New Findings Presented at AACR Show Ligand's Targretin Synergizes with Chemotherapeutic Agents to Arrest NSCLC Growth and Prevents or Reverses Acquired Paclitaxel and Taxol Resistance in NSCLC and Advanced Breast Cancer.

Business Editors/Health/Medical Writers

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SAN DIEGO--(BUSINESS WIRE)--March 29, 2004

Three separate studies by Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) scientists being presented at the 95th Annual meeting of the American Association of Cancer Research (AACR) on Monday, March 29, support enhanced activity of chemotherapeutic agents in combination with Targretin(R) (bexarotene) in non-small cell lung cancer (NSCLC) and a novel activity of Targretin preventing or reversing acquired tumor cell resistance to paclitaxel (Taxol(R)) in NSCLC and advanced human breast cancer cell lines.

"The results presented at AACR provide new insights into the mechanism of action of Targretin in NSCLC by uncovering synergistic activity of Targretin together with different commonly used chemotherapeutic agents and by characterizing a unique action of Targretin to prevent or reverse acquired drug resistance to Taxol and other chemo agents," said Andres Negro-Vilar, M.D., Ph.D., Ligand's executive vice president for research and development and chief scientific officer. "We believe these insights on mechanism are particularly relevant to our combination studies SPIRIT I and II (frontline) and our ongoing and planned studies in second and third line."

Targretin Prevents or Reverses Acquired Taxol Resistance in NSCLC Cancer Cells (In Vivo and In Vitro)

Taxol is an important anticancer agent for the treatment of NSCLC, breast and many other types of cancer. Its extended utility, however, is limited by the development of acquired drug resistance by tumor cells, a phenomenon that also affects other taxanes and chemotherapeutic agents. The potential role of Targretin in preventing or reversing Taxol resistance is addressed in a study (abstract #2144) being presented Monday, March 29, 2004. Ligand's scientists developed a model of Taxol resistance NSCLC cell lines and demonstrated that using different regimens of sequential and/or continuous combined treatment of Taxol with Targretin resulted in the prevention and/or reversal of acquired resistance to Taxol. Resistant NSCLC tumor cells not only did not respond to additional Taxol treatment but also showed that the acquired resistance also affected other commonly used chemo agents such as vincristine and doxorubicin. All these agents have been shown to be substrates for the P-glycoprotein pump. Development of resistance was confirmed by the increased expression of the multi drug resistance gene MDR-1 and by the increased efflux activity of PgP. The results further showed that Targretin prevented resistance and cross-resistance by suppressing the expression of the MDR-1 gene and the activity of the P-glycoprotein pump in NSCLC cells.

In vivo studies showed that Targretin and Taxol combined treatment provided a much better antiproliferative response in NSCLC tumors and that the combination of Taxol plus Targretin but not Taxol alone significantly decreased tumor growth in Taxol-resistant tumors.

Synergistic Activity of Targretin and Cytotoxic Agents in Arresting NSCLC Growth

An additional study being presented at AACR (abstract #1989) demonstrates that a combination of Targretin and different therapeutic agents (i.e., Taxol, taxotere, etc.) produced a combined arrest of NSCLC cell tumor growth larger than each single agent alone. The combined activity of Targretin and Taxol was synergistic and the observed effects were seen across a panel of 10 different NSCLC cell lines representative of different tumor histologies seen in NSCLC patients.

"These data support our clinical observations in Phase I/II trials that Targretin has beneficial effects when used in combination or sequentially with cytotoxic agents in advanced (Stage IIIb and IV) NSCLC," said Negro-Vilar. "Ligand has recently completed two Phase III trials, Spirit I and Spirit II (1235 patients), combining Targretin with two commonly used chemo regimens, cisplatin + vinorelbine or carboplatin + paclitaxel, respectively. Patients are currently being followed for survival until the pre-determined trigger point for statistical analysis."

Targretin Prevents and Overcomes Acquired Drug Resistance in Advanced Breast Carcinoma

In a parallel study (abstract #2146) being presented on Monday, March 29, 2004, Ligand scientists demonstrated the activity of Targretin in preventing or reversing acquired drug resistance as well as intrinsic drug resistance in a human advanced breast carcinoma cell line, MDA-MB-231. Cells resistant to Taxol or doxorubicin showed a higher degree of invasiveness and angiogenic activity than those whose resistance had been prevented or reversed by concomitant treatment with Targretin. These results correlated with in vivo studies in which Targretin added to chemotherapy resulted in superior reduction of tumor growth to chemotherapy alone. Overall, the data clearly demonstrates the potential for Targretin to prevent or reverse acquired or intrinsic drug resistance in advanced breast carcinoma by interfering with tumor cell progression to a more malignant drug-resistant, invasive phenotype.

About Targretin

In December 1999, the FDA approved Targretin capsules for the treatment of cutaneous manifestations of CTCL in patients who are refractory to at least one prior systemic therapy. The European Commission granted marketing authorization for Targretin capsules in March 2001, and the product is currently marketed in many major European countries, including Germany, the United Kingdom, Spain, and France. Full prescribing information for Ligand's products can be obtained in the United States from Ligand professional services by calling 800-964-5836, or on Ligand's internet site at www.ligand.com.

About Ligand

Ligand Pharmaceuticals Incorporated discovers, develops and markets new drugs that address critical unmet medical needs of patients in the areas of cancer, pain, 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). For more information, go to www.ligand.com. Full abstracts for the three Targretin studies discussed in this news release are available on the American Association of Cancer Research internet site at www.AACR.org.

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. These include statements regarding prevention or reversal of drug resistance and beneficial effects of Targretin. Actual events or results may differ from Ligand's expectations. There can be no assurance that results of subsequent studies of Targretin, alone or 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. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.