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Michael King, Jr., Senior Biotechnology Analyst (212.356.0533)
Recap and Analysis of the Management of Chronic Hepatitis B Virus: 2006 Conference
NEW INSIGHT INTO STATE-OF-THE-ART IN CHRONIC HEPATITIS B CARE. The Management of Chronic Hepatitis B Virus Conference was held on the NIH campus in Bethesda, Maryland, from April 6-8th, 2006.and offered a unique educational program assessing current understanding of hepatitis B virus (HBV) and the optimal management of chronic hepatitis. Topics covered included the latest results from clinical trials of both marketed compounds and those still in clinical development. The conference also provided a forum for addressing the clinical, histological, and virologic endpoints of therapy. Finally, recommendations for future directions in clinical and basic science research were aired. The meeting is sponsored by the Liver Disease Research Branch of the Division of Digestive Diseases and Nutrition of NIDDK in collaboration with the American Association for the Study of Liver Disease (AASLD).
AN EVALUATION OF CURRENT OR FUTURE THERAPIES, including Bristol-Myers Squibb’s (BMY-Not Covered) Baraclude (entecavir), Gilead’s (GILD-Market Perform) Hepsera (adefovir dipivoxil), Viread (tenofovir) and Emtriva (emtricitabine), GlaxoSmithKline’s (GSK-Not Rated) Epivir_HBV (lamivudine), Idenix’s (IDIX-Not Rated) telbivudine, and the pegylated interferon product from Hoffman-LaRoche (Pegasys) alone and in combination.
1) In the opinion of the experts gathered at the conference, entecavir is clearly the leading drug on the market, providing the strongest combination of efficacy and resistance (0% at two years). In our opinion, based on this best-in-class profile, Baraclude should pick up market share in the front-line setting at the expense of Epivir-HBV. We believe the lackluster sales of Baraclude since launch stem from a combination of Bristol’s conservative marketing practices along with an aggressive price (over $8000 per year). Given this strong endorsement by the key opinion leaders, Baraclude sales may soon begin to pick up. Is it a coincidence that our weekly IMS Prescription Report shows that new Rxs for Baraclude were up 24% during the week of March 31, 2006? We think not, but the trend bears monitoring.
2) The picture was a bit mixed, but mostly positive, for the Gilead family of products. Hepsera has often been the drug of choice for the treatment of patients with lamivudine-resistant HBV due to its excellent resistance profile and good tolerability. However, Viread, which is closely related to Hepsera, has demonstrated that greater potency, less frequent resistance, and strong early suppression of HBV DNA. We would caution that these results have been produced in relatively small studies; however, most of the experts agreed that Viread is the superior drug for the treatment of HBV. Ultimately, the experts believe that Viread will supplant Hepsera in this indication. Apparently, too, does Gilead, as it began a head-to-head trial in June of 2005 of Viread and Hepsera in both HBV “e” antigen positive and negative patients. Emtricitabine, also known as Emtriva, was mentioned as a potential add-on agent by those of whom believe in combination treatment strategies. Of course, tenofovir and emtricitabine are marketed by Gilead as Truvada.
3) Lamivudine has heretofore been the dominant first-line therapy, and has also served as a benchmark in various trials of investigational agents and combination therapies. However, if not for its excellent safety profile and modest cost, lamivudine would have already been replaced by other agents due to its high incidence of resistance. Moreover, the long-term use of lamivudine monotherapy has been associated with compensatory mutations in HBV that can compromise the use of newer, more effective agents such as entecavir, adefovir and tenofovir. We anticipate that lamivduine use will eventually be reserved for use in combination with other, more potent anti-HBV agents.
4) Telbivudine has demonstrated superior efficacy in head-to-head trials against lamivudine, while retaining most, if not all, of lamivudine’s safety. However, the physicians at the conference felt that the positioning of telbivudine would be awkward, given its late arrival to the marketplace, similar resistance profile to lamivudine, and limited activity in lamivudine-resistant HBV. The experts felt that telbivudine would position itself in the market by emphasizing its seroconversion rate in “e” antigen positive patients, as well as a more favorable price structure compared to the other market leaders. The opinion was also that telbivudine could become the drug of choice in combination anti-HBV regimens to the extent that they catch on.
5) The future of pegylated interferon is heavily dependent upon geography, with European physicians favoring it and US physicians remaining skeptical. In the opinion of EU physicians, pegylated interferon remains a viable approach in the front line setting, given its robust antiviral activity, lack of resistance, and positive immune system activity. In contrast, physicians in the US will use very little pegylated interferon due to its injectable route of delivery, poor tolerability, relative lack of efficacy (essentially stated as “if three years of lamivudine equals one year of pegylated interferon, I’ll take the pills thank you very much”) and high cost.
In summary, our view of the rapidly-evolving treatment landscape for HBV, based on the opinions voiced at this conference, is as follows: oral drugs continue to dominate over interferon, entecavir and adefovir/tenofovir are beginning to emerge as the #1 and #1a therapies of choice, lamivudine begins to fade, and telbivudine becomes the drug of choice for combination therapy.
Combination Therapy May Be the Future of HBV Therapy, Although Only A Slight Consensus Emerges Due to Lack of Supporting Clinical Evidence. So far, the results seen in trials examining the combination of nucleoside(tide) drugs have been disappointing. For example, the combination of lamivudine and adefovir failed to demonstrate any clear advantage, while the telbivudine and lamivudine combination actually led to an impaired virologic response. This phenomenon could have been due to a number of factors, including the competition of the two drugs for the same polymerase or phosphorylating enzymes or for some other unknown drug interactions. Furthermore, it is possible that the excellent antiviral activity and low viral resistance profile of entecavir and tenofovir could obviate the need for combination strategies, at least in the up-front setting. In our opinion, there is still a ways to go before combination nucleoside(tide) become standard practice. Several issues still remain, including better characterization of drug-drug interactions, greater antiviral activity of a two-drug regimen vs. monotherapy has yet to be definitively proven, and more mature (i.e., 3-5 years and beyond) resistance data has yet to be gathered on entecavir and tenofovir.
HAART in HBV=HAART in HIV? Despite the similarity between HBV and HIV, HBV is a different virus (DNA in the case of HBV, vs. RNA in the case of HIV). Further, in chronic HBV infection, and especially in “e” antigen negative patients, immunologic response is a key clinical endpoint. Therefore, long-term study/monitoring is necessary for the development of combination therapy of HBV. While we expect numerous investigator-sponsored trials to commence over the next several years, we would also encourage drug companies to emulate the cooperative trials that were initiated in HIV. From an FDA perspective, the risk-reward calculus is slightly more skewed towards safety in the case of HBV, given the linger latency of the disease and the relative number of acceptable treatment options available to patients.
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