Entecavir approved for first-line hepatitis B treatment

April 2005

The FDA recently approved the oral hepatitis B antiviral entecavir (Baraclude, Bristol-Myers Squibb) as first-line treatment for chronic hepatitis B virus (HBV).

Entecavir is a nucleoside analogue indicated for the treatment of chronic HBV in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Indications are based on histologic, virologic, biochemical and serologic responses of HBV patients after one year of treatment.

Treatment recommendations indicate dosage of a single 0.5 mg tablet once a day for chronic hepatitis B naive patients, and a one 1 mg tablet once a day for patients experiencing resistance to lamivudine (Epivir, GlaxoSmithKline).

The drug should be available in the United States as early as April 8, 2005.

Clinical development data

This approval comes after the FDA’s Antiviral Drugs Advisory Committee unanimously recommended approval. The committee based its decision upon review of pre-clinical and clinical data presented by the manufacturer. The committee also discussed plans for a long-term efficacy and safety program.

The committee reviewed data from the entecavir clinical development program, the first actively controlled trials of antivirals in chronic HBV.

Clinical trials were designed to compare entecavir to lamivudine, the most commonly used oral HBV therapy in the United States in adult patients with both chronic HBV and evidence of active liver inflammation.

More than 2,300 patients from five continents participated in the clinical program.

A variety of different patients with chronic HBV were studied, including both hepatitis Be antigen-positive (HBeAg+), HBeAg-negative (HBeAg-), nucleoside-naive patients and lamivudine-refractory patients.

The phase-3 data included more than 1,500 patients in three major studies.

The first was AI463-022, which compared entecavir to treatment with lamivudine in nucleoside-naive, HBeAg+ chronic HBV. The second study, AI463-027, compared entecavir to lamivudine in nucleoside-naive patients with HBeAg- chronic HBV and the last, AI463-026, evaluated patients with lamivudine-refractory HBeAg+ chronic HBV who were either switched to entecavir or continued to receive lamivudine.

The results indicated that entecavir demonstrated “significant histological improvement and significantly reduced viral load versus lamivudine with a similar safety profile in these three studies at 48 weeks,” according to a Bristol-Myers Squibb statement.

In these three trials, the most common adverse events of moderate to severe intensity that occurred in greater than or equal to 1% of patients treated with entecavir were headache, fatigue, diarrhea and dyspepsia.

The committee discussed the issue of tumor growth in rodents at maximum tolerated doses and whether it should impact entecavir’s indication. Members agreed that the superior efficacy and similar safety profile, when compared to lamivudine, outweighed any potential risk of carcinogenicity.

The next step

Bristol-Myers Squibb proposed a post-marketing randomized study of 12,500 patients to detect longer-term cancer risk.

The new drug application (NDA) for this indication was submitted to the FDA on Sept. 29, 2004 and was granted a six-month Priority Review status.

According to the FDA, limited data about entecavir use in patients co-infected with HBV and HIV who received prior lamivudine therapy are available on the label based on study AI463-038.

More than half a million people worldwide die each year from primary liver cancer, and up to 80% of these liver cancers are caused by chronic HBV.

In the United States, 12 million people (one out of 20) have acquired HBV, and more than 5,000 Americans die from HBV-related liver complications each year. Of those individuals, more than 1 million people have developed chronic HBV and are at highest risk of death from cirrhosis and liver cancer.

The Department of Health and Human Services recently added HBV to its list of known human carcinogens.