Abstract
IntroductionType I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc.MethodsSubjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes.ResultsOf 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days.ConclusionThe safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.Trial RegistrationClinicalTrials.gov NCT00930683
Highlights
Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc)
The safety population, comprising all subjects who received MEDI546, was used for safety and tolerability evaluations and for measurements of PD; the evaluable population for PK included all subjects in the safety population with ≥1 valid MEDI-546 serum concentration assessment; the evaluable population for immunogenicity included all subjects in the safety population with ≥1 valid immunogenicity test result post dose
MEDI-546 was administered as single (0.1–20.0 mg/kg) and multiple (0.3–5.0 mg/kg/week) escalating IV doses in adult subjects with SSc, who had at least moderate skin thickening
Summary
Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Systemic sclerosis (SSc) is an autoimmune multisystem disease of unknown etiology, characterized by structural abnormalities in small blood vessels and excessive deposition of extracellular matrix components [1,2]. A recent report from the German Network for Systemic Scleroderma showed that 41% of patients with SSc were treated with corticosteroids and 36% received immunosuppressive agents, despite a lack of robust evidence demonstrating the efficacy of these treatments [6]. Immunosuppressive therapy has demonstrated some efficacy in clinical studies, it does not appear to provide benefits during later phases of SSc, and long-term usage is limited by its potential toxicity [5]. Considering the high mortality of SSc, there is a significant unmet need for novel therapies that clearly control or alter the aberrant fibrotic pathways of the disease, with acceptable toxicities [9]
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