A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.

BACKGROUND & AIMS: Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS: This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 µg) or peginterferon alfa-2a (alfa; 180 µg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS: Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 µg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 µg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 µg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION: Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

Human parainfluenza virus 3 neuraminidase activity contributes to dendritic cell maturation.

Mechanisms of dendritic cells (DCs) immunomodulation by parainfluenza viruses have not been characterized. We analyzed whether the human parainfluenza 3 (HPF3) virus hemagglutinin-neuraminidase glycoprotein (HN) might influence DC maturation. HN possesses a receptor binding function and a neuraminidase or desialidating activity. To assess whether the neuraminidase activity of HN affects DC maturation, human myeloid DCs were exposed to either live or UV-inactivated HPF3 viruses containing wild type or a mutated form of HN with decreased neuraminidase activity. Exposure of human DCs to either UV-inactivated or live virus induced up-regulation of CD83 and CD86 surface markers, morphological changes, and a cytokine expression pattern consistent with maturation. However, the level of maturation was found to be lower in DCs infected with the neuraminidase deficient variant as compared to the wild type. These results suggest that during the course of viral infection, HN's neuraminidase activity may play an important role contributing to maturation and activation of DCs.

Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 2: Exposure-response analyses for efficacy and safety variables.

This is the second of two manuscripts detailing the pharmacodynamic derivation of peginterferon lambda-1a (Lambda) dosing and treatment durations for Phase 3 studies in hepatitis C virus (HCV) infection, based on Phase 2 data. Herein, we describe the derivation of regression models for 12-week on-treatment virologic response and safety outcomes at 120, 180, and 240 µg Lambda with ribavirin. In patients with HCV genotypes 1 or 4, there was a significant (P = 0.024) relationship between undetectable HCV-RNA at Week 4 and Lambda exposure (AUC or Cmax ), with the largest difference between adjacent dose levels between the 180 and 120 µg exposure ranges. Risk of Grade 3-4 aminotransferase or bilirubin elevations relative to a peginterferon alfa-2a/ribavirin control were related to Lambda exposure for all patients, and the largest increase between adjacent dose levels was seen for 240 versus 180 µg. Anemia and neutropenia events were lower than control across all doses and exposures. Based on these data and those in our previous manuscript, Phase 3 studies will evaluate fixed 180 µg doses of Lambda in combination with ribavirin and a direct-acting antiviral for 24-48 weeks in HCV genotypes 1 or 4 or 12-24 weeks in genotypes 2 or 3.

Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 1: Modeling optimal treatment duration and sustained virologic response rates.

Peginterferon lambda-1a (Lambda) is under clinical development for the treatment of chronic hepatitis B and C virus (HBV, HCV, respectively) infection. This is the first of two manuscripts detailing the pharmacodynamic derivation of Lambda dosing and treatment durations for Phase 3 studies in HCV, based on Phase 2 data. We describe here the derivation of a population model of Lambda exposure; the adaptation of a previously published viral dynamic model for Lambda treatment and host genotype, and its use to simulate sustained virologic responses (SVR). Lambda population pharmacokinetics was described by a one-compartment model with first-order absorption, and 33.0 L per day clearance with 47% interindividual (36% intra-individual) variability. Weight explained a negligible proportion of the variability. Based on SVR predictions, optimum treatment durations were 48 weeks for HCV genotypes 1 or 4 (SVR estimates for 120, 180, and 240 µg Lambda: 58%, 54%, 47%, respectively) and 24 weeks for genotypes 2 or 3 (75%, 72%, 67%). SVR predictions for 240 µg were lower due to dropout predictions. The SVR model established the optimum treatment duration for Phase 3 studies but did not differentiate between 120 and 180 µg dosing. A companion manuscript describes dose selection based on exposure-response/safety modeling.

Characterization of human metapneumovirus infection of myeloid dendritic cells.

Recent in vivo studies suggest that hMPV is a poor inducer of inflammatory cytokines and that clinical symptoms may not be related to immune-mediated pathogenesis as it has been proposed for respiratory syncytial virus (RSV) and human parainfluenza 3 (HPF3). Dendritic cells (DCs) are specialized antigen presenting cells, and very effective at inducing specific CTLs after encountering invading viruses. Interactions of hMPV with DCs have not been characterized. We hypothesized that the relatively mild inflammatory responses observed in vivo after hMPV infection might be at least in part due to hMPV's poor ability to stimulate and activate DCs. hMPV actively infected immature monocyte-derived CD11c+/HLA-DR+ DCs. However, in contrast to RSV or HPF3, hMPV caused no gross cytopathic effects such as syncytia, lytic infection, or massive apoptosis. DCs exposed to hMPV show no cytopathic effects under tissue culture conditions permissive for viral replication. The surface maturation markers CD83 and CD86 were not significantly up-regulated in infected DCs as compared to uninfected controls, while expression of CD80 appeared increased. Stimulation of hMPV-infected DCs with LPS resulted in the enhanced expression of all these surface markers indicating that hMPV is not generally suppressing DC maturation. Overall, cytokine expression remained low. These results indicate that hMPV does not induce effective DC maturation in vitro and suggest that the weak stimulation of DCs may account for the overall low immunogenicity of this virus observed in vivo.