Data on Experimental Anti-HCV Drugs ITMN-191/R7227, VCH-916, VCH-222, TMC435, ANA598, MK-7009, GS-9450, Abbott/Enanta and Idenix Agents

By Liz Highleyman

Combination therapy consisting of pegylated interferon (Pegasys or PegIntron) plus ribavirin is the current standard of care for chronic hepatitis C virus (HCV) infection, but this regimen causes difficult side effects and does not produce a sustained response in about half of patients with difficult-to-treat HCV genotype 1. Researchers are studying a number of oral drugs that directly target various steps of the HCV lifecycle, an approach referred to as "STAT-C." Data on several such agents were presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

The Vertex HCV NS3/4A serine protease inhibitor telaprevir (formerly VX-950), now in Phase 3 studies, may be the first to exit the development pipeline. Promising results from the Phase 2 PROVE 1 and PROVE 2 studies in treatment-naive patients were published recently in the New England Journal of Medicine, and, as previously reported, findings from the PROVE 3 study were presented at EASL.

Researchers at EASL also reported good results from the SPRINT-1 trial of combination therapy containing Schering-Plough's advanced HCV protease inhibitor candidate boceprevir, as well as early data on the company's newer HCV NS3 protease inhibitor SCH 900518.

One presentation that garnered considerable attention looked at the first data from a clinical trial (INFORM-1) of 2 directly-targeted oral agents -- the Roche HCV polymerase inhibitor R7128 plus the InterMune/Roche HCV NS3/4A protease inhibitor ITMN-191 (also known as R7227) -- without pegylated interferon or ribavirin.

ITMN-191/R7227 + Pegasys/ribavirin

ITMN-191/R7227 is also being studied in combination with the current standard-of-care regimen. Stefan Zeuzem presented findings from a double-blind, placebo-controlled, multiple ascending dose study in which 191 treatment-naive genotype 1 chronic hepatitis C patients were randomly assigned (8:2) to receive ITMN-191/R7227 (100 to 900 mg every 8 or 12 hours) or placebo in combination with standard doses of pegylated interferon alfa-2a and weight-adjusted ribavirin for 14 days.

Viral load levels declined rapidly, with HCV RNA decreasing by about 5.5 log10, compared with 2 log10 in the standard-of-care arm. At the end of dosing, 57% to 88% of participants had HCV RNA < 25 IU/mL (compared with 8% in the standard therapy arm) and 13% to 57% had undetectable HCV RNA < 9.3 IU/mL (vs none in the standard therapy arm). Viral rebound did not occur in any of the treatment arms. Overall, ITMN-191/R7227 was generally safe and well tolerated. There were no serious adverse events (AEs) or laboratory abnormalities, and no AEs leading to treatment discontinuation.

InterMune is planning a Phase 2b trial of triple therapy using ITMN-191/R7227 at doses that appeared promising in this study (600 mg and 900 mg every 12 hours and 300 mg every 8 hours).

"We believe that the viral kinetic and safety results reported today provide evidence that ITMN-191 has the potential to deliver superior sustained virologic response (SVR) rates in patients chronically infected with the hepatitis C virus," said InterMune Chief Medical Officer Steven Porter in a press release issued by the company.

VCH-916 & VCH-222

As telaprevir moves toward the final stages of development, Vertex is developing 2 new STAT-C agents, the non-nucleoside HCV RNA-dependent NS5B polymerase inhibitors VCH-916 and VCH-222, which Vertex acquired from ViroChem Pharma when it acquired the company in March 2009.

Eric Lawitz and colleagues presented results from a study assessing the viral kinetics, pharmacokinetics, safety, and tolerability of VCH-916 monotherapy, administered to 41 patients at doses of 100 and 200 mg every 8 hours for 14 days, and 300 and 400 mg twice-daily for 3 days (or placebo). All participants had HCV genotype 1 and all but 2 were treatment-naive.

VCH-916 displayed linear pharmacokinetics with no accumulation upon repeated administration. The maximal decline in HCV RNA ranged from 0.1 to 2.6 log10, generally rising with higher doses. After 3 days of dosing, the maximal HCV RNA decrease was 1.5 log10 in the 3 highest dose arms.

VCH-916 was generally well tolerated over 14 days; while adverse effects were common, they were usually mild (93% mild, 7% moderate). The most frequently reported adverse events were gastrointestinal symptoms (38%), throat irritation (25%), and central nervous system symptoms (19%) in the three-times-daily cohorts. In the twice-daily groups, three-quarters reported throat irritation and one-third reported nausea. However, no serious AEs, abnormal laboratory findings, or ECG abnormalities were observed.

Curtis Cooper and colleagues looked at the safety, tolerability, and pharmacokinetics of VCH-222 in a Phase 1 double-blind, ascending dose trial. First, healthy HCV-uninfected volunteers received single VCH-222 doses of 250, 500, 1000, and 1500 mg (500 mg with food, the others fasting). VCH-222 was well tolerated at all doses tested, with no serious AEs reported. Under fasting conditions, the rate and extent of absorption appeared relatively proportional across the dose range and the half-life was approximately 4 hours.

Next, 6 patients with HCV genotype 1 received 750 mg VCH-222 twice-daily for 3 days. Preliminary efficacy findings showed a mean HCV RNA reduction of 3.2 log10 within 24 hours of dosing and 3.7 log10 on day 4.

"VCH-222 was safe and well tolerated up to 1,500 mg administered as a single dose or at 750 mg bid for 3 days," the researchers concluded. "In terms of exposure versus in vitro potency, excellent pharmacokinetic properties were exhibited. In vivo, high HCV virological potency was demonstrated."

TMC435

TMC435 is an HCV NS3/NS4A protease inhibitor being developed by Tibotec in collaboration with Medivir. Michael Manns and colleagues presented data from OPERA-1, an ongoing double-blind, placebo-controlled Phase 2a trial to assess the antiviral activity, safety, and pharmacokinetics of once-daily TMC435 in treatment-naive and treatment-experienced genotype 1 patients.

Participants were randomly assigned to receive 7 days of monotherapy with TMC435 (25, 75, or 200 mg once-daily) or placebo, followed by triple therapy with TMC435 or placebo plus pegylated interferon alfa-2a and ribavirin for 21 or 28 days (patients thereafter continued on a standard course of pegylated interferon/ribavirin).

Over 7 days of monotherapy, an antiviral activity to dose relationship was observed. As part of triple therapy, the 75 mg and 200 mg TMC435 doses produced a similar antiviral effect. At week 4, HCV RNA declined by 5.5 and 5.4 log10 IU/mL, respectively, in the 75 mg and 200 mg triple-combination arms. 8 of 9 patients in the 75 mg group and 7 of 10 in the 200 mg group achieved undetectable viral load (< 10 IU/mL) at week 4; at week 12 (4 weeks on triple therapy followed by 8 on pegylated interferon/ribavirin), 6 of 9, 9 of 9 and 10 of 10 patients in the 25, 75, and 200 mg triple therapy arms, respectively, still had HCV RNA < 10 IU/mL. No instances of viral breakthrough were observed. TMC435 doses in combination with pegylated interferon/ribavirin demonstrated antiviral activity superior to that of pegylated interferon/ribavirin alone.

TMC435 was well tolerated at all doses. AST and ALT values improved during therapy. There were no TMC435-related treatment discontinuations, serious AEs, or clinically relevant detrimental changes in laboratory parameters, with no evidence of hepatic, renal, cardiovascular, or hematopoietic toxicities.

In a related report, Patrick Marcellin and colleagues presented results from previous non-responders (n = 25) or relapsers (n = 12) in OPERA-1 who received once-daily TMC435 (75, 150, 200 mg) or placebo plus pegylated interferon/ribavirin for 28 days, then continuing on pegylated interferon/ribavirin alone for up to 48 weeks.

The mean decreases in plasma HCV RNA at week 4 were 4.3, 5.5, and 5.3 log10 IU/mL, respectively, in patients receiving 75, 150 and 200 mg TMC435, versus 1.5 log10 IU/mL in the placebo group. At this time point, 44%, 78%, and 70% patients in the 3 dose groups, respectively, achieved HCV RNA < 25 IU/mL, compared with none in the placebo group; 22%, 56%, and 30%, respectively, had HCV RNA < 10 IU/mL. Only 3 instances of viral breakthrough were observed. Again, there were no serious AEs or discontinuations due to AEs. ALT/AST levels decreased in all TMC435 groups, but some patients -- mostly in the 200 mg group -- experienced mild-to-moderate bilirubin increases.

ANA598

Lawitz also presented findings from a study of ANA598, a non-nucleoside HCV polymerase inhibitor with potent in vitro antiviral activity being developed by Anadys Pharmaceuticals. Study ANA598-502, a randomized, double-blind, placebo-controlled, multiple ascending dose trial, was designed to evaluate the safety, tolerability, and antiviral activity of oral ANA598 in treatment-naive genotype 1 chronic hepatitis C patients. A total of 35 participants were treated with ANA598 at doses of 200, 400, or 800 mg twice-daily, or matching placebo, for 3 days.

ANA598 produced rapid and sustained declines in HCV RNA, with median reductions at the end of dosing exceeding 2 log10 in all dose groups. In the 200, 400, and 800 mg arms, respectively, the median viral load reductions were 2.4, 2.3, and 2.9 log10. Genotype 1a patients had median HCV reductions of 1.4, 1.8, and 2.5 log10, respectively, and viral load was still declining at the end of the 3 days of treatment. Genotype 1b patients had larger median reductions of 2.6, 2.5, and 3.2 log10, respectively. No viral rebound was observed while on ANA598. The drug was well-tolerated in this short study with no serious AEs.

Anadys also recently completed dosing in a 14-day study of ANA598 in 30 healthy HCV negative volunteers. Participants received ANA598 (400 mg once-daily, 800 mg once-daily, or 600 mg twice-daily) or placebo on day 1, followed by pharmacokinetic assessment on days 2-3, then subsequent drug doses on days 4-14.

According to a company press release, preliminary results indicate that ANA598 was generally well tolerated in all cohorts, with no serious adverse events. However, 3 participants receiving ANA598 (2 in the 800 mg once-daily arm and 1 in the 600 mg twice-daily arm) developed a grade 2 rash and discontinued treatment after 6-7 days of consecutive dosing. The company said there were no other instances of rash in this or any other study of ANA598. Data collection and analysis is ongoing.

MK-7009

Manns also presented data from a randomized, placebo-controlled, double-blind Phase 2a study of MK-7009, a HCV NS3/4A protease inhibitor being developed by Merck. A total of 95 treatment-naive genotype 1 chronic hepatitis C patients received MK-7009 (600 or 800 mg once-daily or 300 or 600 mg twice-daily) or placebo for 4 weeks with pegylated interferon/ribavirin; participants then continued on pegylated interferon/ribavirin for an additional 44 weeks.

The proportion of patients who achieved rapid virological response (< 10 IU/mL at week 4) ranged from 69% to 82% in the MK-7009 arms, compared with 6% in the placebo arm. Viral suppression continued after the end of MK-7009 dosing. At day 42, 77% to 94% in the MK-7009 arms still had undetectable HCV viral load, compared with 12% in the placebo arm.

MK-7009 in combination with pegylated interferon/ribavirin was well tolerated, with no serious AEs and no discontinuations due to AEs. The most commonly reported AEs were nausea, headache, and flu-like symptoms; the incidence of nausea and vomiting was higher in the MK-7009 arms compared with the placebo arm, but did not require anti-emetic treatment and did not lead to dose reduction or discontinuation of therapy.
"In this first study of MK-7009 in combination with [pegylated interferon/ribavirin], MK-7009 is a well-tolerated and potent inhibitor of HCV," the researchers concluded. "The results support further development of MK-7009 for HCV treatment."

A Phase 2b study is underway to evaluate the safety, tolerability, and efficacy of MK-7009 in combination with pegylated interferon/ribavirin in approximately 200 previously treated genotype 1 patients, according to a Merck press release. Participants will receive MK-7009 at doses of 300 or 600 mg twice-daily or placebo in combination with standard therapy.

EA-058 and EA-063

Another researcher team presented data on EA-058 and EA-063, novel non-ketoamide HCV protease inhibitors being developed through a collaboration of Abbott Laboratories and Enanta Pharmaceuticals.

Based on laboratory findings, these agents appear highly potent against both wild-type HCV and virus that has developed resistance mutations; it also appears to be active across HCV genotypes. In a comparative study, the new agents were more potent than ITMN-191/R7227, MK-7009, and TMC 435350 against HCV genotypes 2 and 3a.

EA-058 and EA-063 had favorable pharmacokinetic properties, suggesting they could potentially be administered once daily. In studies of rats and dogs, the drugs reached high levels in the liver relative to blood plasma, which the investigators suggested could "minimize extra-hepatic adverse effects in humans."

IDX184, IDX375, IDX136 & IDX316

Finally, researchers from Idenix presented data from studies of 4 investigational agents. The furthest along in development, IDX184, is a liver-targeted nucleotide analog pro-drug that is processed to its nucleoside form in the liver, thus minimizing systemic exposure.

In HCV genotype 1-infected chimpanzees, once-daily oral administration of 10 mg/kg IDX184 for 4 days produced substantial decreases in HCV RNA. Maximal viral load declines in all chimps studied ranged from 1.4 to 3.8 log10 copies/mL. Viral load reductions of >1 log10 were associated with nucleoside metabolite levels > 2 ng/mL. "Oral administration of 10 mg/kg of IDX184 to HCV-infected chimpanzees resulted in potent antiviral activity that was achieved with low systemic levels of the parent drug and its nucleoside metabolite," the researchers concluded.

The first clinical study of IDX184 in humans evaluated the safety and pharmacokinetics of single ascending oral doses of IDX184 (5, 10, 25, 50, 75, and 100 mg) administered sequentially to cohorts of 8 healthy HCV negative volunteers. IDX184 was rapidly absorbed, but plasma concentrations of the nucleoside metabolite increased gradually. The drug was well tolerated and there were no serious AEs, premature discontinuations, or dose-limiting toxicities.

"IDX184 appeared to be safe and well tolerated in this study," the investigators concluded. "Consistent with a liver-targeting approach, systemic exposure of parent drug and metabolite was low. The favorable safety and pharmacokinetic profiles warrant further clinical development of IDX184 in HCV-infected patients."

IDX375 is a potent and selective non-nucleoside HCV polymerase inhibitor. In a preclinical study in mice, rats, and cynomolgus monkeys, IDX375 selectively concentrated in the liver of all 3 species. After oral administration, high systemic exposures were observed in rodents receiving doses up to 250 mg/kg and in monkeys receiving up to 100 mg/kg.

No adverse effects were observed in monkeys given 10 or 100 mg/kg oral doses for 7 days. Furthermore, IDX375 showed no significant inhibition of 5 major human cytochrome P450 enzymes, suggesting it may not interact significantly with other drugs. Based on these findings, the researchers concluded, "IDX375 is a promising clinical candidate based on its favorable safety profile and preclinical pharmacokinetics that suggest once- or twice-daily dosing in humans."

IDX136 and IDX316, 2 specific macrocyclic HCV protease inhibitor candidates, are furthest back in the Idenix development pipeline. The antiviral activity and specificity of these agents were evaluated using a variety of HCV replicon assays.

IDX136 and IDX316 were found to be potent and selective inhibitors of protease enzymes of HCV genotypes 1a, 1b, and 4, but with no activity against human cellular proteases. Treatment of replicon cells for 14 days with each agent reduced HCV RNA by nearly 3 log10. IDX316 remained active against HCV with common NS3 mutations and exhibited enhanced activity when combined with standard-of-care agents (pegylated interferon/ribavirin) and IDX184 or IDX375.

In mice, rats, and monkeys given single oral doses of 10 or 15 mg/kg IDX316, the "parent" drug selectively concentrated in the liver, and plasma concentrations remained high after 24 hours. No AEs were observed in rhesus macaque monkeys given 10 or 100 mg/kg oral doses of either IDX136 or IDX316 for 7 days. Here too, neither drug significantly inhibited 5 major human cytochrome P450 enzymes.

Based on the favorable preclinical safety profile and pharmacokinetics that suggest once- or twice-daily dosing, the researchers said that IDX136 and IDX316 are currently undergoing further pharmacology and toxicology studies to support initiating human studies.

5/12/09

References

N Forestier, D Larrey, P Marcellin, S Zeuzem, and others. Antiviral Activity and Safety of ITMN-191 in Combination with Peginterferon Alfa-2a and Ribavirin in Patients with Chronic Hepatitis C Virus (HCV). 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 85.

E Lawitz, C Cooper, M Rodriguez-Torres, and others. Safety, Tolerability and Antiviral Activity of VCH-916, a Novel Non-Nucleoside HCV Polymerase Inhibitor in Patients with Chronic HCV Genotype-1 Infection. EASL 2009. April 22-26, 2009. Abstract 92.

C Cooper, R. Larouche, B Bourgault, and others. Safety, Tolerability and Pharmacokinetics of the HCV Polymerase Inhibitor VCH-222 Following Single Dose Administration in Healthy Volunteers and Antiviral Activity in HCV-Infected Individuals. EASL 2009. April 22-26, 2009.

M Manns, H Reesink, C Moreno, and others. Opera-1 Trial: Interim Analysis of Safety and Antiviral Activity of TMC435 in Treatment-Naive Genotype 1 HCV Patients. EASL 2009. April 22-26, 2009.

P Marcellin, H Reesink, T Berg, and others. Antiviral Activity and Safety of TMC435 Combined with Peginterferon Alpha-2a and Ribavirin in Patients with Genotype 1 Hepatitis C Infection Who Failed Previous IFN-Based Therapy. EASL 2009. April 22-26, 2009.

E Lawitz, M Rodriguez-Torres, M DeMicco, and others. Antiviral Activity of ANA598, a Potent Non-nucleoside Polymerase Inhibitor, in Chronic Hepatitis C Patients. EASL 2009. April 22-26, 2009.

P Thompson, R Patel, K Steffy, and others. Preclinical Studies of ANA598 Combined with Other Anti-HCV Agents Demonstrate Potential of Combination Treatment. EASL 2009. April 22-26, 2009.

M Manns, E Gane, M Rodriguez-Torres, and others. MK-7009 Significantly Improves Rapid Viral Response (RVR) in Combination with Pegylated Interferon Alfa-2a and Ribavirin in Patients with Chronic Hepatitis C (CHC) Genotype 1 Infection. EASL 2009. April 22-26, 2009. Abstract 2701.

LJ Jiang, Y Gai, T Middleton, and others. Potent HCV Protease Inhibitors with the Potential for Once-Daily Dosing and Broad Genotype Coverage. EASL 2009. April 22-26, 2009.

DN Standring, R Lanford, B Li, and others. Antiviral Activity of the Liver-Targeted Nucleotide HCV Polymerase Inhibitor IDX184 Correlates with Trough Serum Levels of the Nucleoside Metabolite in HCV-Infected Chimpanzees. EASL 2009. April 22-26, 2009.

X-J Zhou, K Pietropaolo, J Sullivan-Bolyai, and others. IDX184, a Liver-Targeted Nucleotide HCV Polymerase Inhibitor: Results of a First-in-Man Safety and Pharmacokinetic Study. EASL 2009. April 22-26, 2009.

SS Good, C Bu, M Camire, and others. Preclinical Pharmacokinetic and Safety Profile of IDX375, a Novel and Potent Non-nucleoside HCV Polymerase Inhibitor. EASL 2009. April 22-26, 2009.

LB Lallos, JP Bilello, MA Soubasakos, and others. Preclinical Profiles of IDX136 and IDX316, Two Novel Macrocyclic HCV Protease Inhibitors. EASL 2009. April 22-26, 2009.

Other Sources

InterMune. InterMune Reports Presentation Of Triple Combination Study of ITMN-191 at European Association for the Study of the Liver (EASL). Press release. April 24, 2009.

Vertex Pharmaceuticals. Vertex Pharmaceuticals Announces Acceptance of Telaprevir and VCH-222 Abstracts for Presentation at EASL Annual Meeting. Press release. March 18, 2009.

Medivir. New Phase IIa Data on TMC435 in Patients with Hepatitis C Presented at the Ongoing EASL Meeting. Press release. April 27, 2009.

Anadys Pharmaceuticals. ANA598 Demonstrates Potent Antiviral Activity at All Dose Levels in Completed Phase Ib Study in Hepatitis C Patients. Press release. April 24, 2009.

Merck & Co. Merck Announces Interim Phase IIa Study Results of MK-7009, an Investigational Oral Hepatitis C Virus Protease Inhibitor, in Patients with Chronic Hepatitis C. Press release. April 23, 2009.

Idenix Pharmaceuticals. Idenix Pharmaceuticals Reports Data from Three Hepatitis C Development Programs. Press release. April 24, 2009.

EASL 2009 MAIN PAGE

15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
HIV and AIDS Treatment News, Experimental News, FDA-approved News

Highlights of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2009) - Coverage by HIV and Hepatitis.com, February 8 - 11, 2009, Montreal