Washington Editor

WASHINGTON - The FDA recently convened a meeting to address key study design issues facing drug developers in the chronic hepatitis C space, an area with a growing number of products in the pipeline.

The industry interest stems from an unmet medical need for many patients with certain types of the disease, in particular those with HCV genotype 1, who don't respond well to standard of care, and other nonresponders.

Genotype 1 patients treated with pegylated interferon and ribavirin in combination, the typical HCV drug regimen for a number of years, typically exhibit low sustained viral response rates to that therapy. In contrast, people with genotypes 2 and 3 are almost three times more likely to respond to that combination. But according to FDA estimates, about 70 percent of Americans with HCV have genotype 1, so most pharmaceutical companies are targeting them.

Other difficult-to-treat populations include patients co-infected with other viruses, often HIV/AIDS, leading to much greater hepatitis viral loads than normal; decompensated patients who have difficulty receiving interferon; and African-Americans, who frequently have genotype 1 and generally don't respond well to interferon and ribavirin.

It's difficult to design studies for all those groups, said Shelley George, the senior medical director of the antiviral firm Idenix Pharmaceuticals Inc., though the FDA is requesting that companies "adequately represent" them in their studies before filing for approval. While that could add development costs, it also could lead to broad labels upon regulatory clearance.

Among other takeaways from the Antiviral Drugs Advisory Committee meeting, FDA staffers indicated their preference for measuring all sustained viral response at the end of 18 months, though there were questions around whether measurements should be made 24 weeks after the end of treatment for all arms or 24 weeks after the end of treatment with the longest duration of therapy. Most panelists said that when a new drug is added to standard of care, and that regimen is on board throughout the treatment, 24-week sustained viral response at the end of treatment would be satisfactory.

Additional recommendations from committee members indicated their preference for sustained viral response at 24 weeks rather than 12 weeks as the primary endpoint in studies of investigational products plus standard care. Also, superiority over standard care was urged for approving any new three-drug regimen. Follow-on studies can test inferiority if the new drug shortens the length of treatment or improves side-effect profiles by replacing ribavirin, for instance.

For nonresponders or patients intolerant to the interferon-ribavirin regime, potential study endpoints include viral load suppression and histologic improvements.

Of the estimated 30 or so HCV drugs in development, a few polymerase and protease inhibitors in Phase II are exhibiting promising profiles in the eyes of several observers: Idenix's valopicitabine (NM-283), the first HCV nucleoside analogue that has been tested in more than 400 patients to date; another polymerase inhibitor, R1626 from F. Hoffmann-La Roche Ltd.; ViroPharma Inc.'s polymerase inhibitor HCV-796 that's partnered with Wyeth; and the protease inhibitor telaprevir (VX-950) from Vertex Pharmaceuticals Inc. Other late-stage drugs of interest include Albuferon (albumin-interferon alpha 2b) from Human Genome Sciences Inc. and Actilon (CPG 10101) from Coley Pharmaceutical Group Inc.

Positive data on those agents were unveiled at last weekend's meeting of the American Association for the Study of Liver Diseases in Boston, along with results on a host of other HCV drugs.

"This is the beginning of the end for the hepatitis C virus," said Douglas Dieterich, a researcher at the Mt. Sinai School of Medicine in New York, who presented findings showing that a 200-mg daily dose of valopicitabine in combination with pegylated interferon produced a mean 4.24 log¹⁰ reduction in viral load at week 24. "But it's going to take a long time - 15 years."

He told BioWorld Today that the treatment community "can't wait" to combine the new antivirals on the horizon because of their non-overlapping resistance profiles to achieve potent antiviral suppression while minimizing resistance over time. Idenix's George seconded his excitement around figuring out new combination therapies that employ those potent antivirals, "a new paradigm" in HCV treatment that follows the HIV treatment model that has made it a manageable disease by employing drug combinations with "strong drug-resistance profiles" and "potent antiviral suppression."

She told BioWorld Today that her company is open to collaboratively testing antiviral agents with valopicitabine. But admittedly, those non-interferon-based combination treatments are still on the horizon, Dieterich said, echoing the thoughts of other observers who expect these competing companies to initially look for the quickest route to market before blazing new clinical study paths for combination regimens.

The HCV stakeholder meeting provided a forum to discuss such testing. Committee members suggested that Phase IIb or later could be the right time to begin testing different classes of investigational drugs in tandem. The open dialogue included regulatory officials from the agency, industry representatives, members of the physician community, patients and their advocates.

About 3.2 million Americans are chronically infected with HCV, part of about 170 million people worldwide, and for most, there's an upside in the near-term future with one or two of the new antivirals likely to reach the market in the next couple of years.