By Mary Welch
Immunex Corp's hunch that Leukine (sargramostim), its white blood cell booster for cancer, may be effective against HIV seems to be on target, according to a Phase III study.
"Right now it is approved for five indications in cancer care," said Cathy Anderson, communications consultant for the Seattle-based company. "But we always knew that Leukine had more potential. There's a whole cascade of immune cells that Leukine stimulates, so we started looking at Leukine to see if and how it could play a role in HIV."
Leukine, a yeast-derived granulocyte macrophage colony stimulating factor, was used in a 105-person Phase III study of AIDS patients with CD4 T cell counts of less than 300. The test, done in Brazil, studied how Leukine, along with AZT or with a combination of nucleoside therapies, would affect patients' CD4 T cell counts and viral load.
AZT, a reverse transcriptase inhibitor, is marketed by Glaxo Wellcome plc, of London.
CD4 T cells are crucial immune system cells that are progressively depleted by HIV. A healthy person has a CD4 T cell count of more than 1,200.
Results of the Leukine study, which were reported at the 12th World AIDS Conference in Geneva, showed the Immunex drug helped reduce viral load when used with AZT alone or with combination therapy.
In fact, patients receiving Leukine showed a 69 percent reduction in viral load, compared to a 2 percent reduction in the placebo group, which received antiretroviral drugs without Leukine.
In addition, Leukine-receiving patients had an increase of 30 percent or more in CD4 T cell counts during therapy. Eighty percent reached this level, compared with 58 percent in the placebo group.
"The study showed that Leukine worked with AZT and the other nucleosides and got a reduction in viral loads and increased the number of CD4 T cells. What we think this suggests is that Leukine helps AZT's intracellular activity. It may boost the AZT action and that of the other nucleoside analogs," Anderson said.
This completed study is part of a continuing clinical development program exploring Leukine in HIV. Data from a second, 300-person trial at 48 U.S. sites will be finished at the end of next year. That Phase III study is looking at what role the drug may have in eradicating HIV.
Earlier tests show Leukine may block and decrease the number of co-receptors necessary for HIV entry into a cell.
"Even when [standard] treatment has reduced the virus in the body to undetectable levels, there are still some latent traces of the virus around, in the brain and in the macrophage cells (the immune system's scavenger cells)," Anderson said. "We're looking at how to protect these cells from HIV and also if stimulating them can help eradicate the virus."
Preclinical tests indicated Leukine-treated macrophage cells stop expressing two chemokine receptors (CCR5 and CXCR4) that HIV needs to invade the macrophage cell. In fact, the Leukine-treated macrophages showed a 70- to 100-fold decrease in entry of HIV.
These treated cells also expressed beta chemokine, which blocked the same receptors on nearby uninfected T cells, again denying entrance of the virus.
Leukine is marketed for bone-marrow transplantation, acute myelogenous leukemia, peripheral blood progenitor cell mobilization and post-transplantation support.
It first came on the market in 1991. Immunex reported 1997 Leukine sales of $52.7 million, a 22 percent increase over 1996 sales. For the first quarter of 1998, which ended March 31, Leukine posted sales of $15.1 million, a 16 percent increase over the same period last year.
Immunex's shares (NASDAQ:IMNX) closed Tuesday at $66.25, up $1.188.
In other news from the Geneva AIDS conference:
* Vertex Pharmaceuticals Inc., of Cambridge, Mass., and Glaxo Wellcome plc, of London, reported that Vertex's second-generation protease inhibitor, amprenavir, might help recover the immune systems of HIV patients. Data showed amprenavir, in combination with abacavir (a nucleoside reverse transcriptase inhibitor developed by Glaxo), brought about a normalization of the ratio of CD4 cells to CD8 cells (white blood cells) in lymph nodes. This balance suggests that the abnormal activation of the immune system in the lymph nodes induced by HIV may have been suppressed. Amprenavir is in Phase III development and is being tested for use in treating adults and children.
* Cell Genesys Inc., of Foster City, Calif., reported that its AIDS gene therapy showed decreased levels of HIV in gastrointestinal lymphoid tissue in four out of five patients. The therapy involves modifying a patent's T cells to attack HIV-infected cells. The company's Phase II trial, with more than 60 patients who failed antiviral drug therapy, showed decrease of the virus in the tissue and evidence of antiviral activity in the blood. Most importantly, the therapy demonstrated that the modified T cells remained healthy for at least 100 days after infusion back into the body.
* E.I. DuPont & Co. Inc., of Wilmington, Del., reported that Sustiva, in combination with a standard three-drug regimen, suppressed HIV levels to below quantifiable amounts in a significantly greater percentage of patients than the three-drug regimen alone. Sustiva is a once-daily non-nucleoside reverse transcriptase inhibitor. It was given in combination with the protease inhibitor Crixivan (indinavir) and two nucleoside analogues. DuPont also reported Sustiva in combination with Viracept, another protease inhibitor, reduced viral load and boosted CD4 cell counts. Crixivan is marketed by Merck & Co. Inc., of Whitehouse Station, N.J. Viracept is sold by Agouron Pharmaceuticals Inc., of La Jolla, Calif.
* Ligand Pharmaceuticals Inc., of San Diego, Calif., reported that Panretin gel (alitretinoin) is clinically effective in treating dermal lesions of AIDS-related Kaposi's sarcoma (KS) in up to 50 percent of the patients studied in a Phase III trial. Patients treated with the Panretin gel were six times more likely to have a complete or partial regression of KS lesions compared with patients receiving a placebo. The data reported at the AIDS conference was used to support a new drug application the company submitted to the FDA in May. *