Targretin(R) Capsules Show Positive Results in Moderate to Severe Plaque Psoriasis; Targretin Capsules Also Effective in Treating All Stages Of CTCL.

Business Editors/Health & Medical Writers

BIOWIRE2K

SAN DIEGO--(BW HealthWire)--May 3, 2000

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) announced today that abstracts published in the Journal of Investigative Dermatology and to be presented in Chicago at the Society of Investigative Dermatology's (SID) 61st Annual Meeting (May 10-14) reported (1) results of Phase II clinical trials of Targretin(R) capsules to treat patients with moderate to severe plaque psoriasis, (2) results of two Phase II-III clinical trials of Targretin(R) capsules to treat patients with refractory or persistent CTCL, and (3) the development of a composite assessment method for evaluating CTCL.

Targretin capsules therapy was approved by the Food and Drug Administration (FDA) in December 1999 and is marketed in the U.S. by Ligand Pharmaceuticals for once-daily oral administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy.

"The results of studies presented at the SID Annual Meeting demonstrate the monotherapy activity of Targretin capsules in CTCL and, most recently, psoriasis," said Steven D. Reich, M.D., Ligand Senior Vice President, Clinical Research. "It is particularly encouraging that the studies of skin changes at the microscopic level by immunohistochemical techniques, as described by Dr. Jurgen Smit, confirm therapeutic benefits for patients suffering from psoriasis. Dr. Madeleine Duvic's presentation summarizes the clinical information in patients with CTCL that helped gain FDA approval of Targretin capsules in December 1999. The composite assessment for evaluating CTCL presented by Dr. Patricia Myskowski is an important advance to clinical research in patients with CTCL as it provides a firm basis for determining objective response rates in a disease that is notoriously hard to evaluate.

"Ligand will continue its clinical program to expand the safety and efficacy of Targretin capsules in CTCL and psoriasis as well as other cancer and benign disease indications. It is expected that a new Phase II multi-center trial to further explore safety, efficacy and dose of Targretin capsules in psoriasis will be initiated in the U.S. as a result of this positive initial trial."

Phase II Clinical Trials in 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 37 patients with moderate to severe plaque psoriasis. Patients typically had three to six prior therapies which commonly included corticosteroids, Vitamin D derivatives, PUVA and RAR retinoids. Jurgen Smit, M.D., University Hospital Nijmegen, Nijmegen, The Netherlands, reported an interim analysis of three of the four dose groups. In these three groups, Targretin capsules achieved at least 50% improvement in up to 46% of patients after 12 to 24 weeks of therapy. Data from the 3 mg/kg/day panel are pending.

         Percent of Patients with Moderate to Severe Psoriasis
 Who Achieved At Least 50% Improvement with Targretin Capsules Therapy


Dose             Plaque      Physician's Global  Psoriasis Area and
milligrams per   Elevation   Assessment (PGA)    Severity Index (PASI)
kilogram of      (PEL)(1)                        score
body weight
per day

0.5              38%                46%               31%
(13 patients)

1                25%                42%               25%
(12 patients)

2                50%                50%               25%
(12 patients)

3                Analysis pending   Analysis pending  Analysis pending
(12 patients)

      (1) At least two-grade improvement on a five-point scale.

"Psoriasis is a chronic skin disease that requires sequential therapies as the disease progresses and may become drug resistant," said Dr. Smit. "New treatments are required and Targretin capsules appear to be a promising new candidate for psoriasis therapy. The results of our study suggest both clinical activity and changes in skin of immunohistochemical markers that are associated with improvement of the disease. Based on the positive results of this study, additional clinical trials with Targretin capsules alone and in combination with other therapies are warranted in patients with psoriasis, in order to find the profile of clinical efficacy and its side effects." Dr. Smit will discuss the interim results of this trial on Friday, May 12, at 9:00 a.m.

Immunohistochemical studies based on skin biopsies showed changes in cellular markers that were supportive of the clinical observations of improvement in psoriasis, and demonstrated that bexarotene 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.

Targretin capsules therapy was generally well tolerated at all doses, with adverse events with an overall incidence greater than 10% and without regard to relatedness to Targretin capsules consisting of hyperlipidemia (57% incidence), pharyngitis (19%), asthenia (11%), and pruritus (11%). The side effect profile was dose-dependent, and more favorable at the lower doses. Notably absent or reduced were traditional retinoid toxicities such as dry mucous membranes, skin cracking, skin peeling, hair loss and sticky skin.

Psoriasis is a chronic immune-mediated skin disorder that affects more than 6.4 million people in the United States and appears to be slightly more prevalent among women than men. Approximately 150,000 new cases of psoriasis occur in the U.S. each year. Psoriasis is categorized into degrees of severity based on the amount of body surface area affected, which is useful in determining an individual's treatment. Mild psoriasis is defined as affecting less than 2% of the body's surface, moderate psoriasis is defined as affecting 2-10% and severe psoriasis is defined as affecting greater than 10%.

Advanced Stage CTCL Pivotal Trial Design and Results

Targretin capsules therapy was evaluated for safety and efficacy in two international open-label, multi-center, Phase II-III clinical trials of patients with refractory or persistent CTCL of Tumor, Nodule, Metastasis (TNM) Stages I-IIA or TNM Stages IIB-IV. Patients had failed at least two CTCL therapies (for Stages I-IIA) or were refractory to at least one systemic anticancer therapy (IIB-IV). Response was determined using standard oncologic criteria for monthly evaluations by a Physician's Global Assessment (PGA) of disease and a Composite Assessment (CA) of the sum of scores of five clinical signs of representative index lesions.

"Overall, 49% of patients (74 of 152) achieved response by PGA or CA," said Madeleine Duvic, M.D., Chief, Section of Dermatology, University of Texas MD Anderson Cancer Center. Dr. Duvic will present the results of the trials in an oral presentation at SID on May 12 at 8:48 a.m. "These trials show Targretin capsules to be an effective and well-tolerated oral treatment for patients with all stages of CTCL that has been refractory following prior systemic anti-cancer therapy.

"Cutaneous T-cell lymphoma is a chronic, highly symptomatic, debilitating malignancy of T-cells that infiltrate the skin. While there are multiple conventional therapies, most patients become refractory to them. With the efficacy, durability and manageable side effects profile of Targretin capsules as shown in these two studies, I would expect that Targretin capsules would be used at some point in almost all patients with CTCL. Targretin capsules therapy is convenient for patients as it does not require specialized equipment or frequent visits to health care facilities other than for laboratory monitoring of blood for side effects."

Data were analyzed for responses at the initial doses of 6.5 (15 patients), 300 (84 patients) and over 300 milligrams per square meter of body surface area per day (mg/m2/day). Based on the CA and PGA endpoints, 49% of patients achieved clinical complete response (CCR) or partial response (PR) of greater than 50% improvement to treatment at any dose.

            Percent of CTCL Patients in Trial Who Achieved
     Greater than 50% Improvement with Targretin Capsules Therapy

Initial        Patients       Patient       CCR      Median Duration
Dose Level                    Response               of Rate
(mg/m2/day)                                          Disease Control

300            84             48%           4%       299 days

over 300       53             59%           17%      385 days

Targretin capsules therapy was well tolerated, and side effects were mostly mild to moderate. Side effects experienced by more than 10% of patients at least possibly related to treatment at the 300 mg/m2/day dose level included hypertriglyceridemia, hypercholesteremia, central hypothyroidism, headache, weakness and leukopenia. However, the side effects were generally easily managed, often required concomitant therapy for elevated triglycerides and hypothyroidism, and were reversible upon discontinuing treatment. Among the other less frequent side effects were diarrhea, fatigue, liver function test abnormalities, rash, pancreatitis and itching. In general, side effects increased at doses greater than 300 mg/m2/day.

Composite Method for Evaluating CTCL

The Targretin capsules early and advanced stage studies provided the opportunity for the development of a composite assessment (CA) method for evaluating CTCL during clinical trials, as described by Patricia Myskowski, M.D., Associate Attending Physician, Dermatology Service, Memorial Sloan-Kettering Cancer Center in New York City. No widely used method exists for the measurement of CTCL disease severity or therapy response. The CA measured changes in five representative index lesions, combined with a consideration of cutaneous tumor and all extra-cutaneous systemic involvement (lymph nodes and visceral tumors), when present.

In two Phase II-III pivotal trials of Targretin capsules in early and advanced stage refractory CTCL, the CA endpoint was used effectively in conjunction with a PGA endpoint. At the optimal starting Targretin dose (300 mg per mg2 per day), the CA response rate was 36% and PGA was 50% in the early stage trial and CA was 27% and PGA was 48% in the advanced stage trial.

"CTCL tends to be multi-focal and may be heterogeneous in its presentation, so objective response criteria developed for solid tumors may not be applicable," noted Dr. Myskowski. "The composite assessment allows detailed evaluation of the signs and symptoms of selected lesions to reflect the overall response of the patient. Use of the CA response rate will allow cross-study comparison of results." Dr. Myskowski will discuss the methodology in a poster session on Wednesday, May 10, 7:30-9:30 p.m.

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 in the U.S. Targretin(R) gel is currently under review by the FDA for marketing approval in the U.S., and two additional oncology-related products -- Morphelan(TM) (licensed from Elan) and Panretin(R) capsules -- are 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 including, but not limited to, the following. There can be no assurance that final clinical data will be consistent with interim clinical data; Targretin capsules or any product in the Ligand pipeline will be successfully developed for psoriasis, or any other indication; regulatory filings will be made and regulatory approvals will be granted in a timely manner or at all; or that Targretin capsules 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, which are available via Ligand's web site at http://www.ligand.com. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release.

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. For prescribing information, call [phone].