title: Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection.
abstract: OBJECTIVE
  BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.
  
  
  METHODS
  Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.
  
  
  RESULTS
  In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.
  
  
  CONCLUSIONS
  BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.
authors.affiliation: Hannover Medical School, Department of Gastroenterology, Hepatology, and Endocrinology, Center for Internal Medicine, Hannover, Germany. Manns.Michael@mh-hannover.de
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.forename: Yves
authors.initials: Y
authors.lastname: Benhamou
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bonacini
authors.forename: Christian
authors.initials: C
authors.lastname: Trepo
authors.forename: David
authors.initials: D
authors.lastname: Wright
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: José L
authors.initials: JL
authors.lastname: Calleja
authors.forename: Peter W
authors.initials: PW
authors.lastname: White
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
authors.forename: Gerhard
authors.initials: G
authors.lastname: Steinmann
authors.forename: Chan-Loi
authors.initials: CL
authors.lastname: Yong
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Joe
authors.initials: J
authors.lastname: Scherer
authors.forename: Wulf O
authors.initials: WO
authors.lastname: Boecher
mesh_terms: D000328:Adult; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D002352:Carrier Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D012254:Ribavirin; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C552340:faldaprevir; C100416:peginterferon alfa-2a