By Randall Osborne
West Coast Editor
Gilead Sciences Inc.¿s adefovir dipivoxil came out of a pilot study in 29 patients looking strong against chronic, lamivudine-resistant hepatitis B in patients who also are infected with HIV, the condition for which the reverse transcriptase inhibitor originally was investigated.
Published in the Sept. 1 issue of The Lancet, results from the independent, open-label study showed 10 mg of the drug once daily reduced HBV in DNA by 4.01 1 0.17 log10 copies/mL (p<0.0001) at 48 weeks.
¿It¿s about in line with what we¿ve seen in other studies,¿ said Eric Ende, analyst with Banc of America Securities in New York. He pointed to interim data disclosed in June from one of two Phase III studies with adefovir dipivoxil in chronic hepatitis B patients, noting The Lancet article ¿confirms what we¿ve been thinking all along.¿ (See BioWorld Today, June 25, 2001.)
John Milligan, vice president of corporate development at Foster City, Calif.-based Gilead, acknowledged that the positive outcome in the pilot study was about the same as the Phase III trial, but said the co-infected, lamivudine-treated HIV group in the pilot study made it especially significant.
¿This is an important patient population, and a highly unmet medical need,¿ he said. ¿Also, this was the first time we¿d looked at patient populations for the long term that weren¿t taking other medications, like cyclosporin.¿
Adefovir dipivoxil was well tolerated in the pilot study, and worked no matter how many lamivudine-associated resistance mutations had developed, or in what pattern, Gilead said. No HBV or HIV resistance mutations showed up during the 48 weeks of treatment. Lamivudine and alpha-interferon are the current treatments for HBV.
About 10 percent of HIV-infected patients also are infected with HBV, which reduces their survival rate. Half of such patients develop HBV resistance to lamivudine after two years. After four years, the number rises to 90 percent. Even in HBV patients with competent immune systems, resistance develops in 15 percent to 32 percent of those treated with lamivudine.
Gilead expects to file for regulatory approval of adefovir dipivoxil for HBV in the first half of 2002. The drug has not fared as well as a treatment for HIV alone. Two years ago, an FDA advisory panel refused to endorse it for that indication. (See BioWorld Today, Nov. 2, 1999, and June 25, 2001.)
Ende said an ¿important thing to look for¿ is kidney toxicity. ¿That was the problem before, and there wasn¿t any [in the more recent trials],¿ he said.
Milligan acknowledged ¿that it was the toxicity that led us to discontinue the drug at the 120-mg dose.¿ The HIV program with adefovir dipivoxil ¿has been completely terminated,¿ he added.
In November, Gilead will present more complete data from the Phase III HBV study than was disclosed in June, Milligan said. Liver histology, another key factor, had improved in the Phase III study, and ¿we¿re starting to analyze liver biopsies done on some patients in the pilot study,¿ Milligan said.
Also due for the spotlight shortly is another Gilead drug for HIV, Viread (tenofovir disoproxil fumarate), for which the company submitted a new drug application in May. Viread is slated for review in early October by the FDA¿s Antiviral Advisory Committee, and Gilead will offer data from a Phase III study later this month at the Interscience Conference on Antimicrobial Agents.
Viread, a blocker of the reverse transcriptase enzyme in tablet form, is ¿a bigger product, and more near term,¿ Ende noted.
Already approved for marketing are Gilead¿s AmBisome, for systemic fungal infections; Tamiflu, for the flu; DaunoXome, for HIV-associated Kaposi¿s sarcoma; and Vistide, for AIDS-related cytomegalovirus.