By Randall Osborne
Aiming to use its profitable white blood cell booster, Leukine, as a treatment for AIDS, Immunex Corp. came up with positive results in two trials showing the drug may block HIV's entry into immune system cells.
Leukine (sargramostim) is a yeast-derived granulocyte macrophage colony stimulating factor already marketed in several indications. Because it plays a role in differentiating and activating the long-lived cells in the immune system called macrophages, it's also being examined as a treatment for AIDS.
"We've known that Leukine could have applications in AIDS," said Cathy Anderson, spokesperson for Seattle-based Immunex, "but we wanted to make sure we didn't have an inverse impact by increasing the viral load. There had been some early theoretical studies [suggesting] macrophages could do that."
A preclinical trial showed, in vitro, Leukine directly inhibited the expression of CCR5, a beta chemokine receptor, and another co-receptor, CXCR4, thereby blocking entry of HIV-1 into macrophages. Leukine-treated macrophages exhibited a 70-fold to 100-fold decrease in the entry of HIV-1.
Treatment of macrophages with Leukine raised production of beta chemokines as well. These are the soluble proteins which can block HIV from entering T cells.
A second, Phase I trial studied 20 HIV patients with CD4+ T cells depleted by the disease who were on stable anti-retroviral therapy, including ritonavir or indinavir, which are protease inhibitors. The patients were randomized to receive either Leukine or a placebo for eight weeks.
During the study and for four weeks afterward, eight of the 10 Leukine patients showed an increase of 30 percent or more in CD4+ T cells, compared to three of the 10 placebo patients.
The increase was shown in nearly all patients (seven) treated with Leukine who had a CD4+ T cell count greater than 50 at baseline. Of the seven, six had an increase equal to or greater than 30 percent. The same could be said of only one in eight comparable placebo patients.
In five of the same seven Leukine patients, viral loads decreased somewhat -- a result shown by none of the placebo patients.
Leukine Would Supplement Current Therapies
"In terms of the AIDS community, the more exciting data is the preclinical data," Anderson said. "Now that we have anti-retroviral therapy, everybody is looking at two things: How do you get rid of the virus and keep it from infecting those long-lived cells? And how do you reconstitute an immune system?"
Leukine is approved for bone-marrow transplantation, acute myelogenous leukemia and peripheral blood progenitor cell mobilization and post-transplantation support.
Immunex, in which American Home Products Corp., of Madison, N.J., holds a majority interest, reported sales of $52.7 million for Leukine last year, a 22 percent increase over 1996.
Soluble, trimeric CD40 ligand also was tested in the preclinical study. Like Leukine, it led to lower expression of CCR5, and decreased entry of HIV-1 into macrophages. The CD40 ligand, also called the gp39 antigen, is an immune system trigger for B cell activation and antibody production.
"The level of detail in that component of the trial was not as extensive," Anderson said. "We have more preclinical work to do."
Meanwhile, Immunex has completed enrollment in a 300-patient, Phase III trial evaluating Leukine in reducing incidence of infections and death among AIDS patients.
"We should be reporting results in early 1999," Anderson said
A 24-patient, multi-center pilot study is under way to determine if Leukine can eliminate HIV from long-lived immune system cells.
Results from the two trials were presented at the 5th Conference on Retroviruses and Opportunistic Infections, in Chicago, last week.
David Stone, an analyst with Cowen & Co., in Boston, said the conference was "upbeat" with new drugs, and new combinations of drugs, lined up as future treatment options for AIDS patients.
Best poised to benefit is Glaxo Wellcome plc, of London, with its nucleoside analogue, 3TC.
The "next three potent, well-tolerated agents" up for FDA approval, Stone predicted, are Wilmington, Del.-based DuPont Merck Pharmaceutical Co.'s Sustiva, a non-nucleoside reverse transcriptase inhibitor; Glaxo's abacavir, a nucleoside reverse transcriptase inhibitor; and Glaxo's amprenavir, a protease inhibitor partnered with Vertex Pharmaceuticals Inc., of Cambridge, Mass., and Kissei Pharmaceutical Co., Ltd., of Matsumoto, Japan.
"[The new options] should enable doctors to have more choices and a higher success rate in finding some regimen that each patient can go on and stay on," Stone said. "And that should grow the market for all participants."
AIDS Gene Therapy Promising
In other news from the conference:
* Cell Genesys Inc., of Foster City, Calif., said ongoing clinical trials of its AIDS gene therapy show that the engineered T cells, CD4 and CD8, survive for longer than 10 weeks, the last measurement date, after treatment. The report of prolonged survival is believed to be the first in which patients' immune cells are genetically engineered to be HIV-specific. With no significant side effects related to treatment, the modified CD4 and CD8 T cells persist at levels greater than one percent of circulating white blood cells, during the measurement period.
* SaraWak MediChem Pharmaceuticals Inc., of Lemont, Ill., said a Phase Ia clinical trial of (+)-Calanolide A, a non-nucleoside reverse transcriptase inhibitor, showed the drug is absorbed and circulated in the blood at levels higher than anticipated from animal data. The natural compound has shown activity against HIV-1, including strains resistant to AZT, nevirapine and other antiretrovirals. The study involved 47 volunteers who received single doses in escalating levels. Taken orally, the drug is minimally affected by food. Side effects include dizziness, oily aftertaste, headache, belching and nausea.
* U.S. Bioscience Inc., of West Conshohocken, Pa., said a Phase I trial of its anti-HIV drug, lodenosine (FddA), showed a reduction in viral load even in patients who had failed in AZT, 3TC and d4T therapies. Lodenosine is an acid stable, purine based reverse transcriptase inhibitor. *