Combination therapy with two experimental, oral, direct-acting antivirals in treatment-naïve hepatitis C patients showed significant viral-load reductions and a clean safety profile, Roche and its biotech partners on the two drugs announced April 25 during the European Association for the Study of the Liver conference in Copenhagen, Denmark.

The Phase I INFORM-1 trial, which dosed protease inhibitor R7227/ITMN-191 and nucleoside polymerase inhibitor R7128 in 57 patients for 14 days, was the first study to test a combination therapy exclusive of the current standard of care in HCV patients, ribvarin and pegylated interferon.

Numerous biopharmaceutical companies, ranging from mammoth to tiny, are trying to take the lead in a highly competitive race to bring the first combination of specifically targeted antiviral therapies for HCV (STAT-C) drugs to market.

At stake is the top spot in a potentially $10 billion annual market for HCV therapies. The various competitors hope to produce a regimen that would shorten duration of therapy with fewer side effects and/or better efficacy compared to the current standard of care (¹ Also see "Vertex And Schering Hold Hep C Lead, But Others Look To Deal Themselves In" - Pink Sheet, 20 April, 2009., p. 14).

Ribavirin and peginterferon produce sustained virological response - undetectable levels of virus after six months of therapy - in roughly half of HCV patients, but over a 48-week treatment period. Interferon also features a significant side-effect profile, which can include flu-like symptoms for the duration of therapy.

Roche said early INFORM-1 data offer hope for an interferon-free HCV regimen as well as potential for a shorter regimen using interferon at more potent doses.

Although Vertex and Schering-Plough have advanced protease inhibitors for HCV further along than Roche's R7227, the interim INFORM-1 results may give the Swiss pharma a perceived lead in the STAT-C combination competition. Roche licensed R7227 from InterMune in 2006 (² [See Deal]) and R7128 from Pharmasset in 2004 (³ [See Deal]).

"The INFORM-1 data met our expectations and represented the most exciting and provocative data at EASL," Lazard Capital analyst Terence Flynn wrote in an April 27 note.

Howard Liang of Leerink Swank showed similar enthusiasm, calling the trial data "the most significant" presented at the conference in his own April 27 note.

Malte Schutz, Roche's Senior Director of Disease Area Management, Virology, said in an interview that his company sees lack of resistance as one of the key attributes the 7227/7128 combination could offer. Resistance to a protease inhibitor can occur easily, he explained, but when combined with a nucleoside polymerase inhibitor, it is much harder for the virus to develop resistance.

"Adding a drug with a high barrier to resistance to a protease inhibitor should greatly decrease the development of resistance toward those drugs, and we hope this effect is more pronounced when you combine a nucleoside with a protease as opposed to a non-nucleoside, because the non-nucs are actually quite vulnerable when it comes to development of resistance," Schutz said. "They tend to have a narrower focus when it comes to activity."

Safety Benefits Of Nucs Versus Non-Nucs Debated

The question of whether nucleosides or non-nucleosides offer more promise in hepatitis C should play a key role in developing a successful combination therapy, with many in the industry leaning toward the non-nucs because they often produce a cleaner safety profile. The non-nucs in development, however, only work in HCV genotype 1, while the nucs are effective across all genotypes of the virus.

Because of this, the clean safety record so far in INFORM-1 has been a crucial success for Roche and its partners. Roche reported there were no serious adverse events reported during the initial stage of the double-blind, ascending dose trial.

This is just the start of demonstrating safety for '7128 and the combination therapy, however, as numerous polymerase inhibitors have been abandoned after producing poor safety results in Phase II. Among these is R1626, for which Roche halted development last October after a Phase IIb trial produced "new and unexpected safety findings" (⁴ Also see "Roche’s HCV Changes Boost Pharmasset Compound" - Pink Sheet, 21 October, 2008.).

Schutz said the 14-day regimen was used because safety was the primary concern in the trial's first stage. All patients then were given the option to begin a standard of care regimen, with Roche continuing to track their viral levels.

"If you look at the study design carefully, you'll see it is driven by safety considerations," he said. "One of those considerations was the treatment duration. Initially [we kept it] really short so we could get a readout on drug interactions, on the types of antiviral effects we see, but even more importantly how well it is tolerated."

For the highest doses tested in INFORM-1, median reduction in viral load levels ranged -4.8 log10 to -5.2log10. The two drugs produced sustained viral load reductions over the dosing period with 63 percent of patients' viral levels falling below the quantification limit according to the diagnostic assay used. In addition, 25 percent had undetectable levels of virus in their blood at the end of the treatment period, Roche reported. The low-dose cohort produced mean viral load reductions of 3.9 log10.

Meanwhile, early low-dosing results also showed the combination produced viral reductions 0.6 log10 greater compared to the study drugs administered as monotherapy, suggesting an additive effect for the combination, Roche stated.

Going forward, Roche will test the combination in treatment-experienced patients, as well as in trials with 28-week duration and in tandem with ribavirin. The next stage, testing the combination in treatment-experienced patients, will involve null-responders - patients who did not show significant viral load reduction while on the standard of care - and non-responders - those who did not attain SVR.

In addition, Roche will study twice-daily dosing of '7227, as well as higher total daily dosages (600 mg and 900 mg twice-daily).

Pharmasset meanwhile has advanced '7128 into a Phase IIb study, along with standard of care in treatment-naïve patients. Dosing of the first patient in this trial, announced April 24, triggered a $10 million milestone payment to the biotech from Roche.

In February, InterMune reported data from a Phase Ib study of '7227 with standard of care. After 14 days of therapy, the triple combination produced a median change in HCV RNA from baseline exceeding 5 log10 in five of the study's six cohorts. On April 24, InterMune announced it will initiate a Phase IIb study of the triple combination therapy this summer.

- Joseph Haas (j.haas@elsevier.com)

INFORM-1 Data Show Potential Efficacy And Safety Of Roche HCV Combo

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