生物活性

• 描述Hepatitis C virus (HCV) NS5A protein supports the replication of HCV by interacting with viral and cellular proteins to form the HCV replicase complex, the micro-organelle that replicates HCV RNA, thus making it an excellent target for the discovery of anti-HCV therapeutics. Pibrentasvir is a novel and pan-genotypic HCV NS5A inhibitor with EC₅₀ values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir inhibited HCV genotype 1a-H77, 1b-Con1, and 2a-JFH-1 subgenomic replicons with EC₅₀ values of 1.8, 4.3 and 5.0 pM, respectively; EC₅₀ values ranged between 1.4 and 2.8 pM against chimeric stable replicons containing NS5A derived from HCV genotypes 2a, 2b, 3a, 4a, 5a, and 6a. The 50% cytotoxicity concentration (CC₅₀) value of pibrentasvir in an HCV genotype 1a replicon cell line was > 32,000,000 pM, producing an in vitro therapeutic index that exceeded 107-fold. Furthermore, pibrentasvir retained full activity against all of the genotype 1a and 1b single-position NS5A substitutions tested, except Y93H and Y93N of genotype 1a, which conferred ≤ 7-fold increase in EC₅₀ to pibrentasvir (EC₅₀ ≤ 5.1 pM)^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03164902	Hepatitis C, Chronic ... more >> Nonadherence, Patient Collapse <<	Not Applicable	Active, not recruiting	April 30, 2019	United States, Alabama ... more >> University of Alabama Birmingham, Alabama, United States, 35294 United States, California Zuckerberg San Francisco General Hospital San Francisco, California, United States, 94110 United States, Colorado Peak Gastroenterology Associates Colorado Springs, Colorado, United States, 80907 Denver Health Denver, Colorado, United States, 80204 United States, District of Columbia Providence Health System Washington, District of Columbia, United States, 20017 United States, Florida Orlando Immunology Center Orlando, Florida, United States, 32803 Apex Clinical Research Tampa, Florida, United States, 33612 United States, Illinois The Ruth M. Rothstein CORE Center Chicago, Illinois, United States, 60637 United States, Maryland Johns Hopkins University Baltimore, Maryland, United States, 21205 United States, Massachusetts The Research Institute Springfield, Massachusetts, United States, 01105 United States, Michigan Harper University Hospital Detroit, Michigan, United States, 48201 Henry Ford Health System Detroit, Michigan, United States, 48202 United States, New Mexico Southwest Care Center Santa Fe, New Mexico, United States, 87502 United States, North Carolina Duke University Medical Center Durham, North Carolina, United States, 27710 United States, Washington Harborview Medical Center Seattle, Washington, United States, 98104 United States, Wisconsin SSM Health Dean Medical Group Madison, Wisconsin, United States, 53713 Collapse <<
  NCT02640157	Chronic Hepatitis C ... more >> Hepatitis C Virus Genotype 3 Hepatitis C Virus Collapse <<	Phase 3	Completed	-	-
  NCT02640157	-	-	Completed	-	-

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• 参考文献

• [1] Gane E, Poordad F, et al. High Efficacy of ABT-493 and ABT-530 Treatment in Patients With HCV Genotype 1 or 3 Infection and Compensated Cirrhosis. Gastroenterology. 2016 Oct;151(4):651-659.e1.

  [2] Lin CW, Dutta S, et al. Pharmacokinetics, Safety, and Tolerability Following Single and Multiple Doses of Pibrentasvir in a First-in-Human Study. Clin Pharmacol Drug Dev. 2017 May 2.

  [3] Ng TI, Krishnan P, Pilot-Matias T, et al. In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02558-16