title: A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.
abstract: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naïve and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00703469.
authors.affiliation: Bristol-Myers Squibb, Pennington, New Jersey, USA. david.gardiner@bms.com
authors.forename: David
authors.initials: D
authors.lastname: Gardiner
authors.forename: Jay
authors.initials: J
authors.lastname: Lalezari
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.forename: Michael
authors.initials: M
authors.lastname: DiMicco
authors.forename: Rheem
authors.initials: R
authors.lastname: Ghalib
authors.forename: K Rajender
authors.initials: KR
authors.lastname: Reddy
authors.forename: Kyong-Mi
authors.initials: KM
authors.lastname: Chang
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
authors.forename: Steven O'
authors.initials: SO
authors.lastname: Marro
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Anderson
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Vikram
authors.initials: V
authors.lastname: Kansra
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.forename: Dennis
authors.initials: D
authors.lastname: Grasela
authors.forename: Mark
authors.initials: M
authors.lastname: Selby
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics; D019562:Viral Load / Q000187:drug effects / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D016898:Interferon-alpha; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral; D000077594:Nivolumab