AEGiS-GMHC: Promising Anti-HIV Therapy in Limbo

Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.

Promising Anti-HIV Therapy in Limbo

Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 11 December 1994
David Gold

According to a Phase I study released at this fall's Interscience Conference on Anti-Microbial Agents and Chemotherapy (ICAAC), a unique therapy, Seragen's IL-2 diphtheria "fusion toxin," is well tolerated and shows possible anti-viral effects at higher doses. Yet the therapy, known as DAB389 IL-2, may be dropped because Seragen, a small biotechnology company based in Hopkinton, Massachusetts does not have the capital to pursue additional studies of the drug. Eli Lilly, the pharmaceutical giant that licenses the compound from Seragen, is currently supporting phase III trials of the drug for lymphoma, but may be unwilling to fund the HIV studies.

The theory behind using the fusion toxin is that cell activation, required for HIV replication, leads to the expression of IL-2 receptors on T-cells to which the toxin can attach and target the cells. In the test tube, DAB389 inhibited HIV replication.

DAB389 has shown significant promise in other diseases. Phase III trials are about to begin in cutaneous T-cell lymphoma, and it is hoped that the drug will have activity in other cancers that express IL-2 receptors (such as non-Hodgkin's lymphoma). DAB389 has also shown activity in early trials in autoimmune diseases where activated T-cells play a role, such as rheumatoid arthritis, psoriasis and early onset type 1 diabetes.

The study presented at ICAAC is the first study of DAB389 in HIV. A note of caution about the drug: it is important to monitor blood to ensure that too many immune cells (CD4s or CD8s) are not destroyed by the drug and that serious toxicities do not result from the diphtheria toxin.

The Study

In the study, 22 HIV-positive, p24-positive individuals with CD4 cells between 300 and 600 were randomized to one of three doses. DAB 389 was administered five times daily for three cycles three weeks apart. A response was defined as a 50 percent decline in p24 antigen and a hundred-fold reduction in HIV in the blood as measured in two successive blood cultures.

While no patient met the defined criteria for anti-HIV response, there was a dose-dependent trend. Six individuals had a ten-fold decline in HIV cultured in the blood cultures (PBMC cultures), four of which were in the highest dose. One individual in the highest dose had a ten-fold reduction in PBMC culture and a 50 percent decline in p24.

Adverse experiences, including headache, night sweats, fever/chills, myalgia and/or rash, occurred in approximately twenty percent of those treated. Transient elevated liver functions (three to five times normal) occurred in two individuals. Levels of CD4 and CD8 cells remained stable.

Future Plans

Investigators believe that the viral data suggest the beginning of an anti-HIV effect at the higher doses and that adverse effects were well tolerated and not dose-limiting. They recommend continued study of this agent in approximately 30 HIV-infected individuals at higher doses, with PCR tests to be used to measure viral load.

However, such a study would require additional funding from either Seragen or Lilly. Seragen is short of funds and Lilly has in the past publicly disclosed its lack of interest in developing AIDS therapeutics (after terminating a joint HIV protease inhibitor with another small biotech company, Agouron).

Activists plan to begin contacts with Lilly to obtain financing of a phase II trial of DAB389. In a time of limited numbers of potential anti-HIV therapies beyond nucleoside analogs (AZT, ddI, etc.) or protease inhibitors, it is important that this unique antiviral therapy, which has shown real promise in other conditions, not be dropped prematurely.

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