FDA APPROVES LIGAND'S TARGRET CAPSULES FOR REFRACTORY CTCL.
The indication includes patients diagnosed with all stages of refractory CTCL. At the request of the FDA, Ligand has agreed to conduct certain post approval Phase IV clinical and pharmacokinetic studies.
"We are extremely pleased with the FDA decision to rapidly approve Targretin capsules for refractory patients of all stages of CTCL," said Ligand chairman, president and CEO David E. Robinson. "Our efforts have resulted in the availability of a major new oral cancer drug that offers significant benefits for the treatment of these early- and advanced-stage CTCL patients suffering from a chronic, largely incurable, debilitating malignancy.
"This has been a momentous year for Ligand's product pipeline. With the approval of Targretin capsules by the FDA, we have accomplished another significant milestone in our strategic business plan, our third new drug approval during the course of 1999 (in February 1999, Panretin(R) gel and ONTAK(R) received FDA marketing approvals). These three products and Targretin gel, currently under review by the FDA, provide us with the product assets which our commercial organization requires to move the company towards profitability in 2000. During the fourth quarter of this year, we completed the doubling of our sales force from 20 to 40 representatives in order to support the Targretin launch and accelerate ONTAK growth. The approval of Targretin capsules for both early- and late-stage refractory CTCL is a welcome sign of progress for suffering patients as well as very positive for the company."
The recommended dose regimen is a once daily oral dose of Targretin capsules (taken with a meal) at an initial dose level of 300 milligrams per square meter of body surface area (mg/m2/day). This initial dose level provided efficacy that exceeded the protocol-defined targets of response rates and afforded most patients the optimal risk-benefit ratio.
"Targretin capsules have an attractive efficacy and safety profile and offer treating physicians an important novel oral therapeutic option for patients with early or advanced-stage CTCL who have failed other therapies," said Ligand Senior Medical Director and Physician Team Leader for the CTCL project, Richard C. Yocum, M.D. "For these patients, whose treatment alternatives may include electron beam therapy, photophoresis or psoralen plus UV-A light (PUVA) that require visits to a clinic, hospital or doctor's office for administration by a health care professional, Targretin capsules offer a more convenient and less time-consuming therapy with manageable side effects."
In granting marketing approval for Targretin capsules, the FDA took into consideration the December 13 recommendation of the Oncologic Drugs Advisory Committee (ODAC), which voted 11 to 4 (with one abstention) that a clinically meaningful tumor response rate using acceptable tumor response criteria had been demonstrated with Targretin capsules. The Committee reviewed data from two Phase II-III multicenter, open-label, historically-controlled clinical studies conducted in the U.S., Canada, Europe, and Australia involving 152 patients with CTCL.
Clinical Trial Results
The study in patients with early-stage CTCL assessed tolerability, safety, and antitumor efficacy, allocating 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; they had been exposed to a median of 3.5 (range: two to 13) prior systemic, irradiation, and/or topical therapies.
The study in patients with advanced-stage CTCL assessed the tolerability, safety, and anti-tumor efficacy of Targretin capsules in patients with advanced-stage CTCL (TNM Stages IIB, III, IVA, or IVB) who were refractory to one or more systemic anti-cancer therapies. The 94 patients enrolled in this trial were refractory to a median of two (range: one to six) 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.
Of the 152 patients enrolled in the two studies, 102 patients had been refractory to at least one anti-cancer therapy that was administered systemically, and therefore would be considered the patient population covered by the label indication. Fifty-eight percent of patients were men, 81% were white, and the median age was 65 years (range 27 to 89). The overall response rate (clinical complete response plus partial response) according to the Composite Assessment primary endpoint for these patients refractory to at least one systemic therapy was 32% (20/62) at the 300 mg/m2/day initial dose.
The side effects were mostly mild to moderate. Most patients at the 300 mg/m2/day experienced reversible lipid abnormalities (79%), hypothyroidism (29%) and leukopenia (17%), which frequently required concomitant medications. Among the other less frequent side effects were diarrhea, fatigue, headache, liver function test abnormalities, rash, pancreatitis and itching.
Targretin Capsules and Targretin Gel
In November 1999, Ligand submitted a Marketing Authorization Application (MAA) via the European Agency for the Evaluation of Medicinal Products (EMEA) seeking marketing clearance in Europe for Targretin capsules for the treatment of patients with CTCL. In addition, Ligand is conducting Phase II trials with Targretin capsules for the treatment of patients with moderate to severe plaque psoriasis and for the treatment of women with advanced breast cancer.
In December 1999, Ligand submitted to the FDA a New Drug Application (NDA) for Targretin(R) (bexarotene) gel 1%, a novel topical therapy for the treatment of cutaneous lesions in patients with Stage IA, IB or IIA CTCL who have not tolerated other therapies or who have refractory or persistent disease. The FDA has granted Targretin gel orphan drug designation for the treatment of patients with CTCL, and Ligand has requested priority review status of the NDA filing. If the Targretin gel NDA is granted priority review status, the FDA is expected to complete its review of the application within six months of the submission.
Ligand has the worldwide rights to Targretin capsules. 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 capsules and other oncology products. Ligand expects to have additional distribution partners for select European and Asian markets.
Affecting an estimated 16,000 to 20,000 people in the U.S., CTCL 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. Novel therapies which are preferably both effective and without toxicity overlapping with currently available treatment modalities are needed for the treatment of patients with CTCL.
Background Information on Targretin
Discovered by Ligand scientists, Targretin (pronounced tar-GRET-tin) capsules and gel, generically known as bexarotene, contain a synthetic compound representing a novel class 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-selective retinoids have a biological activity that is different from that of the endogenous retinoid 9-cis-retinoic acid (alitretinoin), the active substance in Panretin(R) gel and capsules. Alitretinoin is a panagonist that activates all RAR and RXR receptor subtypes. RXRs play an important role in the control of a variety of cellular functions. Ligand's pre-clinical research has indicated that Targretin may be useful in the treatment of CTCL, psoriasis and some solid tumors; Targretin has also proven effective in the treatment and prevention of breast cancer in pre-clinical models, including tamoxifen resistant breast tumors.
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. In addition to this approval of Targretin capsules, Ligand had two drugs approved during 1999 for marketing in the U.S. -- ONTAK(R) and Panretin(R) gel -- that are being marketed through its specialty cancer and HIV-center sales force in the U.S. Targretin(R) gel is currently under review by the FDA for marketing approval in the U.S., and two additional oncology-related products -- Morphelan(TM) (licensed from Elan) and Panretin(R) capsules -- are in late-stage development. 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).
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