Promising Results in Phase II Study of Treatment with Pegasys in HBEAG Positiv

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Adefovir Dipivoxil Significantly Improves Liver Function and Reduces HBV Viral Load Among Patients with Chronic Hepatitis B Virus (HBV) Infection



By Ned Brown, Pharm D



(Dallas, TX)--Gilead Sciences announced results today (11/12/01) at the 52nd AASLD meeting from a large, multinational Phase III clinical trial (study 437) which demonstrated that its experimental drug adefovir dipivoxil 10 mg significantly improved liver function and reduced levels of virus in patients with chronic hepatitis B virus (HBV) infection. Preliminary results from this study were announced on June 22, 2001.



Worldwide, there are approximately 400 million chronic carriers of HBV, of which approximately one million die each year from complications of the disease, making chronic HBV one of the 10 most common causes of death on the planet. Complications of chronic HBV include cirrhosis (scarring of the liver), liver failure and primary liver cancer (hepatocellular carcinoma).



Study 437



Forty-eight week data from Study 437 demonstrate that patients with chronic HBV infection who received adefovir dipivoxil 10 mg once daily as monotherapy experienced statistically significant improvements in liver histology, reductions in HBV DNA and ALT levels, and a higher rate of seroconversion compared with patients given placebo. Change in liver histology is an important marker of disease progression in patients with chronic HBV infection, while HBV DNA and ALT levels are indicators of disease severity. These data were discussed in an oral presentation given today (11/12/01) by Patrick Marcellin, MD.



Additional data presented yesterday (11/11/01) by Elizabeth J Heathcote, MD, at the 52nd AASLD describe results of long-term treatment (48 weeks) with adefovir dipivoxil, including the drug's effect on HBV DNA suppression, seroconversion and lack of resistance development to treatment with adefovir dipivoxil.



``A therapy's ability to improve liver histology is among the best clinical markers to measure activity against the hepatitis B virus, making the Phase III data from this study very significant for physicians and patients alike,'' said Dr. Marcellin, a clinical investigator on the study. ``These clinical trial results suggest that adefovir dipivoxil holds great potential for patients with chronic hepatitis B infection.''



Study 437 Results



Study 437 is a randomized, double-blind, placebo-controlled Phase III clinical trial evaluating the safety and efficacy of adefovir dipivoxil once daily as monotherapy compared to placebo in patients with chronic HBV infection who were hepatitis B ``e'' antigen positive. This study enrolled 515 patients in the United States, Canada, Europe, Australia and Southeast Asia. In this study, two doses of adefovir dipivoxil were evaluated, including the 10 mg dose for which Gilead intends to seek marketing approval and an exploratory 30 mg dose. During the first year of Study 437, 172 patients were randomized to receive adefovir dipivoxil 10 mg, 173 to receive adefovir dipivoxil 30 mg and 170 to receive placebo.



Liver Histology



For patients with assessable baseline biopsies, improvement in liver histology was observed in 53 percent of patients treated with adefovir dipivoxil 10 mg (n=168), compared to 25 percent of placebo-treated patients (n=161), as measured by liver biopsies (p less than 0.001). In addition to improvement in liver histology, seroconversion was observed in 12 percent of patients treated with adefovir dipivoxil 10 mg for 48 weeks, compared to six percent of patients on placebo (p=0.049). Seroconversion is defined as both the disappearance of the hepatitis B ``e'' antigen (HBe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for this antigen (HBe-antibody positive).



Decreases in HBV DNA



Reductions in HBV DNA also were observed. Following 48 weeks of treatment, patients in the adefovir dipivoxil 10 mg arm had a median reduction in HBV DNA from baseline of 3.52 log10 copies/mL (n=152), compared to a reduction of 0.55 log10 copies/mL in patients receiving placebo (n=148, p less than 0.001). This equates to a 99.97 percent reduction in circulating virus in patients on adefovir dipivoxil 10 mg treatment. Additionally, following 48 weeks of treatment with adefovir dipivoxil 10 mg, a median reduction in ALT levels of 51 IU/L was observed, compared to a reduction of 17 IU/L in the placebo group (p less than 0.0001). Forty-eight percent of patients treated with adefovir dipivoxil achieved normalization of ALT levels, compared to 16 percent of patients receiving placebo (p less than 0.001).



After 48 weeks, the study drug discontinuation rate was similar between the treatment and placebo arms, with seven percent of patients receiving adefovir dipivoxil 10 mg and eight percent of patients receiving placebo discontinuing from study. Additionally, the incidence of grade 3 and 4 laboratory abnormalities and clinical adverse events was similar between the adefovir dipivoxil 10 mg and placebo arms of this study. No patients in either the adefovir dipivoxil 10 mg or placebo groups had increases in serum creatinine of greater than or equal to 0.5 mg/dL from baseline or a serum phosphorus level less than 1.5 mg/dL, both laboratory markers of renal function, as confirmed by two consecutive laboratory assessments.



Resistance Profile



Data from a prospective, blinded genotypic analysis performed at baseline and week 48 on samples from patients in Study 437 who had detectable levels of HBV DNA suggest no resistance mutations to adefovir dipivoxil were observed after 48 weeks of therapy (n=381). Further surveillance to monitor the potential emergence of resistance mutations in patients treated with adefovir dipivoxil beyond one year is ongoing. These data will be discussed in detail in an oral presentation on 11/13/01.



Long-term Therapy with Adefovir Dipivoxil -- Clinical Results



An extension study of 39 patients with wild type and precore mutant HBV who had completed adefovir dipivoxil dose-ranging Phase II clinical trials (Studies 412 and 413) showed that long-term treatment with adefovir dipivoxil was associated with statistically significant and sustained reductions in HBV DNA. Patients were treated with adefovir dipivoxil for up to 136 weeks, receiving 5, 30 or 60 mg for the initial 12 weeks of these studies. Patients entered the extension phase first receiving adefovir dipivoxil 30 mg. That dose was later reduced to 10 mg.



Median serum HBV DNA reductions of greater than 3.0 log10 copies/mL from baseline were sustained throughout the study with a median reduction of 3.68 log10 copies/mL at week 24 (n=37, p less than 0.0001), 3.40 log10 copies/mL at week 48 (n=33, p less than 0.0001), 3.33 log10 copies/mL at week 76 (n=27, p less than 0.0001) and 3.36 log10 copies/mL at week 100 (n=23, p less than 0.0001). Twenty-one percent of patients seroconverted (n=28), based on all available data to date. The most common adverse events reported were pharyngitis, abdominal pain and headache. One patient receiving adefovir dipivoxil 30 mg experienced a mild increase in serum creatinine from baseline that remained within normal range and was reversible with discontinuation of study drug. These data were presented on 11/11/01 in a poster session (abstract 575) by Elizabeth Heathcote, MD, Toronto Western Hospital.



Long-term Therapy with Adefovir Dipivoxil -- Virology



Data from this study also demonstrate that no HBV polymerase mutations associated with adefovir resistance developed following up to 136 weeks of once-daily treatment with adefovir dipivoxil. These data were presented by Shelly Xiong, Ph.D., Gilead Sciences in a poster session (Presentation No. 40854) also on Sunday (11/11/01).



``The breadth of data presented at this conference are indicative of the important role we believe adefovir dipivoxil 10 mg may pla