Ligand Provides Update and Answers to Frequently Asked Questions on th

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    SAN DIEGO--(BUSINESS WIRE)--Jan. 26, 2005--Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) today provided a status report on its two pivotal Phase III studies of Targretin(R) (bexarotene) capsules in front-line combination therapy to treat advanced non-small cell lung cancer (NSCLC). To assist in understanding the trials, this release contains a list of the questions being most frequently asked and their answers.
    The two randomized trials, titled "Studies Providing Investigational Research in Targretin," and known as SPIRIT I and II, are being conducted at about 260 sites worldwide. They are designed to evaluate whether adding Targretin to front-line cisplatin/vinorelbine or carboplatin/paclitaxel chemotherapy extends the survival of patients with advanced (Stage IIIB with pleural effusion or Stage IV) NSCLC.
    For both studies, the primary endpoint is overall survival calculated using a stratified log-rank test, with a secondary endpoint of a Kaplan-Meier projected two-year survival. The studies are powered to show a 30% improvement in overall survival among Targretin-treated patients compared to patients who receive combination chemotherapy only.
    Patient enrollments were completed in August and September 2003, respectively. The statistical plan specifies the analysis trigger to be at the 456th death event or 18 months of follow-up from the date the last patient was entered into each study, whichever occurs later. Based on enrollment dates, that 18-month time point will be reached in mid-March 2005. The company expects to publicly release top-line data within approximately two weeks after the commencement of final data analysis.
    No efficacy results, preliminary or otherwise, from either study are known at this time. The study protocols do not provide for an interim analysis and the company will not provide any interim release of results of the studies nor speculate on the outcomes prior to final data analysis.
    Following is a list of the questions being most frequently asked about the two studies.

Question: What is the design of the clinical trials?

Answer: There are two, fully enrolled, randomized Phase III studies. Spirit I enrolled 623 patients at 94 sites in 13 countries. Spirit II enrolled 612 patients at about 166 sites in six countries. Eligibility requirements included stage IIIB with pleural effusion or stage IV disease and ECOG performance status 0 or 1. Patients who had received prior platinum-based chemotherapy for any indication or any prior chemotherapy for NSCLC were excluded. In Spirit I, patients were randomized to receive either cisplatin/vinorelbine alone or cisplatin/vinorelbine in combination with Targretin capsules. In Spirit II, patients were randomized to receive either carboplatin/paclitaxel alone or carboplatin/paclitaxel in combination with Targretin capsules. In both trials, the initial starting dose for Targretin patients was 400 mg per meter squared (body surface) per day, given once daily.

Question: When were the trials fully accrued?

Answer: Patient accrual was completed in SPIRIT I in August 2003 and SPIRIT II in September 2003.

Question: What percentage of the patients were enrolled in the last six months of the accrual period?

Answer: In SPIRIT I, 34% of the patients were enrolled in the last six months of the 24 months of patient accrual. In SPIRIT II, 61% were enrolled in the last six months of the 18 months of patient accrual.

Question: What are the endpoints?

Answer: For both studies, the primary endpoint is overall survival with a secondary endpoint of projected two-year survival. The studies are powered to show a 30% improvement in overall survival among Targretin-treated patients compared to patients who receive combination chemotherapy only.

Question: What is the statistical plan? Why did it change?

Answer: The original statistical plan called for efficacy data analysis at the later of 456 deaths or twelve months following the last patient entered into each study. That plan, combined with the actual pace of accrual rates as observed in the last six months of the SPIRIT II study, would have resulted in a limited number of patients whose actual survival could be observed for two years or longer. The final statistical plan was modified as agreed with the FDA to specify the analysis trigger to be at the 456th death event or 18 months of follow-up from the date the last patient was entered into each study, whichever occurs later. A March 31, 2004, news release regarding the agreement with the FDA on the final statistical plan contained the following paragraph:

"We are pleased, and believe this modification in the SPIRIT I and II statistical plan will strengthen the statistical information in the survival region between one and two years, thus enhancing the assessment of overall survival differences, and will be consistent with the timing of statistical analyses of other published Phase III studies in this patient population," said Andres Negro-Vilar, M.D., Ph.D., Ligand's executive vice president of research and development and chief scientific officer. "This modification should result in the majority of patients having between 1.5 and 2.5 years of follow-up observation based upon SPIRIT I and II accrual rates. We also expect the assessment of projected two-year survival, the study secondary endpoint, to be enhanced by the revised statistical plan."

Question: What other data analysis will you do?

Answer: The company intends to do a full analysis of the data from both studies.

Question: What will be the timing of the release of the data?

Answer: The company intends to release the top-line data - whether primary and secondary endpoints were met - within approximately two weeks after the commencement of data analysis. Depending on the progress and quality control of the analysis some additional data may also be available at that time. We expect to present a more complete analysis of the data at appropriate scientific conferences in the period of May - December 2005, as is practical. While the extension of the follow-up period to 18 months could be expected to be the trigger, under extended survival conditions (control or treated arms) it is theoretically possible that the 456th death event in each trial may not have occurred by the 18-month point. If that were to be the case, data analysis could be delayed until the later trigger point is reached. However, we will not know that until the data is analyzed on the target date.

Question: Which study will you analyze first?

Answer: Both studies will be analyzed concurrently when the trigger point has been met in BOTH studies. Question: What are the demographics of the patient population in the trials?

Answer: The following table contains preliminary demographic data on the patients (as of April 2004) including stage of disease and ECOG performance status.

L1069-48 (SPIRIT II) L1069-49 (SPIRIT I) ---------------------------------------- A B A B ---------------------------------------- Pts Enrolled 306 306 311 312 Female 34% 34% 28% 29% Age 63 63 61 61

Stage III B 14% 14% 17% 17% Stage IV 86% 86% 83% 83%

ECOG 0 35% 35% 26% 22% 1 64% 65% 74% 78%

Question: What other studies have been done on Targretin in NSCLC?

Answer: Targretin has been the subject of numerous Phase I and II studies in NSCLC. A list of key studies is available in the slides of the company's current presentation on the company web site at www.ligand.com.

Question: What is your overall development strategy for Targretin in Non-Small Cell Lung Cancer?

Answer: In addition to the SPIRIT studies, the overall strategy includes testing Targretin in front-line, second-line, and third-line settings both in combination and as a monotherapy.

In front-line, Phase II studies are nearly complete and a manuscript in preparation using Targretin in combination with gemcitabine. The other Phase II studies in combination with carboplatin/taxol and with Taxotere are underway.

In second-line, Phase II studies are underway using Targretin in combination with Taxotere.

In third-line, a Phase II study using Targretin as a monotherapy is nearly complete. A Phase I/II study of Targretin with Tarceva is complete and Phase II studies to test Targretin in combination with EGF receptor tyrosine kinase inhibitors are expected to commence in 2005. Additional information on these studies is available on the company web site at www.ligand.com.

    Lung Cancer

    Lung cancer is the leading cause of cancer death for both men and women in the United States. The American Cancer Society (ACS) estimates that more that 170,000 Americans are diagnosed with lung cancer each year, approximately 80% of whom will be diagnosed with NSCLC. The ACS also estimates that more than 160,000 Americans will die from lung cancer each year. Ligand estimates that the NSCLC market potential in first-line therapy - combination and monotherapy - could be approximately $1.5-2.0 billion. The total market potential, including second- and third-line mono and combination therapy is estimated at about $3 billion.

    About Targretin

    In December 1999, the FDA approved Targretin capsules for the treatment of cutaneous manifestations of cutaneous t-cell lymphoma 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, France, and Italy.

    About Ligand

    Ligand 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.

    Caution Regarding Forward-Looking Statements

    This news release may contain certain forward-looking statements that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. Actual events or results may differ from our expectations. These include statements regarding strengthening statistical information, period of patient follow-up observation, assessment of survival, improvement in survival, data analysis, the analysis trigger, timing of release of data, and market potential. There can be no assurance that results of these studies of Targretin will be favorable or that they will confirm results of previous trials, that data will be available in a timely fashion or demonstrate any hypothesis or endpoint, that Targretin will be useful in NSCLC alone or in combination with other drugs, nor that marketing applications will be filed or, if filed, approved. Additional information concerning these and other risk factors affecting Targretin capsules and Ligand can be found in prior press releases as well as in public periodic filings with the Securities and Exchange Commission, available via 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.

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CONTACT: Ligand Pharmaceuticals Incorporated Paul V. Maier, 858-550-7573 or Abe Wischnia, 858-550-7850

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