by Liz Highleyman
The 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in April featured data on several experimental direct-acting antiviral drugs for hepatitis C. (For more information see “How Do Targeted Anti-HCV Drugs Work?” in the December 2009 HCV Advocate).
This report covers HCV polymerase inhibitors, NS4A inhibitors, and all-oral combinations. See last month’s HCV Advocate for coverage of HCV protease inhibitors.
Nucleoside Analog RG7128
E. Gane and colleagues reported on RG7128, the NS5B polymerase inhibitor being developed by Roche/Genentech and Pharmasset. Polymerase is a viral enzyme needed to copy genetic material. NS5B refers to the segment of the HCV genome that encodes the polymerase. RG7128 is a nucleoside analog, or defective mimic of natural DNA and RNA building blocks.
Researchers looked at RG7128 in combination with pegylated interferon plus ribavirin in 10 chronic hepatitis C patients with HCV genotype 2 and 15 people with genotype 3 who did not achieve sustained response with prior interferon-based therapy; most trials of direct-acting agents have focused on genotype 1, which is hardest to treat. Participants were randomly assigned to receive 1,500 mg RG7128 twice-daily or placebo with pegylated interferon alfa-2a (Pegasys) plus ribavirin for 28 days, followed by standard therapy for an additional 20-44 weeks.
HCV viral load decreased by an average of 5.0 log10 IU/mL at week 4 in the RG7128 arm compared with 3.7 log10 in the placebo arm. All but one patient (95%) receiving RG7128 and 60% in the placebo arm achieved rapid virological response, or undetectable HCV RNA at week 4 of therapy. Sustained virological response (SVR) rates 24 weeks after completion of treatment were 65% and 60%, respectively. Although the standard treatment duration for HCV genotypes 2 and 3 is 24 weeks, this study saw better outcomes for patients who received a longer course of RG7128 triple therapy (SVR 90% with 48 weeks, 67% with 24 weeks, and none who discontinued before 24 weeks). Response rates were similar for genotypes 2 and 3 (63% vs. 67%) and for prior nonresponders and relapsers (60% vs. 70%).
Roche/Genentech discontinued development of another nucleoside analog polymerase inhibitor candidate, RG1626 or balapiravir (the prodrug of RG1479), due to safety concerns. A Phase IIb study showed that the drug increased the likelihood of RVR at week 4 and complete early virological response (EVR) at week 12, but caused unexpected loss of neutrophils and lymphocytes¾an effect not seen with other nucleoside polymerase inhibitors.
RG7128 + RG7227
Gane also reported findings from INFORM-1, the first clinical trial of a combination oral hepatitis C regimen. This study looked at RG7128 in combination with the protease inhibitor RG7227, now named danoprevir. Combining agents that target different steps of the viral lifecycle may be more potent and make it harder for the virus to develop resistance.
INFORM-1 enrolled treatment-naive and treatment-experienced genotype 1 chronic hepatitis C patients. They were randomly assigned to receive RG7128 (500 or 1,000 mg twice-daily) and RG7227 (100 or 200 mg three-times-daily or 600 or 900 mg twice-daily), or else placebo, for 7 or 13 days, after which they continued on pegylated interferon/ribavirin for 24 or 48 weeks.
Outcomes were better with higher doses and longer duration of oral therapy. Treatment-naive patients receiving the high doses of both drugs achieved a 5.1 log10 IU/mL decline in HCV RNA by the end of dosing, while prior nonresponders and relapsers saw drops of 4.0-4.9 log10 IU/mL and placebo recipients showed no significant change. RVR rates were 88% for treatment-naive patients, 38% for prior partial responders or relapsers, and 13% for prior null responders; complete EVR rates at week 12 were 100%, 75%, and 38%, respectively. Among treatment-naive patients who received the high-dose regimen and were followed for 12 weeks after completion of therapy (SVR-12), 44% maintained an undetectable viral load. The researchers concluded that the large initial viral load reduction with RG7128/RG7227 prior to initiating standard therapy enhanced on-treatment and sustained virological response rates.
Nucleotide Analogs PSI-7977 and PSI-938
Nucleotide analogs are similar to nucleoside analogs but require less processing to make them active in the body. V. Zennou and colleagues from Pharmasset reported results from a laboratory study of two complementary nucleotide polymerase inhibitors, PSI-7977 (a pyrimidine analog) and PSI-938 (a purine analog). The combination demonstrated additive to synergistic antiviral activity in replicon models of wild-type (non-mutated) HCV and virus with various known resistance mutations. In addition, either PSI-7977 or PSI-938 plus a non-nucleoside polymerase inhibitor led to better viral clearance.
After EASL Pharmasset announced findings from a Phase IIa clinical trial of once-daily PSI-7977 in combination with Pegasys plus ribavirin for 28 days. In this study, which included 63 treatment-naive genotype 1 patients, 88% in the PSI-7977 100 mg arm, 94% in the 200 mg arm, and 93% in the 400 mg arm achieved undetectable viral load, significantly higher than the 21% in the placebo arm; safety and tolerability were comparable in the PSI-7977 and placebo arms and no serious adverse events were reported.
Non-nucleoside ANA598
Anadys Pharmaceuticals presented findings from a Phase II trial of its non-nucleoside polymerase inhibitor ANA598 at EASL, with follow-up data announced in May. Non-nucleosides also interfere with the HCV polymerase enzyme, but do so by a different mechanism than nucleoside/nucleotide analogs, making the two classes suitable for combination therapy.
This ascending-dose study included 90 treatment-naive genotype 1 patients randomly assigned to receive 200 mg or 400 mg ANA598 twice-daily, or else placebo, in combination with Pegasys plus ribavirin for 12 weeks; they then continued on standard therapy for 24 or 48 weeks.
Response rates were similar in the 200 mg and 400 mg dose groups, with 73% and 75%, respectively, achieving complete EVR at week 12, compared with 63% in the placebo group. Tolerability was better and the frequency of skin rash was lower in the 200 mg arm, however, and the company will focus on this dose going forward.
While the Phase II trial looked at ANA598 in combination with pegylated interferon/ribavirin, Anadys researchers also reported in vitro data at EASL showing that it demonstrates enhanced activity when combined with other direct-acting agents and retains activity against HCV with mutations conferring resistance to these drugs.
Non-nucleoside VX-222
M. Rodriguez-Torres and colleagues presented data on Vertex’s non-nucleoside HCV NS5B polymerase inhibitor candidate VX-222. The researchers conducted a Phase Ib/IIa dose-ascending study that included 32 previously untreated genotype 1 chronic hepatitis C patients. Participants were randomly assigned to receive VX-222 at doses of 250 mg, 500 mg, or 750 mg twice-daily, or 1500 mg once-daily, or placebo for three days. They were then offered Pegasys plus ribavirin for 48 weeks.
HCV RNA decreased by about 3.0 log10 IU/mL in all VX-222 arms by day 4; the drug was active against both genotypes 1a and 1b. VX-222 was generally safe and well-tolerated with no serious adverse events. Vertex recently announced that it will test VX-222 in combination with telaprevir, the company’s HCV protease inhibitor, both as an all-oral regimen and in combination with pegylated interferon/ribavirin.
Other Non-nucleosides
Filibuvir (PF-00868554) is Pfizer’s non-nucleoside polymerase inhibitor candidate. In a Phase II study, 35 treatment-naive genotype 1 patients were randomly assigned to receive filibuvir at doses of 200 mg, 300 mg, or 500 mg twice-daily, or else placebo, in combination with Pegasys plus weight-adjusted ribavirin for four weeks, then continuing on standard therapy for 44 more weeks.
Participants receiving the triple combination had RVR rates of 60%-75% at week 4, compared with none in the placebo arm, with the best results in the 300 mg dose arm. Filibuvir recipients maintained higher response rates at week 12 (up to 88%) and at the end of treatment (up to 75%). However, 20%-50% of filibuvir recipients relapsed after completing therapy, compared with none in the placebo arm, resulting in similar SVR-12 rates. The researchers suggested longer use of filibuvir may be needed for sustained response; a study of triple therapy for 24 weeks of treatment is underway.
BI 207127 is a non-nucleoside polymerase inhibitor being developed by Boehringer Ingelheim. D. Larrey and colleagues conducted a phase I study of 27 treatment-naive and 30 treatment-experienced genotype 1 patients randomly assigned to receive 400 mg, 600 mg, or 800 mg BI 207127, or else placebo, three times daily for 28 days in combination with pegylated interferon plus ribavirin, then continuing on standard therapy.
Among treatment-naive participants, the 600 mg and 800 mg BI 207127 doses had similar potency and worked equally well against genotypes 1a and 1b; among treatment-experienced patients, however, those with 1b had better response. All treatment-naive patients and about half of treatment-experienced patients who received BI 207127 experienced at least a 3.0 log10 IU/mL decrease in HCV RNA; median decreases in the two higher dose groups were about 5.5 log10 for treatment-naive patients and about 4.4 log10 for treatment-experienced patients. BI 207127 combination therapy was generally well-tolerated, but there was one case of serious rash in the 800 mg group.
Abbott also presented data on its non-nucleoside polymerase inhibitor ABT-333, and another further back in the pipeline, ABT-072. In a Phase IIa study, 30 genotype 1 hepatitis C patients received ABT-333 or placebo monotherapy for two days followed by the same agents with pegylated interferon plus ribavirin for 26 days. The triple combination produced about a 2.0 log10 greater reduction in viral load than standard therapy alone. Some drug resistance was detected, but this did not appear to compromise continued treatment response.
NS4A Inhibitors
In addition to drugs targeting the HCV NS5B polymerase, researchers are also looking at agents that interfere with the nonstructural NS4A protein; the function of this protein is not fully understood, but it appears to play an important role in HCV replication.
S. Pol and colleagues conducted a Phase IIa trial looking at Bristol-Myers Squibb’s NS5A inhibitor BMS-790052. Treatment-naive genotype 1 patients (12 per arm) were randomly assigned to receive BMS-790052 at doses of 3 mg, 10 mg, or 60 mg once-daily, or else placebo, with Pegasys plus ribavirin for 48 weeks. Participants in all BMS-790052 arms had significantly higher response rates than placebo recipients, but the two higher doses were more effective. RVR rates at week 4 were 42% in the 3 mg arm, 92% in the 10 mg arm, and 83% in the 60 mg arm, compared with 8% in the placebo arm. Complete EVR rates at week 12 were 58%, 83%, and 42%, respectively. BMS-700952 was generally safe and well-tolerated.
Presidio Pharmaceuticals is developing another NS5A inhibitor, PPI-461. R. Colonno and colleagues reported that PPI-461 demonstrated potent activity against all HCV genotypes in a replicon model and showed good tolerability and oral bioavailability in animal studies, suggesting the feasibility of once-daily dosing.
Idenix and Tibotec Combination Therapy
In an effort to delay the emergence of drug resistance¾and ultimately enable people to use direct-acting agents without interferon¾pharmaceutical companies are now testing combinations of candidates from different drug classes early in the development process.
Idenix Pharmaceuticals presented data on agents from multiple classes alone and in combination. J. Lalezari and colleagues evaluated the safety, antiviral activity, and pharmacokinetics of the nucleotide analog polymerase inhibitor IDX184. In a Phase IIa ascending-dose trial, sequential groups of 20 previously untreated genotype 1 patients received IDX184 at doses of 50, 100, 150, or 200 mg once or twice daily, or else placebo, for 14 days; participants also received Pegasys plus ribavirin during the IDX184 dosing period and for 14 days thereafter.
After 14 days, HCV viral load decreased by 2.7 log10 IU/mL in the 50 mg once-daily IDX184 arm, 4.0 log10 IU/mL in the 50 mg twice-daily arm, and 4.2 log10 IU/mL in the 100 mg once-daily arm, compared with just 1.2 log10 IU/mL in the placebo arm. By the end of dosing, half the patients in the 50 mg twice-daily and 100 mg once-daily arms achieved undetectable viral load. Most participants experienced viral rebound after the last day of IDX184 dosing, however, even though they remained on pegylated interferon/ribavirin. The drug was generally well-tolerated and no participants discontinued treatment early.
M. La Colla and colleagues from Idenix evaluated various two- and three-drug regimens containing IDX184, the protease inhibitor candidate IDX320, the non-nucleoside polymerase inhibitor IDX375, and a prototype NS5A inhibitor known as IDX-NS5A in a genotype 1b laboratory replicon model. Over three days IDX320 + IDX375 demonstrated additive activity, while IDX320 + IDX-NS5A produced additive to synergistic activity. Triple combinations of IDX184 + IDX320 + either IDX375 or IDX-NS5A produced clear synergistic activity. Over 14 days, IDX184, IDX320, and IDX375 individually produced viral load reductions of about 0.5-1.5 log10 IU/mL. Any two-drug combination demonstrated additive activity, with a reduction of about 2.0 log10; combining all three drugs led to a decrease of nearly 4.0 log10.
Researchers from Tibotec likewise tested combinations of the HCV NS3/4A protease inhibitor TMC435 with a nucleoside analog or non-nucleoside polymerase inhibitor in a replicon model. Both combinations showed additive or synergistic antiviral activity and a higher genetic barrier to resistance than the drugs used alone. The investigators concluded that combining all three agents at low concentrations resulted in a “pronounced reduction in replicon HCV RNA and the most efficient replicon clearance.”
Source: hcvadvocate.org
