PMID- 30902820
OWN - NLM
STAT- MEDLINE
DCOM- 20200129
LR  - 20231012
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Print)
IS  - 0003-4967 (Linking)
VI  - 78
IP  - 6
DP  - 2019 Jun
TI  - Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and 
      biomarker variables in patients with active rheumatoid arthritis: a randomised, 
      double-blind, placebo-controlled, phase IIa study.
PG  - 754-760
LID - 10.1136/annrheumdis-2018-214729 [doi]
AB  - OBJECTIVE: To evaluate the safety, efficacy and therapeutic mechanism of BI 
      655064, an antagonistic anti-CD40 monoclonal antibody, in patients with 
      rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). 
      METHODS: In total, 67 patients were randomised to receive weekly subcutaneous 
      doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary 
      endpoint was the proportion of patients who achieved 20% improvement in American 
      College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in 
      patients who received at least one dose of study drug. RESULTS: At week 12, the 
      primary endpoint was not met, with 68.2% of patients treated with BI 655064 
      achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the 
      posterior probability of seeing a difference greater than 35% was 42.9%. BI 
      655064 was associated with greater changes in CD40-CD40L pathway-related markers, 
      including reductions in inflammatory and bone resorption markers (interleukin-6, 
      matrix metalloproteinase-3, receptor activator of nuclear factor-kappaB ligand), 
      concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM 
      RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) 
      related to BI 655064 treatment or thromboembolic events occurred; reported AEs 
      were mainly of mild intensity. CONCLUSION: Although blockade of the CD40-CD40L 
      pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in 
      clinical and biological parameters, including reductions in activated B-cells, 
      autoantibody production and inflammatory and bone resorption markers, with a 
      favourable safety profile, clinical efficacy was not demonstrated in this small 
      phase IIa study. TRIAL REGISTRATION NUMBER: NCT01751776.
CI  - (c) Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Visvanathan, Sudha
AU  - Visvanathan S
AUID- ORCID: 0000-0002-1170-9272
AD  - Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA 
      sudha.visvanathan@boehringer-ingelheim.com.
FAU - Daniluk, Stefan
AU  - Daniluk S
AD  - ClinicMed Badurski and Partners, Bialystok, Poland.
FAU - Ptaszynski, Rafal
AU  - Ptaszynski R
AD  - Rheumatica, Warsaw, Poland.
FAU - Muller-Ladner, Ulf
AU  - Muller-Ladner U
AD  - Justus Liebig University Giessen, Bad Nauheim, Germany.
FAU - Ramanujam, Meera
AU  - Ramanujam M
AD  - Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA.
FAU - Rosenstock, Bernd
AU  - Rosenstock B
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
FAU - Eleftheraki, Anastasia G
AU  - Eleftheraki AG
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
FAU - Vinisko, Richard
AU  - Vinisko R
AD  - Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA.
FAU - Petrikova, Alena
AU  - Petrikova A
AD  - CTCenter MaVe, Olomouc, Czech Republic.
FAU - Kellner, Herbert
AU  - Kellner H
AD  - Centre for Inflammatory Joint Diseases, Munich, Germany.
FAU - Dokoupilova, Eva
AU  - Dokoupilova E
AD  - Medical Plus, s.r.o, Uherske Hradiste, Czech Republic.
AD  - Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, 
      Czech Republic.
FAU - Kwiatkowska, Brygida
AU  - Kwiatkowska B
AD  - Prof. Eleonora Reicher Memorial National Institute of Geriatrics, Rheumatology 
      and Rehabilitation, Warsaw, Poland.
FAU - Alten, Rieke
AU  - Alten R
AD  - Schlosspark-Klinik, Berlin, Germany.
FAU - Schwabe, Christian
AU  - Schwabe C
AD  - Auckland Clinical Studies, Auckland, New Zealand.
FAU - Baum, Patrick
AU  - Baum P
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
FAU - Joseph, David
AU  - Joseph D
AD  - Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA.
FAU - Fine, Jay S
AU  - Fine JS
AD  - Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA.
FAU - Padula, Steven J
AU  - Padula SJ
AD  - Boehringer Ingelheim International GmbH, Ingelheim, Germany.
FAU - Steffgen, Jurgen
AU  - Steffgen J
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT01751776
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190322
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Autoantibodies)
RN  - 0 (BI 655064)
RN  - 0 (Biomarkers)
RN  - 0 (Inflammation Mediators)
RN  - 147205-72-9 (CD40 Ligand)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use
MH  - Antirheumatic Agents/adverse effects/*therapeutic use
MH  - Arthritis, Rheumatoid/*drug therapy/immunology/physiopathology
MH  - Autoantibodies/blood
MH  - B-Lymphocyte Subsets/drug effects
MH  - Biomarkers/blood
MH  - Bone Remodeling/drug effects
MH  - CD40 Ligand/antagonists & inhibitors
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Inflammation Mediators/metabolism
MH  - Injections, Subcutaneous
MH  - Male
MH  - Methotrexate/therapeutic use
MH  - Middle Aged
MH  - Severity of Illness Index
MH  - Young Adult
PMC - PMC6579552
OTO - NOTNLM
OT  - B-cells
OT  - autoantibodies
OT  - rheumatoid arthritis
COIS- Competing interests: SD, RP, AP, HK, ED and BK report no disclosures; UM-L 
      reports being an advisor for Boehringer Ingelheim; RA and CS report having 
      received research/grant support from Boehringer Ingelheim; SV, MR, BR, AGE, RV, 
      PB, DJ, JSF, SJP and JS report being employed by Boehringer Ingelheim.
EDAT- 2019/03/25 06:00
MHDA- 2020/01/30 06:00
PMCR- 2019/06/17
CRDT- 2019/03/24 06:00
PHST- 2018/11/08 00:00 [received]
PHST- 2019/02/20 00:00 [revised]
PHST- 2019/02/24 00:00 [accepted]
PHST- 2019/03/25 06:00 [pubmed]
PHST- 2020/01/30 06:00 [medline]
PHST- 2019/03/24 06:00 [entrez]
PHST- 2019/06/17 00:00 [pmc-release]
AID - annrheumdis-2018-214729 [pii]
AID - 10.1136/annrheumdis-2018-214729 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2019 Jun;78(6):754-760. doi: 10.1136/annrheumdis-2018-214729. Epub 
      2019 Mar 22.