Gilead Sciences today announced that the European Commission has granted marketing authorisation for Hepsera™ (adefovir dipivoxil 10 mg) in all 15 member states of the European Union. Adefovir is indicated in Europe for the treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotranseferase (ALT) levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease.
More than 400 million people worldwide have chronic hepatitis B, which is caused by infection with the hepatitis B virus (HBV), and between one quarter and one third of these individuals are expected to develop progressive liver disease, such as cirrhosis and liver cancer. An estimated one million people die annually from complications of chronic hepatitis B making it one of the leading causes of death worldwide.
In July 2002, Gilead initiated an early access program to provide adefovir to chronic hepatitis B patients with 3TC-resistant virus. To date, over 1,600 patients have enrolled in the adefovir early access programmes in France, Italy, Greece, Spain, Portugal, Germany, the United Kingdom, Canada and Australia. The adefovir early access programs will continue until the drug is commercially available to patients in these countries.
Two placebo-controlled studies and a number of additional studies have evaluated adefovir for hepatitis B infection in a wide range of patients. The placebo-controlled studies included patients with compensated liver function and either "e" antigen-positive (HBeAg-positive) or "e" antigen-negative (HBeAg-negative, or precore mutant) chronic hepatitis B. The 48-week results from these two pivotal studies were published in the February 27 edition of the New England Journal of Medicine. Precore mutant hepatitis B infects up to approximately 50 percent of chronic hepatitis B carriers worldwide, and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30 and 80 percent of chronic hepatitis B patients are estimated to be infected with this strain. Adefovir also has been studied in patients who were treated with and developed resistance to 3TC, including patients wait-listed for liver transplantation, post-liver transplantation patients and patients co-infected with HIV.
In clinical studies, Adefovir reversed or slowed the progression of liver damage, reduced HBV DNA levels in the blood and increased rates of seroconversion and normalisation of ALT levels (an indicator of liver function) significantly more effectively than placebo in treatment-naïve patients and in patients with prior interferon treatment.
The adverse reactions considered at least possibly related to treatment in the first 48 weeks of therapy with adefovir were asthenia (weakness), headache, abdominal pain, nausea, flatulence, diarrhoea and dyspepsia. With extended treatment, mild to moderate, reversible, increases in serum creatinine were observed infrequently in patients with chronic hepatitis B and compensated liver disease treated with adefovir for a median of 49 weeks and a maximum of 109 weeks. Changes in serum creatinine were observed very commonly in patients with pre- and post-liver transplantation with 3TC-resistant hepatitis B and multiple risk factors for changes in renal function who were treated with adefovir for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively. Clinical and laboratory evidence of exacerbations of hepatitis has been observed after discontinuation of treatment with adefovir.
Adefovir has previously been evaluated as an anti-HIV drug at 60mg and 120mg doses, but US authorities refused licensing on the grounds that (at these doses) the risk of kidney toxicity was too profound. Gilead soon shelved plans to develop adefovir as an anti-HIV drug and instead concentrated on developing the more potent tenofovir, which received licensing as an anti-HIV drug last year.