Treatment With Targretin-R- -Bexarotene- Reduces Cell Proliferation in Psoriatic Skin, One of Several Ligand-Related Studies Presented at SID Demonstrates.

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SAN DIEGO--(BW HealthWire)--May 17, 2002

Second Study Suggests New Mechanism Behind Bexarotene's

Anti-Cancer Activity In Vitro; Targretin + PUVA May be Useful

in Early-Stage CTCL, Third Study Shows

Treatment with Ligand's approved cancer drug Targretin(R) (bexarotene) capsules reduced the number of proliferating skin cells in 24 of 29 patients (83%) with moderate-to-severe psoriasis, according to one of several Ligand-related abstracts presented at this week's annual meeting of the Society for Investigative Dermatology (SID).

Hyperproliferation of skin cells is a hallmark of psoriasis, an autoimmune disease that affects more than 7 million people in the United States. In the study, by J.V. Smit and colleagues from the University Medical Center in Nijmegen, The Netherlands, patients received one of four doses of Targretin capsules: 0.5, 1.0, 2.0, or 3.0 mg/kg/day. In the three highest dose regimens, mean cell proliferation decreased by more than 30% after 12 weeks of treatment. The five patients who had no significant reductions in proliferation while on therapy all received the lowest dose of Targretin.

Targretin is approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. The recommended starting dose of Targretin in CTCL is 300/mg/m2/day, more than twice the highest dose used in the psoriasis study.

In a second study, Xiao Ni and colleagues from the MD Anderson Cancer Center in Houston demonstrated that in vitro, bexarotene may inhibit expression of Fas ligand (FasL, CD95L), a protein involved in regulating apoptosis, or programmed cell death. FasL and its receptor, Fas, which are collectively referred to as the Fas-FasL system, form a signal transduction pathway localized on the cell surface that can signal Fas-bearing cells to die, or undergo apoptosis. Through the Fas-FasL system, many cancerous cells that express FasL, including CTCL cells, are able to evade destruction by, and instead kill, healthy immune system cells that display Fas on their surface. In the study, the researchers exposed several CTCL cell lines to Fas-bearing target cells at ratios of one target cell to one, five, 10 or 20 CTCL cells. The most potent of the CTCL cell lines killed 9%, 28%, 49% and 72% of the Fas-bearing target cells at the four ratios, respectively. However, adding bexarotene reduced the number of Fas-bearing target cells killed by 9%, 46%, 40% and 53%, respectively. The findings are significant because they suggest a new potential mechanism of action through which bexarotene provides benefit against cancerous cells.

In a third study, Joan Guitart and colleagues from Northwestern University showed that early-stage CTCL can be cleared rapidly by treating patients with Targretin capsules and PUVA (psoralen + ultraviolet light). At the time of an interim study assessment, six patients had completed at least eight weeks of therapy with 150 or 300 mg/day of Targretin in combination with PUVA. All six patients responded to treatment, with three showing a complete clinical response and three a partial response. The three patients with a complete response achieved remission after six, seven and eight weeks of combination therapy, respectively. Mild elevations in triglycerides were observed in all patients, and were controlled by reducing the Targretin dose or by increasing the dose of a lipid-lowering drug. The only serious adverse event was a case of cholelithiasis (gallstones) considered to be possibly related to Targretin.

In addition to the studies presented at SID, several other physician-driven trials of Targretin are underway in non-small cell lung cancer, psoriasis and CTCL.

Summary of Ligand-Related Posters at SID

-- Poster #57: Functional Fas ligand is expressed on human cutaneous T-cell
lymphoma cells and inhibited by bexarotene. Xiao Ni, C Zhang, P Hazarika, M
Duvic. MD Anderson Cancer Center, Houston.

-- Poster #199: Low-dose bexarotene (Targretin) capsules and phototherapy for
early-stage cutaneous T-cell lymphoma. Joan Guitart, R Tucker, Northwestern
University, Chicago; V Stevens, Ligand Pharmaceuticals, San Diego.

-- Poster #212: Immunohistochemistry and flow cytometry of psoriatic skin
before and after oral bexarotene treatment. JV Smit, MEJ Franssen, EMGJ de
Jong, PCM van de Kerkhof, University Medical Center, Nijmegen, Netherlands; VJ
Stevens, Ligand Pharmaceuticals, San Diego.

-- Poster #827: Peroxisome proliferation activator receptor-gamma and retinoid
X receptor agonists exert synergistic proapoptotic effects on cutaneous T-cell
lymphoma cells. CL Zhang, X Ni, M Konopleva, M Milella, P Hazarika, M Andreeff
and M Duvic. MD Anderson Cancer Center, Houston.

-- Poster #838: CD25 expression in mycosis fungoides by stage, histology and
response to ONTAK therapy. Rakhshandra Talpur, A Alencar, N Apisarnthanrax, D
Jones, M Duvic. MD Anderson Cancer Center, Houston.

About Ligand

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, skin diseases, men's and women's hormone-related diseases, 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).

Caution Regarding Forward-Looking Statements

This news release may contain certain forward-looking statements by Ligand that 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 Targretin capsules, alone or 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 internet site at 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 can be obtained in the United States from Ligand Professional Services by calling 800-964-5836, or on Ligand's internet site at www.ligand.com.

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