Biomodulation of ONTAK Increases In Vitro Cytotoxicity in Leukemia and Lymphoma Cells.

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SAN DIEGO--(BW HealthWire)--May 23, 2000

Data Presented at ASCO Demonstrate Role of Biomodulators such as

Retinoids In Increasing In Vitro Cytotoxicity of ONTAK

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) announced the presentation of preclinical study results today suggesting that the addition of biomodulatory strategies to the ONTAK(R) (denileukin diftitox/DAB389IL-2) treatment regimen may increase the activity of ONTAK in patients whose lymphoma cells do not express the Interleukin-2 receptor (IL-2R). The results were presented in New Orleans at the 36th Annual Meeting of the American Society of Clinical Oncology in an afternoon poster session.

ONTAK, a targeted cytotoxic biologic from a new class of drugs called fusion proteins, is selectively lethal to IL-2R-expressing leukemia and lymphoma cells. This in vitro study suggests that biomodulatory strategies, such as the addition of arginine butyrate or retinoids to the treatment regimen, may be useful in increasing the affinity of the malignant cells to ONTAK in subsets of lymphoma patients whose tumors lack IL-2R isoform expression.

"We have previously demonstrated that butyrate and retinoids are capable of upregulating IL-2R expression on chronic lymphocytic leukemia cells and Sezary cells," said Francine M. Foss, M.D., Director, Experimental Therapeutics Program, New England Medical Center (Boston, MA) and co-author of the abstract. "In this study, we showed that butyrate alone, or in combination with a retinoid (all-trans retinoic acid), enhances the cytotoxic activity of ONTAK in vitro."

According to Steven D. Reich, M.D., Ligand's Senior Vice President of Clinical Research, results of this study suggest that biomodulation of ONTAK may assist in providing an important new therapeutic option for patients regardless of IL-2 receptor status. "We are continually looking for ways to enhance the benefits of our drugs and to expand their applicability to new groups of patients," he said. "This study paves the way for future research to determine appropriate therapy combinations with ONTAK to provide additional treatment options for patients with leukemia and non-Hodgkin's lymphoma."

Details of the Study

The abstract, "Modulation of DAB389IL-2 (ONTAK(R)) Cytotoxicity in Leukemia and Lymphoma by Arginine Butyrate and All-Trans Retinoic Acid," was presented at the Adult Leukemia/Lymphoma poster session (Tuesday, May 23, 12:30 to 3:30 p.m.; Hall E, Main Lobby). Study co-authors were Richard Shao, Alexander Urbano and Francine Foss. In the in vitro study, the HUT 78 leukemia cell line was exposed to various concentrations of either arginine butyrate, all-trans retinoic acid (ATRA), or the combination, for 48 hours, and expression of the p55, p75, and p64 components of the IL-2R were determined by western immunoblot and flow cytometry. Both p55 and p75 expression increased with butyrate and ATRA, but p64 expression decreased twofold with the combination. After exposure to ONTAK, enhanced cytotoxicity was observed. Additive but not synergistic cytotoxicity was observed when ATRA and butyrate were combined.

Dr. Foss notes, "Our conclusions are that the cytotoxic activity of ONTAK is enhanced by pharmacologically achievable concentrations of butyrate or ATRA in certain malignant cells, perhaps related to upregulation of the IL-2 receptor, but also possibly due to effects on membrane-related events important for uptake or processing of ONTAK."

Cutaneous T-Cell Lymphoma (CTCL)

Adult non-Hodgkin's lymphoma is a disease in which cancer (malignant) cells are found in the lymph system. With CTCL, certain cells of the lymph system (called T-lymphocytes) become cancerous (malignant) and affect the skin. CTCL, often known as mycosis fungoides, usually develops slowly over many years. In the early stages, the skin may itch, and dry, dark patches may develop on the skin. As the disease worsens, tumors may form on the skin. As more and more of the skin becomes involved, the skin may become infected. The disease can spread to lymph nodes or to other organs in the body, such as the spleen, lungs, or liver. When large numbers of the tumor cells are found circulating in the blood along with erythroderma and lymphadenopathy, the condition is called the Sezary syndrome.

ONTAK

In February 1999, the U.S Food and Drug Administration (FDA) granted Seragen, Inc., a wholly owned subsidiary of Ligand, marketing approval for ONTAK(R) for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. ONTAK, a fusion protein, consists of a fragment of diphtheria toxin genetically fused to IL-2. ONTAK targets IL-2 receptors on the surface of malignant cells and the diphtheria toxin is rapidly incorporated through endocytosis, killing the cell within hours. Phase II clinical trials also are underway to evaluate ONTAK for the treatment of patients with low- and intermediate-grade non-Hodgkin's lymphoma and severe psoriasis.

Ligand Pharmaceuticals Incorporated

Ligand Pharmaceuticals Incorporated discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, skin diseases, and men's and women's hormone-related diseases, as well as osteoporosis, metabolic disorders and cardiovascular and inflammatory diseases. Ligand had three drugs approved during 1999 for marketing in the U.S. -- Targretin(R) (bexarotene) capsules, ONTAK(R) and Panretin(R) (alitretinoin) gel -- that are being marketed through its specialty cancer and HIV-center sales force. Targretin(R) gel is currently under review by the FDA for marketing approval in the U.S., and Morphelan(TM) (licensed from Elan) is in late-stage development. Ligand's proprietary drug discovery and development programs are based on its leadership position in gene transcription technology, primarily related to Intracellular Receptors (IRs) and Signal Transducers and Activators of Transcription (STATs).

This news release may contain certain forward-looking statements by Ligand and actual results could differ materially from those described as a result of factors including but not limited to the following. There can be no assurance that results shown in in-vitro studies will be repeated in any patient population, that any development candidate or any compound or product in the Ligand pipeline will be successfully developed, that any regulatory filings will be made, that any regulatory approvals will be granted in a timely manner, or at all, that if approved any product will be accepted by physicians for prescribing, by patients for use and by insurance companies/agencies for reimbursement, or that any products will be commercially successful. Additional information concerning these and other factors affecting Ligand's business can be found in prior press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission, available via Ligand's website at http://www.ligand.com. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release.

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Note: Targretin(R)and Panretin(R)are registered trademarks of Ligand Pharmaceuticals Incorporated, and ONTAK(R)is a registered trademark of Seragen, Inc., a wholly owned subsidiary of Ligand. Morphelan(TM)is a trademark of Elan Corporation plc (NYSE:ELN). Full prescribing information for our marketed products may be obtained from Ligand Professional Services by calling toll-free 1-800-964-5836.