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According to the WHO, 350-400 million individuals are chronically infected with the hepatitis B virus (HBV). Chronic infection with hepatitis viruses causes cirrhosis and hepatocellular carcinoma, both devastating diseases with few treatments and the demand for effective treatments for hepatitis infection is therefore high. Lamivudine dominates first-line therapy for HBV (see our feature on hepatitis B & C). Gilead's Adefovir prodrug (Hepsera) represent a second line option although nephrotoxicity limits its use to sub-optimal dosing. Valeant are now developing a new prodrug which employs Metabasis' technology to facilitate targeting of adefovir to the liver thus reducing the risk of adverse effects and improving efficacy.

According to the WHO, 350-400 million individuals are chronically infected with the hepatitis B virus (HBV). Chronic infection with hepatitis viruses causes cirrhosis and hepatocellular carcinoma, both devastating diseases with few treatments and the demand for effective treatments for hepatitis infection is therefore high. Lamivudine dominates first-line therapy for HBV (see our feature on hepatitis B & C).

Adefovir (PMEA) is an acyclic phosphonate analogue of adenine shown to be effective against HBV in in vitro and in vivo models. Adefovir is phosphorylated to PMEA diphosphate which is able to competitively inhibit HBV-DNA polymerase and cause DNA chain termination. The limited oral biovailability of adefovir has driven companies to develop prodrugs of this antiviral. In September, 2002, the US FDA approved one such prodrug, adefovir dipivoxil (Hepsera, Gilead) for the treatment of chronic hepatitis B infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (an indication of liver disease) or histologically active disease. The European Commission approved adefovir dipivoxil in March 2003, and by early 2004 the drug was driving annual revenues in excess of $72 million. This figure has been predicted to rise to $250 million by 2006. Adefovir dipivoxil is now the most common second line treatment for HBV when resistance to lamivudine occurs.

Despite the approval of adefovir dipivoxil some experts have expressed concern regarding its safety and indeed an earlier attempt by Gilead to gain approval for its use as a trearment of HIV infection was unsuccessful due to an insufficiently wide therapeutic window. Renal toxicity is dose limiting and prevents adefovir dipivoxil being administered at its maximal HBV antiviral dose. As an alternative to adefovir dipivoxil, the California based Valeant Pharmaceuticals are developing remofovir mesylate.

Metabasis Therapeutics discovered remofovir mesylate using its HepDirect prodrug technology and in October 2001, Valeant in-licensed the drug. HepDirect involves the development of inactive prodrugs that are activated by liver-specific enzymes allowing hepatic targeting of active drug. In the case of remofovir mesylate, conversion of the prodrug to PMEA is driven by cytochrome P4503A4, which is predominantly present in the liver. This contrasts with the activation of adefovir dipivoxil which occurs in the plasma. In a recent edition of the journal Antiviral Chemistry & Chemotherapy Lin et al evaluate the improved targeting and the safety margin of remofovir mesylate.

In an initial whole body autoradiography study, when administered orally at equal doses, Lin et al reported that labelled remofovir mesylate produced 15-fold greater levels of radioactivity in the liver than that after the administration of labelled adefovir dipivoxil. In contract renal radioactivity was 3-fold lower following remofovir mesylate dosing. This suggests markedly improved liver targeting with remofovir mesylate, a finding that was even more evident in monkeys. Although whole body autoradiography provides an indication of the distribution of test compounds it cannot distinguish between administered agents and their metabolites. Further studies were thus conducted to determine the levels of remofovir mesylate and its active metabolite, PMEA in the portal and systemic circulations.

The slow appearance of PMEA in the portal circulation provides evidence of limited intestinal prodrug activation. In contrast the ratio of remofovir mesylate to PMEA in the portal and systemic circulations suggests that activation occurs within the liver.

Toxicology studies revealed that after 28 days of treatment remofovir mesylate was without adverse effects up to 30mg/kg in rats and that in monkeys safety was acceptable at doses of up to 60mg/kg. This compares to adefovir dipivoxil, which in previous studies produced nephropathy at 12mg/kg and 25mg/kg respectively in rats and monkeys over a similar time period.

The present study therefore demonstrates the liver targeting and greater safety profile for remofovir mesylate compared to adefovir dipivoxil. Valeant initiated the first in-man study for remofovir in Europe in August 2002. Dose dependent anti-viral activity was reported and consequently Valeant filed an IND with the FDA in October 2002; a phase 2 trial was initiated in July 2004 and will compare head-to-head remofovir mesylate with adefovir dipivoxil.

Entry date Thursday, February 24, 2005

Antivir Chem Chemother. 2004 Nov;15(6):307-17.