PMID- 32198939
OWN - NLM
STAT- MEDLINE
DCOM- 20210702
LR  - 20210702
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 86
IP  - 9
DP  - 2020 Sep
TI  - Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a 
      covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, 
      placebo-controlled trial in healthy participants.
PG  - 1849-1859
LID - 10.1111/bcp.14290 [doi]
AB  - AIMS: Branebrutinib (BMS-986195) is a potent, highly selective, oral, 
      small-molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study 
      evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in 
      healthy participants. METHODS: This double-blind, placebo-controlled, single- and 
      multiple-ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled 
      participants into 3 parts: SAD, MAD and JMAD (MAD in first-generation Japanese 
      participants). In each part, participants were randomised 3:1 to receive 
      branebrutinib (SAD: 0.3-30 mg; [J]MAD: 0.3-10 mg) or placebo. Participants in the 
      MAD parts received branebrutinib daily for 14 days and were followed for 14 days 
      postdosing. Safety was assessed by monitoring, laboratory and physical 
      examinations, vital signs, and recording adverse events (AEs). Pharmacodynamics 
      were assessed with a mass spectrometry assay that measured drug-occupied and free 
      BTK. RESULTS: The SAD, MAD and JMAD parts of the study included 40, 32 and 24 
      participants. Branebrutinib was well tolerated and AEs were mild/moderate, except 
      for 1 serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, 
      with maximum plasma concentration occurring within 1 hour and a half-life of 
      1.2-1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was 
      rapid, with 100% occupancy reached after a single 10-mg dose. BTK occupancy 
      decayed predictably over time (mean half-life in MAD panels: 115-154 hours), such 
      that pharmacodynamic effects were maintained after branebrutinib plasma levels 
      fell below the lower limit of quantification. CONCLUSION: Rapid and high 
      occupancy of BTK and the lack of notable safety findings support further clinical 
      development of branebrutinib.
CI  - (c) 2020 Bristol Myers Squibb Inc. British Journal of Clinical Pharmacology 
      published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Catlett, Ian M
AU  - Catlett IM
AUID- ORCID: 0000-0001-6220-2626
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Nowak, Miroslawa
AU  - Nowak M
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Kundu, Sudeep
AU  - Kundu S
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Zheng, Naiyu
AU  - Zheng N
AUID- ORCID: 0000-0002-5121-9024
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Liu, Ang
AU  - Liu A
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - He, Bing
AU  - He B
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Girgis, Ihab G
AU  - Girgis IG
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
FAU - Grasela, Dennis M
AU  - Grasela DM
AD  - Bristol Myers Squibb, Princeton, NJ, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20200412
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Indoles)
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 7LBRZUYSHU (branebrutinib)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
SB  - IM
MH  - Agammaglobulinaemia Tyrosine Kinase
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Humans
MH  - Indoles/*pharmacokinetics/pharmacology
MH  - Piperidines/*pharmacokinetics/pharmacology
MH  - Protein Kinase Inhibitors/*pharmacokinetics/pharmacology
PMC - PMC7444767
OTO - NOTNLM
OT  - Phase I
OT  - clinical trials
OT  - drug safety
OT  - pharmacodynamics
OT  - pharmacokinetics
COIS- All authors are employees and stockholders of Bristol Myers Squibb and receive 
      salary and stock grants commensurate with employment.
EDAT- 2020/03/22 06:00
MHDA- 2021/07/03 06:00
PMCR- 2020/04/12
CRDT- 2020/03/22 06:00
PHST- 2019/07/31 00:00 [received]
PHST- 2020/03/03 00:00 [revised]
PHST- 2020/03/10 00:00 [accepted]
PHST- 2020/03/22 06:00 [pubmed]
PHST- 2021/07/03 06:00 [medline]
PHST- 2020/03/22 06:00 [entrez]
PHST- 2020/04/12 00:00 [pmc-release]
AID - BCP14290 [pii]
AID - 10.1111/bcp.14290 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2020 Sep;86(9):1849-1859. doi: 10.1111/bcp.14290. Epub 2020 
      Apr 12.