Targretin Capsules Benefit Patients in Treating Refractory Advanced Stage CTCL, Including Palliation and Remission of Erythrodermic CTCL.

SAN DIEGO--(BUSINESS WIRE)--Dec. 7, 1999--

Investigators Present Results at American Society of Hematology

Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) announced today that, in one of three presentations made in New Orleans at the American Society of Hematology (ASH) 41st Annual Meeting on the results of Phase II-III clinical trials of Targretin capsules to treat patients with various stages of cutaneous T-cell lymphoma (CTCL), investigators presented findings indicating that Targretin(R) (bexarotene) capsules benefit patients with refractory advanced stage (Tumor, Nodule, Metastasis (TNM) Stage IIB, III, IVA, IVB) CTCL. In a separate presentation at the ASH Annual Meeting, investigators found that Targretin capsules produced palliation and remission of erythrodermic CTCL, a difficult-to-treat form of CTCL. The presentation regarding trials for patients with refractory advanced stage CTCL was made by Kenneth Hymes, M.D., New York University Medical Center in New York City. The presentation regarding patients with erythrodermic CTCL was made by Peter Heald, M.D., Department of Dermatology, Yale University School of Medicine in New Haven, CT.

"Cutaneous T-cell lymphoma is a chronic, highly symptomatic, debilitating malignancy of T-cells that infiltrate the skin," said Madeleine Duvic, M.D., Chief, Section of Dermatology at the University of Texas MD Anderson Cancer Center in Houston, TX. "While there are multiple conventional therapies, most patients become refractory to them.

"Targretin capsules are an effective and well-tolerated oral treatment for patients with all stages of CTCL that has been refractory following prior systemic anti-cancer therapy. A rapid onset of response was observed in over 50% of patients at MD Anderson, and the duration of responses have been long-lasting, even in patients with large cell transformation and in erythrodermic patients with Sezary syndrome. I would expect that Targretin capsules would be used at some point in almost all patients with CTCL. Targretin capsules has the added benefit of not requiring specialized equipment and frequent visits to health care facilities." Dr. Duvic co-authored both presentations, as well as a presentation titled "Oral Bexarotene is Safe and Effective in a Phase II-III Clinical Trial in Refractory or Persistent Early Stage CTCL," also given yesterday at the ASH Annual Meeting.

ADVANCED STAGE CTCL CLINICAL TRIAL DESIGN AND RESULTS

The open-label, multi-center, Phase II-III clinical trial included 94 patients who were refractory to a median of two prior systemic therapies (range: 1-6) and had been exposed to a median of five prior CTCL therapies (range: 1-11). The median age was 64 years with a range of 27 to 89 years; 57% of the patients were men; 82% were white.

Data were analyzed for responses at the initial doses of 300 and over 300 mg/m2/day (the original starting dose, 650 mg/m2/day, was reduced to 300 mg/m2/day primarily due to hypertriglyceridemia and neutropenia). Monthly evaluations included a Composite Assessment (CA) adding scores of all clinical signs and body area involved and a Physician's Global Assessment (PGA) of change from the baseline. Responses required confirmation over at least four study weeks.

Based on CA and PGA, 49% of patients achieved response (clinical complete response (CCR)) and partial response of greater than 50% improvement (PR)) to treatment at any dose. Patient response rates were 45% at 300 mg/m2/day and 55% at over 300 mg/m2/day. The CCR rate was 2% at 300 mg/m2/day and 13% at over 300 mg/m2/day in this heavily previously treated population. Response rates for TNM stages were 57% at IIB, 32% at III, 44% at IVA, and 40% at IVB. -0-

   Initial Dose Level         CCR+PR                     CCR
     (mg/m2/day)              %(n)                      %(n)
     -----------              ------                    -----
      300                   45% (25/56)                2% (1/56)
    > 300                   55% (21/38)               13% (5/38)
    All Doses               49% (46/94)                6% (6/94)

Investigators reported that at the initial dose level of 300 mg/m2/day, the Kaplan-Meier projected time to best response was a median of 180 days; the projected duration of disease control from treatment onset was a median of 299 days; and 36% of patient responders relapsed over a median 19.1 weeks of monitoring. On a scale of 0 to 8, patients experienced a decrease in median pruritus by Week 16 of 1.5 grades from a median 3.2 at baseline. Responses to a CTCL-specific quality of life questionnaire showed consistent improvement during treatment. -0-

   Initial Dose:  300 mg/m2/day          Median               Range
     Time to Best Response              180 days           15-197 days
     Response Duration                  299 days           57-299 days

Adverse events experienced by more than 10% of patients at least possibly related to treatment at the 300 mg/m2/day dose level included hyperlipemia (primarily hypertriglyceridemia, 82%), hypercholesteremia (30%), central hypothyroidism (29%), headache (20%), asthenia (16%), pruritus (13%), leukopenia (11%), rash (11%) and skin disorder (11%). Serious adverse events at least possibly related to treatment at the 300 mg/m2/day dose level included one case of increased pruritus and one case of hemorrhage, coagulopathy and liver failure prior to death. In general, side effects increased at doses greater than 300 mg/m2/day.

Titled "Oral Bexarotene Benefits Patients with Refractory Advanced Stage CTCL," this presentation was authored by Kenneth Hymes, M.D., New York University Medical Center in New York City; Madeleine Duvic, M.D., Chief, Section of Dermatology at the University of Texas MD Anderson Cancer Center in Houston, TX; Peter Heald, M.D., Department of Dermatology, Yale University School of Medicine in New Haven, CT; Debra Breneman, M.D. of University of Cincinnati in Cincinatti, OH; Ann G. Martin, M.D. of Washington University in St. Louis, MO; Patricia Myskowski, M.D. of Memorial Sloan Kettering Cancer Center in New York, NY; Victor J. Stevens, Ph.D. and Richard C. Yocum, M.D. of Ligand Pharmaceuticals Incorporated in San Diego, CA; and the Worldwide Bexarotene Study Group.

ERYTHRODERMIC CTCL CLINICAL TRIAL DESIGN AND RESULTS

One of three presentations made at the ASH Annual Meeting on the results of multi-center clinical trials of Targretin capsules to treat patients with various stages of CTCL presented nine patients with generalized erythroderma from two study centers. This presentation was titled "Palliation and Remission of Erythrodermic Cutaneous T-Cell Lymphoma with a Novel Oral RXR-Selective Retinoid" and was authored by Dr. Duvic and Dr. Heald.

Investigators found that Targretin capsule therapy reliably induced rapid responses in these erythrodemic patients who had been refractory to interferon, extracorporeal photochemotherapy, electron beam radiotherapy, photochemotherapy with ultraviolet-A, topical chemotherapy, systemic chemotherapy, and combinations of these therapies. These patients had a mean age of 72 years, and there were seven men and two women. The first patients enrolled started with a dosage of 500 mg/m2/day and later patients were enrolled at 300 mg/m2/day to increase safety. Disease parameters measured every four weeks included body surface area of involvement, hematologic parameters including flow cytometry and CT measurement of adenopathy.

All nine patients had clearing of over 70% cutaneous involvement. Responses were noted within 12 weeks of therapy in all patients and as early as four weeks in three patients. By 28 weeks, two patients had achieved complete remission (two with resolution of adenopathy on imaging studies) and seven others had stable partial responses. Five patients had Sezary syndrome with lymphocytosis and peripheral blood CD4/CD8 ratio over 20. The marked cutaneous improvement in the Sezary syndrome patients was accompanied by persistence of the hematologic abnormalities of CTCL in the peripheral blood and no significant change of the CD4/CD8 ratio.

Targretin capsule dose reductions and antilipemic therapy were used to control hypertriglyceridemia in five of the nine patients. Seven of the patients developed reversible hypothyroidism and one diabetic patient was able to safely discontinue oral hypoglycemic therapy.

The dose responsiveness of CTCL to Targretin capsules was also observed during dose adjustments and resumption of the drug following temporary suspension. No serious adverse events occurred in these patients.

Targretin Capsules NDA

Ligand filed with the FDA an NDA for Targretin capsules in the treatment of CTCL in June 1999; at that time the FDA granted orphan drug designation to Targretin capsules 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).

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.