PMID- 24559157
OWN - NLM
STAT- MEDLINE
DCOM- 20150916
LR  - 20220317
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 16
IP  - 1
DP  - 2014 Feb 24
TI  - Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 
      in subjects with systemic sclerosis: a phase 1, multicenter, open label study.
PG  - R57
LID - 10.1186/ar4492 [doi]
AB  - 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.
FAU - Goldberg, Avram
AU  - Goldberg A
FAU - Geppert, Thomas
AU  - Geppert T
FAU - Schiopu, Elena
AU  - Schiopu E
FAU - Frech, Tracy
AU  - Frech T
FAU - Hsu, Vivien
AU  - Hsu V
FAU - Simms, Robert W
AU  - Simms RW
FAU - Peng, Stanford L
AU  - Peng SL
FAU - Yao, Yihong
AU  - Yao Y
FAU - Elgeioushi, Nairouz
AU  - Elgeioushi N
FAU - Chang, Linda
AU  - Chang L
FAU - Wang, Bing
AU  - Wang B
FAU - Yoo, Stephen
AU  - Yoo S
LA  - eng
SI  - ClinicalTrials.gov/NCT00930683
GR  - KL2 TR001065/TR/NCATS NIH HHS/United States
GR  - P50 AR060780/AR/NIAMS NIH HHS/United States
GR  - UL1 TR001067/TR/NCATS NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20140224
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 156986-95-7 (Receptor, Interferon alpha-beta)
RN  - 38RL9AE51Q (anifrolumab)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antibodies, Monoclonal, Humanized
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Receptor, Interferon alpha-beta/*immunology
MH  - Scleroderma, Systemic/*drug therapy
PMC - PMC3978926
EDAT- 2014/02/25 06:00
MHDA- 2015/09/17 06:00
PMCR- 2014/02/24
CRDT- 2014/02/25 06:00
PHST- 2013/04/29 00:00 [received]
PHST- 2014/01/29 00:00 [accepted]
PHST- 2014/02/25 06:00 [entrez]
PHST- 2014/02/25 06:00 [pubmed]
PHST- 2015/09/17 06:00 [medline]
PHST- 2014/02/24 00:00 [pmc-release]
AID - ar4492 [pii]
AID - 10.1186/ar4492 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2014 Feb 24;16(1):R57. doi: 10.1186/ar4492.