PMID- 24286136
OWN - NLM
STAT- MEDLINE
DCOM- 20140804
LR  - 20240318
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 15
IP  - 5
DP  - 2013 Oct 25
TI  - A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and 
      early clinical response of brodalumab, a human anti-IL-17R antibody, in 
      methotrexate-resistant rheumatoid arthritis.
PG  - R164
LID - 10.1186/ar4347 [doi]
AB  - INTRODUCTION: The aim of this study was to evaluate the safety, pharmacokinetics, 
      and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A 
      (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid 
      arthritis (RA). METHODS: This phase Ib, randomized, placebo-controlled, 
      double-blind multiple ascending dose study enrolled subjects with moderate to 
      severe RA (>/= 6/66 swollen and >/= 8/68 tender joints). Subjects were randomized 3:1 
      to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks 
      for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two 
      doses per group) or placebo. Endpoints included incidence of adverse events (AEs) 
      and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and 
      improvements in RA clinical metrics. RESULTS: Forty subjects were randomized to 
      investigational product; one subject discontinued due to worsening of RA 
      (placebo). The study was not designed to assess efficacy. AEs were reported by 
      70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three 
      serious AEs were reported in two subjects; there were no opportunistic 
      infections. Brodalumab treatment resulted in inhibition of IL-17 receptor 
      signaling and receptor occupancy on circulating leukocytes. No treatment effects 
      were observed with individual measures of RA disease activity. On day 85 (week 
      13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved 
      ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved 
      ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects 
      achieved ACR70. CONCLUSIONS: Multiple dose administration of brodalumab was 
      tolerated in subjects with active RA. There was no evidence of a clinical 
      response to brodalumab in subjects with RA. TRIAL REGISTRATION: 
      ClinicalTrials.gov, NCT00771030.
FAU - Martin, David A
AU  - Martin DA
FAU - Churchill, Melvin
AU  - Churchill M
FAU - Flores-Suarez, Luis
AU  - Flores-Suarez L
FAU - Cardiel, Mario H
AU  - Cardiel MH
FAU - Wallace, Daniel
AU  - Wallace D
FAU - Martin, Richard
AU  - Martin R
FAU - Phillips, Kristine
AU  - Phillips K
FAU - Kaine, Jeffrey L
AU  - Kaine JL
FAU - Dong, Hua
AU  - Dong H
FAU - Salinger, David
AU  - Salinger D
FAU - Stevens, Erin
AU  - Stevens E
FAU - Russell, Chris B
AU  - Russell CB
FAU - Chung, James B
AU  - Chung JB
LA  - eng
SI  - ClinicalTrials.gov/NCT00771030
GR  - K23 AR060241/AR/NIAMS NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20131025
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Receptors, Interleukin-17)
RN  - 6ZA31Y954Z (brodalumab)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Abdominal Pain/chemically induced
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/adverse effects/pharmacokinetics/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antirheumatic Agents/therapeutic use
MH  - Area Under Curve
MH  - Arthritis, Rheumatoid/*drug therapy/immunology/metabolism
MH  - Cough/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Drug Resistance
MH  - Female
MH  - Headache/chemically induced
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Methotrexate/*therapeutic use
MH  - Middle Aged
MH  - Receptors, Interleukin-17/*antagonists & inhibitors/immunology
MH  - Treatment Outcome
PMC - PMC3979125
EDAT- 2013/11/30 06:00
MHDA- 2014/08/05 06:00
PMCR- 2013/10/25
CRDT- 2013/11/30 06:00
PHST- 2013/06/28 00:00 [received]
PHST- 2013/10/01 00:00 [accepted]
PHST- 2013/11/30 06:00 [entrez]
PHST- 2013/11/30 06:00 [pubmed]
PHST- 2014/08/05 06:00 [medline]
PHST- 2013/10/25 00:00 [pmc-release]
AID - ar4347 [pii]
AID - 10.1186/ar4347 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2013 Oct 25;15(5):R164. doi: 10.1186/ar4347.