Targretin Capsules Phase II-III Clinical Trial Data Presented by Investigators at American Society of Hematology Meeting.

SAN DIEGO--(BW HealthWire)--Dec. 7, 1999--

Targretin(R) Capsules Effective in Treating Refractory or Persistent

Early Stage CTCL

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) announced today that investigators presented findings indicating that Targretin(R) (bexarotene) capsules are safe and effective in a Phase II-III clinical trial for treating patients with refractory or persistent early stage cutaneous T-cell lymphoma (CTCL).

The presentation was made in New Orleans yesterday at the American Society of Hematology (ASH) 41st Annual Meeting by Madeleine Duvic, M.D., Chief, Section of Dermatology at the University of Texas MD Anderson Cancer Center in Houston, Texas, on behalf of the World Bexarotene Study Group.

"CTCL is a T-cell malignancy that manifests itself in early stages in the skin," said Dr. Duvic. "It is a disfiguring, chronic disease that requires multiple therapies over time. Most of the available therapies for early stage CTCL require topical treatments of cytotoxic chemotherapy or specialized services and equipment that require frequent visits to health care facilities. Once these therapies fail, systemic therapies that require intravenous or subcutaneous injections are often required.

"Targretin capsule therapy is convenient and orally active and has manageable side effects. The greater than 50% response rate and long duration of response is impressive, especially in patients who have failed multiple prior therapies. Furthermore, Targretin capsule therapy is not immunosuppressive like many other systemic treatments for CTCL and does not involve intravenous catheters, so the risk of infection, with the possibility of death due to iatrogenic sepsis, is avoided."

Clinical Trial Design and Results

The Phase II-III randomized, open-label, multi-center clinical trial included 58 patients with histologically confirmed, early stage CTCL (Tumor, Node, Metastases (TNM) Stages IA, IB, or IIA) who were enrolled at 18 centers in the U.S., Canada, Europe, and Australia. Of the participants in the study, 69% were men, 85% were white, and the median age was 64 years with a range of 24 to 88 years. Patients had received a median of 3.5 (range: 2 to 13) prior systemic, irradiation, and/or topical therapies and were refractory to, intolerant to, or reached a response plateau for at least six months on at least two qualifying prior CTCL therapies. Response was determined by a Physician's Global Assessment (PGA) of overall clinical condition and a Composite Assessment (CA) of disease severity based on clinical signs of up to five index lesions.

Patients were assigned randomly to one of two different initial, once-daily dose levels of Targretin capsules (low = 6.5 mg/m2/day; high = 650, 500 or 300 mg/m2/day, depending on protocol version). Dose reduction was permitted for toxicity.

Based on standard oncology criteria as applied to the PGA or CA and confirmed over at least four study weeks, 54% of patients receiving 300 mg/m2/day as the initial dose achieved clinical complete response (CCR, 100% cleared) or partial response (PR, equal to or greater than 50% improved). Higher (> 300 mg/m2/day) dose levels showed a greater response rate (67%) but with a greater incidence of side effects. Only 20% of patients at the 6.5 mg/m2/day dose level responded partially or completely. The CCR rate rose substantially with increased dosage: 7% (1/15) at 6.5 mg/m2/day; 7% (2/28) at 300 mg/m2/day and 27% (4/15) at over 300 mg/m2/day. -0-

   Initial Dose Level        CCR+PR                        CCR

     (mg/m2/day)              % (n)                       % (n)

        6.5                20% (3/15)                   7% (1/15)
        300                54% (15/28)                  7% (2/28)
      > 300                67% (10/15)                 27% (4/15)

Investigators reported that, at the 300 mg/m2/day dose level, the Kaplan-Meier projected time to first response was a median of 57 days, and the time to best response was 87 days. The median duration of response could not be calculated because only two (13%) patients of 15 who responded to 300 mg/m2/day have relapsed.

Initial Dose:  300 mg/m2/day          Median                Range

              First Response          57 days            27-114 days
               Best Response          87 days            27-153 days

Adverse events reported in more than 15% of patients at least possibly related to treatment at the 300 mg/m2/day dose level included hyperlipemia (primarily hypertriglyceridemia 71%), hypercholesteremia (36%), headache (36%), hypothyroidism (29%), leukopenia (18%), pruritus (18%), and nausea (18%). Serious adverse events at least possibly related to treatment included one case of pancreatitis at the 300 mg/m2/day dose level; and at the over 300 mg/m2/day dose level, there were two cases of pancreatitis and one case each of diarrhea, cholestatic jaundice and dehydration. All of these serious adverse events resolved.

One of three presentations made at the ASH meeting on the results of clinical trials of Targretin capsules to treat patients with various stages of CTCL, this presentation was titled "Oral Bexarotene is Safe and Effective in a Phase II-III Clinical Trial in Refractory or Persistent Early Stage CTCL" and was authored by Madeleine Duvic, Chief, Section of Dermatology at the University of Texas MD Anderson Cancer Center in Houston, Texas; Ann Martin of Washington University in St. Louis, MO; Youn Kim of Stanford University in Palo Alto, CA; Elise Olsen of Duke University in Durham, NC; Gary Woods of University Hospital of Cleveland, OH; Richard Yocum of Ligand Pharmaceuticals Incorporated in San Diego, CA; and the Worldwide Bexarotene Study Group.

Targretin Capsules NDA

Ligand filed with the Food and Drug Administration (FDA) a new drug application (NDA) for Targretin capsules in the treatment of CTCL in June 1999; at that time the FDA granted orphan drug designation to Targretin for the treatment of patients with CTCL. Having granted the Targretin capsules NDA priority review status, the FDA is expected to complete its review of the Targretin capsules application in December 1999, soon after the FDA's Oncologic Drugs Advisory Committee (ODAC) meeting on December 13.

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 first two drugs -- Panretin(R) gel and ONTAK(R) -- were approved for marketing in the U.S. in early 1999 and are being marketed through its specialty cancer and HIV-center sales force in the U.S. Four additional oncology-related products are in late-stage development, including Targretin(R) capsules, Targretin(R) gel, Panretin(R) capsules, and Morphelan(TM) (licensed from Elan). 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).

Except for the historical information contained herein, 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 the Targretin capsules NDA will be approved for the treatment of patients with CTCL in a timely manner or at all; final clinical data will be consistent with interim clinical data; Targretin or any product in the Ligand pipeline will be successfully developed for psoriasis, breast cancer or any other indication; regulatory filings will be made and regulatory approvals will be granted in a timely manner or at all; if approved, 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; Ligand and/or its collaborative partners will successfully develop potential products; or Ligand will be able to hire and retain qualified personnel. 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.

Panretin(R) and Targretin(R) are registered trademarks of Ligand Pharmaceuticals Incorporated, and ONTAK(R)is a registered trademark of Seragen, Inc., a wholly owned subsidiary of Ligand.

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