Hepatitis C combination therapies in pill form move nearer

The latest data on three experimental hepatitis C drug candidates were presented at the American Association for the Study of Liver Diseases meeting, held November 11-15 in San Francisco. Current standard treatment for hepatitis C is based on interferon, an injected cytokine that stimulates immune response. In contrast, several investigational oral agents work by directly targeting the hepatitis C virus, similar to antiretroviral agents used to treat HIV.

Valopicitabine

Christopher O’Brien from the University of Miami presented the first interim data from an American Phase IIb trial of valopicitabine, or NM283, a nucleoside analogue hepatitis C polymerase inhibitor being developed by Idenix Pharmaceuticals.

The study included 190 patients randomly assigned to receive 800mg valopicitabine monotherapy, one of three doses (400mg, ramped dosing from 400 to 800mg, or 800mg once daily) of valopicitabine plus pegylated interferon alpha-2a (Pegasys) 180mg/week, or pegylated interferon plus ribavirin 1000-1200mg daily; 152 participants completed 12 weeks of treatment. Baseline characteristic were similar in the five arms, with a mean age of about 50 years. By ethnicity, 51-76% were Caucasian, 10-23% were East Asian, 10-23% were Middle Eastern or Indian, and fewer than 2% were African-American.

All were previous non-responders who did not clear hepatitis C with twelve weeks or more of pegylated interferon plus ribavirin, the standard treatment for HCV infection; relapsers were excluded. All had genotype 1 hepatitis C, baseline hepatitis C RNA of at least 100,000 copies/ml, and compensated liver disease.

After twelve weeks, patients in the two higher-dose valopicitabine combination arms achieved significantly greater suppression of hepatitis C RNA compared with the pegylated interferon/ribavirin arm. Hepatitis C viral load declined by 0.78 log₁₀ copies/ml in the valopicitabine monotherapy arm, 1.92 log₁₀ copies/ml in the pegylated interferon/ribavirin arm, 2.22 log₁₀ copies/ml in the 400 mg valopicitabine combination arm, 2.51 log₁₀ copies/ml in the in 400-800 mg valopicitabine combination arm, and 2.77 log₁₀ copies/ml in the 800mg valopicitabine combination arm (p=0.001 for the latter two arms compared with pegylated interferon/ribavirin).

Percentages achieving early virological response (at least a 2-log reduction in hepatitis C virus RNA at twelve weeks) were 5%, 41%, 54%, 71%, and 63%, respectively (p

SCH503034

Stefan Zeuzem from Saarland University Hospital in Homburg, Germany, reported on a Phase Ib study of Shering-Plough’s NS3 serine protease inhibitor, SCH503034. In this international multicentre trial, 61 patients were randomly assigned to receive one of four different schedules of SCH503034 (100, 200, or 400mg twice daily or 400mg three times daily), or placebo, for 14 days. Baseline characteristics were similar across the arms, with a mean age of about 50 years. All patients were non-responders to prior treatment with pegylated interferon plus ribavirin (less than 2-log reduction in hepatitis C virus RNA after twelve weeks of treatment) and had genotype 1 hepatitis C. Participants had baseline hepatitis C viral loads of at least 30,000 copies/mL, mean ALT levels of 82-112 IU/L, and compensated liver disease.

SCH503034 was rapidly absorbed, reaching a maximum concentration at 1-2 hours post-dosing. The most pronounced reduction in hepatitis C viral load was seen in the 400mg three times daily arm, with a mean maximum decline of 2.06 log₁₀ copies/ml from baseline (range 1.1-2.7 log₁₀ copies/ml). The magnitude of hepatitis C viral load reduction was positively correlated with SCH503034 trough level. Participants in all three twice-daily arms experienced smaller hepatitis C viral load decreases than seen in the three times daily group, but still did better than the placebo arm. Sixty percent of patients in the 400mg three times daily arm achieved a maximum hepatitis C viral load reduction of more than 2 log₁₀ copies/ml, compared with 18%, 17%, and 8%, respectively, in the 400mg, 200mg, and 100mg twice daily arms. Conversely, no patient in the 400mg three times daily group had less than a 1-log viral load decrease, compared with 18%, 50%, and 67%, respectively, in the 400mg, 200mg, and 100mg twice daily arms. ALT reduction corresponded with viral load decreases.

Zeuzem also presented data from a second small trial showing that SCH503034 exhibited promising antiviral activity when combined with pegylated interferon in previous non-responders. In this open-label crossover study, all participants received 200 or 400mg SCH503034 monotherapy for seven days, pegylated interferon alpha-2b (Peg-Intron) 1.5 mcg/kg/week for 14 days, and SCH503034 plus pegylated interferon for 14 days, but in different orders (i.e., some started with SCH503034 alone, some with pegylated interferon alone, and some with the combination). The mean hepatitis C viral load decrease was more than 2 log₁₀ copies/ml in both the 200mg and 400mg SCH503034 combination arms, compared with 1 log₁₀ copies/ml in the pegylated interferon monotherapy arm; 40% of patients (4 out of 10) in the 400mg arm achieved undetectable hepatitis C viral load, compared with none of those receiving only pegylated interferon. Zeuzem concluded that combination therapy produced at least an additive decline in HCV RNA.

In both studies, SCH503034 appeared self and well-tolerated at all dose levels. In the monotherapy study, adverse events were mild and similar in the SCH53034 and placebo arms. The adverse event profiles in the second study were similar in the SCH503034 and combination therapy arms, consisting mostly of well-known pegylated interferon side effects. Importantly, in animal and human studies to date, researchers have seen no clinical or histopathological evidence of the type of cardiac toxicity that led to the discontinuation of an earlier hepatitis C protease inhibitor, BILN-2061. While one patient did develop the V170A mutation (shown to cause resistance to SCH503034 in laboratory studies), no phenotypic resistance was observed and no viral rebound was seen during treatment in the 400mg three times daily arm. Phase II studies assessing 24 and 48 week VX-950/pegylated interferon combination therapy are underway.

VX-950

Finally, Henk Reesink from the Academic Medical Centre in Amsterdam reported data from a Phase Ib dose-ranging trial of a second hepatitis C protease inhibitor, VX-950 (Vertex Pharmaceuticals). This study included 36 individuals with genotype 1 hepatitis C, mostly prior non-responders, but also a few treatment-naive patients. Participants were assigned to receive either placebo or an oral suspension of VX-950 as monotherapy, 450 or 750mg every 8 hours (three times daily) or 1250mg every twelve hours (twice daily), for 14 days. Here, too, baseline characteristics were generally similar across the study arms.

Participants in all VX-950 dose groups showed steep declines in hepatitis C during the first two-to-three days of treatment. All patients receiving VX-950 experienced at least a 2-log viral load decrease from baseline. Most individuals in the three VX-950 arms (26 out of 28) had a maximum hepatitis C viral load decrease of at least 3 log₁₀ copies/ml, and four patients had a greater than 5-log decrease. The 750mg three times daily dose produced the highest VX-950 trough levels and the largest mean HCV RNA decrease: 4.4 log₁₀ copies/ml, or a 25,000-fold reduction. Four patients in this arm had undetectable viral load (below 30 IU/mL) at the end of the treatment period. Hepatitis C viral load also decreased in the other two dose groups, but started to climb again after seven days. VX-950 appeared to work as well in prior non-responders as in naive patients. ALT levels declined during treatment in all dose groups. There were no severe adverse events, dose reductions, or treatment discontinuations. The most commonly reported side effects (headache and diarrhoea) occurred with similar frequency in the VX-950 and placebo arms. As with SCH503034, no cardiotoxicity was observed.

In a companion resistance study presented by Christoph Sarrazin, also from Homburg, researchers sequenced the HCV NS3 gene from 34 patients at baseline, day 14, and day 21-24. Several variants were seen with reduced sensitivity to VX-950, at amino acid positions 36, 54, 155, and 156. A single V36 change conferred minimal resistance, while A156V/T was associated with high-level resistance. These mutations were detected in patients who experienced hepatitis C viral load rebound or plateau rather than continued decline. Variants with reduced sensitivity to VX-950 also had decreased replicative fitness, allowing wild-type hepatitis C virus to re-emerge after treatment discontinuation.

According to Reesink, VX-950 produced “the most rapid and dramatic response” seen to date with a single agent. Based on viral kinetic analysis, he suggested that the drug may reduce hepatitis C to undetectable levels in approximately 12 weeks - substantially shorter than the standard 48 week therapy for genotype 1 hepatitis C. Based on data collected so far, Vertex filed an investigational new drug application with the U.S. Food and Drug Administration on November 11. A 14-day Phase Ib study of a new tablet formulation of VX-950 in combination with pegylated interferon is underway in Europe, and a 12 week combination study is planned for next year.

While all three of these experimental agents look promising, it is too soon to say whether they will ultimately produce sustained virological response. Nevertheless, based on research to date, many experts believe antiviral drugs - potentially in combination regimens consisting entirely of oral agents - are the wave of the future for hepatitis C therapy.

References

O’Brien C. et al. Randomized trial of valopicitabine (NM283), alone or with peg-interferon, vs. retreatment with peg-interferon plus ribavirin (PegIFN/RBV) in hepatitis C patients with previous non-response to PegIFN/RBV: first interim results. 56^th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, abstract 63186, 2005.

Reesink H. et al. Final results of a phase 1B, multiple-dose study of VX-950, a hepatitis C virus protease inhibitor. 56^th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, abstract 62580, 2005.

Sarrazin C. et al. Characterization of viral variants in the HCV NS3 protease domain of genotype 1 patients that are selected during 14 days of dosing with VX-950. 56^th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, abstract 72562, 2005.

Zeuzem S. et al. Anti-viral activity of SCH 503034, a HCV protease inhibitor, administered as monotherapy in hepatitis C genotype-1 (HCV-1) patients refractory to pegylated interferon (Peg-IFN-a). 56^th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, abstract 67484, 2005.

Zeuzem S. et al. Combination therapy with the HCV protease inhibitor, SCH 503034, plus PEG-Intron in hepatitis C genotype-1 PEG-Intron non-responders: phase Ib results. 56^th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, abstract 67627, 2005.