Report 13 from Dallas Liver Meeting, 50th AASLD, Nov 5-9

Infergen
Jules Levin, NATAP

Following are several infergen or consensus interferon papers reported in Dallas.

EFFECTS OF INTERFERON ALFACON-1 (INFERGEN) ON THE VIRAL KINETICS OF HEPATITIS C VIRUS 

Thomas J Layden, Univ of Illinois, Chicago, IL; Blaine F Hollinger, Baylor Coll of Medicine, Houston, TX; Rajender K Reddy, Univ of Miami, Miami, FL; Nancy Lam, Tenshang Joh, Shekman Wong, Amgen Inc, Thousand Oaks, CA

The viral dynamics of hepatitis C virus (HCV) following initiation of high dose interferon therapy have been characterized indicating that HCV RNA levels decline in a biphasic manner. It was also suggested that interferon leads to rapid reduction of HCV RNA by inhibiting the production and/or release of HCV from infected cells. In the present study, viral kinetics and dynamics were assessed over a 4-week treatment period in genotype 1 HCV infected subjects receiving high dose Infergen at 9 µg QD (n=9), 15 µg QD (n=9) and 7.5 µg BID (n=7). Reported here are interim data for 25 subjects. Serum HCV RNA was measured by quantitative RT-PCR (lower sensitivity, 100 copies/mL) and genotype was determined at baseline by modified line probe assay. In the first 60 hours of treatment, HCV RNA levels were measured frequently and results from individual subjects were fitted to the mathematical model described by Neuman et al (Science 282:103-107, 1998). Baseline HCV RNA levels were highly variable among subjects, ranging from 4.4 x 104 to 4.8 x 107 copies/mL. Following the initiation of treatment, there was a pharmacological delay of 8.9 ± 4.6 hours that was independent of Infergen dose. After which, HCV RNA levels decreased in an exponential manner. When the HCV RNA values were fitted to the mathematical model and the data from the three dose groups were combined as a grand mean, the intrinsic viral clearance averaged 5.9/day giving rise to a calculated viral half life of 4.8 ± 3.4 hours. Calculated viral production averaged 1.2 x 1012 copies/day and varied widely among subjects (6 x 109 - 14 x 1012 copies/day). Treatment efficacy, defined as the percentage of inhibition of HCV viral production and/or release from infected cells by treatment, averaged 88% ± 18%. The viral kinetic parameters (mean ± SD) derived using mathematical modeling for the 15 mg QD dose group are reported in the table below. Viral kinetic parameters estimated in this study are comparable to those that have previously been reported. After the first 60 hours viral decline slowed giving rise to a biphasic pattern of response. In addition, viral decline in the second phase was highly variable among subjects. These kinetic results confirm that HCV has a rapid production and clearance rate and that Infergen causes a biphasic reduction in HCV RNA levels. 
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DAILY OR TWICE DAILY INTERFERON ALFACON-1 (INFERGEN) ADMINISTRATION ACHIEVES OPTIMAL VIRAL SUPPRESSION COMPARED TO THRICE WEEKLY DOSING SCHEDULES IN SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C VIRUS (HCV) INFECTION 

Rajender K Reddy, Univ of Miami, Miami, FL; F Blaine Hollinger, Baylor Coll of Medicine, Houston, TX; Thomas Layden, Univ of Illinois at Chicago, Chicago, IL; Jennifer Poulakos, Tenshang Joh, Amgen Inc, Thousand Oaks, CA

Recent data from viral kinetic and viral dynamic studies necessitate the re-evaluation of optimal interferon dosing schedules. The present analyses report the relationship of varying doses and schedules of Infergen and HCV viral suppression in subjects with HCV genotype 1. In an ongoing multicenter clinical trial, subjects with chronic HCV infection were randomized to receive one of five 4-week Infergen regimens: 7.5 mg twice daily (BID), 15 mg once daily (QD), 15 mg three times weekly (TIW), 9 mg QD, and 9 mg TIW. A subset of forty-one HCV genotype 1 subjects consented to participate in the viral kinetic portion of this study. The objective was to describe the relationship of varying doses and schedules of Infergen and HCV genotype 1 viral suppression. Following the first dose of Infergen, serial blood samples were drawn at baseline and throughout a 60 hour time interval (baseline, 1 hour after the first dose, every three hours after the first dose until 24 hours and then every 6 hours up to 60 hours) to measure serum HCV RNA levels. Serum HCV RNA was measured by quantitative RT-PCR (lower sensitivity, 100 copies/mL). Mean log reductions of HCV RNA at 12, 24 and 48 hours after the initial dose are reported below. There was no difference in the magnitude of serum HCV RNA mean log reduction at 12 and 24 hours after the initial dose of Infergen among the five dosing regimens. However, 48 hours after the initial dose, the greatest mean log reduction of serum HCV RNA was observed in the BID and QD groups (p=0.05 15 QD v 9 TIW). In contrast, serum HCV RNA levels began to rebound 24 hours after administration of the first dose in the TIW groups. These data suggest that daily or twice daily administration of Infergen is needed to achieve continual serum HCV RNA suppression in genotype 1 subjects. 

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INTERFERON AFLACON-1 (INFERGEN) INDUCTION THERAPY IN SUBJECTS WITH CHRONIC HEPATITIS C VIRUS (HCV) INFECTION 

Paul Pockros, Scripps Clin, La Jolla, CA; William Lee, Univ of Texas, Dallas, TX; Robert W Reindollar, Charlotte Clin for Gastrointestinal and Liver Diseases, Charlotte, NC; Myron J Tong, Huntington Memorial Hospital Liver Ctr, Pasadena, CA; Robert Carithers, Univ of Washington Med Ctr, Seattle, WA; Teresa Wright, Veterans Admin Med Ctr, San Francisco, CA; Bernard Willems, St Luc Hospital, Montreal, PQ Canada; Rajender K Reddy, Univ of Miami School of Medicine, Miami, FL; Thomas Layden, Univ of Illinois at Chicago, Chicago, IL; Heidi Grant, Amgen Inc, Thousand Oaks, CA; F Blaine Hollinger, Baylor, Houston, TX

In this ongoing multicenter clinical trial, the efficacy of five Infergen induction regimens is under investigation in interferon-naive subjects with chronic HCV infection. Reported here are interim data for the first 169 evaluable subjects treated for 12 weeks. Subjects were stratified by baseline HCV RNA levels (2 strata: £ 106 copies/mL and > 106 copies/mL) and randomized in equal allocation to one of five 4-week Infergen induction regimens: (1) 7.5 mg BID; (2) 15 mg QD; (3) 15 mg TIW; (4) 9 mg QD; and (5) 9 mg TIW. The 4-week induction period was followed by 44 weeks of 9 µg TIW Infergen therapy and 24 weeks of observation. Serum HCV RNA was quantified by RT-PCR (lower sensitivity, 100 copies/mL). There were no significant differences in baseline characteristics among groups at baseline. Mean log reduction of HCV RNA for subjects with high and low baseline viral titers at week 4 of induction is reported below. Mean log reduction in HCV RNA levels at the end of induction (week 4) was the greatest in the 15 mg QD group both for subjects with high (p=0.013 vs 9 TIW; p=0.039 vs 15 TIW) and low (p=0.015 vs 9 TIW) baseline viral titers. Daily induction treatment resulted in undetectable HCV RNA in 25 - 29% of subjects with high viral titers at week 4. In contrast, 64 - 78% of subjects with low viral titers had undetectable HCV RNA at week 4. Following the 4-week induction period at which time the dose and dose frequency was altered, viral suppression was maintained in subjects with low baseline viral titers in all treatment groups. However, viral rebound after induction was observed for subjects with high baseline viral titers in the BID and QD groups. At the end of induction, mean log reduction of HCV RNA was comparable between the 7.5 mg BID and 15 mg QD groups. However, the 7.5 mg BID group was less tolerable with a dose reduction/interruption rate of 17% and a drop out rate of 6%. These data suggest that daily administration of 15 mg Infergen for 4 weeks was well tolerated and effective in viral suppression. 

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TAILORING INTERFERON ALFACON-1 (INFERGEN) TREATMENT OF CHRONIC HCV BY BASELINE PARAMETERS 

Blaine F Hollinger, Baylor Coll of Medicine, Houston, TX; Rajender K Reddy, The Univ of Miami, School of Medicine, Miami, FL; Thomas Layden, The Univ of Illinois at Chicago, Chicago, IL; Paul Pockros, Scripps Clin, La Jolla, CA; William Lee, Univ of Texas, Dallas, CA; Robert W Reindollar, Charlotte Clin for Gastrointestinal and Liver Disease, Charlotte, NC; Myron J Tong, Huntington Memorial Hospital Liver Ctr, Pasadena, CA; Robert Carithers, Univ of Washington Med Ctr, Seattle, WA; Teresa Wright, Acad Admin Med Ctr, San Francisco, CA; Jorge Gorjon, Baylor Coll of Medicine, Houston, TX; Jennifer Poulakos, Amgen Inc, Thousand Oaks, CA; Bernard Willems, St Luc Hospital, Montreal, PQ Canada

It has been known that specific baseline parameters such as genotype and baseline HCV RNA are predictors of response to IFN treatment of chronic HCV. Data from a new study, in which the efficacy of five Infergen induction regimens was investigated, have shown that optimum IFN dose and schedules may differ depending on HCV genotype and baseline viral concentration. Subjects were stratified by baseline HCV RNA levels (2 strata: £ 106 copies/mL and > 106 copies/mL) and randomized in equal allocation to one of five 4-week Infergen induction regimens: (1) 7.5 mg BID; (2) 15 mg QD; (3) 15 mg TIW; (4) 9 mg QD; and (5) 9 mg TIW. This was followed by 44 weeks of 9 µg TIW. Reported here are interim data for 64 subjects who received either 9 mg Infergen or 15 mg Infergen daily during induction followed by 9 mg TIW for up to 12 weeks. Serum HCV RNA was quantified by RT-PCR (lower sensitivity, 100 copies/mL). HCV genotype was determined at baseline by modified line probe assay. Subjects who have either low baseline HCV RNA titers (£ 106 copies/mL) or who are not genotype 1 can be treated with 9 mg Infergen daily for 4 weeks followed by additional treatment with 9 mg TIW. At week 12, this regimen induced a 73% virologic response rate among subjects with low viral titer and an 83% response rate among non-genotype 1 subjects. Additional benefit of higher doses or longer induction periods may be minimal for these subjects. In contrast, subjects who are either genotype 1 or have a high baseline viral concentration (> 106 copies/mL) will probably benefit from extended treatment with 15 mg Infergen daily. When these subjects received 15 mg Infergen daily for 4 weeks followed by 9 mg TIW, the virologic response rate at week 12 for genotype 1 subjects was 35% and for those with high baseline viral concentration was 42%. For these subjects, virus level either plateaued or increased after induction. This suggests that a 4-week induction period may not be sufficient for either high titer or genotype 1 subjects. Extrapolation from a simple linear regression on the rate of HCV RNA viral decline during the induction period suggests that a minimum of 10 weeks of 15 mg Infergen daily is optimal to achieve maximum benefit for high viral titer genotype 1 subjects. In contrast, as these data suggest, for low viral titer subjects who are not genotype 1, a minimum of 4 weeks of 9 mg Infergen daily followed by TIW dosing is optimal to achieve maximum benefit.