Oral HCV Polymerase Inhibitor RG7128 plus Protease Inhibitor RG7227 (ITMN-191) Suppresses HCV Viral Load without Interferon or Ribavirin

SUMMARY: Combination hepatitis C treatment using the nucleoside analog hepatitis C virus (HCV) polymerase inhibitor RG7128 (formerly R7128) plus the HCV NS3/4A protease inhibitor RG7227 (formerly R7227, also known as ITMN-191) produced potent antiviral activity in a 2 week study, researchers reported this month at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) in Boston. If confirmed in larger studies, these findings from the INFORM-1 trial -- the first to test an all-oral combination anti-HCV regimen -- suggest that effective treatment may be possible without interferon or ribavirin.

By Liz Highleyman

Combination therapy consisting of pegylated interferon plus ribavirin is the current standard of care for chronic hepatitis C, but there is a need for treatments that are more effective, easier to administer (oral rather than injected), and have fewer side effects.

The INFORM-1 trial -- conducted by Roche in collaborations with InterMune and Pharmasset -- tested a combination regimen consisting of 2 directly targeted oral anti-HCV agents without interferon or ribavirin. As with antiretroviral therapy for HIV, combining agents targeting multiple steps of the viral lifecycle may offer greater potency and reduce the emergence of drug resistance.

In this Phase 1 double-blind, ascending-dose trial, 64 adults with genotype 1 chronic hepatitis C were randomly assigned (8 per cohort) to receive various combinations of RG7128 and RG7227 (or placebo) for up to 14 days. Some participants were treatment-naive and others were treatment experienced, including some who had a null response to previous interferon-based therapy (HCV RNA decrease <1 log10 in 4 weeks or <2 log10 in 12 weeks).

The first 2 study cohorts received low-dose monotherapy with either 500 mg RG7128 twice-daily or 100 mg RG7227 3-times-daily on days 1-3. Both cohorts then received a combination of both drugs on days 4-7. Next, additional cohorts received escalating doses of RG7128 (500 or 1000 mg twice-daily) plus RG7227 (600 or 900 mg twice-daily, or 100 or 200 mg 3-times-dialy) for 14 days.

None of the participants took pegylated interferon or ribavirin during RG7128/RG7227 dosing, but did received standard of care therapy using pegylated interferon alfa-2a (Pegasys) plus ribavirin after the initial 2-week dosing period.

The results presented at the AASLD meeting focused on the final 3 cohorts, consisting of patients who received the higher-dose twice-daily regimens. Data from the initial lower-dose cohorts were previously reported at the European Association for the Study of the Liver (EASL) meeting this past April.

Results

	All patients receiving twice-daily RG7128/RG7227 regimens experienced a continual decline in HCV RNA during the study period, with viral decline showing a biphasic pattern.
	The highest response rate at day 13 -- 88% with viral load below the lower limit of quantification (LLOQ, <43 IU/mL) and 63% below the lower limit of detection (LLOD, <15 IU/mL) -- was seen in treatment-naive patients receiving 1000 mg RG7128 plus 900 mg RG7227 twice-daily.
	In previous null responders receiving the same doses, the corresponding response rates were 50% below LLOQ and 25% below LLOD.
	In the 1000/900 mg dose cohorts, HCV RNA fell by a median -5.1 log10 IU/mL for treatment-naive participants and -4.9 log10 for prior null responders.
	Participants who received the lower 600 mg dose of RG7227 plus 1000 mg RG7128 had lower response rates, 50% below LLOQ and 13% below LLOD.
	However, there were also no significant differences between twice-daily and 3-times-daily dosing.
	Patients with HCV genotype 1a and 1b also responded similarly.
	1 patient who received a lower dose (500/200 mg) of RG7128/RG7227 experienced viral rebound, but had no identified resistance mutations and went on to achieve undetectable viral load on standard-of-care therapy.
	The RG7128/RG7227 combination was generally well-tolerated.
	No treatment-related serious adverse events, dose modifications, or drug discontinuations were reported.
	The most commonly reported adverse events were headache, nausea, and diarrhea, which occurred with a frequency similar to that seen in the lower-dose cohorts.
	No emergent resistance to RG7128 or RG7227 was observed during the study period.

Based on these findings, the researchers concluded that the combination of RG7128 and RG7227 for up to 14 days "provided significant antiviral potency in treatment-naive and experienced patients, sustained viral reductions, and appears safe and well-tolerated as a twice-daily oral regimen."

"The results from this study of the RG7227/RG7128 combination raise hopes that we can deliver an interferon-free regimen for our patients in the future," said lead investigator Edward Gane, MD, in a press release issued by InterMune. "Current HCV therapy includes up to 12 months of weekly interferon injections which can be associated with significant side effects. In addition, not all patients can take interferon due to intolerance or contraindications. We look forward to the results of additional studies with these potent compounds."

The collaborating companies announced that Roche will initiate a Phase 2 trial program in the first quarter of 2010. INFORM-2 will assess rapid virological response (undetectable HCV RNA after 4 weeks of therapy) in prior non-responder genotype 1 patients receiving twice-daily RG7128/RG7227 alone and in combination with pegylated interferon alfa-2a, ribavirin, or both. Longer-term studies evaluating sustained virological response (undetectable HCV RNA 24 weeks after completing therapy) are anticipated for the first half of 2010.

Roche, Palo Alto, CA; Intermune, Brisbane, CA; Pharmasset, Princeton, NJ; Auckland Clinical Studies, Auckland, New Zealand; The Alfred, Melbourne, Victoria, Australia; Christchurch Clinical Studies, Christchurch, New Zealand; Austin Hospital, Heidelberg, Victoria, Australia; Royal Adelaide Hospital, Adelaide, SA, Australia.

11/10/09

Reference
EJ Gane, SK Roberts, CA Stedman, and others. Combination Therapy with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 193. (Slides available online).

S Le Pogam, M Chhabra, S Ali, and others. Combination Therapy with Nucleoside Polymerase R7128 and Protease R7227/ITMN-191 Inhibitors in Genotype 1 HCV Infected Patients: Interim Resistance Analysis of INFORM-1 Cohorts A-D. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1585.

PN Morcos, R Kulkarni, D Ipe, and others. Pharmacokinetics/Pharmacodynamics (PK/PD) of Combination R7227 and R7128 Therapy from INFORM-1 Demonstrates Similar Early HCV Viral Dynamics when R7227 is Combined with either PEG-IFN/Ribavirin (SOC) or R7128. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1594.

Other Sources

InterMune. INFORM-1 Results: Robust Antiviral Suppression Achieved with Combination of Nucleoside Analog Polymerase Inhibitor RG7128 and Protease Inhibitor RG7227. Press release. November 3, 2009.

AASLD. INFORM Study: HCV Protease R7227+HCV Nucleoside R7128; Twice Daily Oral Medication Shows Promise in Treating Patients with Hepatitis C. Press release. November 2, 2009.