The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691)

The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691)

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‐o...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics Vol. 89; no. 6; pp. 821 - 829
Main Authors: Fidock, MD, Souberbielle, BE, Laxton, C, Rawal, J, Delpuech‐Adams, 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
Format: Journal Article
Language:English
Published: Basingstoke Nature Publishing Group 01-06-2011
Subjects:
Adult
Antiviral Agents - pharmacology
Biological and medical sciences
Cohort Studies
Dose-Response Relationship, Drug
Female
Hepacivirus - drug effects
Hepacivirus - immunology
Human viral diseases
Humans
Immunity, Innate - drug effects
Infectious diseases
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Toll-Like Receptor 7 - agonists
Toll-Like Receptor 7 - biosynthesis
Toll-Like Receptor 7 - immunology
Treatment Outcome
Viral diseases
Viral hepatitis
Young Adult
Human
Toll like receptor 7
Agonist
Prognosis
Immune response
Treatment efficiency
Hepatic disease
Natural immunity
Infection
Virus
Ex vivo
Viral disease
Digestive diseases
Antiviral
Flaviviridae
Hepatitis C virus
Hepacivirus
Viral hepatitis C
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Summary: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
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ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2011.60