PMID- 37150935
OWN - NLM
STAT- MEDLINE
DCOM- 20240119
LR  - 20240119
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Linking)
VI  - 114
IP  - 2
DP  - 2023 Aug
TI  - Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp 
      Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical 
      Trials.
PG  - 371-380
LID - 10.1002/cpt.2929 [doi]
AB  - Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion 
      designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell 
      activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of 
      rozibafusp alfa were investigated in two randomized, placebo-controlled clinical 
      studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.)) 
      in healthy subjects and a phase Ib multiple ascending-dose study (70-420 mg s.c. 
      every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa 
      exhibited nonlinear PK and dose-related and reversible dual-target engagement. 
      Maximal reduction of naive B cells from baseline (> 40%), reflective of BAFF 
      inhibition, was achieved with rozibafusp alfa exposure (area under the 
      concentration-time curve from time 0 to time infinity (AUC(inf) ) and AUC within 
      a dosing interval from day 0 to day 14 (AUC(tau) )) above 51 and 57 days*mug/mL 
      for the single-dose (>/= 70 mg) and multiple-dose studies (>/= 70 mg q2w), 
      respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end 
      point for ICOSL inhibition, was directly related to drug concentration. PK/PD 
      analysis showed > 90% RO at rozibafusp alfa >/= 22.2 mug/mL (>/= 420-mg single dose or 
      >/= 210 mg q2w multiple dose), with saturation occurring at higher drug 
      concentrations. These results informed the design and dose selection of a phase 
      IIb study assessing the safety and efficacy of rozibafusp alfa in patients with 
      active systemic lupus erythematosus.
CI  - (c) 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley 
      Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Abuqayyas, Lubna
AU  - Abuqayyas L
AUID- ORCID: 0000-0001-5188-1010
AD  - Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, 
      California, USA.
FAU - Chen, Po-Wei
AU  - Chen PW
AD  - Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, 
      California, USA.
FAU - Dos Santos, Marcia Teixeira
AU  - Dos Santos MT
AD  - Clinical Biomarkers, Amgen Inc., Thousand Oaks, California, USA.
FAU - Parnes, Jane R
AU  - Parnes JR
AD  - Early Development, Amgen Inc., Thousand Oaks, California, USA.
FAU - Doshi, Sameer
AU  - Doshi S
AD  - Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, 
      California, USA.
FAU - Dutta, Sandeep
AU  - Dutta S
AD  - Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, 
      California, USA.
FAU - Houk, Brett E
AU  - Houk BE
AD  - Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., Thousand Oaks, 
      California, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20230524
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (B-Cell Activating Factor)
RN  - 0 (Inducible T-Cell Co-Stimulator Ligand)
RN  - 0 (rozibafusp alfa)
SB  - IM
MH  - Humans
MH  - Area Under Curve
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - B-Cell Activating Factor/antagonists & inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Inducible T-Cell Co-Stimulator Ligand/antagonists & inhibitors
MH  - *Lupus Erythematosus, Systemic/drug therapy
EDAT- 2023/05/08 06:41
MHDA- 2023/07/24 06:43
CRDT- 2023/05/08 00:53
PHST- 2022/09/30 00:00 [received]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/07/24 06:43 [medline]
PHST- 2023/05/08 06:41 [pubmed]
PHST- 2023/05/08 00:53 [entrez]
AID - 10.1002/cpt.2929 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2023 Aug;114(2):371-380. doi: 10.1002/cpt.2929. Epub 2023 
      May 24.