Targretin--R-- Capsules May Increase Survival in Patients with Non-Small Cell Lung Cancer; Follow-Up Results of Clinical Studies Support FDA Dialogue/Phase III Program.

Business Editors & Health/Medical Writers

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SAN DIEGO--(BW HealthWire)--Aug. 14, 2000

Ligand Pharmaceuticals Incorporated (Nasdaq: LGND) today announced additional follow-up study results suggesting that Targretin(R) (bexarotene) capsules in combination with chemotherapy may increase survival in patients with non-small cell lung cancer (NSCLC). These results add to recently reported Phase II/III results and to a growing body of data that suggests Targretin therapy may, in some solid tumors, delay disease progression and extend survival.

Follow-up results from a Phase I/II trial of Targretin with a cisplatin-based chemotherapy regimen in patients with advanced NSCLC showed a 25% response rate and a 14-month median survival at the maximum tolerated dose (MTD) determined in the Phase I portion of the trial. Nine (32%) of the 28 patients remained alive at more than two years of follow-up. One-year survival by life table analysis was 61% and projected three-year survival was 30%.

"These results from this multi-center study are most notable in terms of the high survival rate, perhaps the best reported for Phase II trials of NSCLC, even though the tumor response rate is comparable to results of other Phase II platinum-based combination trials," said Steven D. Reich, M.D., Ligand's Senior Vice President of Clinical Research. "In the trials of patients with NSCLC reporting two-year survival rates, few have reported two-year survival rates better than 15%, which is less than half of the experience with Targretin for actual two-year survival and half of the projection for three-year survival. At the maximum tolerated dose of 400 mg/m2/day, Targretin showed substantial activity in combination with a third-generation NSCLC chemotherapy regimen with a tolerable safety profile."

Previously reported results of a Phase II/III study of Targretin therapy in patients with advanced NSCLC who had prior treatment with platinum-based chemotherapy suggested a similar biological effect as demonstrated by a dose-responsive lengthening of time to progression. These studies build upon evidence provided by previously reported results of two Phase I/II studies of Targretin in patients with advanced cancers where the Principal Investigators of both studies noted stabilization of disease in a number of patients with NSCLC treated with Targretin monotherapy.

Andres Negro-Vilar, M.D., Ligand's Senior Vice President of Research and Development and Chief Scientific Officer, said, "Now that our Phase II studies have matured and we are able to look at survival data, we are excited by our findings. In addition to the survival data in our two NSCLC studies, we have recently assessed survival in our Phase I/II trial of Targretin as monotherapy in patients with head and neck cancer and our Phase I/II study in patients with advanced renal cell cancer with Targretin in combination with interferon, and we find a similar pattern. Compared to published literature in these patient populations, Targretin therapy appears to be adding to survival time. This body of evidence is now large enough that Ligand is compelled to proceed to dialogue with the FDA and European health authorities to agree upon the design of adequately powered Phase III studies in NSCLC to conclusively demonstrate this clinical benefit.

"There is growing evidence that novel chemotherapeutic or biological agents that are non-cytotoxic can provide survival advantage by mechanisms that do not necessarily involve tumor shrinkage. Preclinical and clinical studies indicate that Targretin belongs to this novel group of response modifiers with cellular activity that involves cell differentiation, inhibition of proliferation, and apoptosis with the resulting decrease in tumor malignancy and enhanced survival in a number of solid tumors."

NSCLC Study: Targretin therapy in Combination with Chemotherapy Regimen

In a multi-center open-label Phase I/II trial, the administration of Targretin was combined with a chemotherapy regimen in patients who had not received prior chemotherapy for advanced NSCLC to determine the MTD and the response rate at MTD, median survival and one-year survival.

The study included 43 patients with Stage IIIB with pleural effusion or Stage IV NSCLC with Karnofsky Performance Status greater than 70.

In the Phase I portion of the trial, the dose of Targretin was escalated in cohorts of patients from 150 mg/m2/day through 600 mg/m2/day starting one week prior to commencement of the chemotherapy regimen of cisplatin (cycles of 100 mg/m2) along with vinorelbine (cycles of alternating doses of 30 mg/m2 and 15 mg/m2). Based on the 21 patients treated in this portion of the trial, the MTD of Targretin in combination with the chemotherapy regimen was determined to be 400 mg/m2/day.

In the Phase II portion of the trial, 28 patients were treated at the MTD, including all six who had received 400 mg/m2/day of Targretin during Phase I.

At MTD, seven (25%) of the 28 patients manifested a partial response including one with near complete resolution of all radiographic lesions. Median duration of treatment for this MTD group was 152 days (range: 13-259). Nine (32%) of the 28 patients remain alive with a minimum follow-up of two years. Median survival by Kaplan-Meier analysis in the entire Phase I/II study was 351 days (range: 19-1284), while median survival at MTD was 410 days, or 14 months (range: 55-1284). One-year survival by life table was 61% and projected three-year survival was 30%. Side effects observed in more than half the patients were asthenia, leukopenia, nausea, hyperlipemia, vomiting, headache, exfoliative dermatitis, and anorexia. Grade 3 (moderately severe) or 4 (severe) adverse events with an incidence of greater than 5% in either category without regard to relationship to Targretin therapy were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with an incidence of greater than 5% in either category were decreased hemoglobin, white blood cells, absolute neutrophil counts, and absolute lymphocyte counts and increased prothrombin time, creatine, and amylase. Toxicities in the Phase II portion of the trial were consistent with Targretin monotherapy and with what one would expect with combination chemotherapy with cisplatin and vinorelbine.

NSCLC Study: Targretin Therapy following Chemotherapy Regimen

In a multicenter, randomized, double-blinded, placebo-controlled Phase II/III trial, the administration of Targretin was studied to determine whether high or moderate doses were more effective than placebo in postponing disease progression in patients with advanced NSCLC who were previously treated with platinum-based chemotherapy.

The study included patients with Stage IIIB with pleural effusion, Stage IV, or recurrent NSCLC who had stable or responsive disease following first-line, platinum-based combination chemotherapy. An interim assessment was scheduled after 90 patients had been enrolled, but the study was prematurely terminated for administrative reasons after 54 patients entered. Of the 54 patients, 52 received at least one dose of Targretin or placebo. Patients were randomized by center to placebo (16 patients, 31%), 300 mg/m2/day (21 patients, 40%), or 600 mg/m2/day (15 patients, 29%).

Median time-to-progression (TTP) from first treatment with Targretin was 56 days for placebo, 82 days for moderate dose, and 128 days for high dose (p=0.56, Log-rank). Patients who had a response to chemotherapy prior to receiving Targretin had longer TTP than those with stable disease.

           Targretin Therapy following Chemotherapy Regimen
              in Patients with Non-Small Cell Lung Cancer

Patient Category         Placebo              Targretin Therapy
                                        300 mg/m2/day    600 mg/m2/day
Number of Patients,
 % of Treated Patients   16, 31%           21, 40%          15, 29%
Number of Patients
 Responsive to
 Chemotherapy,
 % of Patients in
 Treatment Group         10, 63%           10, 48%           7, 47%

Time to Progression (Days)
    All Patients             56                82              128
    Responsive to
     Chemotherapy            56               146              177

For patients who responded to chemotherapy, median TTP was 56, 146 and 177 days for placebo, moderate and high dose of Targretin, respectively. The percentage of patients with response to prior chemotherapy was higher in the placebo group (63%) than the active treatment arms (48%; 47%) suggesting that the effect on TTP is Targretin-related. Because of the small number of patients, the study does not have the statistical power to detect differences among the treatment groups. However, the study shows that patients with NSCLC can tolerate Targretin therapy at doses up to 600 mg/m2/day after platinum-based chemotherapy and that Targretin may have the potential to delay TTP in some patients with advanced NSCLC. Side effects observed were asthenia, hyperlipemia, skin scaling and dryness, peripheral edema, pruritus, anorexia, and dyspnea.

"Results indicate that higher doses of Targretin may potentially delay disease progression in non-small cell lung cancer patients," said Naiyer Rizvi, M.D., a medical oncologist at the Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C., and a Principal Investigator for the study. "We are excited by these initial results and are hopeful that with further successful clinical research, Targretin may be added to the treatment for lung cancer, which is the leading cause of cancer death among men and women in the United States."

The results of the study were published in the abstract "Placebo-Controlled Trial of Bexarotene (Targretin, LGD1069), a Retinoid X Receptor (RXR) Agonist, as Maintenance Therapy for Patients Treated with Chemotherapy for Advanced Non-Small Cell Lung Cancer (NSCLC): An L1069-20 Study Group Trial" in the Proceedings of the 36th Annual Meeting of the American Society of Clinical Oncology.

Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death for both men and women. The American Cancer Society estimates that 164,100 individuals will be diagnosed with lung cancer in 2000; of those, 131,200, or approximately 80%, will be diagnosed with NSCLC. The four stages of NSCLC are identified using the Tumor, Nodule, Metastasis (TNM) system, also known as the American Joint Committee of Cancer (AJCC) system. Early stage NSCLC is usually treated by surgery or radiation, sometimes combined with chemotherapy. The five-year survival rate for lung cancers treated by surgery before the cancer has spread to lymph nodes or other organs is about 42%. Less than half of patients with advanced stages of disease will survive one year, even with standard chemotherapy regimens.

Targretin Capsules

In December 1999, the U.S. Food and Drug Administration (FDA) approved Targretin for the treatment of all stages of CTCL refractory to at least one prior systemic therapy. The European Agency for the Evaluation of Medicinal Products (EMEA) is reviewing a Marketing Authorization Application submitted by Ligand in November 1999 for Targretin for the treatment of patients with CTCL.

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 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).

This news release may contain certain forward-looking statements by Ligand which involve risks and uncertainties and reflect Ligand's judgement as of the date of this release. Actual events or results may differ from Ligand's expectations There can be no assurance that final results will be supportive of regulatory approvals required to market Targretin for NSCLC. 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 website at http://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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