Parallel Sessions – Monday Nov 3: 3 PM

Parallel XVII: HCV: Early non-STadjuvant therapy-C Clinical Development – Monday Nov 3: 3 PM

HCV Treatment - General

167. Pioglitazone improves early virologic kinetic response to Peg IFN/RBV combination therapy in hepatitis C genotype 1 naïve patients.

H. M. Elgouhari; K. B. Cesario; R. Lopez; N. N. Zein

Introduction:

Insulin resistance, a common finding in obese patients (pts), emerged as a strong predictor of treatment failure using standard HCV therapy (ST) with Peg IFN/RBV. The use of insulin sensitizing agents (ISA) has been proposed to improve therapy outcome.

Aim:

Assess the impact of pioglitazone (30 mg/d) on early viral kinetic response in obese HCV non-diabetics.

Methods:

We analyzed viral kinetic drop in lean patients (BMI<25, n=10) receiving standard HCV therapy, obese patients (BMI>30, n=10) receiving standard HCV therapy, and obese patients (BMI>30, n=10) receiving standard HCV therapy plus pioglitazone. All patients were Caucasians, treatment-naïve, non-diabetic with HCV genotype 1. Standard doses of Peg IFN/RBV were given to all patients. Pioglitazone was started 4 weeks prior to standard HCV therapy and continued for 4 weeks after standard HCV therapy initiation for those assigned to the triple regimen. HCV RNA level immediately before first Peg IFN/RBV dose (day 0) then at day 1, 2, 7, 14, and 28 of therapy were measured.

Results:

Demographic, clinical, and histological characteristics as well as baseline HCV RNA were similar in all groups. Log drop in HCV RNA from baseline was smaller in obese compared to lean patients receiving standard HCV therapy at day 2 (0.3 vs 1.9 log), day 7 (1.1 vs 2.7 log), day 14 (1.4 vs 3.8 log) and day 28 (3.8 vs 4.3 log). Obese patients receiving the triple regimen had greater log decline at each time point compared to obese patients on standard HCV therapy [day 2 (1.2 vs 0.3 log), day 7 (1.6 vs 1.1 log), day 14 (2.3 vs 1.4 log), day 28 (5.3 vs 3.8 log)]. Rapid virologic response (RVR) occurred in 50% of lean patients, 20% of obese patients receiving standard HCV therapy, and in 60% of patients receiving standard HCV therapy + pioglitazone.

Conclusions:

Pioglitazone given adjuvant to Peg IFN/RBV in HCV genotype 1 patients improves viral kinetic response during the first 4 weeks of therapy.

HCV Treatment - General

168. A Randomized, Double-Blind, Placebo-Controlled Study of PPAR-gamma Agonist Pioglitazone Given in Combination with Peginterferon and Ribavirin in Patients with Genotype-1 Chronic Hepatitis C.

H. Conjeevaram; C. F. Burant; B. McKenna; D. Harsh; H. Kang; A. K. Das; L. Everett; D. White; A. F. Lok

The presence of insulin resistance (IR) appears to be a key factor in the development of steatosis and disease progression in patients with hepatitis C virus (HCV) genotype 1 infection similar to that seen in NAFLD. Insulin resistance also is an independent factor for lower sustained virological response (SVR) in type 1 infection. Pioglitazine (PIO) has been shown to decrease IR and improve histologic features in NAFLD.

Aim:

To assess the effect of pioglitazine on insulin sensitivity, liver histology and SVR in treatment-naïve patients with type 1 HCV infection with insulin resistance (HOMA index > 2.0) receiving standard antiviral therapy.

Methods:

A total of 40 patients were randomly assigned to receive pioglitazine 30 mg (n, 20) or placebo (PLA) (n, 20) along with peginterferon alfa 2b + ribavirin. All pts were treated for 48 wks and followed for 24 wks. HOMA index and HCV RNA levels were measured at baseline, during therapy and follow-up. Liver biopsies at baseline and at 12 wk follow-up were assessed for steatosis, inflammation and fibrosis.

Results:

Mean age was 48.6 yrs; 22 were female and 35 Caucasian. At entry, mean HOMA index was 5.8 (2.01-12.3) and hepatic steatosis was present in 65% of patients. There was a significant reduction in HOMA index in the pioglitazine group (–1.72 and –1.88) and no change in the PLA group (+1.12 and +0.86) at wks 24 and 48 of therapy respectively (p=0.008 at both time points). The effect on insulin resistance persisted even during follow-up in the pioglitazine group (p=0.012). Mean body weight decreased on therapy in both groups; on follow-up it was no different from baseline in the pioglitazine group but remained significantly lower in the PLA group (p=0.013). In an intention-to-treat analysis, 16 patients on pioglitazine (80%) and 10 patients on PLA (50%) had undetectable HCV RNA at the end of therapy (89% vs. 56% among 36 patients who completed therapy, p=0.060); however, SVR rates were similar (45%) in both groups. Patients on pioglitazine were more likely to have reversal of steatosis compared to those on PLA (54% vs. 30%, p<0.05). Analysis of serum lipomic profiles showed a significant increase in monounsaturated fatty acids and 18:1/18:0 ratio at wk 48 compared to baseline (p<0.05) only in the pioglitazine group. Similarly, lipomic profiles from paired liver biopsies showed a decrease in relative amount of monounsaturated fatty acids and a significant increase in polyunsaturated fatty acids only in the pioglitazine group (p<0.05).

Conclusions:

Pioglitazone treatment led to a significant reduction in insulin resistance and reversal of hepatic steatosis in HCV genotype-1 patients with insulin resistance. Patients in pioglitazine group had higher rate of end of treatment response but SVR was similar in both groups. pioglitazine treatment led to increased desaturation of fatty acids, which may explain the decreased hepatic steatosis.

HCV Drug Pipeline - General

170. Interim Results from a Phase 1b Dose-Escalation Study of 4 Weeks of PEG-Interferon Lambda (PEG-rIL-29) Treatment in Subjects with Hepatitis C Virus (HCV) Genotype 1 with Prior Virologic Response and Relapse to Peginterferon Alfa and Ribavirin.

E. J. Lawitz; A. Zaman; A. J. Muir; M. L. Shiffman; B. Yoffe; T. Zhang; S. Souza; D. F. Hausman

Introduction:

PEG-interferon lambda is a novel Type III interferon (IFN) that binds to a unique receptor complex with a more limited distribution than the receptor for Type I IFNs. In a Phase 1 dose-escalation study in healthy volunteers, PEG-IFN lambda was pharmacologically active and well-tolerated without flu-like symptoms or hematologic effects. A Phase 1b study was initiated to evaluate the safety and efficacy of PEG-IFN lambda in subjects with genotype 1 HCV who had previously relapsed following peginterferon alfa and ribavirin therapy.

Methods:

This open-label, dose- and schedule-escalation study is evaluating PEG-IFN lambda administered subcutaneously either every other week (QoW) on Days 1 and 15 or weekly over a 4-week period in cohorts of 6 subjects each. HCV RNA was assessed prior to dosing on Days 1, 2, 4, 8, 15, 22 and 29.

Results:

Cohort 1 (1.5 μg/kg PEG-IFN lambda QoW) has been completed; enrollment into Cohort 2 (3.0 μg/kg QoW) is ongoing. 6 subjects (4 M, 2 F) were treated in Cohort 1, mean age = 53 yrs, mean baseline log10 HCV RNA = 7.3. Treatment was well-tolerated with no dose reductions or discontinuations. No subject experienced fever related to PEG-IFN lambda dosing. Adverse events, all Grade 1-2, were reported for 1 of 6 subjects and included myalgia, fatigue and irritability considered possibly related to PEG-IFN lambda in the setting of a concurrent, unrelated respiratory infection. All laboratory abnormalities were Grade 1 or 2. No subject had a clinically significant increase from baseline in ALT, AST or bilirubin during treatment and 1 of 4 subjects with baseline elevation had normalization of ALT. No hematologic toxicities were seen. Antiviral activity, defined as a decrease of ≥1-log10 in HCV RNA, was observed in 4/6 subjects. The mean maximum log decrease any time on study was 2.15 (range 0.59-5.18;Table 1).

Conclusions:

Repeat dosing with PEG-IFN lambda was well-tolerated and associated with antiviral activity. Five of six subjects reported no adverse events. Data on additional cohorts will be presented at the meeting. Continued evaluation of the safety and antiviral activity of PEG-IFN lambda, both alone and in combination with ribavirin, is planned.

Table 1. Log¹⁰ Decrease in HCV RNA

	Subj 1	Subj 2	Subj 3	Subj 4	Subj 5	Subj 6
Baseline (Day 1)	7.56	7.37	7.29	7.08	7.52	7.24
Day 4	-2.46	-0.59	-3.71	-1.90	-1.95	-0.72
Day 8	-1.74	-0.21	-2.73	-0.63	-0.95	-0.66
Day 15	-0.69	-0.37	-3.71	-0.86	-0.26	-0.25
Day 22	-1.70	-0.24	-5.18	-1.29	-1.24	-0.76
Day 29	-0.65	-0.37	-4.80	-0.67	-0.35	-0.3

PEG-IFN lambda administered on Days 1 and 15.

Parallel XXIV: HCV Therapy: Clinical – Monday Nov 3: 4:45 PM

HCV Treatment – Side Effect Management

209. Do growth factors improve SVR in chronic HCV-genotype 1 patients treated with Peg-Interferon and Ribavirin?

M. Kugelmas; M. A. Mah'moud

Background:

Hematologic toxicity is one of the most common reasons for dose reduction or discontinuation when treating patients with chronic hepatitis C. In turn, these dose reductions may negatively affect the chance of achieving early and sustained viral response (EVR and SVR) during treatment of genotype 1 chronic hepatitis C (HCV-1).

Aims and Methods:

We compared standard of therapy (ST) with pegylated interferon alfa 2b (Peg-IFN) plus weight-based ribavirin (RBV) in patients with HCV-1 to an adjuvant therapy (adjuvant therapy) regimen where anemia was pre-emptively treated with darbepoetin alfa (3 mcg/kg SQ Q2W starting with hemoglobin <12 g/dL or <75% of baseline), neutropenia was pre-emptively treated with filgrastim (300 mcg SQ QW for ANC <900 mm3), and more lenient cut-off levels for thrombocytopenia were allowed in order to try to prevent dose reductions due to hematologic toxicity. The study was powered to show a 22% difference in SVR in favor of the adjuvant therapy arm.

Results:

One hundred and thirty patients (of 148 randomized) infected with HCV-1 received at least 1 dose of medications, 63 in the standard of HCV therapy arm and 67 in the adjuvant therapy arm. The groups were comparable in regards to age, weight, fibrosis stage and baseline viral load, but the adjuvant therapy arm had twice as many African Americans randomized to it (7 and 15, respectively; p=0.043). There was no difference in SVR in between the two treatment arms: p=0.42 (see table). The hemoglobin nadir was noted around week 16-18 of therapy in both arms. No cardiovascular or bone marrow serious adverse events occurred with the use of growth factors.

Conclusions:

We have previously shown (DDW ’06) that the use of growth factors prevents dose reductions of Peg-IFN and RBV in patients receiving anti HCV-1 therapy and maintains more physiologic hemoglobin levels. This final analysis of the KATT study database show no benefit in SVR rates in the adjuvant therapy arm when patients received pre-emptive growth factors to prevent dose reductions in Peg-IFN and RBV therapy. Study drugs and support were provided by Amgen Inc. (Darbepoetin and Filgrastim) and Schering Plough (Peg-Intron and Rebetol).

	N	EVR	cEVR	EOTR	SVR
ST(%)	63	42 (66.7)	33 (53.4)	31 (49.2)	22 (34.9)
Adjuvant therapy(%)	67	44 (65.7)	28 (41.8)	25 (37.3)	19 (28.4)

HCV Drug Pipeline – General

211. Safety, Tolerability and Antiviral Activity of MK-7009, a Novel Inhibitor of the Hepatitis C Virus NS3/4A Protease, in Patients with Chronic HCV Genotype 1 Infection.

E. J. Lawitz; M. S. Sulkowski; I. M. Jacobson; S. Faruqui; W. K. Kraft; B. Maliakkal; M. Al-Ibrahim; R. H. Ghalib; S. C. Gordon; P. Kwo; J. Rockstroh; M. Miller; P. Hwang; J. Gress; E. Quirk

Purpose:

MK-7009 is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent activity in HCV replicon systems and chronically-infected chimpanzees. This placebo-controlled dose-ranging study assessed the safety, tolerability and antiviral efficacy of multiple doses of MK-7009 administered as short-term monotherapy to adult patients with chronic HCV infection.

Methods:

Treatment-naïve and treatment-experienced noncirrhotic patients,18-55 years old, with high viral load, genotype 1, chronic HCV infection were randomized to receive placebo or MK-7009 monotherapy at doses of 125 mg q.d. (four times a day), 600 mg q.d., 25 mg b.i.d (twice a day)., 75 mg b.i.d., 250 mg b.i.d. and 500 mg b.i.d. for 8 days. Patients were followed for 14 days after the last dose. Safety and tolerability were evaluated using laboratory values (chemistry and hematology), electrocardiogram (ECG), and patient report and investigator evaluation of adverse experiences (AE). Antiviral efficacy was assessed through quantitation of plasma HCV RNA using the Roche Cobas TaqMAN 2.0 assay (lower limit of detection = 9.3 IU/mL) at multiple time points before, during and after the MK-7009/placebo dosing period.

Results:

Thirty-three patients (85% male, 73% genotype 1a) were randomized and received at least one dose of placebo or MK-7009. All randomized patients had HCV viral RNA >1x106 IU/mL at the screening visit. No serious AEs were reported. The most commonly reported adverse events (AEs) were diarrhea (n=6) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed. No patient discontinued the study or the study drug as a result of a clinical or laboratory AE, and all AEs resolved during the study. After one week of placebo or MK-7009 therapy, the mean blinded decrease in HCV RNA from baseline was 2.1 log10 IU/mL across all treatment groups, including placebo. Final unblinded data by treatment group will be reported. The maximum viral RNA decrease observed during the treatment period was 4.4 log10 IU/mL. In this blinded, pooled analysis of all treatment groups, including placebo, 23 of the 33 patients (70%) achieved a >3 log10 IU/mL HCV RNA decrease at least once during the 8-day treatment period.

Conclusion:

MK-7009 has potent antiviral activity during 8 days of monotherapy in patients with chronic genotype 1 HCV infection. In these patients, MK-7009 was generally well-tolerated with no serious AEs, discontinuations due to AEs or safety laboratory abnormalities. Further development of this HCV NS3/4A protease inhibitor, including studies in combination with other anti-HCV agents, is warranted.