Data Suggest Targretin Capsules May Improve Effectiveness of ONTAK Through Upregulation of IL-2 Receptor.

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SAN DIEGO--(BW HealthWire)--Aug. 29, 2000

Presentations at ISH 2000 Suggest Role of Drug in Combination Therapy

and Report Australian Cohort Experience from Targretin Capsules and

Gel Phase II - III CTCL Trials

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) announced today that results of two studies of Targretin(R) (bexarotene) were presented at the 28th World Congress of the International Society of Hematology in Toronto, Ontario. In the first study presented, researchers concluded from in vitro data that Targretin capsules may improve the efficacy of ONTAK(R) (denileukin diftitox) for the treatment of patients with cutaneous T-cell lymphoma (CTCL). In the second presentation, researchers reported results from the Australian cohort of patients with CTCL in the Phase II - III clinical trials for Targretin capsules and gel.

In vitro studies done at Tufts New England Medical Center in Boston on leukemic cell lines demonstrated that Targretin was able to enhance the cytotoxicity of ONTAK. A Phase I-II evaluation of Targretin capsules in a cohort dose-escalation study is planned to measure modulation of Interleukin-2 receptor (IL-2R) expression in vivo after escalating doses of Targretin. The trial will assess the safety and tolerability of the combination of Targretin and ONTAK.

"It is becoming widely recognized that Targretin capsules and gel are effective treatments for patients with CTCL who have not benefited from other therapies," said Francine Foss, M.D., of Tufts New England Medical Center in Boston, Mass. "Now we are beginning to see from our in vitro studies that Targretin may have an expanded role, possibly helping more patients with CTCL benefit from ONTAK and other systemic treatments."

ONTAK, a targeted cytotoxic biologic, is a novel fusion protein comprised of IL-2 fragments genetically fused to portions of diphtheria toxin. ONTAK selectively kills cells bearing the high-affinity IL-2R by inhibiting protein synthesis through internalization of the diphtheria toxin. Although 65 percent of patients with CTCL express at least one component of the IL-2R, the response rate to ONTAK in published clinical trials has been 30 percent in patients whose malignant cells express the IL-2R.

Targretin is a RXR-selective retinoid which has been demonstrated in vitro to induce apoptosis (programmed cell death) and to upregulate expression of the high-affinity IL-2R. Targretin has demonstrated a 32 percent response rate as a single agent therapy in patients with refractory CTCL when treated at the recommended initial dose. Because clinical improvement with Targretin is most pronounced in the skin, Targretin may also affect cytokine expression by keratinocytes and accessory cells in the local milieu of the skin. Additional studies are needed to show if Targretin may also act synergistically when used in combination therapy with other systemic treatments, particularly ONTAK, and perhaps PUVA and photopheresis.

In the second presentation, Australian lead investigator H. Miles Prince, M.D., of St. Vincent's and Peter MacCallum Hospitals in Melbourne reviewed the Australian experience from the Phase II - III studies with Targretin capsules and gel. These two dosage forms of Targretin were shown to be active and generally well tolerated in a cohort of Australian patients with CTCL who had failed other treatments. Researchers concluded that additional studies examining the role of Targretin in previously untreated patients are warranted.

"Targretin has proven to be an effective monotherapy for patients with difficult-to-treat disease," said Steven D. Reich, M.D., Ligand Senior Vice President, Clinical Research. "We are hopeful that additional studies involving previously untreated patients will yield similar if not better results."

The Australian Phase II-III studies of Targretin capsules and gel, led by Dr. Prince, involved eight patients: seven were treated with Targretin capsules and one with Targretin gel. Of the seven patients who started at 300 mg/m2/day Targretin capsules, five achieved a partial response, with mean time to onset response of 27 days. One patient with Sezary syndrome (an advanced hematological expression of CTCL) had a rapid and dramatic fall in blood Sezary cell (SC) count with apoptotic SCs visible following treatment with Targretin capsules. Three of five patients relapsed, with a mean time to relapse of 92 days. The major toxicity seen in patients treated with Targretin capsules was hypertriglyceridemia requiring therapy. One patient each discontinued treatment due to headache and edema. The patient receiving Targretin gel remains in partial response at 337 days.

Cutaneous T-Cell Lymphoma

Affecting an estimated 16,000 people in the U.S., CTCL is a form of non-Hodgkin's lymphoma that results in circulating malignant T-lymphocytes (white blood cells involved in the body's immune system). CTCL typically 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 years or more after diagnosis. Some patients, however, have a much more aggressive form of this disease, and the median survival for advanced-stage patients is less than three years.

Targretin Gel, Targretin Capsules, and ONTAK: A Comprehensive Portfolio for Early- to Late-Stage CTCL

Ligand Pharmaceuticals Incorporated provides clinicians and patients with a comprehensive portfolio of effective treatments for the management of CTCL. Ligand offers topical (Targretin gel), oral (Targretin capsules) and injectable (ONTAK) treatment options for appropriate patients suffering from CTCL. These three products are the first new agents approved for use in patients with CTCL in the last 10 years.

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 judgement 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 clinical studies of Targretin capsules or gel in conjunction with ONTAK or any other therapy for CTCL will confirm pre-clinical results or that Targretin will prove effective in combination therapy with ONTAK or any other drug. 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.

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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 website at http://www.ligand.com.