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The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691)
Author(s) -
Fidock MD,
Souberbielle BE,
Laxton C,
Rawal J,
DelpuechAdams O,
Corey TP,
Colman P,
Kumar V,
Cheng JB,
Wright K,
Srinivasan S,
Rana K,
Craig C,
Horscroft N,
Perros M,
Westby M,
Webster R,
Ryst E
Publication year - 2011
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.60
Subject(s) - tlr7 , medicine , agonist , adverse effect , in vivo , immunology , immune system , pharmacology , hepatitis c virus , ex vivo , interferon , innate immune system , toll like receptor , receptor , virus , biology , microbiology and biotechnology
Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF‐4878691 is a Toll‐like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof‐of‐mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF‐4878691 twice a week for 2 weeks, PF‐4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose‐dependent and dose‐frequency‐related manner. A novel finding was induction of TLR7 expression in vivo in response to PF‐4878691, leading to an amplified biomarker response. A nonresponder at the 9‐mg dose had a polymorphism in the IFN‐α receptor 1 subunit (Val168Leu). Two subjects who had received 9‐mg doses experienced serious adverse events (SAEs), characterized by flu‐like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection. Clinical Pharmacology & Therapeutics (2011) 89 6, 821–829. doi: 10.1038/clpt.2011.60