Clinical Trial Results of Targretin(R) Gel in Early-Stage CTCL To Be Presented at SID Annual Meeting.

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SAN DIEGO--(BW HealthWire)--May 9, 2000

A 63% Overall Response Rate in Phase I/II and 44% in Phase III 

Trial Reported

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) today announced that two abstracts summarizing the results of two open-label evaluations of topical Targretin(R) (bexarotene) gel 1% in patients with early-stage cutaneous T-cell lymphoma (CTCL) were published in the April 2000 edition of The Journal of Investigative Dermatology. The abstracts will be presented in poster sessions at the 61st annual meeting of The Society for Investigative Dermatology, May 10-14, in Chicago. Timothy M. Kuzel, M.D., Associate Professor of Medicine, Northwestern University Medical School, will present Phase I - II clinical trial results of Targretin gel in the treatment of patients with early-stage CTCL. Peter Heald, M.D., Associate Professor, Department of Dermatology, Yale University School of Medicine, will present Phase III clinical trial results of Targretin gel in the treatment of patients with refractory or persistent early-stage CTCL.

Phase I - II Study Discussion

The objectives of the Phase I - II study were to evaluate topically applied Targretin gel for safety, dose tolerance and efficacy in the treatment of patients with early-stage (Tumor, Nodule Metastasis (TNM) Stages IA, IB and IIA) CTCL. Researchers noted a 63% overall response rate according to the Physician's Global Assessment (PGA) for the 67 patients enrolled at three study centers. Fourteen patients (21%) achieved clinical complete clearing. Some patients achieved the onset of response (greater than 50% improvement) as early as four weeks, with a projected median time to response of 20 weeks. Eighty-seven percent of treated patients reached the most potent of three gel concentrations (1% bexarotene).

"Topically applied Targretin gel offers an effective, safe, and well-tolerated approach for the long-term therapy of patients with early-stage CTCL," said Dr. Kuzel. "Additionally, Targretin gel offers a convenient therapy with manageable side effects; this may increase patient treatment compliance. Early-stage CTCL may persist for many years in some patients, leaving them with few effective treatment options. There is a need for active agents that can be applied for the long-term treatment of early-stage CTCL."

Three study centers enrolled a total of 67 patients in the Phase I-II program. Patients applied Targretin gel directly to lesions, and doses were escalated in concentration and application frequency every two weeks as tolerated until patients reached maximum concentration of 1% bexarotene. The initial dose escalation schedule began with 0.1% gel applied once daily, increasing every two weeks as tolerated to 0.1% gel applied twice daily, 0.5% gel applied once daily, 0.5% gel applied twice daily, 1.0% gel applied once daily, and finally 1.0% gel applied twice daily, with option to increase to three to four times daily. The starting dose was later changed by protocol amendment to 1% every other day, then escalating in frequency every one to two weeks to once, twice, three and four times daily, as tolerated. Each patient's signs and symptoms were monitored, and a Physician's Global Assessment (PGA) of therapy was evaluated monthly.

Mean grades of clinical signs and symptoms for patients' index CTCL lesions improved during the initial 24 weeks of treatment: erythema by 41%, plaque elevation by 74%, scaling by 73%, and pruritus by 33%. The projected median time to response was 20 weeks (range 4 - 86 weeks). The median duration of therapy was 315 days and the longest treated patient is ongoing at 4.25 years. Responses were sustained with a Kaplan-Meier projected median duration of response at 428 days (14 months with a range of 57 - 428 days). By the end of the study, 58 patients (87%) were treated with the highest gel concentration (1%), demonstrating good topical tolerance.

Adverse events at least possibly related to treatment were generally mild to moderate in severity and mainly occurred at the site of application. These adverse events included rash (erythema, 73% of patients), itching (pruritus, 33%), and pain (burning at the site of application, 24%). There were no serious adverse events related to study treatment. Treatment-limiting toxicities (rash and pain) occurred in 16 patients, 14 of whom continued treatment at a lower concentration and/or frequency.

Phase III Study Discussion

The Phase III study was designed to assess efficacy and safety of Targretin gel 1% in a relatively heavily pretreated population of patients with TNM Stage IA - IIA CTCL who were intolerant to, refractory to or had persistent disease with a six-month or longer response plateau following at least two prior treatments for CTCL. The data showed that Targretin gel appeared to be a safe and effective novel treatment for patients with treatment-resistant early-stage CTCL. Importantly, there was a rapid clinical response from the initiation of treatment, with the earliest time to onset of response of 28 days and the latest time of 128 days. Most patients (78%) responding to a CTCL-specific quality of life questionnaire indicated a general improvement (moderate improvement or much improved) in their condition during the course of treatment.

Dr. Peter Heald states, "Patients who took part in the study had failed at least two previous treatments for CTCL. The study data have shown that Targretin gel can provide these patients with a treatment alternative that is both generally well tolerated and effective against the cutaneous manifestations of CTCL, a progressive and symptomatic disease."

The 50 patients enrolled in this multicenter study had received from two to seven prior treatment modalities for CTCL. Targretin gel was topically applied by all patients on a schedule beginning with once every other day. Gel application frequency was then gradually increased to a maximum of four times a day depending on patient tolerance.

Twenty-two of the 50 patients (44%) achieved a complete or partial response (greater than 50% improvement) based on PGA and a composite assessment of index lesion severity, and four patients (8%) experienced a clinical complete response of all cutaneous lesions. Patients were treated for a median of 165 days, with the longest treatment period lasting 687 days.

Patients experienced a long duration of response, calculated from the first day of treatment. As of the cut-off date for this analysis, 68% of the responding patients were still in remission, and a total of 32% of responding patients relapsed over a median of 165 days on study.

The adverse events occurring with greater than 10% incidence and that were at least possibly related to treatment included rash (skin irritation, redness, scaling in 72% of patients), pruritus (itching, 32%), pain (primarily burning at site of application, 22%), skin disorder (skin inflammation, excoriation, raw plaques, new lesions, 16%) and contact dermatitis (12%). Most events were mild to moderate in severity and mainly occurred at the site of application. There were no serious adverse events related to study treatment, and relatively few patients (14%) were withdrawn for the primary reason of adverse event.

"We are pleased these studies have shown that Targretin gel may offer patients and physicians an effective, convenient and well-tolerated option for the treatment of early-stage CTCL," said Richard C. Yocum, M.D., Senior Medical Director, Clinical Research at Ligand. "Targretin gel, if approved, would complement Targretin(R) capsules and ONTAK(R) in offering a comprehensive range of novel products to patients and physicians in the management and treatment of CTCL, a debilitating and largely incurable disease. Orally administered Targretin capsules and topically-applied Targretin gel offer substantial convenience compared to currently available treatments."

Targretin gel and capsules

In February 2000, the U.S. Food and Drug Administration (FDA) granted priority review to Ligand's New Drug Application (NDA) for Targretin(R) (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 a Marketing Authorization Application (MAA) with the European Agency for the Evaluation of Medicinal Products (EMEA) for Targretin gel during 2000. In June 1999, the FDA granted orphan drug designation to Targretin for the treatment of patients with CTCL and, in December 1999, approved the capsule formulation of Targretin for the treatment of all stages of CTCL refractory to at least one prior systemic therapy. In November 1999, Ligand submitted an MAA in Europe for Targretin capsules for the treatment of patients with CTCL, and this application is under review by the EMEA. 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.

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 (IR) 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 gel or any other Ligand product; 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 press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission. Public information about Ligand is 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.

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. Full prescribing information for Targretin capsules, Panretin gel and ONTAK may be obtained from Ligand Professional Services by calling toll-free 1-800-964-5836.

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