By Lisa Seachrist
Ligand Pharmaceuticals Inc. filed a new drug application (NDA) with the FDA for the oral version of its anti- cancer retinoid Targretin (bexarotene).
The San Diego-based company already has been awarded orphan drug status for the drug as a treatment for cutaneous T-cell lymphoma (CTCL), a disfiguring form of non-Hodgkin's lymphoma, has requested a priority review by the FDA, and is seeking a label indication for patients with refractory or persistent early stage CTCL.
Paul Maier, Ligand's senior vice president and chief financial officer, said he was pleased with the drug's progress.
"Targretin showed a high level of clinical activity in a disease where the medical need is still unmet," he said.
The drug is a synthetic retinoid analogue developed by Ligand. Retinoids are naturally occurring hormones chemically related to vitamin A, and are known to regulate a number of cellular activities, including cell growth. They work through six receptors that can be classified into two groups: retinoid A receptor (RAR) and retinoid X receptor (RXR). Targretin acts through RXR.
In filing the NDA, Ligand supported it with results from two multicenter, multinational Phase II/III clinical trials involving 152 patients with CTCL. The studies were open-label with historical controls conducted in the U.S., Canada, Europe and Australia. Out of the early phase of those studies, the company established that a once-daily dose of Targretin capsules at a dose level of 300 milligrams per square meter provided the best results. Targretin capsules at this dose provided at last 50 percent improvement in 48 percent of patients. That cleared the FDA's hurdle requiring that 20 percent of patients show a 50 percent improvement.
The company reported the only drug-related serious adverse event that occurred in more than one patient with CTCL was pancreatitis, which occurred in association with elevated serum triglycerides in four, all of whom recovered. Targretin is also associated with hypothyroidism, which could be successfully treated with thyroid stimulating hormone. Some patients developed hyperlipemia and, rarely, neutropenia.
CTCL affects an estimated 16,000 people in the U.S., and initially manifests in the skin, causing itching and susceptibility to infection. Over time, the condition may involve other organs. The prognosis for CTCL depends on the stage at which the cancer is identified. Early-stage CTCL has a median survival of 10 years. Late-stage disease has a median survival of three years.
Ligand and its wholly-owned subsidiary, Seragen Inc., of Hopkinton, Mass., received accelerated approval for Ontak, a fusion protein therapy in February. Ontak is a diphtheria toxin fragment A-fragment B, genetically fused to human interleukin-2, which was approved for use in patients with later stage recurrent or persistent CTCL.
With Targretin capsules, the company moves to the position of having drugs capable to treat both early- and late-stage disease. The company intends to file an NDA for Targretin gel in the second half of this year. If it is approved, patients would likely first encounter Targretin gel in the very earliest stages of the disease, but could use the topical product for any cutaneous lesion at any stage of the disease.
"While the CTCL market is a niche market, it is growing rapidly," Maier said. "And it is a subset of the bigger T-cell lymphoma market."
The company has Phase II studies of Targretin capsules ongoing in breast cancer and psoriasis. In severe plaque psoriasis, the company is conducting a dose-ranging study. An interim assessment of the data show Targretin is providing efficacy, and the company has decided to add two more doses (a high and a low dose) to the study to determine the optimal dose for treating these patients.
"At the end of this trial, we will determine whether to move forward with oral Targretin or oral Panretin," Maier said.
Panretin is a formulation of 9-cis retinoic acid, which is a derivative of vitamin A. In its gel formulation, it has been approved as a therapy for Kaposi's sarcoma, a cancer common in people who have AIDS. Its oral formulation has been tested in plaque psoriasis, breast cancer, and myelodysplastic syndrome, among other oncology indications.
The company will present interim results in the second half of this year from the Phase II study of Targretin capsules in women with advanced tamoxifen-resistant breast cancer.
Maier said that the company is working on Canadian and European marketing filings for Targretin capsules in CTCL, and expects to have them completed by the end of 1999.
Ligand's stock (NASDAQ:LGND) closed Thursday at $11.062, up $0.187 a share.