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For complete prescribing information on the products discussed during this CME activity, please see your current Physicians’ Desk Reference (PDR).

Michael P. Manns, MD, has received grant/research support from Bristol-Myers Squibb Company, Gilead Sciences, Inc, GlaxoSmithKline, Idenix Pharmaceuticals Inc, Intercell AG, Novartis Pharmaceuticals Corporation, Roche Pharmaceuticals, and Schering-Plough Corporation; is a consultant for Bristol-Myers Squibb Company, Gilead Sciences, Inc, Intercell AG, Schering-Plough Corporation, and Valeant Pharmaceuticals International; and is on the speakers bureau of Gilead Sciences, Inc, GlaxoSmithKline, Roche Pharmaceuticals, and Schering-Plough Corporation.

John G. McHutchison, MD, FRACP, has received grant/research support from Akros Pharma Inc, Amgen Inc, Bayer Pharmaceuticals, Biomedicines, Bristol-Myers Squibb Company, Cytel Corporation, Fujisawa Healthcare, Inc, Gen-Probe, Gilead Sciences, Inc, Idun Pharmaceuticals, Isis Pharmaceuticals, Inc, Ortho Diagnostic Systems, Inc, Prometheus Laboratories, Ribozyme Pharmaceuticals, Inc, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, Triangle Pharmaceuticals Inc, and Vertex Pharmaceuticals, Inc; is a consultant for Amgen Inc, Anadys Pharmaceuticals, Inc, Centocor, Inc, GlaxoSmithKline, InterMune Inc, Isis Pharmaceuticals, Inc, National Genetics Institute Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Prometheus Laboratories, Ribozyme Pharmaceuticals, Inc, and Schering-Plough Corporation; and is on the speakers bureau of InterMune Inc, Roche Pharmaceuticals, and Schering-Plough Corporation.

Peer Reviewer has received grant/research support from Roche Pharmaceuticals, Valeant Pharmaceuticals International, and Wyeth Pharmaceuticals; is a consultant for Amgen Inc, and Roche Pharmaceuticals; is on the speakers bureau of Gilead Sciences, Inc, and Roche Pharmaceuticals; and has received honoraria from Amgen Inc, Gilead Sciences, Inc, and Roche Pharmaceuticals.

This activity will include a discussion of the investigational uses of albumin-interferon alfa, CPG 10101, IC41 vaccine, isatoribine, merimepodib, NM283, and viramidine.

The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge.

This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the physician caring for the patient.

This independent CME activity is supported by an educational grant from Valeant Pharmaceuticals International.

Two studies reported in poster sessions clarified the potential role of oral viramidine in treatment-naive HCV-infected patients. Lin et al³ found that viramidine yielded lower mean ribavirin concentrations in plasma and red blood cells (RBCs) and a smaller mean decrease in Hgb levels compared with ribavirin. In an open-label, randomized trial, 87 treatment-naive HCV infected patients received either viramidine 600 mg twice daily (n = 42) or weight-based ribavirin 600 mg BID or 600 mg AM and 400 mg PM (n = 45). Measurements of Hgb and ribavirin levels in plasma and RBCs were taken at baseline and at weeks 12 and 24.

Viramidine resulted in lower mean drug concentrations compared with ribavirin in both plasma (0.931 µg/mL versus 1.88 µg/mL) and RBCs (145 µg/mL versus 251µg/mL). Viramidine also caused a smaller mean decrease in Hgb compared with ribavirin (11.4% versus 19.7%). These effects, observed initially at week 12, remained steady through week 24. Overall, the findings of this study suggest that the potential to develop hemolytic anemia is much lower with viramidine than with ribavirin.³

In a phase II dose-ranging study of 180 treatment-naive HCV-infected patients, Gish et al⁴ compared the safety and antiviral efficacy of viramidine and ribavirin. Participants receiving subcutaneous pegylated interferon alfa-2a 180 µg/wk were randomized to receive oral viramidine 400 mg (n = 47), 600 mg (n = 43), or 800 mg (n = 45) twice daily or ribavirin 1000 to 1200 mg/d (n = 45). Patients with genotype 2 or 3 infection were treated for 24 weeks, and those with genotype 1, 4, 5, or 6 infection were treated for 48 weeks.

Patients had a median HCV RNA of 6.5 log₁₀ copies/mL at baseline. At the end of treatment, no significant differences were found between the viramidine and ribavirin treatment groups in the proportion of patients with undetectable HCV RNA levels (range, 55%–63%), regardless of HCV genotype (Figure 1a). However, the incidence of anemia was significantly lower among patients treated with 400 mg or 600 mg BID viramidine compared with those treated with 1000 to 1200 mg/d ribavirin (P < .01) (Figure 1b). All other adverse events were similar between treatment arms. Final safety and SVR data are expected in 2005.

lower incidence of anemia 

In the first clinical trial of this agent, McHutchison and colleagues showed that CPG 10101 induces high levels of endogenous interferon gamma, helping to restore immune function that is compromised by chronic viral infection.⁷ In the phase Ib study, 31 patients who either had relapsed after interferon-based therapy or were treatment naive for anti-HCV therapy were randomized to control (n = 7) or CPG 10101 (n = 24) in five sequential dose groups (0.25 mg, 1 mg, 4 mg, 10 mg, 20 mg). Data from an ongoing fifth treatment arm of CPG 10101 20 mg was not included in this analysis. Patients received subcutaneous CPG 10101 twice weekly for 4 weeks and were monitored for an additional 4 weeks.

Innate immune response was activated 24 hours after the first CPG 10101 injection in patients treated with low-dose CPG 10101, including 0.25 mg (n = 4) and 1.0 mg (n = 6). Compared with baseline, serum IP-10 levels increased 1.2- to 8.4-fold. This CPG 10101-induced immunologic response also translated into antiviral activity. Among those who received 1, 4, or 10 mg CPG 10101 (n = 18), six patients had a ≥1-log reduction in HCV RNA and three had a ≥2-log reduction. RNA reductions were seen in patients with HCV genotypes 1a (n = 3), 1b (n = 2), and 2b (n = 1). Viral RNA levels were reduced from days 1 to 29 but rebounded after dosing was completed.

Local injection site reactions, which reflect the immunostimulatory action of CPG 10101, included erythema, pain, pruritus, inflammation, and swelling. At the highest dose (10 mg), there was one report each of grade 3 fatigue, asthenia, pyrexia, rigors, and back pain, and two reports each of arthralgia and myalgia. One patient (4 mg) developed grade 3 neutropenia and one other patient (10 mg) withdrew due to grade 2 vomiting and diarrhea. No clinically significant changes in alanine aminotransferase (ALT), aspartate aminotransaminase (AST), or creatinine phosphokinase were observed. Results of additional dose escalation to 20 mg are pending.⁷

In a phase IIa study reported by Zha et al, merimepodib enhanced the antiviral effect of peginterferon/ribavirin combination therapy without exacerbating ribavirin-associated anemia.¹⁰ The study enrolled 31 patients with genotype 1 infection who were nonresponsive to interferon/ribavirin therapy. Patients were given peginterferon/ribavirin and one of three study treatments: placebo, merimepodib 25 mg every 12 hours, or merimepodib 50 mg every 12 hours. Pharmacokinetic and pharmacodynamic parameters included steady-state area under the plasma concentration-time curve  (AUC_0-12h) and trough plasma concentration (C_trough) of ribavirin.

At week 12, patients were categorized as virologic responders (≥2-log drop in HCV RNA viral load) or nonresponders. Virologic responders had a significantly higher merimepodib AUC_0-12h compared with nonresponders (P = .0103). Given that virologic responses were seen in 0%, 60%, 75%, and 80% of patients in quartiles 1, 2, 3, and 4, respectively, of merimepodib exposure, this relationship appears to follow a linear dose-response curve. Younger age and ribavirin C_trough levels were the only other significant predictors of virologic response at week 12. In addition, anemia was correlated with ribavirin C_trough levels but not with merimepodib exposure. On the basis of these findings, higher doses (50 and 100 mg every 12 hours) of merimepodib are being explored in a phase IIb study.¹⁰

Balan and colleagues presented data that show that nearly half of HCV-infected patients who have failed prior interferon-based therapy can achieve an antiviral response with the albumin-interferon alfa fusion protein.¹⁴

The phase I/II, open-label, albumin-interferon dose escalation study enrolled 119 patients (93% HCV genotype 1) who failed prior interferon-based therapy. Patients received 7 to 900 µg albumin-interferon in one or two subcutaneous injections every 2 weeks for a mean treatment period of 68 weeks.¹⁴

Albumin-interferon reduced HCV RNA by at least 0.5 log₁₀ in each dose group (Figure 2). Among patients receiving 120 to 900 µg albumin-interferon (n = 78), 47% achieved an antiviral response (>1-log reduction at any time point). In addition, gene expression analysis showed that interferon response genes were induced. Viral kinetics shows a biphasic decline of HCV RNA after administration of albumin-interferon.

Over the 120 to 600 µg dose range, median terminal half-life was approximately 143 hours. Given its reduced clearance and extended half-life, the pharmacokinetic profile of albumin-interferon supports dosing every 2 to 4 weeks. Therefore, albumin-interferon may be dosed less frequently than peginterferon.

Albumin-interferon was well tolerated with no discontinuations. Adverse events were transient, and most were mild to moderate. Most common adverse events were headache (49%), fatigue (41%), injection site erythema (31%) and pyrexia (27%). Reversible neutropenia (ANC < 750) occurred in 23% of patients.