Targretin Capsules Shows Activity in Clinical Trials in Patients with Non-Small Cell Lung Cancer and Cutaneous T-Cell Lymphoma.

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SAN DIEGO--(BW HealthWire)--May 23, 2000

Data Reported at the ASCO Meeting Suggest Potential Improvement in

Therapy of NSCLC and Demonstrate Activity of Two Dose Levels in

Patients with CTCL

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) today announced the publication of abstracts on study results suggesting that Targretin(R) (bexarotene) capsules may delay disease progression in patients with non-small cell lung cancer (NSCLC) and showing that Targretin capsules provide a convenient, oral, treatment option for patients with cutaneous T-cell lymphoma (CTCL). The results of the second abstract were presented in a poster session at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO) in New Orleans.

In the first study, a multicenter, randomized, double-blinded, placebo-controlled Phase II trial, the administration of Targretin capsules, a novel synthetic retinoid, was studied to determine whether high or moderate doses were more effective than placebo in postponing disease progression in patients with advanced NSCLC who were previously treated with platinum-based chemotherapy.

"Results indicate that higher doses of Targretin capsules may potentially delay disease progression in non-small cell lung cancer patients," said Naiyer Rizvi, M.D., a medical oncologist at the Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C., and a principal investigator for the study. "We are excited by these initial results and are hopeful that with further successful clinical research, Targretin capsules may be added to the treatment for lung cancer, which is the leading cause of cancer death among men and women in the United States."

In other results presented at the ASCO meeting, researchers who participated in two Phase II-III, multicenter, international, open-label trials found that Targretin capsules can provide a novel, convenient, oral therapy for patients with any stage CTCL who have failed prior treatments.

"There are many therapies available to treat CTCL, but over time, patients become refractory to them," said Kenneth Hymes, M.D., Associate Professor of Clinical Medicine, Hematology, Coagulation and Medical Oncology at New York University School of Medicine. "These results show that Targretin capsules appear to be an effective treatment. We are excited to be able to offer our patients another treatment option that may help to control their disease."

According to Steven D. Reich, M.D., Ligand's Senior Vice President of Clinical Research, results of these studies show that Targretin capsules may have future applications beyond its current approved use. "We are pleased that the results reported at the ASCO meeting suggest that Targretin capsules therapy can fill a true need for patients with different types of cancers," he said. "Ligand is committed to finding solutions for patients with difficult-to-treat conditions."

Non-Small Cell Lung Cancer (NSCLC) Study

The study included patients with Stage IIIB with pleural effusion, Stage IV, or recurrent, NSCLC who had stable or responsive disease following first-line, platinum-based combination chemotherapy (ChRx). An interim assessment was scheduled after 90 patients had been enrolled, but the study was prematurely terminated for administrative reasons after 54 patients entered. Of the 54 patients, 52 received at least one dose of Targretin or placebo. Patients were randomized by center to placebo (16 patients, 31 percent), 300 milligrams per square meter of body surface area per day (mg/m2/day) (21 patients, 40 percent), or 600 mg/m2/day (15 patients, 29 percent). Median time to progression (TTP) from first treatment with Targretin capsules was 56 days for placebo, 85 days for moderate dose, and 128 days for high dose (p=0.67, Log-rank). Patients who had a response to ChRx prior to receiving Targretin capsules had longer TTP than those with stable disease. For patients who responded to ChRx, median TTP was 56, 165 and 178 days for placebo, moderate and high dose of Targretin capsules, respectively. The percentage of patients with response to prior ChRx was higher in the placebo group (69 percent) than the active treatment arms (52 percent; 47 percent) suggesting that the effect on TTP is Targretin-related. Because of the number of patients, the study does not have the statistical power to detect differences among the treatment groups. However, the study shows that patients with NSCLC can tolerate Targretin capsule therapy at doses up to 600 mg/m2/day after platinum-based ChRx and that Targretin capsules may have the potential to delay TTP in some patients with advanced NSCLC. Side effects observed were asthenia, hyperlipemia, skin scaling and dryness, peripheral edema, pruritus, anorexia, and dyspnea.

The abstract, "Placebo-Controlled Trial of Bexarotene (Targretin, LGD1069), a Retinoid X Receptor (RXR) Agonist, as Maintenance Therapy for Patients Treated with Chemotherapy for Advanced Non-Small Cell Lung Cancer (NSCLC): An L1069-20 Study Group Trial," was published in the Proceedings of the 36th Annual Meeting of the American Society of Clinical Oncology. Study co-authors were Peter D. Eisenberg, M.D., of Marin Oncology Associates in Greenbrae, California, and Steven D. Reich, M.D., of Ligand Pharmaceuticals.

Cutaneous T-Cell Lymphoma (CTCL) Study

The data from trials of patients with refractory or persistent CTCL of Tumor, Nodule Metastasis (TNM) Stage I-IIA or TNM Stage IIB-IV were analyzed by disease stage for response and safety at initial doses of 300 and greater than 300 mg/m2/day. Response was determined by standard oncologic criteria applied to monthly evaluations of both a physician's global assessment (PGA) of disease and a composite assessment (CA) of index lesion clinical signs and body area involved. The highest response by PGA or CA were used to determine response rates (percent) by stage. Response rates for the 84 patients initially treated with 300 mg/m2/day and for the 53 patients receiving initial doses of greater than 300 mg/m2/day are summarized below.

             300 mg/m2/day                         >300 mg/m2/day

TNM Stage      Percent      Number              Percent         Number
   IA           50.0%         2/4                85.7%            6/7
   IB           52.4         11/21               66.7             4/6
   IIA          66.7          2/3                33.3             1/3
   IIB          56.5         13/23               82.4            14/17
   III          31.6          6/19               40.0             4/10
   IVA          44.4          4/9                   0             0/6
   IVB          40.0          2/5                50.0             2/4
   All          47.6         40/84               58.5            31/53

There were three of 84 patients (4 percent) with complete clinical response (CCR) at 300 mg/m2/day (Stages IB, IIA and III) and nine of 53 patients (17 percent) with CCR at greater than 300 mg/m2/day (IA-3, IB-1, IIA-1, IIB-4). Kaplan-Meier projected median durability of response was 176 days (range 29-176 days) for 300 mg/m2/day and 306 days (range 55-453 days) for greater than 300 mg/m2/day. At 300 mg/m2/day, adverse events (AEs) of greater than or equal to 15 percent incidence, at least possibly related to treatment were hyperlipemia (primarily hypertriglyceridemia, 79 percent), hypercholesteremia (32 percent), central hypothyroidism (29 percent), headache 25 (percent), and asthenia (16 percent). At greater than 300 mg/m2/day, AEs of greater than or equal to 15 percent incidence were hyperlipemia (79 percent), hypercholesteremia (62 percent), central hypothyroidism (49 percent), asthenia (43 percent), leukopenia (43 percent), headache (30 percent), diarrhea (28 percent), skin flaking (28 percent), anorexia (23 percent) and anemia (17 percent). Serious AEs at least possibly related occurred in 3 of 84 patients (4 percent) at 300 mg/m2/day (pancreatitis, hemorrhage, liver failure, bilirubinemia, coagulation disorder, neuropathy, pruritus). At greater than 300 mg/m2/day, 6 of 53 patients (11 percent) had serious AEs (fever, chest pain, diarrhea, cholestasis, pancreatitis, dehydration, Herpes zoster).

The abstract, "Oral Bexarotene in CTCL Patients by TNM Stage of Disease," was published in the ASCO Proceedings. Study co-authors were Kenneth J. Washenik, M.D., Ph.D., of New York University Hospital, New York, New York; Madeleine Duvic, M.D., of the University of Texas MD Anderson Cancer Center, Houston, Texas; Ann Martin, M.D., of Washington University, St. Louis, Missouri; and Patricia Myskowski, M.D., of Memorial Sloan-Kettering Cancer Center, New York, New York.

Targretin Capsules and Gel

In December 1999, the U.S. Food and Drug Administration (FDA) approved the capsule formulation of Targretin for the treatment of all stages of CTCL refractory to at least one prior systemic therapy. The FDA granted orphan drug designation to Targretin in June 1999 for the treatment of patients with CTCL. The European Agency for the Evaluation of Medicinal Products (EMEA) is reviewing a Marketing Authorization Application (MAA) submitted in November 1999 by Ligand for Targretin capsules for the treatment of patients with CTCL. Ligand is currently conducting Phase II trials with Targretin capsules for the treatment of patients with moderate to severe plaque psoriasis and for the treatment of women with advanced breast cancer.

In February 2000, the FDA granted priority review to Ligand's New Drug Application (NDA) for Targretin (bexarotene) gel 1%, a novel topical therapy intended for the treatment of cutaneous lesions in patients with Stage IA, IB or IIA CTCL who have not tolerated other therapies or who have refractory or persistent disease. Under priority review, the FDA is expected to complete its review of the application within six months of the December 9, 1999 submission date. Ligand is targeting submission of an MAA with the EMEA for Targretin gel during 2000.

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 had three drugs approved during 1999 for marketing in the U.S. -- Targretin(R) capsules, ONTAK(R) and Panretin(R) gel -- that are being marketed through its specialty cancer and HIV-center sales force. Targretin(R) gel is currently under review by the FDA for marketing approval in the U.S., and Morphelan(TM) (licensed from Elan) is in late-stage development. 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 and actual results could differ materially from those described as a result of factors outside of the control of Ligand. There can be no assurance that final results will be supportive of regulatory approvals required to market Targretin or any other Ligand product for NSCLC or any other indication; that regulatory approvals, including labeling approvals, will be granted in a timely manner, or at all; that patient and physician acceptance of any of these Ligand products will be achieved; or that Targretin gel or any other Ligand product will be accepted by physicians for prescribing, by patients for use and by insurance companies/agencies for reimbursement. Additional information concerning these and other 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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Note: Targretin(R)and Panretin(R)are registered trademarks of Ligand Pharmaceuticals Incorporated, and ONTAK(R)is a registered trademark of Seragen, Inc., a wholly owned subsidiary of Ligand. Morphelan(TM)is a trademark of Elan. Full prescribing information for our marketed products may be obtained from Ligand Professional Services by calling toll-free 1-800-964-5836.