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SAN DIEGO--(BW HealthWire)--June 23, 1999-- Ligand Pharmaceuticals Incorporated (Nasdaq:LGND - news) announced today that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking marketing clearance for Targretin® (bexarotene) capsules. The indication sought is for once daily oral administration of Targretin capsules for the treatment of patients with early stage cutaneous T-cell lymphoma (CTCL) who have not tolerated other therapies, patients with refractory or persistent early stage CTCL, and patients with refractory advanced stage CTCL. Ligand has received approval from the FDA to file Targretin capsules under orphan drug designation for this indication and has requested priority review status of the NDA filing. If the Targretin capsules NDA is granted priority review status, the FDA is expected to respond to the application within six months of the submission.
``The Targretin capsules NDA filing is a significant milestone within our overall 1999 strategic goals,'' said Ligand Chairman, President and CEO David E. Robinson. ``Coming shortly after the approval and early launch of our two marketed drugs, ONTAK(TM) and Panretin® gel, the filing of the NDA for Targretin capsules is another tangible demonstration of Ligand's commitment to provide innovative and improved therapeutic products in the treatment of various cancers. With ongoing clinical trials in breast cancer and psoriasis, Targretin represents perhaps our most important late-stage product and is central to our next several years' revenue growth in the U.S. and Europe.''
Based on the results from two multicenter, multinational clinical trials involving 152 patients with CTCL, the dose regimen recommended in the NDA is a single daily oral dose of Targretin capsules at an initial dose level of 300 milligrams per square meter (mg/m2 ) of body surface area, administered with a meal. In both clinical trials, this initial dose level provided efficacy that exceeded the protocol-defined targets of response rates of at least 20% and a lower bound of the 95% confidence intervals statistically superior to a theoretical spontaneous remission rate of 5% or less.
``The approval of Targretin capsules would, we believe, represent a significant step forward for those who suffer from CTCL, a progressive and devastating disease,'' said Steven D. Reich, M.D., Ligand Senior Vice President, Clinical Research. ``If approved, Targretin capsules will be the first oral retinoid approved for CTCL. With an attractive safety and efficacy profile, Targretin capsules may offer treating physicians an important new non-cytotoxic therapeutic option for patients with CTCL who have failed other therapies, such as chemotherapy and radiation.
``Targretin capsules, together with Targretin gel, targeted for a fourth quarter 1999 NDA filing, and ONTAK, recently approved for CTCL, forms a product portfolio that could offer patients and physicians a range of therapeutic options for all clinical stages of CTCL.''
Marketing Rights
Ligand has the worldwide rights to Targretin. If approved, Ligand will market and sell Targretin capsules in the U.S., Canada and selected European markets through its specialty oncology sales and marketing group. In Spain, Portugal, Greece, and Central and South America, Ferrer Internacional, S.A., will market and distribute, if approved in the respective jurisdictions, Targretin and other oncology products. A Marketing Authorization Application is expected to be submitted to the European Agency for the Evaluation of Medicinal Products (EMEA) for Targretin capsules in the second half of 1999.
CTCL Background
Affecting an estimated 16,000 people in the U.S., cutaneous T-cell lymphoma is a cancer of T-lymphocytes (white blood cells involved in the body's immune system). T-cell lymphomas, of which CTCL is a subclass, represent approximately 10% of the non-Hodgkin's lymphomas (NHL), which affect approximately 300,000 individuals in the U.S.
CTCL ordinarily manifests itself initially in the skin, but over time may progress to involve other organs. The prognosis for CTCL is based in part on the stage of the disease when diagnosed. CTCL is most commonly a slowly progressing cancer, and many patients live with the complications of CTCL for 10 or more years after diagnosis. Some patients, however, have a much more aggressive form of this disease, and the median survival for late-stage patients is less than three years.
Currently available approved treatment options for CTCL are limited. CTCL continues to be a devastating, highly-symptomatic, very visible, chronic malignancy often characterized by years of deforming symptomatic skin lesions that culminate in ulceration with secondary infection and visceral tumor invasion. Nearly all patients have symptoms relating to skin lesions that may itch and cause pain, bleeding, infection, or disfigurement. New therapies which are preferably both effective and without toxicity overlapping with currently available treatment modalities are needed for the treatment of patients with CTCL.
CTCL Clinical Trial Designs
The NDA is based on two Phase II/III multicenter, open-label, historically controlled clinical studies conducted in the U.S., Canada, Europe and Australia. A total of 200 patients with CTCL have been treated with Targretin capsules, of whom 152 in the Phase II/III studies met the cutoff date for inclusion in the NDA: 38% of patients from the early stage study and 62% from the advanced stage study. For the two studies combined, 62% of patients were men, 83% were white, and the median age was 64 years. A total of 84 patients with CTCL were treated at the initial dose of 300 mg/m2/day proposed for marketing.
The early stage study assessed tolerability, safety, and antitumor efficacy, randomizing patients with refractory or persistent early stage CTCL (Tumor, Node, Metastases [TNM] Stages IA, IB, or IIA) to two different initial dose levels of Targretin capsules (low = 6.5 mg/m2/day; high = 650, 500 or 300 mg/m2/day, depending on protocol version). Patients progressing on the low dose level could cross over to high dose therapy after eight weeks. The 58 patients enrolled in this trial were refractory to, intolerant to, or reached a response plateau for at least six months on at least two qualifying prior CTCL therapies, and had been exposed to a median of 3.5 (range: two to 13) prior systemic, irradiation, and/or topical therapies.
The advanced stage study assessed the tolerability, safety, and antitumor efficacy of only the high dose level of Targretin capsules (650, 500 or 300 mg/m2/day, depending on protocol version) in patients with refractory advanced stage CTCL (TNM Stages IIB, III, IVA, or IVB). The 94 patients enrolled in this trial were refractory to a median of 3.5 prior systemic therapies for CTCL, and had been exposed to a median of five (range: one to 11) prior systemic, irradiation, and/or topical therapies.
Highlights of Clinical Study Efficacy Results
At the initial dose level of 300 mg/m2/day proposed for marketing, Targretin capsules produced at least 50% improvement (partial response or clinical complete response) in 48% (40/84, 95% confidence intervals [C.I.] 37% to 58%) of patients according to the primary endpoint classification for the study. The response rate for patients starting at doses greater than 300 mg/m2/day was 58% (31/53, 95% C.I. 45% to 72%). As of the database closure for these ongoing clinical trials, clinical complete responses were observed for 3.6% (3/84, 95% C.I. 0% to 7.5%) of patients in the 300 mg/m2/day initial dose group and 17% (9/53, 95% C.I. 6.9% to 27%) of patients in the greater than 300 mg/m2/day initial dose group.
Both the 300 and the greater than 300 mg/m2/day initial dose levels were superior to the 6.5 mg/m2/day initial dose level, with a dose response relationship for response rate, rate of progressive disease, and time to onset of progressive disease. Findings from the low dose of 6.5 mg/m2/day did not meet the protocol-defined targets for efficacy. Additionally, for the 11 of 15 patients who crossed over from low dose to high dose therapy, disease progression noted on the low dose was reversed and response criteria for at least 50% improvement were met in 55% (6/11) of patients.
Some patients had at least 50% improvement by the first assessment on Targretin capsule therapy, at two weeks, and the response rate was 12% (10/84) within the first month. The projected median time to response was 16 weeks. Responses were generally durable, with a 28% (11/40) rate of relapse over a median of 17 weeks monitoring, and a projected median time to relapse of 43 weeks.
Responses were observed in all TNM clinical stages of disease. Response as determined by the primary efficacy endpoints were reinforced by findings for all secondary efficacy endpoints, including the body surface area involvement; individual index lesion clinical signs and symptoms of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, surface area, and pruritus; and patients' self-assessments on the quality of life questionnaire CTCL-specific questions. Responding patients in the 300 mg/m2/day initial dose group were broadly distributed across 18 international study centers.
``The Phase II/III clinical data support our conclusion that Targretin capsules are a safe and effective therapy for CTCL that can be orally administered,'' said Ligand Senior Medical Director and Physician Team Leader for the CTCL project, Richard C. Yocum, M.D. ``The prompt and durable responses to Targretin capsule therapy are especially remarkable in this heavily-pretreated patient population with refractory or persistent CTCL and with few if any remaining treatment options.''
Tolerance and Principal Side Effects
The safety of Targretin capsules has been demonstrated in clinical studies for patients with CTCL over a mean duration of therapy of 23 weeks, and maximum treatment duration of 97 weeks in the ongoing Phase II/III studies. Targretin capsules at an initial dose of 300 mg/m2/day were generally well tolerated. Adverse events were generally mild to moderate in severity and occurred more frequently in patients at initial doses greater than 300 mg/m2/day than in patients in the 300 mg/m2/day initial dose group. The most common adverse events (with incidence =>25% and without regard to relatedness to study drug) in the 84 CTCL patients in the 300 mg/m2/day initial dose group were hyperlipemia (79%), hypercholesteremia (32%), headache (30%), hypothyroidism (29%), and pruritus (25%).
The only drug-related serious adverse event that occurred in more than one patient with CTCL was pancreatitis, occurring in association with elevated serum triglycerides in four CTCL patients, all of whom recovered. Institution of protocol amendments lowering the initial dose to 300 mg/m2/day in CTCL studies and specifying stricter monitoring and management guidelines for hypertriglyceridemia led to an apparent decrease in occurrence of pancreatitis.
Hypothyroidism observed in association with Targretin capsules appears to be due to a thyroid axis alteration consistent with a temporary central hypothyroidism (suppression of thyroid stimulating hormone). This condition was readily managed by thyroid hormone replacement therapy, rarely required treatment discontinuation, was not associated with clinical sequelae, and appeared to be rapidly and completely reversible with cessation of Targretin therapy. A lower level incidence of leukopenia and neutropenia observed during the studies was rarely associated with severe sequelae or serious adverse events, infrequently required concomitant growth factor therapy, and resolved after dose reduction or discontinuation on average within 30 days in at least 93% of the patients with CTCL.
In summary, although some toxicities (i.e., hypertriglyceridemia, hypothyroidism and, less frequently, neutropenia) often warranted concurrent administration of an additional drug, the required concurrent therapy was easily administered and monitored, and the toxicities were generally well-tolerated, easily managed, nearly always lacked clinical complications, and were reversible upon dose reduction, suspension or discontinuation.
``Targretin capsules are an effective and well-tolerated oral treatment for patients with all stages of CTCL that has been refractory or persistent following prior therapy,'' noted Madeleine Duvic, M.D., Chief, Section of Dermatology at the University of Texas M.D. Anderson Cancer Center. ``A rapid onset of response was observed in over 50% of patients at M.D. 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 and believe that additional clinical evaluation with Targretin capsules in combination therapeutic regimens with other agents would prove to be very productive.''
Background Information on Targretin
Discovered by Ligand scientists, Targretin (pronounced tar-GRET-tin), generically known as bexarotene, is a synthetic compound representing a novel subclass of retinoids that selectively activate retinoid X receptors (RXRs). This subclass of retinoid receptors has biologic activity distinct from that of retinoic acid receptors (RARs). The RXR subclass activity is different from that of the endogenous retinoid 9-cis-retinoic acid (alitretinoin), the active substance in Panretin® gel and capsules. RXRs play an important role in the control of a variety of cellular functions. Ligand's pre-clinical research has indicated bexarotene may be useful in the treatment CTCL, psoriasis, some solid tumors, and tamoxifen-resistant breast tumors; bexarotene has also proven effective in the treatment and prevention of breast cancer in pre-clinical models.
Psoriasis and Breast Cancer Trials
Ligand is also conducting a multicenter dose-ranging (0.5 milligram per kilogram to 3 milligram per kilogram per day) Phase II trial with Targretin capsules for the treatment of patients with moderate to severe plaque psoriasis, a condition that is estimated to affect between 1.4 and 1.9 million people in the U.S. To date, 34 patients have been enrolled at four study centers in The Netherlands and Belgium in this open-label study. An interim assessment of the first two dose panels, based on 12 patients in each panel, has revealed encouraging evidence of efficacy, with at least a two-grade improvement (on a nine-grade scale) in plaque elevation in up to 67% of patients, at least 50% improvement in Psoriasis Area and Severity Index (PASI) scores in up to 33% of patients, and at least 50% improvement according to a Physician's Global Assessment in up to 42% of patients. Encouraging interim results to date have led Ligand to explore further the therapeutic index profile in two additional dose level panels (one low and one high dose) in order to determine the optimal dose regimen. Targretin capsules have been generally well tolerated by patients with psoriasis, with a 17% rate of withdrawal due to treatment-related adverse events before completion of the 24-week treatment duration. The most common adverse events are hypertriglyceridemia and mucocutaneous dryness. Additional results are expected during the second half of 1999.
As a result of the positive findings from multiple pre-clinical studies, in November 1998, Ligand launched a human Phase II clinical trial of Targretin capsules for the treatment of women with advanced breast cancer. Interim results are expected in the second half of 1999 from this ongoing clinical trial. Data from pre-clinical studies have shown that Targretin caused complete and partial regression of breast cancer tumors that grew despite tamoxifen therapy. Tamoxifen is currently the most widely prescribed hormonal breast cancer therapy. This year, experts predict that more than 180,000 cases of breast cancer will be diagnosed, making it the most common non-skin malignancy in the U.S. among women. The prevalence of breast cancer in the U.S. is estimated to have reached more than 2 million.
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 were approved for marketing in the U.S. in early 1999 -- Panretin® gel and ONTAK(TM) -- 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® capsules, Targretin® gel, Panretin® 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).
Except for the historical information contained herein, 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: the Targretin capsules NDA may not be approved for the treatment of patients with CTCL in a timely manner or at all; final clinical data may not be consistent with interim clinical data; Targretin or any product in the Ligand pipeline may not be successfully developed for psoriasis, breast cancer or any other indication; regulatory filings may not be made and regulatory approvals may not be granted in a timely manner or at all; if approved, Targretin capsules or any other Ligand product may not be accepted by physicians for prescribing, by patients for use and by insurance companies / agencies for reimbursement; Ligand and/or its collaborative partners may not successfully develop potential products; and Ligand's ability to hire and retain qualified personnel. Additional information concerning these factors can be found in press releases as well as in Ligand's public periodic filings with the Securities and Exchange Commission. Actual results may differ materially from those projected. Any forward-looking statements represent Ligand's judgment as of the date of this release. Ligand disclaims any intent or obligation to update these forward-looking statements beyond the date of this release.
Note: Public information on Ligand Pharmaceuticals Incorporated, including our financial statements and other filings with the Securities and Exchange Commission, our recent press releases and the package inserts for products approved for sales and distribution in the United States, is available on our website at http://www.ligand.com.
Panretin® and Targretin® are registered trademarks of Ligand Pharmaceuticals Incorporated, and ONTAK(TM) is a trademark of Seragen, Inc., a wholly owned subsidiary of Ligand.
Ligand Pharmaceuticals' releases are available via fax at no charge by calling 888/329-9832 or on the World Wide Web at www.businesswire.com/cnn/lgnd.htm.
Ligand Pharmaceuticals Incorporated
Paul V. Maier, 858/550-7573
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