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Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978926/ https://www.ncbi.nlm.nih.gov/pubmed/24559157 http://dx.doi.org/10.1186/ar4492 |
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author | Goldberg, Avram Geppert, Thomas Schiopu, Elena Frech, Tracy Hsu, Vivien Simms, Robert W Peng, Stanford L Yao, Yihong Elgeioushi, Nairouz Chang, Linda Wang, Bing Yoo, Stephen |
author_facet | Goldberg, Avram Geppert, Thomas Schiopu, Elena Frech, Tracy Hsu, Vivien Simms, Robert W Peng, Stanford L Yao, Yihong Elgeioushi, Nairouz Chang, Linda Wang, Bing Yoo, Stephen |
author_sort | Goldberg, Avram |
collection | PubMed |
description | 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 |
format | Online Article Text |
id | pubmed-3978926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-39789262014-04-09 Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study Goldberg, Avram Geppert, Thomas Schiopu, Elena Frech, Tracy Hsu, Vivien Simms, Robert W Peng, Stanford L Yao, Yihong Elgeioushi, Nairouz Chang, Linda Wang, Bing Yoo, Stephen Arthritis Res Ther Research Article 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 BioMed Central 2014 2014-02-24 /pmc/articles/PMC3978926/ /pubmed/24559157 http://dx.doi.org/10.1186/ar4492 Text en Copyright © 2014 Goldberg et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. |
spellingShingle | Research Article Goldberg, Avram Geppert, Thomas Schiopu, Elena Frech, Tracy Hsu, Vivien Simms, Robert W Peng, Stanford L Yao, Yihong Elgeioushi, Nairouz Chang, Linda Wang, Bing Yoo, Stephen Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title | Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title_full | Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title_fullStr | Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title_full_unstemmed | Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title_short | Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
title_sort | dose-escalation of human anti-interferon-α receptor monoclonal antibody medi-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978926/ https://www.ncbi.nlm.nih.gov/pubmed/24559157 http://dx.doi.org/10.1186/ar4492 |
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