Hepatitis B - pradefovir
The hepatitis B virus causes acute liver infection, and in many of those infected the disease becomes chronic. The symptoms of the acute form are generally mild and the patient may not even notice them, although some can develop fulminant hepatic failure, which requires a liver transplant.
The hepatitis B virus causes acute liver infection, and in many of those infected the disease becomes chronic. The symptoms of the acute form are generally mild and the patient may not even notice them, although some can develop fulminant hepatic failure, which requires a liver transplant.
In chronic patients, liver disease may be minimal and there may be no complications, but some will develop cirrhosis, and there is an increased risk of liver cancer.
While infection can be prevented by vaccination, once the disease develops it can sometimes be cleared by drug treatment. Initially, this focused on interferons, but these have the disadvantage of being expensive and not orally available. More recently, antiviral drugs have been used to treat it, at first drugs originally designed for HIV infection, and now there are specific hepatitis B antivirals.
A potential new drug targeted at hepatitis B, pradefovir, was developed by Metabasis Therapeutics, and has been licensed to Schering-Plough.1 It is prodrug for the acyclic phosphonate adenine analogue adefovir which inhibits hepatitis B reverse transcriptase, but its poor intestinal permeability means its oral bioavailability is low. It is activated by CYP3A4 mediated oxidation, and has improved properties over the parent adefovir.
A total of 40 chronic hepatitis B patients were given the drug in oral doses of 5, 10, 30 or 60mg/day for 28 days in a placebo-controlled, dose escalation study to look at its safety, tolerability and pharmacokinetics.2 It was well tolerated and most of the adverse events were mild, and similar across those given the drug and placebo. It was absorbed rapidly, and quickly converted into adefovir, and all doses produced significant decreases in serum hepatitis B viral DNA. A similar trial was also carried out in 45 Asian chronic hepatitis B patients, and again adverse events were mild and all doses reduced serum hepatitis B viral DNA levels.3
A multicentre randomised open label parallel group Phase II trial has been carried out in 244 adult Asian patients with compensated hepatitis B infection.4 Subjects were given 5, 10, 20 or 30mg daily oral doses of pradefovir or 10mg/day of the earlier prodrug adefovir dipivoxil for 48 weeks. Most adverse events were mild, and were most common in those given the highest dose of pradefovir. These included headache, dyspepsia, diarrhoea and upper respiratory tract infections. Of those given pradefovir, 45%, 63%, 56% and 71% of patients given the respective increasing doses had their hepatitis B viral DNA levels reduced below 400 copies/ml, compared with 36% of those given adefovir dipivoxil. Trials are continuing.