September 23, 2010

Weight-Based Dosing Best for New HCV Drug

By Michael Smith, North American Correspondent, MedPage Today Published: September 23, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

When given in doses based on weight, an investigational prodrug of ribavirin had efficacy comparable to ribavirin in chronic hepatitis C but with less hemolytic anemia, researchers reported.

In a phase IIb trial, the drug -- taribavirin -- yielded early response rates that were statistically identical with those achieved with ribavirin when both drugs were given with pegylated interferon alfa-2b, according to Fred Poordad, MD, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

At the same time, two of the tested doses of the drug caused significantly less anemia (at P<0.05) than ribavirin, they reported online in Hepatology.

Taribavirin, formerly known as viramidine, is a nucleoside analogue and oral prodrug of ribavirin that is converted to ribavirin in the body. But its structural difference from the older drug means that it is less likely to enter and damage red blood cells, the researchers noted.

Indeed, in earlier studies using a fixed dose of taribavirin, that benefit was demonstrated, but efficacy was inferior to that of ribavirin, they said. Analysis suggested that the fixed-dose approach, as well as selection of inadequate doses, was responsible for the lack of efficacy.

To clarify the issue, Poordad and colleagues tested three doses of taribavirin -- 20, 25, or 30 mg per kilogram a day -- against ribavirin at 800 to 1,400 mg a day in 278 treatment-naïve patients with genotype 1 hepatitis C.

The primary efficacy endpoint was early virologic response, defined as the proportion of patients with at least a two-log decrease from baseline in serum hepatitis C RNA levels after two weeks of therapy. The researchers also looked at sustained virologic response after 48 weeks of therapy.

The main safety endpoint was the proportion of patients with hemoglobin less than 10 grams per deciliter at any time during the study.

The researchers found that:

• 43 patients in the 20-mg/kg (64.2%) had an early virologic response, as did 40 (57.1%) and 37 (54.4%) in the 25- and 30-mg/kg arms.

• At the same time, 36 ribavirin patients (51.4%) had an early virologic response, not significantly different from any of the taribavirin arms.

• Fewer patients on taribavirin required dose reductions (13% to 28%, depending on the dose) compared with 32% of ribavirin.

• The anemia rates were 13.4% and 15.7%, respectively, in the 20- and 30-mg/kg taribavirin arms, compared with 32.9% among ribavirin patients, significantly different at P<0.05 in both cases.

All told, 41% of patients in the three taribavirin arms completed treatment and follow-up, compared with 36% of the ribavirin patients, with 29% of those who dropped out citing lack of response as the reason and 20% citing adverse events.

The data suggest the drug "may be an effective agent" to substitute for ribavirin in the future, the researchers concluded.

On the other hand, the treatment picture is changing rapidly and could leave the drug with a "finite life cycle," according to Paul Kwo, MD and Rakesh Vinayek, MBBS, both of Indiana University in Indianapolis.

Taribavirin "may have a role in populations particularly sensitive to ribavirin-related anemia," they said in an accompanying editorial, and might be a "welcome addition" to the list of drugs available to treat hepatitis C.

But several clinical trials are beginning with combinations of direct-acting antiviral agents, with and without pegylated interferon, and protease inhibitors under development could also have lower rates of anemia, they said.

For those reasons, "the role of (taribavirin) remains less precisely defined," they argued.

The study was supported by Valeant Pharmaceuticals, which is developing the drug.

Poordad said he had no financial conflicts to report. Several authors are employees of the company.

Primary source: Hepatology
Source reference:
Poordad F, et al. "Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C" Hepatology 2010; DOI: 10.1002/hep.23827.

Additional source: Hepatology
Source reference:
Kwo PY, Vinayek R. "The next step for taribavirin" Hepatology 2010; DOI: 10.1002/hep.2395.

Also See: Taribavirin Offers a Safe, Effective Alternative for Chronic Hepatitis C, Study Finds

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