Ligand's Targretin Gel Shows Promise for Chronic Severe Hand Dermatitis Patients.

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SAN DIEGO--(BUSINESS WIRE)--Feb. 20, 2003

Final Results of 55-Patient, Randomized Phase I/II Study: 39% of

Patients on Targretin Alone Achieved 90% Improvement; 79% of Patients

Improved by at Least 50%

Nearly 40% of patients with chronic severe hand dermatitis who were treated with Ligand's (Nasdaq: LGND) Targretin(R) (bexarotene) gel 1% experienced clinical improvement of 90% or more, and almost 80% of patients improved by at least 50%, according to final results of a Phase I/II dose escalation study to be presented tomorrow at the 27th Hawaii dermatology seminar conducted by the Skin Disease Education Foundation.

"These final results confirm that Targretin gel may effect significant improvement in severe hand dermatitis, a common, sometimes disabling condition," said lead investigator Jon Hanifin, M.D., Professor, Department of Dermatology, Oregon Health & Science University. "Severe hand dermatitis is a difficult disease to treat, and topical steroids, the current standard of care, show progressively less effectiveness and cause troublesome side effects such as skin atrophy. New therapies are needed in this area, and Targretin gel may play an important role in filling an unmet medical need. We are particularly encouraged by the fact that these final results are even stronger than the preliminary data reported last September."

Fifty-five patients with a history of chronic severe hand dermatitis for at least six months were enrolled in the 22-week, randomized, open-label study, which was designed to evaluate safety, tolerability and activity. Most of the patients were resistant to standard treatments for hand dermatitis. Patients were randomized to Targretin alone; Targretin in combination with mometasone furoate, a medium potency topical steroid; or Targretin in combination with hydrocortisone, a low potency topical steroid. By study design, half of the patients were included in the Targretin monotherapy arm and the other half were equally divided into the two steroid combination arms. In order to assess tolerability, all Targretin doses were escalated every two weeks, starting every other day, then once per day, twice per day and, finally, three times per day. The steroidal ointments were applied twice daily.

The investigators evaluated efficacy based on:

-- Physician's Static Assessment (PSA). This primary, FDA-recommended endpoint, which calls for 90% or greater improvement in the disease, is equivalent to a clear or almost clear condition on at least two observations 14 days apart.

-- Physician's Global Assessment (PGA), which calls for 50% or greater improvement in the condition on at least two observations two weeks apart.

Primary efficacy results were:

                 Targretin Gel only   Targretin Gel +  Targretin Gel +
                   (28 patients)       mometasone       hydrocortisone
                                       furoate (13)          (14)
PSA (at least 90%
 improvement)            39%              46%                 21%

PGA (at least 50%
 improvement)            79%              77%                 50%

Secondary endpoints were the sum of severity scores (for erythema, scaling, edema, vesiculation, fissuring and lichenification) and the percent of hand area affected by dermatitis. These measures were used to generate an objective endpoint called the hand eczema area-severity index, or HEASI. All these secondary endpoints confirmed the response rates as assessed by physicians.

Median time to at least 50% improvement was 6.1 weeks, and median time to at least 90% improvement was 12.6 weeks. In addition, patients' responses were durable. Among patients who achieved at least 90% improvement, the median duration of response was 12 weeks, and among patients who achieved at least 50% improvement, the median duration of response was 18 weeks. Duration of response was defined as the time between a patient's first observed response and their last observed response, or the end of the study's 26-week follow-up period.

Most adverse events were mild to moderate in severity. Adverse events that occurred in more than 5% of patients, and that were thought to be at least possibly treatment-related, were:

                 Targretin Gel only  Targretin Gel +   Targretin Gel +
                   (28 patients)    mometasone furoate  hydrocortisone
                                          (13)               (14)

Irritation/rash         29%                31%                29%
Stinging/burning         7%                31%                14%
Dermatitis flare        18%                 0%                29%

Three cases of irritation/rash were classified as moderate-to-severe, none of which occurred in the Targretin gel monotherapy arm. One patient in the Targretin gel plus hydrocortisone arm had a severe case of stinging/burning. Three patients in the Targretin gel monotherapy arm had a moderate-to-severe dermatitis flare, as did three patients who received Targretin gel plus hydrocortisone. Only four patients withdrew from the study due to adverse events, one of whom received Targretin gel monotherapy.

All treatment frequencies were tolerated by patients, as measured by compliance with the dose-escalation regimen. Forty patients (73%) reached three-times-daily dosing, and 48 patients (87%) reached twice-daily dosing. Only seven patients (13%) withdrew before reaching twice-daily dosing.

"We are extremely pleased with these final results, and intend to move forward to design and implement Phase II/III registration trials of Targretin gel in hand dermatitis," said Andres Negro-Vilar, M.D., Ph.D., Ligand's Senior Vice President for Research and Development and Chief Scientific Officer. "Activation of RXR receptors in the skin promotes the proliferation and differentiation of epidermal keratinocytes, improves skin thickening and stratification of the epidermal layers, and promotes homeostasis of the skin and its immune system. Targretin is an RXR-selective ligand that modulates genes essential to maintaining skin homeostasis, without causing the side effects commonly observed with the application of retinoic acid receptor (RAR) selective compounds."

About Hand Dermatitis and Targretin Gel

There are many subtypes of hand dermatitis, and many causes. Some subtypes may have a hereditary component. Most hand dermatitis is caused by contact with irritating environmental substances, such as chemicals, soaps and cleaning fluids, and some cases are caused by allergic reactions to a wide variety of environmental substances, including foods, plants, metals and cosmetics. Chronic hand dermatitis will repeatedly relapse or flare. It can involve 15-90% of the hands and affect one or both surfaces. Topical steroids are the primary first-line treatment.

Prevalence estimates of hand dermatitis vary widely due to survey limitations, under-reporting, under-recognition and misclassification. Ligand estimates that more than four million people in the United States have hand dermatitis and seek treatment. Slightly more than half of these patients have moderate to severe disease, providing a market opportunity in excess of $1 billion.

Targretin gel 1% was granted marketing clearance by the U.S. Food and Drug Administration (FDA) in June of 2000 for the topical treatment of cutaneous lesions in patients with early-stage (TNM Stage 1A and 1B) CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

About Ligand

Ligand 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 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 Targretin gel 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 toll-free 800-964-5836, or on Ligand's internet site at www.ligand.com.

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