By Lisa Seachrist
GAITHERSBURG, Md. — An FDA advisory panel unanimously endorsed Seragen Inc.'s interleukin-2 (IL-2) fusion protein, Ontak, for the treatment of persistent cutaneous T cell lymphoma (CTCL).
The Oncologic Drugs Advisory Committee agreed 14 to 0 the Hopkinton, Mass.-based company's drug offered an acceptable toxicity profile and enough clinical benefit to patients to recommend the FDA grant accelerated approval. Under the guidelines for accelerated approval, the panel members don't offer an official recommendation or vote.
"The panel's comments really validated the product for use in a population with a critical medical need," said Jean Nichols, president and chief technology officer for Seragen. "You couldn't have a better outcome. We will be working with the FDA to get this drug available."
Ontak, or DAB389IL-2, is a diphtheria toxin fragment A-fragment B genetically fused to human IL-2 through amino acid 389 on the toxin chain. The construct targets high-affinity IL-2 receptors on activated T lymphocytes. Once bound, it enters the cell, where fragment A of the toxin inhibits protein synthesis and kills the cell.
Seragen received Orphan Drug designation for Ontak in 1996 and an expedited review after filing a biologics license application in December because there is no drug approved that has a specific CTCL indication.
CTCL is a disfiguring form of non-Hodgkin's lymphoma that manifests initially in the skin, causing itching and susceptibility to infection. Approximately 800 patients are diagnosed with the disease each year in the U.S. As the disease progresses, it can affect other organs; the median survival for late-stage patients is less than three years.
The pivotal Phase III trial studied 71 patients in whom an average of five prior therapies had failed, and used a range of criteria including tumor burden and quality-of-life assessments.
The company employed two doses: 9 micrograms per kilogram per day and 18 micrograms per kilogram per day. Infusions were given every day for a week for eight cycles of therapy.
Overall 30 percent of patients responded to treatment with a 50 percent or greater reduction in tumor burden. Ten percent achieved a complete response lasting more than six weeks following therapy. The company reported a trend for better response at the higher dose for patients with more advanced disease.
Side Effects Cause 37 Percent Dropout In Trial
All patients, however, suffered from side effects, some of which were severe. Thirty-seven percent of patients withdrew as a result of adverse reactions. Fifty-five percent of patients experienced serious side effects, including flu-like symptoms, hypersensitivity reactions, vascular leak syndrome, nausea and diarrhea leading to dehydration. Forty-eight percent of patients developed infections. However CTCL patients are prone to serious infections as a result of their disease.
Patients also developed antibodies against the molecule. The FDA had concerns that the bulk of the benefit comes in the first few infusions of the drug, after which the antibodies quickly clear the drug from the body. In addition, the agency contended that patients who responded to therapy didn't necessarily have a reduction in symptoms.
However, panel members noted that the toxicities were likely tolerable for patients suffering from CTCL.
"This is almost biblical in its ability to cause disfigurement and discomfort," said Edward Sausville, associate director of developmental therapeutics program at the National Cancer Institute, in Bethesda, Md. "Toxicities alone should not disqualify this drug. In addition, the infection rate is clearly not increased over what we see with this disease in the first place."
Panel Calls For More Studies
While recommending the drug, the panel called for additional studies to assess the exact dosage which will provide the greatest benefit and to assess the durability of the therapy. The panel was concerned that should the agency grant accelerated approval, the company may find it impossible to complete a confirmatory trial currently underway which treats earlier-stage patients and contains a placebo arm.
"We will be working with the agency to adjust the trial design if need be," Nichols said. She also noted that even without Ontak available on the market many investigators refuse to enroll patients into a study that has a placebo arm, even though the treatments that are normally used have never been tested on patients with CTCL.
Ontak was developed by Seragen in collaboration with Indianapolis-based Eli Lilly and Co.
In May, Ligand Pharmaceuticals Inc., of San Diego agreed to buy Seragen for $67 million. Upon completion of the merger, Ligand will buy rights to Ontak from Lilly. (See BioWorld Today May 12, 1998, p.1).
Seragen also has tested the drug as a potential therapeutic for HIV infection, though further clinical development will be at the discretion of Ligand.
Ligand's stock (NASDQ:LGND) closed Tuesday at $13.25, down $0.50. Seragen (NASDAQ:SRGN) ended the day at $0.62, up $0.08. *