By Randall Osborne
Glaxo Wellcome plc submitted a total of three new drug applications (NDAs) with the FDA for two nucleoside analogue reverse transcriptase inhibitors: one NDA for Epivir (lamivudine) against chronic hepatitis B; and two for Ziagen (abacavir) against HIV, in adult and pediatric formulations.
"We feel very strongly about trying to develop formulas for children," said Jennifer McMillan, spokeswoman for London-based Glaxo. "The pediatric formulations of HIV drugs historically have lagged behind."
Epivir, also known as 3TC when used as an AIDS treatment, has been approved for the hepatitis B indication by 30 regulatory agencies, in China, Japan, Canada and the European Union. Glaxo's partner in Epivir to treat hepatitis B is BioChem Pharma, of Laval, Quebec.
Christine Lennon, spokeswoman for BioChem, said the company is "hopeful it will meet a large need out there, since it's a once-a-day oral and lowers the levels of the virus. We're not at a loss for a market."
About 350 million people are chronically infected with hepatitis B, which is responsible for more than 80 percent of all cases of primary liver cancer. Hepatitis B, the ninth most common cause of death worldwide, accounts for 2 million deaths per year.
With potential earnings for Glaxo of $2 billion per year, Epivir has proven in Phase III trial to slow liver damage and lower the level of virus in the bloodstream. Patients in earlier Phase II trials showed sustained benefit for at least two years. (See BioWorld Today, May 21, 1998, p.2, and April 11, 1997, p. 1.)
Glaxo has a history with lamivudine — and with double NDA submissions. In 1995, the company submitted NDAs for adult and pediatric formulations of lamivudine against HIV, McMillan said. Now, Glaxo, which discovered and developed Ziagen, is asking for FDA approval of both formulations of Ziagen.
"It's a daunting task, implementing trials and getting the data back, and to have the two formulations creates additional challenges," McMillan said.
Adult patients using Ziagen take one 300 milligram tablet twice daily. Children are given a strawberry/banana flavored liquid at doses of 8 milligrams per kilogram of body weight, twice daily. The liquid formulation is also provided for adults who cannot take solid medication. Ziagen can be taken with or without food, and does not require fluids to keep the patient hydrated.
Efficacy and safety data related to Ziagen will be provided in 27 presentations at next week's 12th World AIDS Conference in Geneva, Switzerland. Preliminary data will be included from pivotal Phase III studies of Ziagen combined with Epivir and Retrovir (zidovudine, also known as AZT) in adults and children.
Almost 8,000 patients have been treated with Ziagen through clinical trials, open-label access programs and a recently begun expanded-access program.
Direct comparisons are not final, but data from 16-week surrogate endpoint studies indicate that in some previously untreated patients, regimens with Ziagen achieve a level of antiviral activity often gained by those containing a protease inhibitor and two nucleosides.
Outsmarting the virus has proven anything but simple, McMillan said, and the proliferation of HIV drugs is a testament to the difficulty.
"What we're trying to do is find as many ways as we can," she said. "If you start with one combination, say, of nucleoside analogues, switching at least two drugs in your regimen gives you another option."
Glaxo also is developing amprenavir, an anti-HIV protease inhibitor, with Vertex Pharmaceuticals Inc., of Cambridge, Mass. The drug — now in Phase III trials — performed positively in two Phase II studies: one pairing it with approved protease inhibitors and the other combining amprenavir with Glaxo's Ziagen. (See BioWorld Today, Feb. 3, 1998, p. 1.)
"It's a bit behind, in terms of time frame, from [Ziagen], but it did not take a back seat," McMillan told BioWorld Today. "It's just a different development program. Things happen to either speed up or slow down the process, including how quickly you can recruit patients for clinical trials."
Data from amprenavir's trials will be presented next week in Geneva, she added. *