Ligand Provides Targretin Registration/Clinical Data Update in Non-Small Cell Lung Cancer, Breast Cancer and Psoriasis.

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SAN DIEGO--(BW HealthWire)--March 19, 2001

NSCLC Registration Program Initiated after FDA Meeting Agreement

on Studies and Endpoints; Results of Phase II Trials

in Breast Cancer and Psoriasis Summarized

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) announced today the initiation of its non-small cell lung cancer (NSCLC) registration program with Targretin(R) capsules after a productive meeting with the FDA in December 2000. The program is designed to support a supplemental indication for Targretin capsules in first-line treatment of patients with advanced NSCLC. In the next few weeks, the first study in this program is expected to be ready for patient enrollment.

"Based on a productive meeting with the FDA in December, we have designed and initiated a program that, if successful, can lead to an expanded label indication for Targretin capsules as first-line therapy for the treatment of patients with advanced NSCLC," said David E. Robinson, Ligand Chairman, President and CEO. "As this is a large program that is expected to involve well over 1,000 patients, our primary focus for Targretin capsules during 2001 and 2002 will be on NSCLC. We will, however, continue to explore in Phase II trials the potential of Targretin capsules in combination regimens for the treatment of patients in solid tumor indications as well as psoriasis."

Targretin Capsules NSCLC Registration Program

Ligand plans to conduct two randomized Phase III trials of approximately 600 patients each. One of these trials will compare the combination of cisplatin and vinorelbine with the same combination plus Targretin capsules and expects to begin accruing as early as the second quarter 2001. The second trial of similar design will study Targretin capsules in combination with carboplatin and paclitaxel. Prior to starting this trial, Ligand will be conducting a tolerability study of 15 to 30 patients of the three-drug combination of carboplatin, paclitaxel and Targretin capsules to further define safety parameters for the Phase III trial. This tolerability trial will shortly be ready for patient enrollment. A fourth trial is designed to study in approximately 30 patients the pharmacokinetics and potential drug interactions of the two combinations used in the Phase III program. The results of this final study, scheduled to start in mid-2001, will be needed at the time of the supplemental NDA submission.

Targretin Capsules and NSCLC

Ligand has conducted two Phase I/II trials in advanced cancers that included 36 patients with NSCLC (long-term survival data for this subset of patients will be published as an abstract in the Proceedings of the American Society of Clinical Oncology in May 2001). Ligand also conducted two clinical trials exclusively in patients with NSCLC.

One study (L1069-20) explored the use of Targretin capsules in patients with locally advanced or metastatic NSCLC who had stable or responsive disease after chemotherapy with a platinum-containing regimen. This was a Phase II/III placebo-controlled trial of two dose levels (300 and 600 mg/m2/day) of Targretin capsules. While the trial was terminated short of full accrual, results from the 52 patients treated on the study showed that Targretin capsule therapy given daily may have the potential to delay disease progression in patients with advanced NSCLC with previously stable or responsive disease following platinum-based chemotherapy. The results of this trial have been published in Clinical Lung Cancer (February 2001).

The second trial (L1069-18) was a Phase I/II study of patients with locally advanced NSCLC with malignant pleural effusion or metastatic disease treated with the combination of cisplatin, vinorelbine and Targretin capsules. The initial starting dose of 150 mg/m2/day of Targretin capsules was escalated within cohorts of patients in the Phase I portion of the study. A dose of 400 mg/m2/day of Targretin capsules was determined to be the maximum tolerated dose for the combination, and this dose was carried into the Phase II portion of the study. A total of 43 patients were enrolled and 28 of these were treated at 400 mg/m2/day.

The results of this Phase I/II experience were presented at the NCI-EORTC-AACR meeting in Amsterdam in November 2000 and have been accepted for full publication in a leading oncology journal in the first half of this year. These results indicated an overall response rate using standard oncology objective criteria for response for these 28 patients of 25 percent. These patients had a one-year survival of 61 percent and two-year survival of 32 percent, with a projected median survival of 14 months. In contrast, results from a recently reported, large-scale, randomized, Eastern Cooperative Oncology Group study (ECOG 1594) indicate that median survival of late-stage NSCLC patients treated with leading combination chemotherapy regimens with two agents is approximately eight months, and only approximately one-third of these patients survive one year. Adverse events in Study L1069-18 included asthenia, nausea, hyperlipemia, vomiting, headache, exfoliative dermatitis, and anorexia. Hematologic toxicities were not greater than expected with cisplatin and vinorelbine alone. One death from renal insufficiency occurred during the Phase I trial. Toxicities in the Phase II portion of the trial were consistent with Targretin monotherapy and with what one would expect with combination chemotherapy with cisplatin and vinorelbine. Because of the positive efficacy results of this trial and the manageable toxicity profile of the combination, Ligand is able to proceed directly to a Phase III trial comparing the chemotherapy of cisplatin and vinorelbine with the same regimen plus Targretin capsules at 400 mg/m2/day.

Targretin Capsules and Breast Cancer Summary Results

A Phase II study of Targretin capsules in patients with metastatic breast cancer has been fully accrued and nearly all patients have completed treatment. The patients were entered into three groups based on their prior treatment. All groups required that patients have metastatic breast cancer. Eligibility for a particular group was based on a patient's prior treatment for her metastatic disease. The three groups included: patients whose disease had progressed while being treated with standard chemotherapy; patients whose disease had progressed while being treated with hormone therapy; and patients whose disease had progressed while being treated with tamoxifen. The patients included in the tamoxifen-resistant group of the study remained on tamoxifen and Targretin was added to their therapy regimen. Each group had two dose levels: 200 and 500 mg/m2/day. The study was designed such that if there were one or more objective tumor responses in the first 14 patients of any dose group, that group was to be expanded to 30 patients. Patients were evaluated for response every eight weeks for the first six months of the study and every 12 weeks thereafter.

There were 148 patients randomized in the study to obtain at least 132 evaluable patients. There was at least one sustained objective response in each of the low dose (200 mg/m2/day) groups across the three patient populations and none at the high dose (500 mg/m2/day). All three low dose groups were expanded to at least 30 evaluable patients.

All objective responses were in the low dose groups with point estimates of response of six percent for patients refractory to hormonal therapy or chemotherapy and three percent for patients who failed tamoxifen. The time to progression across all groups of patients was eight to ten weeks. About 20 percent of patients in the low dose hormone-refractory and the low dose and high dose tamoxifen-resistant groups had stabilization of disease for at least six months. About one-third of the patients had at least transient, single-time point, measurable tumor reduction. Although a number of patients appeared to benefit from treatment with Targretin capsules, the overall observed objective anti-tumor response did not meet the protocol-defined target for activity.

There were no drug-related deaths and only two patients had drug-related serious adverse events. The most common adverse drug events were hyperlipemia (84 percent), dry skin (34 percent), asthenia (30 percent) and headache (27 percent). There were no new or unusual adverse events compared to the existing database.

"The breast cancer study was initiated on the basis of positive preclinical data using the rat, NMU-induced breast cancer model as published in the Journal of the National Cancer Institute in December 1999," said Steven D. Reich, M.D., Ligand Senior Vice President, Clinical Research. "Although there appears to be limited activity in advanced-stage patients, the compelling findings in the animal model do not appear to translate clearly to the clinical situation. While we continue to assess whether Phase II combination studies are warranted, it is clear that further laboratory experiments are needed to understand the mechanism of action of Targretin in breast cancer."

A study of changes in various tissue biomarkers that are potentially associated with breast cancer after treatment with Targretin capsules in patients at high risk of developing breast cancer is scheduled to begin soon under the sponsorship of the National Cancer Institute to further evaluate the mechanism.

Targretin Capsules and Psoriasis

A multi-center dose-ranging Phase II clinical trial to evaluate activity and safety of Targretin capsules in non-oncologic doses was conducted in 50 patients with moderate to severe plaque psoriasis. Patients typically had three to six prior therapies that commonly included corticosteroids, Vitamin D derivatives, psoralen with ultraviolet A light therapy (PUVA) and retinoic acid receptor (RAR) retinoids. Four dose levels were studied with at least 12 patients in each group receiving 0.5, 1.0, 2.0, or 3.0 mg/kg (approximately 35 to 240 mg/m2) daily. Primary efficacy endpoints included Plaque Elevation (PE), Physician's Global Assessment (PGA), and Psoriasis Area and Severity Index (PASI) score. Intended duration of therapy was 12 weeks with an option for patients to continue to 24 weeks of therapy. Targretin capsules induced at least 50 percent improvement in up to 50 percent of patients by PE, up to 42 percent of patients by PGA, and up to 25 percent of patients by PASI score. Complete responses, either sustained or as of the last assessment, were observed in up to 17 percent of patients by PE, up to 8 percent by PGA, and up to 17 percent by PASI score. There did not appear to be a dose response by any of the primary efficacy endpoints. As expected, hypertriglyceridemia was the most common drug-related adverse event. Full histochemical analysis of biopsy samples has not been completed, but an interim analysis reported at the Annual Meeting of the Society of Dermatology in May 2000 demonstrated that Targretin capsule therapy was capable of reducing cell proliferation and hyperproliferation, as well as improving cell differentiation. The changes in cellular markers included statistically significant reductions in keratinocyte hyperproliferation and in overall dermal infiltrate, both key elements in the pathogenesis of psoriasis.

"Our study of Targretin capsules in patients with psoriasis shows that Targretin capsules have activity in psoriasis as monotherapy at daily doses substantially lower than approved oncology doses," said Richard C. Yocum, M.D., Ligand Senior Medical Director, Clinical Research. "This activity is sufficiently interesting to stimulate further dose-ranging trials in patients with psoriasis and, more importantly, evaluation in the context of a combination drug regimen or as part of multimodality therapy, such as phototherapies."

Targretin Capsules and CTCL 

Targretin capsules received U.S. Food and Drug Administration (FDA) approval for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy. Ligand submitted its marketing application to the European Agency for Medicinal Products in November 1999 and received a positive recommendation in November 2000; final approval by the European Commission for the marketing of Targretin capsules is expected shortly. In the U.S., Ligand currently markets its approved products, Targretin capsules, Targretin gel, ONTAK(R) and Panretin(R) gel, through its specialty oncology and dermatology sales forces.

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).

Information contained in this press release which is not historical may be forward-looking. Forward-looking statements and actual results could differ materially from those described as a result of factors including, but not limited to the following. There can be no assurance that results of additional clinical trials of Targretin capsules will confirm results of earlier clinical trials; that Targretin capsules will be approved for additional indications; or that any Ligand product will be accepted by patients and physicians. Additional information concerning these and other factors affecting Ligand's business can be found in press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission, which are available via Ligand's web site at www.ligand.com. Ligand disclaims any intent or obligation to update any forward-looking statements beyond the date of this release.

Targretin(R) and Panretin(R) are registered trademarks of Ligand Pharmaceuticals Incorporated. ONTAK(R) is a registered trademark of Seragen, Inc., a wholly owned subsidiary of Ligand. Full prescribing information for Ligand's products may be obtained by calling Ligand Professional Services at 800-964-5836, or, in Europe, Ligand Pharmaceuticals International, Inc., at [phone].

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