The Food and Drug Administration has given approval to a new drug to treat chronic hepatitis B (HBV). Entecavir, to be marketed as Baraclude, will be available in tablet or oral solution form, says drugmaker Bristol-Myers Squibb.
The FDA Antiviral Drugs Advisory Committee voted unanimously on March 11 to recommend approval of the medication.
Pending the agency's stamp of approval at the end of the month, the medication will then be made available to patients "within several weeks" after that, explained Kathy Baum, spokesperson for the drug's maker, Bristol-Myers Squibb.
Blocking an HBV Enzyme
The oral medication is a nucleoside analog, similar to the already available Epivir-HBV (lamivudine/GlaxoSmithKline) and Hepsera (adefovir dipivoxil/Gilead Sciences). It works by disrupting the activity of an enzyme the helps the hepatitis B virus replicate.1 It was given 6-month Priority Review Status by the FDA, a status reserved for investigational medicines that may address unmet medical needs.
"Bristol-Myers Squibb is dedicated to conducting research and developing therapies designed to aid in the fight against serious diseases with significant unmet medical needs," said Elliott Sigal, MD, PhD, Chief Scientific Officer and President of the Pharmaceutical Research Institute at Bristol-Myers Squibb. "Our global Baraclude clinical program spans five continents, and we are committed to advancing treatment for this disease around the world."
Head-to-Head Analysis
The FDA panel reviewed data from a clinical development program involving Baraclude. The trials compared the drug to Epivir-HBV in more than 2,300 patients with both chronic HBV infection and evidence of active liver inflammation. The program consisted of three Phase III clinical trials. The first study2 compared Baraclude with Epivir in patients with chronic hepatitis B. The second3 compared the two medications in patients with HBV e antigen negative chronic hepatitis B, which has been linked with a mutant form of HBV.4 The final trial5 evaluated patients with lamivudine-refractory HBV e antigen positive chronic hepatitis B who were either switched directly to Baraclude or continued to receive lamivudine.
In the first trial,2 after 48 weeks of treatment with either Baraclude or lamivudine, nearly two-thirds of patients taking Baraclude saw improvements in the appearance of their liver compared to 62 percent of those taking lamivudine. In the second trial,3 70 percent of those taking Baraclude saw histologic improvement after 48 weeks compared to 61 percent of those in the lamivudine group. In the final trial,5 55 percent of Baraclude saw improvement in the appearance of their livers compared to 28 percent of those taking lamivudine. In all three studies, those taking Baraclude also saw significantly greater reductions in viral load compared to those taking Epivir. (-6.98 vs -5.46 reduction in HBV DNA from baseline in those taking entecavir versus lamivudine, respectively,2 -5.20 versus -4.66 reduction in HBV DINA from baseline in the entecavir versus lamivudine group, respectively,3 and -5.14 versus -0.48 reduction in HBV DNA from baseline in those taking entecavir compared to those taking Epivir, respectively5)
'First Line Therapy' Labeling
"I think that the drug should be labeled for first line therapy, and I think that it will be an important addition for the treatment of those patients," said FDA panel member Kenneth Sherman, MD, PhD, in the division of Digestive Diseases at the University of Cincinnati, at the committee's March 11 meeting.
In the three trials, the most common side effects reported were headache, fatigue, diarrhea, and dyspepsia (indigestion).
The committee's vote to approve Baraclude came after careful consideration of data suggesting that the medication caused cancer in mice at maximum tolerated doses. Still, the panel decided its efficacy outweighed any safety concerns. "I've heard quite universal opinion that there is a favorable risk/benefit for the drug entecavir," said committee chair Janet Englund, MD, a pediatric infectious disease specialist at Children's Hospital and Regional Medical Center in Seattle.
The committee did not find a significant enough risk of tumor growth in the animal studies to warrant a black box warning. In addition, Bristol-Myers Squibb plans to launch a post-marketing safety and efficacy randomized clinical trial involving more than 12,000 patients taking Baraclude.
"We are committed to a large, long-term study," Baum said. "I know we're still in discussions with the [FDA's] Office of Drug Safety, but I don't have any more specifics for you on it."
Patients interested in learning more about Baraclude should speak with their physicians, she said.
1. Zoulim F, Trepo C. New antiviral agents for the therapy of chronic hepatitis B virus infection. Intervirology 1999;42(2):125-44.
2. Chang TT, Gish R, de Man R et al. Entecavir is superior to lamivudine for the treatment of HBeAg(+) chronic hepatitis B: results of Phase III study ETV-022 in nucleoside-naïve patients. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2004 Oct 29 – Nov 2. Boston, MA.
3. Shouval D, Lai CL, Cheinquer H et al. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside naïve HBeAg(-) chronic hepatitis B: results of Phase III trial ETV-027. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2004 Oct 29 – Nov 2. Boston, MA.
4. Lagget M, Rizzetto M. Current pharmacotherapy for the treatment of chronic hepatitis B. Expert Opin Pharmacother 2003 Oct;4(10):1821-7.
5. Sherman M, Yurdaydin C, Sollano J et al. Entecavir is superior to continued lamivudine for the treatment of lamivudine-refractory, HBeAg(+) chronic hepatitis B: results of Phase III study ETV-026. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2004 Oct 29 – Nov 2. Boston, MA.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
Published March 23, 2005
