ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT Safety and Antiviral Activity of Albinterferon Alfa-2b in Prior Interferon Nonresponders With Chronic Hepatitis C DAVID R. NELSON,* VINOD RUSTGI, VIJAYAN BALAN, MARK S. SULKOWSKI, GARY L. DAVIS, ANDREW J. MUIR, # LOUIS R. LAMBIASE,** ROLLAND C. DICKSON, RUSSELL H. WEISNER, MICHELE FISCELLA, PATRICK W. CRONIN, ERIK PULKSTENIS, JOHN G. MCHUTCHISON, and G. MANI SUBRAMANIAN *University of Florida, Gainesville, Florida; Metropolitan Research, Fairfax, Virginia; Mayo Clinic, Scottsdale, Arizona; Johns Hopkins University, Baltimore, Maryland; Baylor University Medical Center, Dallas, Texas; # Duke University, Durham, North Carolina; **University of Florida, Jacksonville, Florida; Mayo Clinic, Jacksonville, Florida; Mayo Clinic, Rochester, Minnesota; Duke Clinical Research Institute, Durham, North Carolina; and Human Genome Sciences, Inc, Rockville, Maryland See Liu C-J et al on page 496 for companion article in the February 2009 issue of Gastroenterology. Background & Aims: Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. Methods: A total of 115 patients were assigned to 5 groups given 1200 g albinterferon every 4 weeks or 900, 1200, 1500, or 1800 g every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. Results: The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the g group. Conclusions: In patients with CHC who did not respond to interferonbased regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon. Chronic hepatitis C (CHC) is one of the most common causes of chronic liver disease, with approximately 3% of the world s population (as many as 170 million people) infected. 1,2 Pegylated interferon (PEG-IFN) alfa-2a or -2b dosed every week in combination with ribavirin (RBV) is the current standard of care for the treatment of CHC based on superior sustained virologic response (SVR) rates compared with standard IFN alfa. An SVR is achieved in approximately 45% to 50% of patients with genotype (Gt) 1 CHC and approximately 76% to 82% with Gt 2 and 3. 3,4 Thus, a substantial number of patients fail to achieve SVR, either because of virologic breakthrough after achieving undetectable hepatitis C virus (HCV) RNA levels at the end of treatment (relapse) or failure to achieve a sufficient reduction in HCV RNA level (nonresponder). Several studies have explored the retreatment of nonresponders with PEG-IFN alfa based regimens, 5 7 longer treatment durations, 8 and the addition of other agents (eg, IFN, amantidine). 5,9 Most of these re-treatment trials, however, have produced modest SVR rates ranging from 7% to 18%. 5 8 Low re-treatment success rates have resulted in a growing pool of patients who have exhausted their treatment options. Albinterferon alfa-2b (alb-ifn) is an 85.7-kilodalton protein consisting of recombinant human IFN alfa-2b genetically fused to recombinant human albumin. In vitro assays have shown that alb-ifn retains the antiviral properties of IFN alfa, with significant suppression of HCV RNA in the replicon system at pharmacologic drug concentrations. 10 Dose-ranging phase 1 studies in patients with CHC showed tolerability at doses up to 1200 g, an extended half-life of approximately 150 hours, and evidence of dose-dependent antiviral activity in IFN treatment experienced and treatment naive patients after the administration of up to 2 doses of alb-ifn at 14-day intervals. 11,12 Administration of alb-ifn was shown to result in detectable drug in serum for up to 28 days. These data provided the rationale for investigating the effects of alb-ifn dosed at 2-week or 4-week intervals. In this study, the safety and antiviral activity of alb-ifn in combination with RBV was assessed in patients with CHC who were nonresponders to IFN alfa containing regimens. Serum concentrations of alb-ifn were obtained over the 48-week treatment duration to evaluate the pharmacokinetics of an every 2 weeks or every 4 weeks alb-ifn dosing schedule. Finally, to explore whether Abbreviations used in this paper: AEs, adverse events; alb-ifn, albinterferon alfa-2b; ANC, absolute neutrophil count; CES-D, Center for Epidemiologic Studies Depression scale; CHC, chronic hepatitis C; Gt, genotype; HCV, hepatitis C virus; LOD, limit of detection; PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response by the AGA Institute /09/$36.00 doi: /j.cgh

2 February 2009 ALBINTERFERON IN IFN NONRESPONDERS 213 Figure 1. Study disposition. a Patients were randomized to either the 1200 g every 4 weeks or every 2 weeks, or 900 g every 2 weeks groups, whereas the and g groups were enrolled sequentially, and were not randomized. b More than 1 reason may be recorded. c Completing the 48-week treatment period (72 weeks for late responders) or discontinuation owing to lack of efficacy and completion of the required posttreatment follow-up period. such patients could benefit from increased exposure to IFN, doses of alb-ifn up to 1800 g every 2 weeks were assessed. Materials and Methods Patient Selection The study comprised adult patients with CHC who previously had received IFN alfa based therapy and experienced a less than 2-log 10 IU/mL reduction in HCV RNA level after 12 weeks of treatment or were unable to clear HCV RNA during a treatment period of 24 weeks or longer, and thus were considered to be treatment nonresponders. Approximately 50% of patients in each treatment arm were required to be nonresponders to a previous treatment regimen of PEG-IFN alfa-2a or -2b in combination with RBV. No limitations were placed on the number of prior treatment regimens a patient could have received. Patients were excluded if they had decompensated liver disease, other possible etiologies for chronic liver disease, thrombocytopenia ( 125,000 platelets/mm 3 ), neutropenia ( 2000 neutrophils/mm 3 ), history of severe psychiatric disease, immunologically mediated disease, uncontrolled thyroid disease, co-infection with hepatitis B virus or human immunodeficiency virus, alcohol or drug dependence, or a significant coexisting medical condition. Study Design This phase 2, open-label, dose-ranging study was conducted at 9 centers between October 2004 and July 2007 (registered on ClinicalTrials.gov [identifier NCT ] at: albuferon&rank 4). The study initially randomized patients to 3 alb-ifn groups: 900 g every 2 weeks, 1200 g every 2 weeks, or 1200 g every 4 weeks. All alb-ifn doses were administered subcutaneously. The protocol subsequently was amended to allow sequential enrollment of patients in treatment arms with alb-ifn dosages of 1500 and 1800 g every 2 weeks. All patients received RBV (Copegus; Roche Laboratories, Nutley, NJ) 1000 or 1200 mg/d in 2 divided doses based on body weight less than 75 kg or body weight 75 kg or greater, respectively. Treatment duration was 48 weeks, with a 24-week follow-up period. A Table 1. Pretreatment Characteristics of Patients q4wk (n 24) Alb-IFN 900 g q2wk (n 23) q2wk (n 24) Alb-IFN 1500 g Alb-IFN 1800 g Male sex, n 15 (62.5%) 14 (60.9%) 14 (58.3%) 19 (86.4%) 13 (59.1%).19 Ethnicity.09 Caucasian, n 23 (95.8%) 21 (91.3%) 21 (87.5%) 15 (68.2%) 20 (90.9%) African American, n 1 (4.2%) 2 (8.7%) 3 (12.5%) 7 (31.8%) 2 (9.1%) Mean age SD, y Mean BMI SD, kg/m BMI 25 kg/m 2,n 19 (79.2%) 20 (87.0%) 21 (87.5%) 18 (81.8%) 17 (77.3%).87 F3 F4, n 4 (16.7%) 7 (33.3%) 7 (33.3%) 9 (45.0%) 7 (33.3%).35 Mean HCV RNA level SD, log 10 IU/mL HCV RNA level 800,000 IU/mL, n 18 (75.0%) 18 (81.8%) 20 (83.3%) 20 (90.9%) 21 (95.5%).34 Gt 1, n 22 (91.7%) 20 (87.0%) 24 (100%) 21 (95.5%) 20 (90.9%).46 2 prior treatment regimens, n 16 (66.7%) 11 (47.8%) 16 (66.7%) 16 (72.7%) 12 (54.5%).41 Gt 1, PEG-IFN alfa RBV nonresponder, n 13 (54.2%) 13 (56.5%) 16 (66.7%) 15 (68.2%) 18 (81.8%).28 BMI, body mass index; F, fibrosis stage; q2wk, every 2 weeks; q4wk, every 4 weeks; SD, standard deviation. a P values for comparison of treatment groups based on likelihood ratio test or the Fisher exact test for categoric variables and 1-way analysis of variance for continuous variables.

3 214 NELSON ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 protocol amendment allowed the treatment duration to be increased to 72 weeks in patients who achieved HCV RNA negativity after week 24, per investigator discretion. The study protocol recommended stepwise ( 1 level) dose reductions of alb-ifn (from 1800 or 1500 to 1200 g, from 1200 to 900 g, from 900 to 700 g, and from 700 to 500 g) to manage adverse events (AEs) and hematologic abnormalities. Criteria for dose reductions based on hematologic assessments included an absolute neutrophil count (ANC) of 500 to 750/mm 3 or a platelet count of 30,000 to 50,000/mm 3. Doses were held or delayed for up to 28 days for an ANC of less than 500/mm 3 or a platelet count of less than 30,000/mm 3. Ribavirin dose was reduced to 600 mg/d for a hemoglobin level of greater than 8.5 to 10 g/dl and held for a level of 8.5 g/dl or less. In addition, hematologic growth factors were allowed to maintain an ANC greater than 750/mm 3 or hemoglobin level greater than 10 g/dl. Dose reductions (or holding the dose) were recommended for managing moderate severe nonhematologic AEs based on the discretion of the clinical investigator. The institutional review boards of the participating centers approved the protocol and all amendments. All patients provided written informed consent. Human Genome Sciences, Inc. (Rockville, MD) sponsored the study and was responsible for all data collection and statistical analysis. The conduct of the study was coordinated centrally by the Duke Clinical Research Institute (Durham, NC). The investigators had full access to the data. The study was conducted according to the guideline provisions of Good Clinical Practices, as defined in the International Conference on Harmonisation Guidelines. 13 Safety, Pharmacokinetic, and Immunogenicity Assessments The primary objective of the study was to evaluate the safety of alb-ifn, including AE monitoring and clinical laboratory assessment (eg, hematology, serum chemistry, and urinalysis). Safety was assessed through completion of treatment (up to 48 or 72 weeks) and for 12 weeks or more after treatment. AEs were assessed for severity using the Division of Microbiology and Infectious Diseases toxicity tables. The Center for Epidemiologic Studies Depression scale (CES-D) 14 was administered at screening, at weeks 4, 12, 24, and 48 (72 for lateresponders) on treatment, and at week 24 after treatment follow-up evaluation to assess changes in neuropsychiatric status. Serum samples to measure alb-ifn concentrations were obtained on day 0 (predose) and before dosing at scheduled visits on weeks 2, 4, 12, 24, and 48 (72 for late responders). Serum Table 2. Assessment of Safety (Discontinuations, Dose Reductions, AE, and Hematology) q4wk (n 24) Alb-IFN 900 g q2wk (n 23) q2wk (n 24) Alb-IFN 1500 g Alb-IFN 1800 g Completed treatment per protocol 19 (79.2%) 17 (73.9%) 22 (91.7%) 16 (72.7%) 14 (63.6%).20 Discontinued owing to AEs 1 (4.2%) 4 (17.4%) 1 (4.2%) 2 (9.1%) 4 (18.2%).36 1 severe AE 4 (16.7%) 7 (30.4%) 9 (37.5%) 10 (45.5%) 12 (54.5%).08 Alb-IFN dose reductions Overall 6 (25.0%) 10 (43.5%) 10 (41.7%) 8 (36.4%) 10 (45.5%).60 Owing to AE 4 (16.7%) 3 (13.0%) 2 (8.3%) 3 (13.6%) 6 (27.3%).53 Owing to hematology 1 (4.2%) 5 (21.7%) 4 (16.7%) 4 (18.2%) 4 (18.2%).46 MedDRA preferred term ( 25% of patients receiving alb-ifn) Fatigue 22 (91.7%) 23 (100.0%) 22 (91.7%) 22 (100.0%) 22 (100.0%) Headache 16 (66.7%) 17 (73.9%) 17 (70.8%) 11 (50.0%) 19 (86.4%) Arthralgia 14 (58.3%) 13 (56.5%) 17 (70.8%) 10 (45.5%) 12 (54.5%) Myalgia 16 (66.7%) 14 (60.9%) 16 (66.7%) 11 (50.0%) 9 (40.9%) Nausea 11 (45.8%) 11 (47.8%) 15 (62.5%) 10 (45.5%) 14 (63.6%) Insomnia 15 (62.5%) 11 (47.8%) 10 (41.7%) 10 (45.5%) 12 (54.5%) Chills 13 (54.2%) 11 (47.8%) 12 (50.0%) 6 (27.3%) 12 (54.5%) Pyrexia 12 (50.0%) 10 (43.5%) 12 (50.0%) 8 (36.4%) 11 (50.0%) Alopecia 10 (41.7%) 7 (30.4%) 13 (54.2%) 10 (45.5%) 12 (54.5%) Influenza-like illness 8 (33.3%) 7 (30.4%) 8 (33.3%) 12 (54.5%) 8 (36.4%) Diarrhea 9 (37.5%) 6 (26.1%) 10 (41.7%) 5 (22.7%) 10 (45.5%) Cough 9 (37.5%) 7 (30.4%) 9 (37.5%) 4 (18.2%) 7 (31.8%) Injection-site erythema 9 (37.5%) 8 (34.8%) 8 (33.3%) 5 (22.7%) 6 (27.3%) Depression 9 (37.5%) 6 (26.1%) 7 (29.2%) 5 (22.7%) 5 (22.7%) Mood altered 10 (41.7%) 4 (17.4%) 5 (20.8%) 6 (27.3%) 7 (31.8%) Dyspnea 5 (20.8%) 4 (17.4%) 10 (41.7%) 4 (18.2%) 8 (36.4%) Decreased appetite 5 (20.8%) 6 (26.1%) 10 (41.7%) 2 (9.1%) 6 (27.3%) Laboratory abnormalities ANC level 750/mm 3 2 (8.3%) 8 (34.8%) 8 (33.3%) 6 (27.3%) 6 (27.3%).17 Platelet level 50,000/mm 3 1 (4.2%) 2 (8.7%) (9.1%).38 Hemoglobin level 10 g/dl 1 (4.2%) 4 (17.4%) 2 (8.3%) 3 (13.6%) 6 (27.3%).22 Immunogenicity Pretreatment antibodies 2 (8.3%) 2 (8.7%) 6 (25%) 5 (22.7%) 4 (18.2%) Emergent antibodies 3 (12.5%) 1 (4.3%) 3 (12.5%) 2 (9.1%) 3 (13.6%) MedDRA, medical dictionary for regulatory activities. a P values for comparison of treatment groups based on likelihood ratio test or the Fisher exact test.

4 February 2009 ALBINTERFERON IN IFN NONRESPONDERS 215 Table 3. Changes in CES-D Score at Treatment Weeks 4, 12, and 24 q4wk (n 24) Alb-IFN 900 g q2wk (n 23) q2wk (n 24) Alb-IFN 1500 g Alb-IFN 1800 g Baseline, mean SD Week 4, mean SD Increase 5 points, n 5 (20.8%) 7 (30.4%) 8 (33.3%) 6 (31.6%) 12 (54.5%).17 Week 12, mean SD Increase 5 points, n 5 (20.8%) 10 (43.5%) 12 (50.0%) 7 (36.8%) 11 (50.0%).16 Week 24, mean SD Increase 5 points, n 8 (33.3%) 10 (43.5%) 14 (58.3%) 7 (36.8%) 11 (50.0%).31 SD, standard deviation. a P value for comparison of treatment groups based on the Kruskal Wallis test for change from baseline and likelihood ratio test (or the Fisher exact test) for increases of more than 5 points. alb-ifn concentrations were measured using a qualified IFN capture, IFN detection sandwich enzyme-linked immunosorbent assay. 15 The presence of anti-ifn antibodies was assessed before dosing (pretreatment antibodies) and during treatment. 11 Serum Hepatitis C Virus RNA and Hepatitis C Virus Genotype HCV RNA levels were assessed by real-time Quantasure PCR (Roche HCV Taqman analyte-specific reagents methodology; LabCorp, Research Triangle Park, NC). The dynamic range of this assay was 10 to 100 million IU/mL; both the lower limit of detection (LOD) and limit of quantitation were 10 IU/mL. All testing was performed by LabCorp. HCV genotyping was based on hybridization of the amplified segment of the 5= nontranslated region of the HCV genome with oligonucleotide probes representing genotypes 1 to 6 (Laboratory Corporation of America, Raritan, NJ). Efficacy Assessment The primary efficacy end point was SVR, defined as undetectable HCV RNA level ( LOD) at 24 weeks after the end of therapy. The major secondary efficacy end points included assessment of the HCV RNA level at week 12 (2-log reduction [early virologic response] and HCV RNA LOD), and HCV RNA level less than the LOD at weeks 24 and 48. Statistical Methods A target sample size of 20 patients per treatment group was chosen to provide initial safety data, rather than power for statistical hypothesis testing. The intent-to-treat analysis included all patients who received at least one dose of alb-ifn. For continuous outcomes such as reduction in HCV RNA level over time or CES-D scores, simple descriptive statistics were presented. For categoric outcomes such as the presence of AEs or SVR, counts and percentages were reported, and testing was performed using the likelihood ratio test or the Fisher exact test when more than 20% of expected contingency table cell counts were less than 5. Univariate analysis of factors associated with SVR was performed rather than multivariate modeling because of the modest SVR rate. Because of the exploratory nature of the study, no -adjustment for multiple end points/analyses was used. All statistical tests were 2-sided, performed at a significance level of.05 (unless otherwise specified), and implemented with SAS version 9.1 (SAS Institute, Inc., Cary, NC) or R statistical package (R Foundation for Statistical Computing). Results Of 158 patients screened, 118 were enrolled and 115 received at least one dose of study drug (Figure 1). Demographics and baseline characteristics are summarized in Table 1. Of note, 84.3% of patients had a high pretreatment HCV RNA level ( 800,000 IU/mL) and 30.0% had fibrosis stages F3 to F4 (METAVIR scoring system). The majority of patients were infected with Gt 1 (93.0%); were nonresponders to prior therapy with PEG-IFN alfa and RBV (69.6%); and of the Gt 1 nonresponders to prior therapy with PEG-IFN alfa and RBV, 57% had received 2 or more prior treatment regimens. Patient demographics generally were comparable across the first 3 randomized treatment groups, although patients enrolled subsequently Figure 2. Serum concentration of albinterferon alfa-2b at steady-state levels for (A) all treatment groups (week 12) and (B) during treatment with 1500 g every 2 weeks (weeks 2 24). Dotted lines represent mean concentrations.

5 216 NELSON ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 Figure 3. Virologic response rates (A) overall and in (B) patients with Gt 1 CHC with a nonresponse to prior treatment with PEG-IFN alfa plus RBV. a P.84; b P.71; c P.17; d P.86; e P.21; f P.35; g P.12; h P.62; i P.64; j P.81. EVR12, early virologic response at week 12; LOD, limit of detection. in the higher-dose groups (especially the g group) had higher baseline HCV RNA levels (P.001) and a greater proportion were nonresponders to a PEG-IFN alfa plus RBV regimen. In all, 88 patients (76.5%) completed treatment per protocol (ie, completed the 48-week treatment period or discontinued because of lack of efficacy); all 6 patients who were offered 72 weeks of treatment completed therapy (Table 2). Safety Assessments Adverse events. The most frequent AEs observed with alb-ifn were those commonly seen and expected with IFN therapy (Table 2). Most AEs were mild moderate in severity and resolved or stabilized after treatment completion. The rate of severe AEs increased with increasing drug exposure (P.08), although there were no specific severe AEs that were more frequent in the higher-dose groups. The overall rates of discontinuation owing to AEs were 10.4% and were comparable among treatment groups. Reductions in alb-ifn dose were used to manage AEs, and the rates of these reductions were comparable across treatment groups. Hematology. Hematologic abnormalities generally were comparable across the alb-ifn every 2 weeks groups, with lower rates in the alb-ifn every 4 weeks group (Table 2). Maximum decreases in the ANC or platelet count occurred by weeks 4 to 8, remained stable during treatment, and returned to pretreatment levels by 12 weeks after treatment completion in all groups. Changes in the ANC did not show an association with incidence or severity of infections. Maximal reductions in hemoglobin level occurred by week 12, and a hemoglobin level less than 10 g/dl was least frequent in the alb-ifn g every 4 weeks group (4.2%) and most frequent in the g every 2 weeks group (27.3%). The rates of RBV dose reduction as a result of hematologic abnormalities were comparable across the every 2 weeks groups, but lower in the every 4 weeks group, which is consistent with the lower number of patients experiencing hematologic abnormalities. No patient discontinued treatment because of neutropenia or thrombocytopenia. In this study, 64.3% of patients received erythropoietin and 13.9% received granulocyte colony stimulating factor. Center for Epidemiologic Studies Depression scale. Assessment of depression using the CES-D is shown in Table 3. As a screening tool, the CES-D has been used to estimate the presence of clinically significant depression, and an increase of 5 points has been shown to be clinically meaningful. 14,16,17 Pretreatment CES-D scores were comparable across treatment groups. Increases in CES-D scores were observed in all treatment groups, with changes observed as early as week 4. No dose-response trend was observed, although the change in CES-D scores and proportion of patients with a score increase of more than 5 points were, in general, lower in the alb-ifn every 4 weeks group and comparable across every 2 weeks groups. Among patients with AEs of depression, there was an association with an increase in CES-D score of greater than 5 points: 78.8% of patients with depression versus 46.8% of patients without depression had a more than 5-point increase (P.001). Pharmacokinetics and Immunogenicity Steady-state drug levels appeared to have been achieved 30 days after the first dose on the every 2 week schedule (ie, 5 times the 6-day half-life of alb-ifn). 11,12 Serum alb-ifn concentrations for each treatment group at steady state at week 12 are shown in Figure 2A. The levels of alb-ifn increased proportionately to dose in the every 2 weeks groups. As expected, drug accumulation (67% 94%) was observed in all of the every 2 weeks groups between weeks 2 and 12 at steady state with representative data from the g every 2 weeks treatment group shown in Figure 2B. In the every 4 week group, there was minimal change in alb-ifn accumulation after the first dose (Figure 2A). Nineteen patients (16.5%) had pre-existing anti-ifn antibodies, whereas the incidence of treatment-emerging anti alb-ifn antibody positivity in pretreatment antibody-negative patients was 10.4% (Table 2). Rates of immunogenicity were comparable across treatment groups. There was no correlation Table 4. Predictors of SVR SVR HCV RNA level undetectable at week (68.4%).001 (n 19) Detectable at week 12 (n 96) 7 (7.3%) PEG-IFN alfa RBV NR (n 80) 9 (11.3%).01 Other (n 35) 11 (31.4%) IFN/RBV adherence (first 24 weeks) 80% (n 90) 19 (21.1%).07 80% (n 25) 1 (4.0%) HCV RNA 800,000 IU/mL (n 17) 6 (35.3%).11 HCV RNA 800,000 IU/mL (n 97) 14 (14.4%) F3 F4 (n 34) 3 (8.8%).15 F0 F2 (n 73) 14 (19.2%) African American (n 15) 1 (6.7%).46 Other (n 100) 19 (19.0%) F, fibrosis stage; NR, nonresponder. a P values for comparison of treatment groups based on the likelihood ratio test or the Fisher exact test.

6 February 2009 ALBINTERFERON IN IFN NONRESPONDERS 217 Figure 4. Antiviral activity of albinterferon alfa-2b in patients with Gt 1 CHC with a nonresponse to prior treatment with PEG-IFN alfa plus RBV. (A) Mean change in HCV RNA level over 24 weeks of treatment; (B) reduction in viral load at week 12 of treatment. between the development of these antibodies and the occurrence of AEs, laboratory abnormalities, or virologic response. Efficacy Assessment Virologic response rates during treatment, and SVR rates for the overall study population and the subset of patients with Gt 1 CHC who were nonresponders to prior treatment with PEG-IFN alfa plus RBV, are shown in Figure 3. At week 12, although 41% to 59% of patients achieved early virologic response at week 12, the proportion of patients who were HCV RNA negative was substantially lower, ranging from 5% to 29%. The proportion of patients who achieved HCV RNA negativity at weeks 24 and 48 were comparable across alb-ifn treatment groups (25% 39%). Rates of virologic breakthrough (ie, detection of HCV RNA in patients who had achieved viral clearance while on treatment) also were comparable across treatment groups and ranged from 11.1% to 25.0%. The overall SVR rate was 17%, and ranged from 9.1% in the higher-dose groups to 30% in the 900- g every 2 weeks group. Of note, 3 of 6 patients who were treated for 72 weeks achieved SVR. Univariate analysis of factors associated with SVR showed that viral clearance by week 12 was highly predictive of SVR, as illustrated by 68% of patients achieving SVR in this subgroup (Table 4). Antiviral activity was explored further in the subgroup of patients with Gt 1 who were nonresponders to prior treatment with PEG-IFN alfa plus RBV to assess whether higher exposure to alb-ifn increased reductions in HCV RNA. The g group showed greater and sustained reductions in HCV RNA in the first 24 weeks of therapy compared with the 900-, and 1200-, and g groups (Figure 4A). The lower rate of HCV RNA level less than the LOD at week 12 in the g group can be explained by the higher HCV RNA levels at baseline in these patients (Figure 3B; Table 1). Antiviral activity also was assessed in the subset of patients for whom prior treatmentresponse data at week 12 were available (Figure 4B). In patients who previously were unable to achieve a 2-log reduction in HCV RNA level with PEG-IFN alfa plus RBV (ie, null responders), the g every 2 weeks group showed a greater virologic response, with 6 of 12 patients achieving early virologic response at week 12 (mean HCV RNA reduction of 4.1 log 10 IU/mL). The overall SVR rate for all groups was 17%. In the subgroup of Gt 1 infected CHC patients who previously had failed PEG-IFN alfa plus RBV treatment, the overall SVR rates were lower (11%). Discussion The pharmacologic rationale for the development of alb-ifn was to optimize drug exposure, thereby maximizing sustained viral suppression with the enhanced convenience of a every 2 week or every 4 week dosing schedule. The present study represents an evaluation of alb-ifn in combination with RBV conducted in IFN treatment-experienced patients with CHC. Although it is likely that these IFN treatment-experienced patients are better able to tolerate IFN-containing regimens than are IFN-naive patients, the maximum tolerated alb-ifn dose was not established in this dose-escalation trial. This study showed that the overall AE profile for alb-ifn at dosages of up to 1800 g every 2 weeks was similar to that of other modified and unmodified IFNs, although patients who received the highest dose of 1800 g every 2 weeks experienced more severe AEs. Hematologic reductions were most apparent in the first 4 to 8 weeks of therapy, comparable across the every 2 week treatment groups, and responded to dose reduction (despite the long half-life of the modified interferon). The pharmacokinetics of alb-ifn were consistent with prior studies that showed a serum half-life of 6 days, 11,12 such that steady-state levels were achieved after the third dose with an every 2 week schedule. The modest SVR rates in Gt 1 infected nonresponders to prior treatment with PEG-IFN alfa plus RBV are similar to those in other studies conducted in similar patient populations. 5 7 This indicates that alb-ifn does not appear to improve the SVR rate substantially in this patient population and additional agents may be required to further increase the rate above this threshold. The best predictor of SVR was the kinetics of HCV RNA reduction; patients with undetectable HCV RNA levels at week 12 were significantly more likely to achieve SVR

7 218 NELSON ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 2 than were those who did not achieve this milestone (68% vs 7%; P.001). Exploratory analysis showed a dose-related increase in antiviral activity in patients with Gt 1 CHC who were nonresponders to prior treatment with PEG-IFN alfa plus RBV, although this did not translate to improvement in SVR rates in the alb-ifn g and g every 2 week dose groups. This likely is related to the inclusion of more treatment-refractory patients in the higher-dose groups, resulting in a longer time to achieve HCV RNA negativity and higher relapse rates. The observed SVR in 50% (3 of 6) of patients who received 72 weeks of alb-ifn therapy is consistent with the recently concluded REPEAT study in nonresponders, which showed that duration of IFN treatment (48 vs 72 weeks) was more important than intensity of IFN dose (180 vs 360 g) in achieving virologic response. 8 Viral breakthrough rates were low in all treatment groups and even the g every 4 week group achieved a 25% SVR rate with a low relapse rate (14%), showing the ability of alb-ifn administered every 4 weeks to maintain HCV RNA negativity and achieve SVR in this nonresponder population. Recently, data on the novel, direct, antiviral agent telaprevir showed promising antiviral activity in a nonresponder population when used in combination with PEG-IFN alfa and RBV. 18 An IFN with a robust pharmocodynamic profile would be of value in preventing the emergence of resistant mutants during combination therapy. In summary, this study showed that alb- IFN can be safely dosed up to 1800 g every 2 weeks in a nonresponder population and showed promising antiviral activity in IFN-treatment nonresponders. Phase 3 trials are ongoing to assess the safety and efficacy of every 2 week alb-ifn at the 900- and g doses in IFN-treatment naive patients, and monthly dosing regimens will be evaluated in phase 2 trials. References 1. Davis GL, Albright JE, Cook SF, et al. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003;9: Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005;5: Fried MW, Shiffman ML, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: Manns MP, McHutchison JG, Gordon SC, et al, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358: Bacon B, Regev A, Ghalib RH, et al. The DIRECT Trial (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy): treatment of non-responders to previous pegylated interferon plus ribavirin: sustained virologic response data. Hepatology 2007;46: A. 6. Poynard T, Schiff E, Terg R, et al. SVR is dependent on baseline characteristics in the retreatment of previous alfa-ifn/rbv NRs: final results from the EPIC3 program. J Hepatol 2008;48(Suppl 2):S Shiffman ML, Di Bisceglie AM, Lindsay KL, et al; Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial Group. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126: Marcellin P, Freilich B, Andreone P, et al. HCV-RNA status at week 12 of treatment with peginterferon alfa-2a/rbv predicts SVR in patients with prior non-response to pegylated interferon alfa-2b/rbv: results from REPEAT study. J Hepatol 2008; 48(Suppl 2):S Gramenzi A, Andreone P, Cursaro C, et al. A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of nonresponder patients with chronic hepatitis C. J Gastroenterol 2007;42: Liu C, Zhu H, Subramanian GM, et al. Anti-hepatitis C virus activity of albinterferon alfa 2b in cell culture. Hepatol Res 2007; 37: Bain VG, Kaita KD, Yoshida EM, et al. A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 2006;44: Balan V, Nelson DR, Sulkowski MS, et al. A phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy. Antivir Ther 2006;11: Cocchetto DM. The investigator s brochure: a comparison of the draft international conference on harmonisation guideline with current Food and Drug Administration requirements. Qual Assur 1995;4: Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Measure 1977; 1: Osborn BL, Olsen HS, Nardelli B, et al. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferonalpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 2002;303: Clark CH, Mahoney JS, Clark DJ, et al. Screening for depression in a hepatitis C population: the reliability and validity of the Center for Epidemiologic Studies Depression Scale (CES-D). J Adv Nurs 2002;40: Wassertheil-Smoller S, Applegate WB, Berge K, et al. Depressive symptoms in coronary artery disease patients after hypertension treatment. Ann Pharmacother 2006;40: Poordad F, Shiffman M, Sherman K, et al. A study of telaprevir (TVR) with peginterferon alfa-2a (P) and ribavirin (R) in subjects with well-documented prior PR null response, non-response or relapse: preliminary results. J Hepatol 2008;48(Suppl 2):S374 S375. Address requests for reprints to: David R. Nelson, MD, Professor of Medicine, Director of Hepatology and Liver Transplantation, University of Florida College of Medicine, Box , Room M-440, Gainesville, Florida nelsodr@medicine.ufl.edu; fax: (352) The conduct of the study was coordinated centrally by the Duke Clinical Research Institute, Durham, North Carolina. The investigators had full access to the data. The authors thank Al Corey for helpful discussions on the pharmacokinetics of alb-ifn; Shannon Benedetto for her contributions to the writing of the clinical study report for this study; Bob Abelson for statistical programming; and BioScience Communications, New York, NY, for editorial assistance. The authors disclose the following: Supported by Human Genome Sciences, Inc., Rockville, MD, and Novartis Pharma AG, Basel, Switzerland. David R. Nelson, Vinod Rustgi, Vijayan Balan, Mark S. Sulkowski, Gary L. Davis, Andrew J. Muir, Louis R. Lambiase, Rolland C. Dickson, Russell H. Weisner, and John G. McHutchison have received research support from Human Genome Sciences. Michele Fiscella, Patrick W. Cronin, Erik Pulkstenis, and G. Mani Subramanian are employees of Human Genome Sciences.