FDA APPROVES LIGAND'S TARGRET CAPSULES FOR REFRACTORY CTCL.Ligand Pharmaceuticals Incorporated (Nasdaq:LGND LGND Luminance Ground ), San Diego, Calif., has announced that the U.S. Food and Drug Administration has granted marketing approval for Targretin (bexarotene) capsules with once daily oral administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma Cutaneous T-Cell Lymphoma Definition
Cutaneous T-cell lymphoma (CTCL) is a malignancy of the T-helper (CD4+) cells of the immune system.
Description (CTCL CTCL Cutaneous T Cell Lymphoma ) in patients who are refractory to at least one prior systemic therapy.
The indication includes patients diagnosed with all stages of refractory CTCL. At the request of the FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. , 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 (1) (Chief Executive Officer) The highest individual in command of an organization. Typically the president of the company, the CEO reports to the Chairman of the Board. 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 de·bil·i·tat·ing
Causing a loss of strength or energy.
Weakening, or reducing the strength of.
Mentioned in: Stress Reduction 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 psoralen /psor·a·len/ (sor´ah-len) any of the constituents of certain plants (e.g., Psoralea corylifolia ) that have the ability to produce phototoxic dermatitis on subsequent exposure of the individual to sunlight; certain plus UV-A UV-A or UVA
ultraviolet radiation with a range of 320-380 nanometres light (PUVA PUVA
Psoralen and ultraviolet light; a treatment for psoriasis combining the oral administration of psoralen with subsequent exposure to long wavelength ultraviolet light. ) 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 ODAC Old Dominion Athletic Conference
ODAC Oracle Data Access Components
ODAC Oil Depletion Analysis Centre
ODAC Oncologic Drugs Advisory Committee
ODAC Open Democracy Advice Centre
ODAC Open Document Architecture Consortium
ODAC Old Dominion Aquatic Club ), 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 TNM tumor-nodes-metastasis; see under staging.
tumor, nodes and metastases; a system of cancer staging (see TNM staging). ] Stages IA, IB, or IIA (1) (Information Industry Association, Washington, DC) In 1999, IIA merged with SPA (Software Publishers Association) to become the Software & Information Industry Association. See SIIA. ) 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 IIB Institute for Independent Business
IIB Institute of International Business
IIB Institute of International Bankers
IIB International Investment Bank
IIB Indian Institute of Banking & Finance
IIB Included in Bankruptcy
IIB Ice, Ice, Baby , III, IVA, or IVB IVB Investment Bond
IVB Independent Verification Body
IVB Inner Vascular Bundle ) 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 hypothyroidism: see thyroid gland. (29%) and leukopenia leukopenia /leu·ko·pe·nia/ (-pe´ne-ah) reduction of the number of leukocytes in the blood below about 5000 per cubic mm.leukope´nic
basophilic leukopenia basophilopenia. (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 MAA
macroaggregated albumin ) via the European Agency for the Evaluation of Medicinal Products (EMEA (Europe, Middle East, Africa) Refers to that region of the world. For example, one might see products packaged differently for the UK, EMEA and Asia Pacific markets. ) 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 (Non Disclosure Agreement) An agreement signed between two parties that have to disclose confidential information to each other in order to do business. In general, the NDA states why the information is being divulged and stipulates that it cannot be used for any ) 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 White blood cells
A group of several cell types that occur in the bloodstream and are essential for a properly functioning immune system.
Mentioned in: Abscess Incision & Drainage, Bone Marrow Transplantation, Complement Deficiencies involved in the body's immune system). T-cell lymphomas, of which CTCL is a subclass In programming, to add custom processing to an existing function or subroutine by hooking into the routine at a predefined point and adding additional lines of code.
subclass - derived class , represent approximately 10% of the non-Hodgkin's lymphomas (NHL NHL Non-Hodgkin's lymphoma, see there ), 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 dis·fig·ure
tr.v. dis·fig·ured, dis·fig·ur·ing, dis·fig·ures
To mar or spoil the appearance or shape of; deform.
[Middle English disfiguren, from Old French desfigurer . 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 Retinoids
A derivative of synthetic Vitamin A.
Mentioned in: Ichthyosis
retinoids (reˑ·t 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 retinoid /ret·i·noid/ (ret´i-noid)
1. resembling the retina.
2. retinal, retinol, or any structurally similar natural derivative or synthetic compound, with or without vitamin A activity. 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 tamoxifen (təmŏk`sĭfĕn'), synthetic hormone used in the treatment of breast cancer. Introduced in 1978, tamoxifen is used to prevent recurrences of cancer in women who have already undergone surgery to remove their tumors. 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).
Full prescribing information for Ligand's products may be obtained from Ligand Professional Services by calling toll-free 1-800-964-5836.
For more information, call 858/550-7573.