By Lisa Seachrist
SILVER SPRING, Md. -- An FDA advisory panel voted unanimously to recommend that the agency approve NeXstar Pharmaceuticals Inc.'s AmBisome for the treatment of suspected fungal infections in patients with fever of unknown origin.
NeXstar's stock (NASDAQ:NXTR) did not trade Wednesday. On Tuesday it closed at $15.25.
The Antiviral Drugs Advisory Committee determined by a 7-to-0 vote that AmBisome -- a liposomal formulation of the antifungal agent amphotericin B -- was as safe and effective as amphotericin B in treating the potentially fatal invasive fungal infection that strikes patients with compromised immune systems.
"We are extremely happy that the committee unanimously agreed that AmBisome was as good as the gold standard for treating [these] patients," said Jerry Johnson, of Fujisawa USA Inc., of Deerfield, Ill., which holds U.S. rights to AmBisome and served as the sponsor for the new drug application. "It is a very important step toward approval."
Should AmBisome gain approval, it will join two other liposomal preparations of amphotericin B -- The Liposome Co.'s Abelcet and Sequus Pharmaceutical's Amphotec -- on the market. It will, however, be the only preparation to obtain labeling for this indication.
Invasive fungal infections are particularly common among patients suffering from neutropenia, or low white blood cell counts, as the result of AIDS, chemotherapy or other factors. Typically, these infections begin with a fever that fails to respond to broad spectrum antibiotics. By the time a physician confirms a diagnosis of a fungal infection, it can be too late to effectively treat a patient. So, physicians must treat patients based on the likelihood that they have a fungal infection.
For approximately 30 years, amphotericin B has been considered an effective treatment for these fungal infections, curing about 50 percent of them. However, it has a number of side effects, including potentially irreversible kidney damage, that make it less than an ideal drug.
Lipid formulations of the drug are designed to lower the frequency of adverse side effects, ranging from fever, chills and nausea to kidney damage, by releasing the drug directly to the fungal cells. This strategy allows physicians to administer more active ingredient -- amphotericin B -- to the patient.
Fujisawa presented data testing AmBisome in neutropenic patients with fever against amphotericin B. The company gave 343 patients infusions of AmBisome and 344 patients infusions of amphotericin B; 171 of the AmBisome patients and 169 of the amphotericin B-treated patients were considered to have "successful" resolutions of their fever. The endpoint was based on a composite of factors, including eradication of fever, neutropenia and suffering no adverse events.
The company also showed that patients receiving AmBisome suffered less fever, chills and nausea and had less indication of kidney damage than those on amphotericin B.
"It appears this was a rigorously designed study using the best advice that was available at the time," said Scott Hammer, panel chair and associate professor of medicine at Harvard Medical School, in Boston. "AmBisome is at least comparable and may be superior to amphotericin B."
However, the committee did take issue with the fact that not all of the fungal infections were confirmed in the study. As a result, the data seemed to indicate that, for patients whose doctors didn't clearly identify a fungal infection, AmBisome treatment resulted in a worse outcome than amphotericin B. The committee on the whole felt that result didn't jeopardize AmBisome's chances for approval, but noted that future clinical trials in these patients should clearly establish whether a patient had a fungal infection rather than just a "presumed" infection, or at the very least should clearly define what constitutes a presumptive infection.
"We may be seeing a situation where AmBisome activity actually makes it difficult to diagnose fungal infections," said Brian Wong, chief of infectious disease at the Veteran's Affairs Healthcare System, in West Haven, Conn.
The agency also asked the committee to recommend appropriate designs for clinical trials for this indication noting that the sponsor had used a composite endpoint rather than a single primary endpoint in this trial.
"Personally, I don't think you can get away from a composite endpoint in this patient population," Hammer said. "But you have to include a pre-specified definition of a presumptive infection and you should separate safety issues from efficacy issues."
While under no obligation to follow the advice of its advisory committee, the agency usually does. David Feigal, director of the Office of Drug Evaluation IV, indicated that approval is likely, stating that the agency believed that the sponsor has demonstrated that AmBisome is equivalent to amphotericin B.
Patrick Mahaffy, president and CEO of NeXstar in Boulder, Colo., told BioWorld Today that he "expects AmBisome to become first-line therapy in these patients.
Don Yarson, vice president of sales and marketing for The Liposome Co., doesn't think that is likely. Yarson noted that liposomal formulations are terrifically expensive in comparison to amphotericin B. He said that his strategy in marketing Abelcet is to offer the drug as a safer alternative to amphotericin B when patients appear to be suffering kidney damage or other adverse effects. *