Clinical Studies of Targretin Capsules and ONTAK Presented at ASCO Underscore Potential of Ligand Drugs to Treat Lung Cancer, Chronic Lymphocytic Leukemia.

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SAN DIEGO--(BUSINESS WIRE)--May 20, 2002

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND):

Results of Second Phase I/II Trial Show that Adding Targretin(R) to Chemotherapy May Improve Activity, Disease Stabilization in Late-Stage NSCLC; Phase III Registration Trials Underway to Evaluate for Survival

Benefit

In Separate Study, Ligand's ONTAK(R) Shows Activity in Patients with

Fludarabine-Refractory CLL

Adding Ligand's approved cancer drug Targretin(R) (bexarotene) capsules to standard chemotherapy may enhance the activity of lung cancer treatment and reduce the growth rate of lung cancer without causing unexpected side effects, according to a preliminary analysis of Phase I/II data presented at the 38th annual meeting of the American Society of Clinical Oncology (ASCO).

"These preliminary data suggest improved activity and disease stabilization with the addition of Targretin capsules to standard carboplatin/paclitaxel chemotherapy, with no evidence of toxicities beyond those expected with each agent," said lead author Naiyer Rizvi, M.D., of the Lombardi Cancer Center in Washington, D.C. "Further evaluation of this combination is merited in the large, Phase III study underway now."

In the open-label, Phase I/II study, 43 patients with advanced non-small cell lung cancer (stage IIIB with pleural effusion or stage IV disease) were enrolled at seven sites. Patients received 400 mg/m2/day of Targretin capsules once-daily in combination with carboplatin/paclitaxel, a widely used chemotherapy for NSCLC. The primary objective of the study was to evaluate the safety and tolerability of the combination treatment; 27 patients had data analyzed for toxicity as of April 30, 2002. Median duration of treatment was two months, with a range of 0 to 9 months.

All patients in the study were treated with a lipid-lowering drug, atorvastatin, from day one since hypertriglyceridemia has been an observed side effect of Targretin treatment. In addition, strict dose reduction guidelines were mandated. Ten of the 43 patients (23%) had their Targretin dose reduced to 300, 200 or 100 mg/m2/day due to hypertriglyceridemia, with 11% of patients developing NCI grade 3 hypertriglyceridemia and 4% developing grade 4 hypertriglyceridemia. One patient experienced abdominal pain that was considered possibly pancreatitis. Grade 3 neutropenia was observed in 26% of patients and the incidence of grade 4 neutropenia also was 26%. Grade 3 anemia was observed in 11% of patients and the incidence of grade 3 thrombocytopenia was 7%. Treatment was otherwise well tolerated, and there were no Targretin-related deaths or serious adverse events. Nine patients withdrew from the study due to adverse events, regardless of relationship to any study drug. Importantly, no adverse events were identified that could be attributed to the combination of Targretin capsules and chemotherapy.

Individual investigators also collected efficacy data based on standard oncology response criteria. Efficacy data are available on 33 patients who completed at least two cycles of therapy. One patient had a complete response (complete regression of tumor) and 10 had partial (defined as more than 50% improvement) responses, for an overall response rate of 33% (11/33). In addition to the objective responders, 17 patients (52%) had stable disease, including two minor responses (25-50% reduction in tumor).

"Targretin's preclinical properties to induce cell differentiation, inhibit tumor growth and trigger apoptosis may translate into clinical benefit, delay time to disease progression, and provide a survival advantage for patients with NSCLC," Dr. Rizvi said. "To date, a total of 174 lung cancer patients have been treated in five different clinical trials of Targretin capsules with compelling results."

Median survival for patients with advanced NSCLC is less than nine months, even with the best current treatment options. These patients are frequently treated with platinum-based combination chemotherapy, with reported overall response rates from 15-21%.

"Consistent findings from studies of numerous combination chemotherapy regimens have led some investigators to believe that a plateau in clinical benefit has been reached," Dr. Rizvi said. "New and effective treatments with separate and distinct mechanisms of action are needed. This may include drugs that act through disease stabilization, rather than classic objective tumor responses, to provide patients survival benefit. Bexarotene, for example, is a novel synthetic retinoid analogue that binds selectively to retinoid X receptors, and this RXR selectivity may confer efficacy and/or safety advantages over other, non-RXR selective retinoids."

In an earlier study of Targretin capsules in advanced NSCLC, median survival was 14 months among 28 patients who were treated with another chemotherapy regimen and Targretin at 400 mg/m2/day. The study was published in the Journal of Clinical Oncology, Vol. 19, No. 10, 2001. Based on these and other encouraging results, two large, phase III studies are underway worldwide to determine whether Targretin capsules plus chemotherapy extends survival among patients with advanced NSCLC. In order to accelerate the studies' time to completion, Ligand recently has decided to expand the number of sites in the studies to approximately 100 each. For more information about these studies, go to www.clinicaltrials.gov and search for "bexarotene."

ONTAK(R) Shows Activity in Patients with Fludarabine-Refractory CLL

In a separate study presented at ASCO, eight of nine (89%) patients with fludarabine-refractory chronic lymphocytic leukemia (CLL) who were treated with at least three courses of Ligand's ONTAK (denileukin diftitox) had reductions in peripheral CLL cells, with two of these patients achieving reductions of 99% or more. Three of the nine patients experienced a greater than 50% reduction in the diameter of their cancerous lymph nodes, based on physician exams and CT scans. One patient has had no evidence of adenopathy (diseased lymph glands) in follow-up exams and scans, and has an ongoing partial remission after more than two months of treatment.

"Most patients with fludarabine-refractory CLL respond poorly to additional chemotherapy, so novel agents that can kill chemo-resistant CLL stem cells and have non-overlapping toxicities are needed," said lead author Donald Fleming, M.D., of the University of Louisville School of Medicine. "This study demonstrates that ONTAK has biologic activity in fludarabine-refractory CLL and can produce partial remissions without significant immunosuppression."

In the study, 14 patients with fludarabine-refractory CLL were treated with 9 or 18 mcg/kg/day of ONTAK in one-hour infusions for five consecutive days, every 21 days, for up to eight cycles. Two patients had Rai stage I disease, five had Rai stage II and seven had Rai stage IV. The patients had been heavily pre-treated with between one and 11 prior therapies, with a mean of four previous treatments.

Adverse events were similar to those previously reported with ONTAK, most commonly transient transaminasemia, hypoalbuminemia and flu-like symptoms. Ten patients did not receive all eight cycles, two of them due to ONTAK-related adverse events (vascular leak syndrome and an anaphylactoid reaction). Most patients tolerated outpatient treatments with ONTAK and were able to maintain their normal daily activities.

The authors note that ONTAK demonstrates activity against CLL because CLL cells express the CD25 component of the interleukin-2 (IL-2) receptor. With this in mind, they plan to study ONTAK in combination with Targretin, which up-regulates, or makes more plentiful, the IL-2 receptor on CLL cells.

Summary of Ligand-Related Studies at ASCO

-- Poster #203: Francisco Esteva, et al. Multicenter phase II study of oral
bexarotene for patients with metastatic breast cancer.

-- Poster #1071: Donald Fleming, et al. Diphtheria fusion protein (ONTAK)
therapy of patients with fludarabine-refractory chronic lymphocytic leukemia.

-- Poster #1177: Jonathan Kurie, Reuben Lotan, at al. Randomized,
placebo-controlled trial of 9-cis retinoic acid (9cRA) versus 13-cis retinoic
acid (13cRA) plus alpha-tocopherol (AT) in the reversal of biomarkers of
bronchial preneoplasia in former smokers.

-- Poster #1334: Naiyer Rizvi, et al. Phase I/II safety evaluation of
bexarotene in combination with carboplatin and paclitaxel in patients with
chemotherapy-naive advanced non-small cell lung cancer (NSCLC).

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 CD25 (p55) 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 March 2001.

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 contains certain forward-looking statements that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from our expectations. There can be no assurance that results of subsequent studies of Targretin capsules or ONTAK, alone or in combination with any therapy, will confirm results discussed here. Additional information concerning these and other risk factors affecting Ligand can be found in prior press releases as well as in public periodic filings with the Securities and Exchange Commission, available via www.ligand.com. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

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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