Investigators Present Detailed Targretin Lung Cancer Data from SPIRIT

Investigators Present Detailed Targretin Lung Cancer Data from SPIRIT I & II Trials at ASCO

    Business Editors/Health/Medical Writers
    BIOWIRE2K

    SAN DIEGO--(BUSINESS WIRE)--May 16, 2005--

Subgroup Analysis Reveals Significant Survival Correlation with Triglyceride Biomarker
    Detailed reports of the results of Ligand Pharmaceuticals Incorporated (Nasdaq:LGND) two pivotal Phase III studies of Targretin(R) (bexarotene) capsules in front-line combination therapy with standard chemotherapy to treat advanced non-small cell lung cancer (NSCLC) were presented Saturday. The oral presentations were given at a lung cancer session at the annual meeting of the American Society of Clinical Oncology in Orlando on Saturday, May 14.
    As previously announced, the two pivotal Phase III studies did not meet their endpoints of improved overall survival and projected two-year survival. Those results were consistent between both trials despite different geographical study sites and chemotherapy regimens on the intent to treat analysis.
    In both trials, additional subset analysis completed after the initial intent to treat results were analyzed reveals a significant correlation between high-grade (grade 3 and 4) hypertriglyceridemia and increased survival, potentially identifying a large subgroup patient population that may receive significant survival benefit of added Targretin treatment in first line therapy.
    The studies were 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. In the SPIRIT I trial, 623 patients were equally randomized to two arms, stratified by sex and disease stage, receiving cisplatin/vinorelbine chemotherapy alone or in combination with Targretin capsules. SPIRIT II enrolled 612 patients equally randomized and stratified to two arms receiving carboplatin/paclitaxel alone or in combination with Targretin capsules.
    Results of the intent to treat analysis for both trials are summarized below:

Parameter SPIRIT I(1) SPIRIT II(1) --------------------------------------------------------------------- Chemo Targ+ P Chemo Targ+ P Arm Chemo value Arm Chemo value --------------------------------------------------------------------- Median survival 9.9 8.7 NS 9.2 8.5 NS --------------------------------------------------------------------- Two year survival (%) 15.7% 13.2% NS 16.3% 12.4% NS --------------------------------------------------------------------- Progression- free survival (mos.) 5.0 4.3 NS 4.9 4.1 NS --------------------------------------------------------------------- (1) No significant differences between the two arms in any of the end points

    Baseline demographics of patients revealed a very uniform distribution between arms in both studies and an overall distribution very similar to that seen in other similar and recently published large trials.
    Further analysis of patients revealed that in the Targretin arm a subset of patients (approximately 35 percent of total SPIRIT I & II Targretin-treated patients) had rapid and sustained elevations (greater than/equal to grade 3 level) in triglyceride levels, a biomarker of Targretin metabolic activity, while another subgroup showed only modest elevations (grades 0, 1 or 2) in triglycerides. These changes were seen very rapidly, usually during the first cycle and persisted in subsequent cycles. Survival analysis in both trials in this subset of patients showed significant differences in overall survival among both groups and between either group and the control chemo arm (except SPIRIT I where the high triglyceride group showed a strong trend, see Table below). The data indicates that high sensitivity to bexarotene in triglyceride response correlates to a benefit in survival.

Parameter SPIRIT I SPIRIT II ---------------------------------------------------------------------- Chemo C+Targ C+Targ Chemo C+Targ C+Targ High Low High Low ---------------------------------------------------------------------- # Patients(2) 312 98 208 306 117 172 ---------------------------------------------------------------------- Median survival (months) 9.9 12.3 7.5 9.2 12.4 6.6 ---------------------------------------------------------------------- p values P=0.08 P=0.009 P=0.014 P=0.001 ----------------------------------------------------------------------

Parameter Pooled Data --------------------------------------------------- Chemo C+Targ C+Targ High Low --------------------------------------------------- # Patients(2) 618 215 380 --------------------------------------------------- Median survival (months) 9.5 12.3 6.9 --------------------------------------------------- p values p less than p=0.0025 0.0001 --------------------------------------------------- (2) Targretin group includes only patients who received at least one dose of Targretin

    An evaluation of risk factors predictive of survival in this trial by multivariate analysis clearly identified triglyceride levels as a highly significant predictor of survival in the bexarotene (Targretin) arm of both SPIRIT I and SPIRIT II (p=0.0004, p=0.0002) but not in the chemo control arms. Other factors (i.e. serum albumin levels) were identified predictors in both arms.
    Hazard ratio analysis of the demographics in the subset of patients with high triglyceride responses and longer, improved survival showed a fairly uniform distribution of patients across the different demographic parameters. A surprising finding was that men, smokers and stage IV patients consistently showed better survival than controls in this subgroup in both trials.
    "While we were disappointed that the SPIRIT trials did not meet their intent-to-treat endpoints, this subset analysis has generated some exciting data that gives us a basis to continue to evaluate the potential of Targretin to benefit an important segment of lung cancer patients. These include certain lung cancer patients such as men, smokers and stage IV patients who are difficult to benefit with other therapies," said Andres Negro-Vilar, M.D. Ph.D., Ligand's executive vice president for research and development and chief scientific officer. "We are also evaluating data from current and prior Phase II studies to see if they show a similar correlation between hypertriglyceridemia and increased survival. The data will further shape our future plans for Targretin, whether conducted on our own or with a partner or cooperative group."
    In the SPIRIT trials, the addition of Targretin to both chemotherapy regimens was generally well tolerated. Adverse events were similar to those previously reported in studies with chemotherapy treatment and with Targretin. Regarding serious adverse events with an incidence greater than 1%, there was an increase in the incidence of neutropenia in SPIRIT I in the Targretin arm principally attributed by the investigators to combo chemotherapy. An increase in febrile neutropenia was seen in the chemotherapy control arm of that study. No significant differences in the incidence of serious adverse events between the arms were seen in SPIRIT II. Adverse events -- grade 3 and 4 -- that occurred more frequently with Targretin included hypertriglyceridemia in both trials, neutropenia, asthenia and dehydration in SPIRIT II and dyspnea in SPIRIT I. These differences were recorded for all AEs that reached a level of 5% frequency in any arm.
    Additional information and the full data set presented at ASCO are available on the Ligand web site at www.ligand.com.

    Comprehensive Clinical Trial Program

    Further assessment of the role of Targretin in combination with different chemotherapy regimens in the first-line setting continues with several additional trials being conducted or recently completed pending analysis. A recently-completed phase II trial evaluated Targretin in combination with gemcitabine plus carboplatin. A phase I/II trial is evaluating a dose-escalation schedule of Targretin in combination with weekly carboplatin plus paclitaxel. A multicenter randomized phase II trial is evaluating Targretin capsules given either concomitantly to or sequentially after the administration of weekly carboplatin plus paclitaxel. A phase II study is evaluating Targretin in combination with taxotere given every three weeks. Two multicenter trials are evaluating the combination of Targretin plus taxotere as second-line treatment for relapsed NSCLC.
    Three additional trials are being conducted or are recently completed pending analysis in patients with NSCLC who have failed at least two prior treatments for their cancer. One multicenter trial is evaluating Targretin monotherapy in 150 patients with relapsed disease and a second trial is evaluating the combination of Targretin plus erlonitib (Tarceva(R)).
    Several of the above studies are scheduled for presentation at ASCO on Tuesday, May 17.

    About Targretin

    Targretin is a selective retinoid X receptor (RXR) modulator with proven efficacy as monotherapy in the treatment of cutaneous T-cell lymphoma (CTCL). RXR levels in the tumor have been shown to be an independent predictor of survival in NSCLC and in other solid tumors.
    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. For more information, go to www.ligand.com.

    Caution Regarding Forward-Looking Statements

    This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that involve risks and uncertainties and reflect Ligand's judgment as of the date of this release. These include statements regarding data analysis and continuing evaluation of Targretin, potential survival benefit, potential benefits for certain patients in lung cancer and continued development and other studies of Targretin. Actual events or results may differ from our expectations. For example, there can be no assurance that other studies or evaluations of Targretin will be favorable or that they will confirm results of previous trials, that data evaluation will be completed or demonstrate any hypothesis or endpoint, that Targretin will provide any benefits or be useful in new indications alone or in combination with other drugs, that marketing applications will be filed or, if filed, approved, either by Ligand or its corporate partners, nor that further clinical or commercial development of Targretin will be completed or successful. Our stock price may suffer if any actual events differ from our expectations. Additional information concerning these and other risk factors affecting 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.

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CONTACT: Ligand Pharmaceuticals Incorporated Paul V. Maier, 858-550-7573 (Senior VP and CFO) Abe Wischnia, 858-550-7850 (Senior Director of Investor Relations and Corporate Communications)

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