusion with escalating doses of 0.3, 1.0, 3.0, and 10 mg/kg and serum concentrations were collected over 350 days. A total of 120 patients provided evaluable pharmacokinetic data with a total of 2,370 serum concentrations. Sifalimumab serum concentrations were determined using a validated colorimetric enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation of 1.25 ?g/mL. Population pharmacokinetic modeling of sifalimumab was performed using a non-linear mixed effects modeling approach with NONMEM VII software. Impact of patient demographics, clinical indices, and biomarkers on pharmacokinetic parameters were explored using a stepwise forward selection and backward elimination approach. The appropriateness of the final model was tested using visual predictive check (VPC). The impact of body WT-based and fixed dosing of sifalimumab was evaluated using a simulation approach. The final population model was utilized for phase IIb dosing projections.Sifalimumab pharmacokinetics were best described using a two-compartment linear model with first order elimination. Following intravenous dosing, the typical clearance (CL) and central volume of distribution (V 1) were estimated to be 176 mL/day and 2.9 L, respectively. The estimates (coefficient of variation) of between-subject variability for CL and V 1 were 28 and 31 %, respectively. Patient baseline body WT, interferon gene signature from 21 genes, steroid use, and sifalimumab dose were identified as significant covariates for CL, whereas only baseline body WT was a significant covariate for V 1 and peripheral volume of distribution (V 2). Although the above-mentioned covariates were statistically significant, they did not explain variability in pharmacokinetic parameters to any relevant extent (<7 %). Thus, no dosing adjustments are necessary. VPC confirmed good predictability of the final population pharmacokinetic model. Simulation results demonstrate that both fixed and body WT-based dosing regimens yield similar median steady state concentrations and overall variability. Fixed sifalimumab doses of 200, 600, and 1,200 mg monthly (with a loading dose at Day 14) were selected for a phase IIb clinical trial.A two-compartment population pharmacokinetic model adequately described sifalimumab pharmacokinetics. The estimated typical pharmacokinetic parameters were similar to other monoclonal antibodies without target mediated elimination. Although the population pharmacokinetic analysis identified some statistically significant covariates, they explained <7 % between-subject variability in pharmacokinetic parameters indicating that these covariates are not clinically relevant. The population pharmacokinetic analysis also demonstrated the feasibility of switching to fixed doses in phase IIb clinical trials of sifalimumab.

Project description:ObjectiveTo assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate-to-severe systemic lupus erythematosus (SLE).MethodsPatients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4-gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent-to-treat (ITT) population and type I IFN-high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2-sided), within each of the 2 study populations for the primary end point analysis.ResultsThe primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo-treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ-specific end points. Herpes zoster was more frequent in the anifrolumab-treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively).ConclusionAnifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE.

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Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

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Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

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