PMID- 35485332
OWN - NLM
STAT- MEDLINE
DCOM- 20220502
LR  - 20220607
IS  - 2040-2058 (Electronic)
IS  - 1359-6535 (Linking)
VI  - 26
IP  - 3-5
DP  - 2021 May
TI  - Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral 
      JNJ-64794964, a TLR-7 agonist, in healthy adults.
PG  - 58-68
LID - 10.1177/13596535211056581 [doi]
AB  - BACKGROUND: This Phase I, two-part, first-in-human study assessed 
      safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending 
      doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, 
      JNJ-64794964 (JNJ-4964) in healthy adults. METHODS: In the SAD phase, 
      participants received JNJ-4964 0.2 (N = 6), 0.6 (N = 6), 1.25 (N = 8) or 1.8 mg 
      (N = 6) or placebo (N = 2/dose cohort) in a fasted state. Food effect was 
      evaluated for the 1.25 mg cohort following >/=6 weeks washout. In the MD phase, 
      participants received JNJ-4964 1.25 mg (N = 6) or placebo (N = 2) weekly (fasted) 
      for 4 weeks. Participants were followed-up for 4 weeks. RESULTS: No serious 
      adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported 
      mild-to-moderate (</=Grade 2), transient, reversible AEs possibly related to 
      JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with 
      interferon-alpha serum levels >/=100 pg/mL and lymphopenia (<1 x 10(9)/L), between 
      24-48 h after dosing and resolving approximately 96 h after dosing. One 
      participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool 
      spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited 
      dose-proportional pharmacokinetics, with rapid absorption (t(max) 0.5-0.75 h) and 
      distribution, and a long terminal half-life (150-591 h). Overall, no significant 
      differences in JNJ-4964 pharmacokinetic parameters were observed in the fed 
      versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines 
      with potential anti-HBV activity, including interferon-alpha, IP-10, IL-1 RA, and/or 
      MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. 
      CONCLUSIONS: In healthy adults, JNJ-4964 was generally well-tolerated, exhibited 
      dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible 
      anti-HBV activity.
FAU - Gane, Edward
AU  - Gane E
AD  - New Zealand Liver Transplant Unit, University of Auckland, Auckland, New Zealand.
FAU - Pastagia, Mina
AU  - Pastagia M
AD  - 333755Janssen BioPharma Inc., South San Francisco, CA, USA.
FAU - Schwertschlag, Ullrich
AU  - Schwertschlag U
AD  - 333755Janssen BioPharma Inc., South San Francisco, CA, USA.
FAU - De Creus, An
AU  - De Creus A
AD  - Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium.
FAU - Schwabe, Christian
AU  - Schwabe C
AD  - Auckland Clinical Studies, Auckland, New Zealand.
FAU - Vandenbossche, Joris
AU  - Vandenbossche J
AD  - Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium.
FAU - Slaets, Leen
AU  - Slaets L
AD  - Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium.
FAU - Fevery, Bart
AU  - Fevery B
AD  - Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium.
FAU - Smyej, Ilham
AU  - Smyej I
AD  - Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium.
FAU - Wu, Liviawati S
AU  - Wu LS
AD  - 333755Janssen BioPharma Inc., South San Francisco, CA, USA.
FAU - Li, Rui
AU  - Li R
AD  - Janssen Research & Development LLC, Titusville, NJ, USA.
FAU - Siddiqui, Samia
AU  - Siddiqui S
AD  - Janssen Research & Development LLC, Titusville, NJ, USA.
FAU - Oey, Abbie
AU  - Oey A
AD  - 333755Janssen BioPharma Inc., South San Francisco, CA, USA.
FAU - Musto, Clark
AU  - Musto C
AD  - 333755Janssen BioPharma Inc., South San Francisco, CA, USA.
FAU - Van Remoortere, Pieter
AU  - Van Remoortere P
AUID- ORCID: 0000-0002-5537-5008
AD  - Janssen Research & Development LLC, Titusville, NJ, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211027
PL  - England
TA  - Antivir Ther
JT  - Antiviral therapy
JID - 9815705
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Cytokines)
RN  - 0 (Interferon-alpha)
RN  - 0 (Toll-Like Receptor 7)
SB  - IM
MH  - *Adjuvants, Immunologic
MH  - Adult
MH  - Area Under Curve
MH  - Cytokines
MH  - Double-Blind Method
MH  - Humans
MH  - Interferon-alpha
MH  - *Toll-Like Receptor 7
EDAT- 2022/04/30 06:00
MHDA- 2022/05/03 06:00
CRDT- 2022/04/29 05:52
PHST- 2022/04/29 05:52 [entrez]
PHST- 2022/04/30 06:00 [pubmed]
PHST- 2022/05/03 06:00 [medline]
AID - 10.1177/13596535211056581 [doi]
PST - ppublish
SO  - Antivir Ther. 2021 May;26(3-5):58-68. doi: 10.1177/13596535211056581. Epub 2021 
      Oct 27.