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Open Access Research article

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study

Avram Goldberg1*, Thomas Geppert2, Elena Schiopu3, Tracy Frech4, Vivien Hsu5, Robert W Simms6, Stanford L Peng7, Yihong Yao8, Nairouz Elgeioushi8, Linda Chang9, Bing Wang9 and Stephen Yoo8

Author Affiliations

1 North Shore LIJ Health Systems and Division of Rheumatology, Hofstra North Shore-LIJ School of Medicine, Lake Success, NY, USA

2 Metroplex Clinical Research Center, LLC, Dallas, TX, USA

3 University of Michigan, Ann Arbor, MI, USA

4 University of Utah, Salt Lake City, UT, USA

5 RWJ Medical School Clinical Research Center, New Brunswick, NJ, USA

6 Boston University School Of Medicine, Boston, MA, USA

7 Benaroya Research Institute at Virginia Mason Medical Center, Seattle, WA, USA

8 MedImmune, Gaithersburg, MD, USA

9 MedImmune, Hayward, CA, USA

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Arthritis Research & Therapy 2014, 16:R57  doi:10.1186/ar4492

Published: 24 February 2014

Abstract

Introduction

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.

Methods

Subjects (≥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.

Results

Of 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.

Conclusion

The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.

Trial Registration

ClinicalTrials.gov NCT00930683