Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation.

Summer 1999 Table of Contents

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WF10: A New, Immunomodulating Approach to HIV Treatment

By Leslie Hanna

WF10 is a novel treatment for HIV disease. An immune system modulator designed to enhance macrophage function, WF10 is intended for use as an adjunctive treatment, i.e., in addition to standard of care antiretroviral therapy in people with HIV. Studies already completed indicate that WF10 may be safely used by people with HIV and that the drug may be especially useful for people with moderate to advanced HIV disease. The agent, which is administered intravenously, also appears to regulate immune responses in people with cancer. OXO Chemie Inc. of South San Francisco, a subsidiary of OXO Chemie AG, a Swiss company, is developing the agent. (OXO Chemie GmbH in Germany is the manufacturer.) A Canadian company called Dimethaid Research holds a 20% interest.

Rationale for This Immune Modulator

The range of antiretroviral drugs used in highly active antiretroviral therapy (HAART) regimens, particularly protease inhibitors, have already resulted in much clinical benefit for people with HIV disease. Yet research has shown that none of the currently available therapies appears likely to eliminate completely HIV replication in most people with HIV. In part, this observation relates to (non-)adherence. But another important aspect of viral control relates to the fact that most therapies are unable to eliminate virus from important tissue reservoirs of HIV-infected immune system blood cells, including CD4 cells and macrophages. These immune system cells are early and ongoing targets of HIV itself. Macrophages are believed to be used by HIV as important viral reservoirs that promote the proliferation of HIV throughout the body.

Macrophages are the particular target of WF10. They are a type of white blood cell that plays a vital role in the immune system's first-line defense against pathogens (disease-causing agents). Often called the "scavengers" of the immune system, macrophages rid the body of harmful organisms such as bacteria and degenerated cells by ingesting them. The active process of destruction by ingestion is called phagocytosis. Indirectly, macrophages play a secondary defensive role, which is to stimulate other immune system cells. Like other white blood cells, macrophages both produce and are influenced by chemical messengers called cytokines.

In HIV infection, the immune system goes through an adjustment that results in the release of certain cytokines with mixed effects. The disturbance in cytokine regulation has various results, one of which is impaired macrophage activity. Macrophages appear to mount an inadequate direct response to pathogens and do not effectively engulf and kill them. Furthermore, macrophages themselves are stimulated to release chemokines such as TNF-alpha at an elevated rate, which actually encourages HIV replication in tissue reservoirs. When important immune cells such as CD4 cells and macrophages are depleted, the weakened immune system is unable to combat successfully other invaders, which is when opportunistic invaders may gain a foothold and their related, life-threatening (opportunistic) infections (OIs) develop.

WF10 is designed to counteract abnormal macrophage activity. WF10 works by promoting phagocytosis and by reducing macrophages' production of TNF-alpha. The idea is that WF10 will help slow disease progression by inducing a more optimal immune response. Furthermore, WF10 may help decrease the likelihood of developing an OI by increasing the ability of macrophages to destroy opportunistic pathogens including fungi and mycobacteria.

Early Development

Clinical development of the compound began in 1985. Several studies already have been completed, including two phase II clinical studies.

Early in vitro (test tube) studies showed that the compound could inhibit extracellular HIV and, at higher doses, reduce the infectivity of HIV in culture. Test-tube studies showed that WF10 was able to enhance macrophage phagocytosis and decrease levels of CD8 CD38 T-cell antigens, a marker for inappropriate antigenic activation, without harming the cell itself. Antigen presentation stimulates TNF-alpha hyperproduction, among other undesirable effects.

Other laboratory data showed that WF10 acted synergistically with other antiretroviral agents such as AZT (Retrovir) to reduce HIV replication and spread. Later studies in people with HIV showed that using WF10 along with AZT reduced symptoms such as night sweats, malaise, and fever, and even helped reduce weight loss, leading persons to report improved quality of life. (The current standard of care recommends that a minimum of two to three antiretrovirals be used in combination in a regular regimen.)

A phase I/II study in Houston in 1994 established that WF10 can be safely administered as an intravenous infusion without causing major toxicity.

Advanced Clinical Studies

A phase II trial at Vanderbilt School of Medicine in 1995 in 19 people offered more evidence of WF10's abilities. Participants all had advanced AIDS (mean CD4 cell count of 39 cells/mm3). Ten people received four cycles of WF10 and nine received four cycles of placebo. The trial was stopped when a planned, interim analysis showed that people taking WF10 were clearly doing much better than those receiving placebo. Those in the WF10 groups had significant improvements relative to those in the control group in immunologic parameters such as median white blood cell, lymphocyte, and other immune system cell (CD19 and CD35) values. People receiving WF10 had a lower incidence of OIs and hospitalizations, and longer survival times. Ten infections including four cases of Pneumocystis carinii pneumonia (PCP) occurred in the control group compared with three in the WF10 group, none of which were PCP. Five people in the control group experienced 53 days of hospitalization and 110 home-care days, while those receiving WF10 required neither hospitalization nor home care. Eighteen months after the study ended, eight of the nine people in the control group had died compared to two of the ten in the WF10 group. Results were published in the August 1998 journal Infection.

A phase II study at the University of California at San Francisco (UCSF) also concluded that the drug was well tolerated and had a positive effect on immune system parameters. The study was open label and non-randomized. Eighteen people with CD4 cell counts greater than 50 cells/mm3 and with viral loads of less than 20,000 copies/mL were enrolled. Seventeen received two cycles of WF10 (at a dose of 0.5 ml/kg/day, diluted in 250-500 ml of normal saline, for five days, with 16 days between cycles) over a 42-day period. Extensive studies of circulating blood cells were conducted to determine the mechanism of action. T-cell subsets were examined, including CD28 and CD38 numbers. Overall, WF10 caused measurable changes that "reflected down regulation of immune activation which is believed in HIV disease to be inappropriately elevated." Although WF10 did not decrease HIV viral loads, investigators concluded that it did appear to benefit people by improving macrophage function and by slowing disease progression. They also concluded that WF10 does not cause hemolysis (red blood cell destruction) and that WF10 is well tolerated, despite some local reaction at the site of infusion, and safe for people with HIV.

Ongoing Clinical Studies

Currently, a large phase III study in people with advanced HIV is ongoing. This randomized, double-blind, placebo-controlled study, which began enrolling in October 1998, is taking place at 25 sites in the U.S. and Canada and ultimately will enroll 240 people. The goal of the study is to evaluate the ability of WF10 when added to a person's standard of care antiretroviral regimen to increase survival and delay disease progression. Investigators will also be looking specifically at the cellular immune response to a combination of WF10 and HAART. Participants will receive treatment with WF10 for 11 weeks, with follow-up to continue for up to two years. For more information, call the AIDS Clinical Trials Information Service (ACTIS) at 1-800-TRIALS-A.

At Stanford University Medical Center, an ongoing, non-HIV-related pilot study is evaluating the utility of WF10 for treating follicular lymphoma.

Conclusion

WF10 has a demonstrated ability to alleviate macrophage dysfunction and immune system self-destruction. As one of only two anti-HIV agents that enhance macrophage function, it represents a unique potential adjunctive treatment option for people with HIV. (GM-CSF is an experimental anti-HIV agent that also stimulates macrophage activity/growth.) WF10 also may be useful for people with cancer and other autoimmune diseases and for people undergoing organ transplantation.

Leslie Hanna is Editor of BETA.

Research, Inc. WF10-a new immune approach for the treatment of HIV disease. January 1999.

Herndier, B. and others. Immunological parameters modified in HIV disease by the macrophage activity immunomodulator WF10 (a phase II pathogenesis study). 12th World AIDS Conference. Geneva, Switzerland. June 28-July 3, 1998. Abstract 22417.

Kahn, J. and others. Immunological parameters modified in HIV disease by the drugs WF10 (a phase II pathogenesis study). 6th Conference on Retroviruses and Opportunistic Infections (CROI). Chicago. January 31-February 4, 1999. Abstract 359.

Kahn, J.O. and others. A single center, phase 2 study evaluating the effects of WF10. 12th World AIDS Conference. Geneva, Switzerland. June 28-July 3, 1998. Abstract 22423.

Raffanti, S.P. and others. Randomized, double-blind, placebo-controlled trial of the immune modulator WF10 in patients with advanced AIDS. Infection 26(4): 202-207. July-August 1998.

Page last updated 5 October 1999