Metabasis Therapeutics has announced the initiation of a multi-center, multi- national Phase 2 study to evaluate the orally administered antiviral compound remofovir mesylate in chronic hepatitis B (HBV) infected patients.
Metabasis discovered remofovir using its HepDirect(TM) prodrug technology. In October 2001, Metabasis entered into an exclusive worldwide development and license agreement with Valeant Pharmaceuticals International, under which Valeant is primarily responsible for the clinical development and registration of remofovir.
This Phase 2 study of remofovir is an open-label, randomized, multiple oral dose study that will enroll 220 patients with compensated hepatitis B infection at approximately 20 sites in the U.S., Taiwan, Singapore and Korea. The study consists of five treatment groups: remofovir -- 5, 10, 20 and 30 mg/day, and Hepsera (adefovir dipivoxil) -- 10 mg/day. Treatment duration will be 48 weeks and an interim analysis will be conducted following 24 weeks of dosing to evaluate drug safety and efficacy and, if warranted, will be used for selection of a dose for Phase 3 studies.
Remofovir was developed using Metabasis' proprietary HepDirect technology, a broadly applicable, liver-targeting prodrug technology that was recently described in a Journal of the American Chemical Society article entitled "Design, Synthesis, and Characterization of a Series of Cytochrome P(450) 3A- Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate- Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154-5163 (2004)). A prodrug is a drug to which a chemical modification has been made that renders the target drug inactive until enzymes in the body convert it to its active form. In the case of a HepDirect prodrug, the enzyme that converts it to an active form is found predominantly in the liver. Remofovir is a HepDirect prodrug of a compound called adefovir. Adefovir is the active component of the approved hepatitis B drug Hepsera (adefovir dipivoxil). Hepsera is also a prodrug, however, it is converted to the active form predominantly in the plasma. Remofovir is designed to generate an active form of adefovir primarily in the liver, where the virus resides, while limiting exposure outside the liver. While the safety and efficacy of this approach remains to be definitively proven in the clinic, this is potentially important because while adefovir is associated with significant decreases in HBV DNA levels, it also appears to be associated with treatment limiting renal toxicity.
"We expect this new clinical trial to build on the pre-clinical and clinical results we have seen to date with remofovir," commented Dr. Paul Laikind, Metabasis' Chairman, President and CEO. "Valeant submitted an abstract to the American Association for the Study of Liver Diseases (AASLD) describing the safety, tolerance, pharmacokinetic and pharmacodynamic results from a recently completed clinical trial of remofovir in patients infected with hepatitis B virus. If the abstract is accepted, the results of this trial would be presented at the 55th Annual Meeting of the AASLD in Boston in October/November 2004. The findings from that trial led to the decision to proceed with the Phase 2 study announced today. This new study is designed to assess the maximally effective dose of remofovir and assist in dose selection for the pivotal Phase 3 studies that are expected to begin next year should the results warrant it."
Hepatitis B remains a significant medical problem that affects an estimated 300 million people worldwide and can cause severe liver damage leading to liver cirrhosis and primary liver cancer. The World Health Organization estimates that hepatitis B infection results in more than one million deaths each year worldwide.
Dr. Mark Erion, Executive Vice President of Research and Development at Metabasis stated, "In addition to representing an important milestone in the development of remofovir, the initiation of this study also gives us further confidence in the potential of our HepDirect technology. In addition to remofovir, the HepDirect technology was used to develop MB07133, a HepDirect prodrug of an oncolytic agent. MB07133 is currently being studied in patients with primary liver cancer, a deadly disease with few treatment options. The HepDirect technology is also being used in our collaboration with Merck & Co., Inc. to discover novel products for the treatment of hepatitis C. Finally, we continue to evaluate the technology and its use in certain other programs."