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 Goldberg, Thomas Geppert, Elena Schiopu, Tracy Frech, Vivien Hsu, Robert W Simms, Stanford L Peng, Yihong Yao, Nairouz Elgeioushi, Linda Chang, Bing Wang, Stephen Yoo, Avram Goldberg, Thomas Geppert, Elena Schiopu, Tracy Frech, Vivien Hsu, Robert W Simms, Stanford L Peng, Yihong Yao, Nairouz Elgeioushi, Linda Chang, Bing Wang, Stephen Yoo

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.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Mean (±SD) serum MEDI-546 concentration. A. Single IV Administration; B. Multiple IV Administrations. LLOQ, lower limit of quantitation; SD, standard deviation. Mean data below LLOQ are not plotted.
Figure 3
Figure 3
Median fold change of type I IFN gene signature by visit for subjects with positive baseline gene signature. A. In Whole Blood in Single-Dose Groups; B. In Whole Blood in Multiple-Dose Groups; C. In Skin in Single-Dose Groups; D. In Skin in Multiple-Dose Groups. IFN, interferon.

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