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

Bristol-Myers Squibb, Pennington, New Jersey, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2013; 8(5):e63818. DOI: 10.1371/journal.pone.0063818
Source: PubMed


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. NCT00703469 NCT00703469.

Download full-text


Available from: Eric Lawitz
  • Source
    • "HBs Not used DNA VLV HBV-tg mice (Reynolds et al. (2015) HBs Not used DNA VSV HBV-tg mice Cobleigh et al. (2013) HBs Lamivudine DNA MVA CHB patients Cavenaugh et al. (2011) HBc Entecavir DNA Ad5 + Ad35 Chronically infected woodchucks Kosinska et al. (2012) and Kosinska et al. (2013) chronic infections (Bengsch et al., 2014; Dietze et al., 2013; Fisicaro et al., 2012). A monoclonal antibody against human PD-1 has already been used in cancer therapy, such as malignant melanoma (Mashima et al., 2015), and is in clinical trials for the treatment of hepatitis C (Fuller et al., 2013; Gardiner et al., 2013). Studies of PD-1 blockade strategy in CHB treatment is still in the stage of animal experiments . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".
    Full-text · Article · Oct 2015 · Antiviral research
  • Source
    • "At the highest administered dose (10 mg/kg), a >4 log10 IU/mL reduction in HCV RNA titer was observed in three of 20 (15%) patients. This suppression of HCV replication persisted for more than 8 weeks in most patients (Gardiner et al., 2013). Third, the recent development of direct acting antivirals (DAAs) provided the opportunity to evaluate whether a rapid decrease in HCV titer results in a phenotypic and functional recovery of HCVspecific CD8 T cell responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV)-specific T cells are key factors in the outcome of acute HCV infection and in protective immunity. This review recapitulates the steps that immunologists have taken in the past 25 years to dissect the role of T cell responses in HCV infection. It describes technical as well as disease-specific challenges that were caused by the inapparent onset of acute HCV infection, the difficulty to identify subjects who spontaneously clear HCV infection, the low frequency of HCV-specific T cells in the blood of chronically infected patients, and the lack of small animal models with intact immune systems to study virus-host interaction. The review provides a historical perspective on techniques and key findings, and identifies areas for future research.
    Full-text · Article · Nov 2014 · Antiviral Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Presently the development of new therapies for hepatitis C virus (HCV) is rapidly moving forward. Almost every week new data appear on how direct acting antivirals (DAAs) succeed or fail in clinical trials. Despite the potency of many of the DAA combinations, the effect exerted by ribavirin (RBV) is still needed for an effective therapy in many new DAA combinations. Due to the strong antiviral effect of DAAs, it is likely that a major complementary therapeutic effect exerted by RBV is immune modulation resulting in an increased barrier to development of resistance. For HCV genotype 1a infections elimination of pegylated interferon, is not possible in many DAA combinations without jeopardizing the results. The host immune response is thus likely to play a key role even during DAA-based therapies. Hence, T cells may recognize and eliminate viral variants with resistance to the DAAs. We herein show several examples where this may be the case, supporting the rationale of including the host response also in the new therapeutic regimens. This review will describe the potential benefits of combining various DAAs with means to activate the specific immune response against HCV.
    No preview · Article · Aug 2013 · Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy
Show more