title: The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691).
abstract: 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.
authors: Sandwich Research Laboratories, Pfizer Ltd, Sandwich, UK. Mark.Fidock@Pfizer.com
authors: M D
authors: MD
authors: Fidock
authors: B E
authors: BE
authors: Souberbielle
authors: C
authors: C
authors: Laxton
authors: J
authors: J
authors: Rawal
authors: O
authors: O
authors: Delpuech-Adams
authors: T P
authors: TP
authors: Corey
authors: P
authors: P
authors: Colman
authors: V
authors: V
authors: Kumar
authors: J B
authors: JB
authors: Cheng
authors: K
authors: K
authors: Wright
authors: S
authors: S
authors: Srinivasan
authors: K
authors: K
authors: Rana
authors: C
authors: C
authors: Craig
authors: N
authors: N
authors: Horscroft
authors: M
authors: M
authors: Perros
authors: M
authors: M
authors: Westby
authors: R
authors: R
authors: Webster
authors: E
authors: E
authors: van der Ryst
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7