title: RNA interference and its potential applications to chronic HBV treatment: results of a Phase I safety and tolerability study.
abstract: BACKGROUND
  RNA interference (RNAi) provides an attractive tool to modulate biological systems, and ultimately, to treat human diseases. We describe early results from a Phase Ib, first-in-human safety and tolerability study of an RNAi-based therapy, NUC B1000, among patients with mild to moderate chronic HBV.
  
  
  METHODS
  Three subjects received a single 5 mg DNA dose of NUC B1000 as part of a planned dose escalation study.
  
  
  RESULTS
  All participants reported pharyngitis, chills, myalgia and fever approximately 4-7 h after dosing. All subjects were asymptomatic after a single antipyretic dose with no symptom recurrences. Measurements of interferon (IFN)-α and -γ, interleukin (IL)-10, 12 18, 8 and 6, and tumour necrosis factor-α performed before and after dosing revealed cytokine increases before study drug administration. After drug administration, IFN-γ and IL-10 increased in two patients; IL-8 increased in one. Most increases returned to pretreatment levels within 1 week. Two patients were subsequently successfully treated with entecavir indicating that NUC B1000 does not compromise subsequent antiviral therapy.
  
  
  CONCLUSIONS
  Thus far, NUC B1000 appears safe and well-tolerated; safety and efficacy studies across a larger, more diverse patient spectrum using increasing doses are needed to determine its appropriate role in the antiviral armamentarium.
authors.affiliation: Center for Hepatobiliary Disease and Abdominal Transplantation, UCSD Medical Center, San Diego, CA, USA. rgish@ucsd.edu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.forename: C
authors.initials: C
authors.lastname: Satishchandran
authors.forename: Michael
authors.initials: M
authors.lastname: Young
authors.forename: Catherine
authors.initials: C
authors.lastname: Pachuk
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D034741:RNA, Small Interfering