Highlights from Nine Ligand-Related Abstracts at American Society of Hematology Meeting.

Business Editors/Health & Medical Writers

BIOWIRE2K

SAN DIEGO--(BW HealthWire)--Dec. 11, 2001

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND):

-- Treatment With Targretin(R) May Increase Response of CTCL Patients to
ONTAK(R), Pilot Phase I Study Shows

-- Separate In Vitro Study Shows Treatment with Targretin May Make CLL Cells
More Susceptible to ONTAK

-- In Third Study, ONTAK Demonstrates Activity in CLL Patients

Treating cutaneous T-cell lymphoma (CTCL) patients with Targretin(R) (bexarotene) boosted the activity of ONTAK(R) (denileukin diftitox) and increased patient response rates in a pilot Phase I study, according to a poster presented Monday by Tufts researchers at the 43rd annual American Society of Hematology (ASH) meeting in Orlando.

In a second, related poster, Tufts researchers reported that in vitro, chronic lymphocytic leukemia (CLL) cells that were exposed to bexarotene were more susceptible to treatment with denileukin diftitox than were cells treated by denileukin diftitox alone.

And in a third study published in the meeting's abstract book, researchers from Wake Forest University's School of Medicine reported for the first time that ONTAK showed anti-cancer activity in patients with fludarabine-refractory CLL.

These abstracts were among nine at ASH related to products from Ligand Pharmaceuticals (Nasdaq: LGND).

ASH Abstract No. 2520: Treatment with Targretin May Increase Patient Response to ONTAK

Previous in vitro studies have demonstrated that treatment with ONTAK, a genetically engineered fusion protein marketed by Ligand, is most efficient in leukemia and lymphoma cells expressing the high-affinity interleukin-2 (IL-2) receptor, consisting of the p55 (CD25), p75 (CD122) and p64 (CD132) subunits. Other in vitro studies have shown that Targretin, an RXR-selective retinoid also marketed by Ligand, modulates IL-2 receptor expression by upregulating, or making more plentiful, the p55 (CD25) and p75 (CD122) subunits of the IL-2 receptor.

In ASH Abstract No. 2520, researchers from the Tufts New England Medical Center in Boston evaluated whether low doses of Targretin would upregulate patients' IL-2 receptor expression, and whether the combination of Targretin and ONTAK was tolerable. Nine CTCL patients were started on Targretin at 75, 150, 225 or 300 mg/day. On day eight of the study, treatment with ONTAK was initiated at a dose of 18 (mu)g/kg/day x 3 every 21 days.

The study results showed that p55 (CD25) expression increased in six of the seven patients treated with 150 mg/day or greater of Targretin for seven days, and that the overall response rate with the combination was approximately 75%. Three patients had a complete response, and three others had a partial response. "These pilot results are promising because upregulation of the IL-2 receptor occurred even at low doses of Targretin, and because response rates exceeded those typically seen with either drug alone," said co-author Francine Foss, M.D., associate professor of medicine and director of the lymphoma program at the Tufts New England Medical Center. "The combination of Targretin and ONTAK also had an acceptable tolerability profile. However, it is important to emphasize that these preliminary results must be validated in a randomized Phase II study, which we plan to pursue."

In terms of side effects, one patient experienced a hypersensitivity reaction to ONTAK and three had vascular leak syndrome. Eight patients experienced hypertriglyceridemia after treatment with Targretin, and seven had thyroid toxicity. Four patients experienced Grade 2 or 3 leukopenia and six experienced Grade 2-4 lymphopenia (four Grade 3, one Grade 4).

ASH Abstract No. 634: Targretin Increases Susceptibility of CLL Cells to ONTAK

In the second (in vitro) study, leukemia cell lines that were exposed to Targretin experienced 40-80% lower survival compared to control cells treated only with ONTAK. "We hypothesize that Targretin increased ONTAK's ability to kill cancer cells through Targretin's ability to upregulate the p75 subunit of the IL-2 receptor," Dr. Foss said. "Targretin increased the susceptibility of cells to ONTAK in a dose-dependent fashion, and the concentrations of Targretin required to upregulate the IL-2 receptor are pharmacologically achievable based on pharmacokinetic data from clinical studies."

ASH Abstract No. 4901: ONTAK Shows Activity in CLL Patients

In the third study, all eight patients treated with ONTAK experienced reductions in peripheral CLL cells, with greater than 80 percent clearance in seven evaluable patients after two or three cycles of treatment. One patient showed a partial remission, with shrinkage of abdominal nodes and clearance of CLL cells from bone marrow. In two of three evaluable patients who were treated with three cycles of ONTAK, the percentage of p55 (CD25) positive cells fell from 76% and 85% to 6% and 0%, respectively. ONTAK-related toxicities, which were similar to those previously reported, included asthenia, vascular leak syndrome, transient elevated transaminases and CPK, fever, nausea, vomiting, myalgias and anorexia.

"These results are encouraging but preliminary," said lead author Arthur Frankel, M.D., professor of medicine and cancer biology at Wake Forest. "We are completing recruitment for this Phase II study and planning a follow-up trial in which we use combination therapy with Targretin to enhance IL-2 receptor expression and sensitivity to ONTAK. Because there are few effective drugs to treat patients with CLL, evaluating the potential clinical utility of ONTAK is an important initiative."

About Targretin and 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 for the treatment of patients with persistent or recurrent CTCL whose malignant cells express the p55 (CD25) component of the IL-2 receptor. In December 1999, the FDA approved Targretin capsules for the treatment of all stages of CTCL refractory to at least one prior systemic therapy. The European Commission granted marketing authorization for Targretin capsules in April 2001.

Ligand-Related Abstracts at the American Society of Hematology Meeting

A complete list of Ligand-related abstracts at ASH follows below. Full abstracts are available from the ASH internet site at www.hematology.org.

Presented in Poster Sessions

-- Abstract No. 634: RXR-Selective Retinoid, Bexarotene

(Targretin(R)) Upregulates IL2R Expression and Enhances

Sensitivity of B-Chronic Lymphocytic Leukemia (CLL) Cells to

Denileukin Diftitox (ONTAK(R)). Gullu Gorgun, Francine Foss.

Tufts New England Medical Center, Boston, MA.

-- Abstract No. 554: Bexarotene Monotherapy and Combination

Therapy for Cutaneous T-Cell Lymphoma. Rakhshandra Talpur,

Staci Ward, Narin Apisarnthanarax, Madeleine Duvic. (Intr. by

Andreas Sarris). M.D. Anderson Cancer Center, Houston, Texas.

-- Abstract No. 1801: Multivariate Analysis of the Factors

Influencing Dose Selection of Denileukin Diftitox (ONTAK(R))

in Patients with CTCL. Francine Foss, Panos Savvides. Tufts

New England Medical Center, Boston, MA.

-- Abstract No. 2520: Phase I Dose Escalation Study of

Targretin(R)and ONTAK(R)in Hematologic Malignancies:

Upregulation of IL2R Expression by Low Dose Targretin. Gina

DiVenuti, Francine Foss. Tufts New England Medical Center,

Boston, MA.

Published in Abstract Book

-- Abstract No. 4901: Phase II Trial of the Diphtheria Fusion

Protein ONTAK(R)in Patients with Fludarabine Refractory

Chronic Lymphocytic Leukemia (CLL). Arthur Frankel, Cynthia

Patrick, Bayard Powell. Wake Forest University School of

Medicine, Winston-Salem, NC.

-- Abstract No. 4730: Treatment of Refractory Peripheral T-Cell

Lymphoma with Denileukin Diftitox (ONTAK(R)). Rakhshandra

Talpur, Narin Apisarnthanarax, Staci Ward, Andreas Sarris,

Madeleine Duvic. M.D. Anderson Cancer Center, Houston, Texas.

-- Abstract No. 4425: Induction of Apoptosis in Cutaneous T-Cell

Lymphoma (CTCL) Cells: A Possible Mechanism of Bexarotene

Action in CTCL. Chunlei Zhang, Parul Hazarika, Xiao Ni,

Madeleine Duvic (Intr. by Andreas Sarris). M.D. Anderson

Cancer Center, Houston, Texas.

-- Abstract No. 4689: Improved Tolerability of

ONTAK(R)(Denileukin Diftitox) with Corticosteroid

Premedication Patients with CTCL. Madeleine Duvic, Rakhshandra

Talpur, Erin Boh, Yousuf Siddique, Victor Stevens (Intr. by

Nam Dang). M.D. Anderson Cancer Center, Houston, Texas; Tulane

University, New Orleans, LA; University of Pittsburgh.

-- Abstract No. 4678: Complete Clinical Resolution of Peripheral

T-Cell Lymphoma (Lennert's Variant) with Denileukin Diftitox

(ONTAK(R)). Zale Bernstein, Kena Miller, Maurice Barcos.

Roswell Park Cancer Center, Buffalo, NY.

About Ligand

Ligand Pharmaceuticals Incorporated 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).

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 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 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.

Ligand Pharmaceuticals' releases are available on the World Wide Web at www.businesswire.com/cnn/lgnd.htm.