title: The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection.
abstract: OBJECTIVE
  SCY-635 is a non-immunosuppressive analog of cyclosporin A that inhibits cyclophilins A and B and hepatitis C virus (HCV) replication in vitro. In a phase 1b multi-dose escalation study, we evaluated the safety, plasma pharmacokinetics, and antiviral activity of 15 days of monotherapy with SCY-635 in adults with chronic genotype 1 HCV infection.
  
  
  METHODS
  Twenty adults with chronic HCV genotype 1 were randomized to SCY-635 oral doses of 100, 200, or 300 mg three times daily for 15 days.
  
  
  RESULTS
  No dose-limiting clinical or laboratory toxicities were identified. On day 15, the mean decline in plasma viremia was 2.24±1.74 log(10) IU/ml with SCY-635 900 mg/d. Individual antiviral responses correlated with host IL28B genotype. Post hoc analyses indicated treatment with SCY-635 increased plasma protein concentrations of interferon α (IFNα), IFNs λ(1) and λ(3), and 2'5' oligoadenylate synthetase 1 (2'5'OAS-1), with the greatest increases in IL28B CC and CT subjects. Changes in plasma concentrations for all markers were coincident with changes in the plasma concentration of SCY-635. Peaks of IFNs α, λ(1), and λ(3) and 2'5'OAS-1 were observed within 2 h after drug administration. In replicon cells, SCY-635 enhanced secretion of type I and type III IFNs and increased the expression of IFN-stimulated genes (ISG).
  
  
  CONCLUSIONS
  These studies establish clinical proof of concept for SCY-635 as a novel antiviral agent and suggest that restoration of the host innate immune response to chronic hepatitis C infection may represent a major mechanism through which cyclophilin inhibitors exert clinical antiviral activity.
authors.affiliation: Scynexis, Inc., Durham, NC, United States. S.Hopkins@autoimmune.com
authors.forename: Sam
authors.initials: S
authors.lastname: Hopkins
authors.forename: Betty
authors.initials: B
authors.lastname: DiMassimo
authors.forename: Pamela
authors.initials: P
authors.lastname: Rusnak
authors.forename: Douglas
authors.initials: D
authors.lastname: Heuman
authors.forename: Jacob
authors.initials: J
authors.lastname: Lalezari
authors.forename: Ann
authors.initials: A
authors.lastname: Sluder
authors.forename: Bernard
authors.initials: B
authors.lastname: Scorneaux
authors.forename: Sarah
authors.initials: S
authors.lastname: Mosier
authors.forename: Paul
authors.initials: P
authors.lastname: Kowalczyk
authors.forename: Yves
authors.initials: Y
authors.lastname: Ribeill
authors.forename: James
authors.initials: J
authors.lastname: Baugh
authors.forename: Philippe
authors.initials: P
authors.lastname: Gallay
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D003524:Cyclosporins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D016899:Interferon-beta / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D021984:Cyclophilin A; D021983:Cyclophilins; D003524:Cyclosporins; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C081786:cyclophilin B; C544142:SCY-635