Ligand's ONTAK in Combination With Steroids Doubled Overall Response Rate In CTCL; Three Posters on ONTAK and Targretin at American Society of Hematology Meeting.

Business Editors/Health & Medical Writers

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SAN DIEGO--(BW HealthWire)--Dec. 5, 2000

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) today announced that investigators presented results of a clinical trial with ONTAK(R) (denileukin diftitox) administered in combination with steroids showing a doubling of overall response rate in a poster session this week at the annual American Society of Hematology (ASH) meeting in San Francisco.

In a second poster presentation, researchers presented data indicating that combination therapy using cytokines and other bioactive agents may have potential in augmenting response to anti-CD25 therapies such as ONTAK. In a third poster presentation, researchers presented a study demonstrating that RXR and RAR retinoid receptors display differential effects in T- and B-leukemia cells and that the combination of retinoids (including Targretin) and the steroid dexamethasone induces apoptosis (cell death) to a more significant degree than retinoids alone.

"These studies provide valuable information that may help increase the activity of ONTAK and Targretin(R) in combination regimens in patients with lymphoma," said Steven D. Reich, M.D., Senior Vice President of Clinical Research at Ligand. "We are particularly pleased to see the doubling of the ONTAK response rate to 60 percent in patients with cutaneous T-cell lymphoma (CTCL) when administered in combination with steroids. Continued research will help determine appropriate therapy combinations with ONTAK and Targretin to provide improved treatment regimens for patients with CTCL, other non-Hodgkin's lymphomas and leukemia."

ONTAK in Combination with Steroids

The results of the clinical study entitled, "COMBINATION OF ONTAK AND STEROIDS IS ASSOCIATED WITH A SIGNIFICANTLY IMPROVED RESPONSE RATE IN REFRACTORY CTCL," demonstrate that combination therapy with ONTAK, a cytotoxic fusion protein, and corticosteroids is associated with a higher response rate and lower side effect profile than treatment with ONTAK alone in patients with refractory CTCL.

"We were impressed by the 60 percent response rate in patients treated with a combination of ONTAK and steroids, given the expected response rate of 30 percent for ONTAK alone," said co-author Francine Foss, MD, Director, Experimental Therapeutics Program at Tufts New England Medical Center. "We are particularly interested in the responses shown by two patients whose skin biopsies lacked IL-2 receptors by CD25 assay because ONTAK selectively intoxicates cells bearing the IL-2 receptor. This clinical response suggests the test for IL-2 receptor by CD25 assay may not be predictive of response."

To assess the impact of steroids on tolerability and response in ONTAK-treated patients, 20 patients with histopathologically confirmed CTCL were treated with either dexamethasone 8mg or prednisone 20mg and ONTAK 18ug/kg daily for five days. Ten patients had Stage III/IV disease; 13 patients had received three or more previous therapies; and 14 patients showed positive CD25 expression through skin biopsies or circulating Sezary leukemia cells. Twelve patients (60 percent), including two of three CD25 negative patients, responded - a significantly higher response rate (p=0.017) than the original Phase III trial, in which steroids were not used. Three of 20 patients (15%) had a complete response. While infusion-related events were significantly decreased (p=0.019), delayed hypersensitivity was noted in three patients: one with angiodema after cycle 8, and one each with uticaria and serum sickness after cycle 4. The incidence of clinically apparent, symptomatic vascular leak (20 percent) was not statistically different with the addition of steroids, despite a significant decrease in the occurrence of grade 3/4 edema (p = 0.004).

Additional Results Reported About ONTAK

In a second poster presentation related to ONTAK titled, "INTERLEUKIN-2 RECEPTOR (CD25) AS A TARGET FOR IMMUNOTHERAPY: AUGMENTATION OF EXPRESSION BY CYTOKINES," researchers presented data demonstrating that cytokines may have potential for combination therapy with anti-CD25 therapies such as ONTAK because they appear to increase the expression of the receptor needed for response to anti-CD25 targeted therapies. The increases in the percentage of peripheral blood mononuclear cells (from nine patients with chronic lymphocytic leukemia [CLL]) expressing CD25 (%P), the intensity of expression per cell (MFI), and the product of %P and MFI were used to study the effects of cytokines on CD25 expression as compared to appropriate controls.

At 24 hours, significant increases in all three parameters were seen in cells incubated in the presence of IL-4, IFN-(alpha), and TNF-(alpha). Nearly 64 percent of samples showed an increase with IL-2, and 50 to 71 percent showed an increase with IL-3. The increases due to IL-4 and TNF were still maintained up to 72 hours with p values of 0.022 and 0.018. These data indicate that combination therapy using cytokines and other bioactive agents may have potential in augmenting response to anti-CD25 targeted therapies, including ONTAK.

Results of Targretin Studies

Researchers presented a study demonstrating that RXR and RAR retinoid receptors display differential effects in T- and B-leukemia cells and that the combination of retinoids and the steroid, dexamethasone, induces apoptosis (cell death) to a more significant degree than retinoids alone. Separately, results reported in a published abstract indicated that Targretin (bexarotene) capsules therapy does not appear to be associated with the redistribution or dissemination of malignant cells in CTCL patients.

The poster presentation about Targretin entitled, "INDUCTION OF APOPTOSIS IN LYMPHOID LEUKEMIA CELLS: DIFFERENTIAL EFFECTS OF RAR AND RXR RETINOIDS WITH DEXAMETHASONE," presented data examining the effects of Targretin (bexarotene) and the RAR-specific retinoid, ATRA, on cell growth and induction of apoptosis in the T-leukemia cell line, HUT78; NALM-6 pre-B cells; and fresh leukemia cells from patients with CLL. A three-fold enhancement in cytotoxicity was demonstrated by Annexin V immunostaining with a combination of Targretin and dexamethasone in the HUT78 T cells compared to either drug alone, with no significant difference in cytotoxicity in the presence of ATRA plus dexamethasone. In the pre-B NALM-6 cells, there was enhancement in the cytotoxicity with ATRA plus dexamethasone but not Targretin plus dexamethasone. In fresh CLL cells, Targretin alone induced apoptosis in 30 to 50 percent of the cells, whereas the combination of dexamethasone and Targretin induced apoptosis in 70 to 75 percent after 48 hours of exposure. These results suggest that further clinical investigation of combination therapy with Targretin and dexamethasone is warranted.

Cutaneous T-Cell Lymphoma (CTCL)

Affecting an estimated 16,000 people in the U.S. and between 12,000 and 14,000 people in Europe, CTCL is a cancer of T-lymphocytes (white blood cells involved in the body's immune system). T-cell lymphomas, of which CTCL is a subclass, represent approximately 10% of the non-Hodgkin's lymphomas (NHL), which affect approximately 300,000 individuals in the U.S.

CTCL ordinarily manifests itself initially in the skin, but over time may progress to involve other organs. CTCL is most commonly a slowly progressing cancer, and many patients live with the complications of CTCL for 10 or more years after diagnosis. Some patients, however, have a much more aggressive form of this disease, and the median survival for late-stage patients is less than three to five years.

ONTAK / Targretin Capsules

In February1999, the U.S Food and Drug Administration (FDA) granted Seragen, Inc., a wholly owned subsidiary of Ligand, marketing approval for ONTAK for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the CD25 component of the IL-2 receptor. In December 1999, the FDA approved Targretin capsules for the treatment of all stages CTCL refractory to at least one prior systemic therapy.

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'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 which involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from Ligand's expectations. There can be no assurance that results of subsequent studies of ONTAK or Targretin capsules in combination with any therapy will confirm results presented here. Additional information concerning these and other risk 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.

Full prescribing information for Ligand's products may be obtained in the U.S. from Ligand Professional Services by calling toll free 800-964-5836 or on Ligand's web site at http://www.ligand.com.

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