By Lisa Seachrist

Washington Editor

BETHESDA, Md. ¿ Uncertain about how the benefits and risks balanced, an FDA advisory panel gave a mixed endorsement for Ligand Pharmaceuticals Inc.¿s Targretin (bexarotene) capsules as a retinoid therapy for cutaneous T-cell lymphoma (CTCL).

The Oncologic Drugs Advisory Committee to the FDA voted 7 to 5, with four abstentions, to deny a recommendation for approval of Targretin in early CTCL. However, the panel voted 13 to 2, with one abstention, to endorse the drug as a therapy for advanced-stage disease. It also suggested the company conduct a randomized clinical trial comparing Targretin to other chemotherapies in order to establish the drug¿s place in the clinical armamentarium.

The panel focused on the lack of long-term data on the side effects of the drug in denying its endorsement for early-stage disease.

¿We¿re pleased with an important part of the recommendation for approval in advanced-stage disease,¿ said David Robinson, president and CEO of the Seattle-based company. ¿We have to express some disappointment with the failure to recommend Targretin for early stage. It¿s not entirely clear what the committee was worried about in early-stage disease.¿

Robinson said the company would work with the agency to establish what additional information would be necessary in a postmarketing environment.

Retinoids are naturally occurring hormones chemically related to vitamin A. They¿re responsible for regulating a number of normal cell activities, including cell growth. Retinoids work through six receptors that can be classified into two groups, retinoid A receptors (RAR) and retinoid X receptors (RXR). Targretin is a synthetic retinoid analogue developed by Ligand to work through RXR.

CTCL affects an estimated 16,000 people in the U.S. and initially manifests itself in the skin, causing itching. The constant itch and pain leaves patients susceptible to infection as a result of skin damage from the scratching as well as an underlying immunosuppression as a result of both the disease and some of the therapies. Over time, the condition may involve other organs. The major cause of death is complicated infection.

Studies Involved 152 Patients, Several Doses

Prognosis for CTCL depends on the stage at which the cancer is identified. Patients with early-stage disease have a median survival rate of 10 years, while patients who are caught later have a median survival of three years.

Many current therapies, such as electron beam treatment, photophoresis and psoralen plus UV-A light, require visits to a clinic, hospital or doctor¿s office for administration. In addition, many chemotherapies such as methotrexate and corticosteroids are immunosuppressive. Targretin capsules are a non-immunosuppressive, self-administered therapy.

The company presented two Phase II/III clinical studies testing Targretin in both early- and late-stage CTCL. The studies tested a total of 152 patients in an open-label, multicenter manner using historical controls for comparison. The company tested several doses of the drug but established that 300 milligrams per square meter per day provided the most acceptable treatment response-side effect ratio.

The early-stage study tested the drug in a total of 58 patients and the advanced-stage trial included 94 patients. All of the patients had proven refractory to at least one therapy and were to have a 30-day washout period before beginning Targretin. In the early-stage study, the company tested a 6.5 milligram per square meter per day dose of the drug and a 650 milligram dose. Only 15 patients were treated with the lower dose because of little effect. The 650 milligram dose was reduced to 300 milligrams per square meter per day in response to unacceptable toxicity. The 300 milligram dose was the only dose used in the advanced-stage disease trial.

Company, FDA Differ On Photography Requirements

The company used a physician¿s global assessment (PGA) and a comprehensive assessment (CA) of index lesions to establish tumor response. In the early-stage trial with doses of drugs greater than or equal to 300 milligrams of Targretin, the company reported 53 percent of patients experienced a partial or complete tumor response based on the PGA and a 40 percent response rate using the CA measure.

The advanced-stage study showed a 50 percent response rate based on PGA and a 35 percent response rate using the CA measure. Patients taking Targretin often developed high blood triglycerides requiring lipid-lowering medication. In addition, patients could develop low production of thyroid hormone, neutropenia and high cholesterol.

The FDA, however, took a different view, claiming the protocol required the company to produce global photographs of patients¿ skin to ensure the accuracy of the PGA.

¿We use the photographs where there were claims of responses,¿ said FDA reviewer Oluwole Odujinrin. ¿The index lesion can improve while the other lesions are increasing in size or haven¿t changed. This happened quite often, I think.¿

The company vehemently disagreed with the agency¿s assessment, highlighting the fact that the agency didn¿t require the photographs to establish the primary endpoint until after the NDA had been filed.

¿The FDA only raised the concept of whole-body photographs after the NDA was completed,¿ said Richard Yocum, project physician at Ligand. ¿We used regional photographs of index lesion because wider views don¿t show the subtle changes in the skin.¿

In addition, the agency focused on the relatively high dropout rate ¿ about 30 percent ¿ for the studies as making it difficult to get an accurate picture of the benefits of the drug. Odujinrin also pointed out the side-effect profile leaves patients susceptible to any number of drug-drug interactions.

Panel member Kim Margolin, staff physician at the City of Hope National Medical Center in Duarte, Calif., took a different view. ¿With all the flaws in this study, this is a relatively well-tolerated drug and there is a fraction of patients who will benefit from it,¿ Margolin said.

With Targretin capsules, the company hoped to move closer to its goal of having comprehensive therapies for all stages of CTCL. In February, Ligand and its wholly-owned subsidiary, Seragen Inc., of Hopkinton , Mass., received accelerated approval for Ontak, a fusion protein therapy. Ontak is a diphtheria toxin fragment A-fragment B genetically fused to a human interleukin-2, which was approved for use in patients with later-stage recurrent or persistent CTCL.

Despite the panel¿s endorsement only for a later stage of disease, Ligand still has the potential to develop Targretin as a therapy for early-stage disease. On Friday the company filed an NDA for Targretin gel for cutaneous lesions in patients with Stage IA, IB or II A CTCL. In addition, the company will continue to seek approval for Targretin capsules for early stage CTCL.

¿Treating clinicians tend to look at how many therapies a patient has failed,¿ Robinson said. ¿We¿re not too concerned clinicians are going to feel too constrained by staging; they¿ll look at the number of therapies they¿ve failed.¿

The agency isn¿t bound by the decisions of its advisory panels; however, it usually often chooses to follow the recommendation. The statutory deadline for a decision from the FDA is Dec. 23.

Ligand has opened a compassionate treatment protocol prior to launch of the drug. The company said it is prepared to provide product to patients in January should Targretin capsules gain approval. The company expects the drug will be priced between $10,000 and $20,000 per course of therapy (between 6 and 12 months).

The company is testing the drug in Phase II studies in psoriasis and breast cancer. The results from the psoriasis study is expected around the middle of next year, with interim results for the breast cancer trial around the same time.