A Phase 1b Dose-Ranging Study of 4 Weeks of PEG-Interferon

AASLD
60th Annual Meeting of the American Association for the Study of Liver Diseases
Boston, MA, Hynes Convention Center
October 30-November 3, 2009 Back grey_arrow_rt.gif





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) Infection


Reported by Jules Levin
AASLD Nov 2 2009, Boston, MA

Andrew J. Muir1, Mitchell L. Shiffman2, Atif Zaman3, Boris Yoffe4, Juan Carlos Lopez-Talavera5, Sherri Souza6, Diana F. Hausman6, Naomi N Hunder6, David Fontana6,Eric Lawitz7
1Duke University, Durham, NC, USA; 2VCU 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 Antonio, 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

ABSTRACT

Background: PEG-IFN-lambda (PEG-IFN-λ) is a unique interferon that has fewer flu-like symptoms and hematologic adverse effects than are typically observed with alpha IFNs, likely due to more focused expression of the IFN-lambda receptor. A Phase 1b study of PEG-IFN-λ in HCV genotype 1 patients who relapsed after treatment with IFN-alpha + RBV or are treatment-naïve is ongoing. Initial results previously presented demonstrated that weekly administration of PEG-IFN-λ as a single agent was well-tolerated and associated with greater HCV RNA reduction than every other week administration.

Methods: This open-label dose-ranging study is evaluating 4 weeks of PEG-IFN-λ administered QW subcutaneously in combination with daily RBV (1000 or 1200 mg/day) in patients with HCV genotype 1 and prior relapse. A treatment-naïve cohort is currently being enrolled. Assessments include adverse events (AEs), laboratory values, and changes in HCV RNA.

Results: A total of 16 patients with chronic HCV and prior relapse have completed 4 weeks of treatment with PEG-IFN-λ QW (0.5 [n=4], 0.75 [n=3], 1.5 [n=6], and 2.25 [n=3] µg/kg) and daily RBV.

Treatment has been well-tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common AEs, regardless of dose level, are fatigue (4/16; 25%), nausea (4/16; 25%), and insomnia (3/16; 19%), all Grade 1 or 2.

As previously reported, one patient treated at PEG-IFN-λ 1.5 µg/kg QW + RBV experienced reversible Grade 3/4 increases in ALT, AST, and bilirubin. No other patient receiving PEG-IFN-λ + RBV has experienced clinically-significant elevations in these parameters.

Dose-dependent antiviral activity in patients completing 4 weeks of treatment has been observed at all dose levels, with 12/16 (75%) relapse patients achieving >2-log decrease (range 0.1-5.6) in HCV RNA, and all 3 subjects treated at 2.25 µg/kg achieving HCV RNA levels <1000 IU/mL at Day 29.


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Conclusions: PEG-IFN-λ QW subcutaneously + daily RBV administered for 4 weeks has been well-tolerated with minimal flu-like symptoms or hematologic effects in patients with chronic HCV and prior relapse. This treatment is also associated with robust antiviral activity across a broad range of doses.

INTRODUCTION

Treatment of chronic hepatitis C (HCV) with PEG-Interferon-α (PEG-IFN-α) and ribavirin (RBV) is frequently associated with significant toxicities, dose reductions and avoidance of treatment1

PEG-IFN Lambda 1a (PEG-IFN-λ) is in development as a new treatment for chronic HCV

- Member of the Type III/λ IFN family2,3 which binds to a unique receptor with more restricted distribution than IFN-α/Type-I IFN receptors

- Potential for more favorable tolerability and side-effect profile (expected to have less hematological toxicity) than IFN-α or other Type-1 IFNs

Here we report the four-week antiviral activity, safety and pharmacokinetic (PK) results from the Phase 1b dose ranging study in IFN-α relapse and treatment naïve genotype-1 HCV patients


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*One patient discontinued due to an unrelated adverse drug reaction to meperidine

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


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

Table 2: PEG-IFN-λ Virological Response


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a Lower limit of detection= HCV RNA <25 IU/mL, b Excludes one patient who discontinued due to an unrelated adverse drug reaction to meperidine

Safety and Tolerability

Table 3: PEG-IFN-λ Adverse Event (AE) Summary


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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)
b Possible grade 3 idiopathic thrombocytopenic purpura
c Grade 3 hepatotoxicity (SAE), pruritus, and increased serum lipase/amylase without signs of pancreatitis, probably related to study drug
d 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 thee 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 and Treatment-Naïve Patients

No clinically-meaningful changes in neutrophil or platelet counts were observed during PEG-IFN-λ treatment



REFERENCES

1. Ghany et al. Hepatology. 2009; 49(9): 1335-1374
2. Kotenko et al. Nature Immunology. 2003; 4(1): 69-77
3. Sheppard et al. Nature Immunology. 2003; 4(1):63-68