A Phase 1b Dose-Ranging Study of 4 Weeks of PEG-Interferon (IFN) Lambda (PEG-rIL

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A Phase 1b Dose-Ranging Study of 4 Weeks of PEG-Interferon (IFN) Lambda (PEG-rIL-29) in Combination with Ribavirin (RBV) in Patients with Chronic Genotype 1 Hepatitis C Virus (HCV) I

Reported by Jules Levin 20th Conference of the APASL, China National Convention Center, 25 - 28 March 2010, Beijing, China J. Muir1, L. Shiffman2, Atif Zaman3, Boris Yoffe4, -Talavera5, Sherri Souza6, F. Hausman6, Naomi N Hunder6, Todd Gray6, Fontana6, Lawitz7 1Duke University, Durham, NC, USA; 2McGuire Research Institute, McGuire VA Medical Center, Richmond, VA, USA; 3Oregon Health Sciences University, Portland, OR, USA; 4Baylor College of Medicine, Houston, TX, USA; 5Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA; 6ZymoGenetics Inc, Seattle, WA, USA; 7Alamo Medical Research, San , TX, USA. AUTHOR CONCLUSIONS PEG-IFN-λ was associated with robust antiviral activity at all dose levels tested in both IFN-α relapse and treatment-naïve HCV patients-- Majority of patients achieved >2 log reduction in HCV RNA during the 4-week treatment period; anti-viral activity appears to be dose-dependent Treatment was generally safe and well-tolerated-- Minimal constitutional symptoms or myelosuppressive hematologic effects were observed-- Dose-limiting toxicities of elevations in ALT or AST with or without increased bilirubin were reversible upon treatment cessation PK data suggest that PEG-IFN-λ exposure is dose dependent and support once-weekly dosing and exploration of fixed dosing These results support the initiation of dose-ranging Phase 2 studies in treatment-naïve HCV patients which are currently ongoing ABSTRACT Background: PEG-IFN-lambda (PEG-IFN-λ) is a type III interferon that may have fewer flu-like symptoms and hematologic adverse effects than are typically observed with alpha IFNs, likely due to more focused expression of the IFN-λ receptor. Here we report the four-week antiviral activity and safety results from the Phase 1b open-label dose-ranging study in IFN-a relapse and treatment-naïve genotype-1 HCV patients. Methods: Part 1 of the study evaluated escalating doses of single-agent PEG-IFN-λ administered either Q2W or QW for 4 weeks to HCV+ IFN-a relapse patients. Parts 2 and 3 of the study evaluated different dose levels of PEG-IFN-λ administered weekly in combination with daily oral ribavirin (RBV) for 4 weeks to IFN-a relapse patients (Part 2), or who were naïve to treatment for HCV (Part 3). Doses of PEG-IFN-λ were body weight-based and ranged from 0.5- 3.0µg/kg. Assessments include adverse events (AEs), laboratory values, and changes in HCV RNA. Results: 56 patients (mean age 51 years, 69% male, mean baseline HCV RNA 6.43 log10 IU/mL) were randomized to treatment. Dose-dependent reductions in antiviral activity at 4 weeks were observed, with 83 and 86% achieving >2-log decrease in HCV RNA at the PEG-IFN-λ 1.5mg/kg + RBV dose in IFN-a relapse and treatment-naïve patients, respectively. Treatment was generally well-tolerated with minimal flu-like symptoms and no clinically meaningful changes observed in neutrophils, platelet counts or hemoglobin levels (apart from RBV associated reductions). 6/56 (11%) of patients experienced reversible increases in ALT/AST with or without increases in bilirubin (majority at the 3.0mg/kg single agent dose, Part 1). Conclusions: PEG-IFN-λ was associated with robust antiviral activity at all dose levels tested in both IFN-a relapse and treatment-naïve patients. Treatment was generally safe with minimal flu-like symptoms or heamatologic effects observed. These favorable results supported the initiation of Phase 2 studies in treatment-naïve patients which are currently underway.

ANTIVIRAL ACTIVITY Anti-viral activity was observed at all dose levels. Higher PEG-IFN-λ doses were associated with greater declines in HCV RNA (Figure 2)· 2 of 7 (29%) patients in treatment-naïve cohort achieved RVR (undetectable HCV RNA by week 4) Figure 2: Mean (SE) Change in HCV RNA from Baseline following Four-Weeks of PEG-IFN-λ + RBV in IFN-α Relapse and Treatment-Naïve Patients

A summary of virological response for each treatment arm is shown in Table 2

a 5 patients met protocol defined DLT criteria due to elevated hepatic lab values, one patient had DLT of possible grade 3 idiopathic thrombocytopenic purpura (ITP) considered possibly related to study drugb Possible grade 3 idiopathic thrombocytopenic purpura considered possibly related to study drugc Grade 3 hepatotoxicity (SAE), pruritus, and increased serum lipase/amylase without signs of pancreatitis, probably related to study drugd Adverse drug reaction to meperidine (acute respiratory distress) in a subject with a history of migraine headaches and COPD, unrelated to study drug PEG-IFN-λ was generally well-tolerated with the majority of AEs mild (Grade 1) or moderate (Grade 2) in severity Most common AEs in all patients were fatigue (29%) and nausea (13%) -- Adverse events were more commonly observed in relapsed patients treated with PEG-IFN-λ + RBV (Part 2) than in naïve subjects treated with PEG-IFN-λ + RBV (Part 3) or when used as a single agent in relapsed subjects (Part 1) 6/56 (11%) experienced reversible increases in ALT/AST with or without increases in bilirubin that met the protocol-defined criteria for DLT or withholding a PEG-IFN-λ dose (majority at the 3.0 µg/kg single agent dose) Figure 3: Neutrophil and Platelet Counts following Four Weeks of PEG-IFN-λ + RBV in IFN-α Relapse andTreatment-Naïve Patients

No clinically-meaningful changes in neutrophil or platelet counts were observed during PEG-IFN-λ treatment Figure 4: Hemoglobin Levels following Four Weeks of PEG-IFN-λ Treatment

No clinically-meaningful changes in hemoglobin levels were observed (apart from RBV associated reductions) PharmacokineticsThe exposure of PEG-IFN-λ appears to be dose dependent. Dose-normalized AUC was similar across the range of dose No strong influence of body weight on exposure was observed Modest accumulation during treatment was expected and observed, supporting the weekly dosing schedule proposed in Phase 2

a One patient excluded due to AUC0-t and Cmax values inconsistent with the nominal dose administeredb One patient excluded due to lack of pharmacokinetic samples as a result of premature discontinuation of the studyc AUC0-t values for some patients were not estimated due to a lack of quantifiable data, and were imputed to be 1/2 of the lowest reported AUC0-t (6.78 h*ng/mL / 2 = 3.39 h*ng/mL).