SILVER SPRING, Md. — An FDA advisory panel endorsed Ligand Pharmaceuticals Inc.'s topical treatment for AIDS-related Kaposi's sarcoma (KS), Panretin Gel, a topical formulation of 9-cis retinoic acid.
The Oncologic Drugs Advisory Committee (ODAC) voted 8-1 to recommend that the FDA approve Panretin Gel 0.1% for the treatment of KS. The drug was granted priority review by the agency, and the deadline for the FDA's decision is Nov. 27.
David Robinson, chairman, president and CEO of San Diego-based Ligand, said he was "delighted" by the decision to recommend approval. "We will continue our intense cooperation with the agency to get a rapid movement of the product to the market," he said.
Robinson estimated that, if the agency approves the drug, Ligand will have it on the market "in a matter of days." He said he expects the drug to eventually garner $35 million to $70 million in annual sales.
KS was first described in 1872 by Austro-Hungarian dermatologist Moritz Kaposi. The disease remained rare until the AIDS epidemic, when patients' weakened immune systems offered the opportunity for Kaposi's to take hold. The cancer is characterized by dark skin lesions and nodules that may also involve the oral mucosa, lymph nodes, lungs and the gastrointestinal tract.
Current therapies include cryotherapy, laser therapy, chemotherapy, surgery and radiation. As several patients pointed out during the public-comment period of the hearing, Panretin Gel offers a patient-controlled therapy without some of the disfiguring side effects of surgery and radiation.
Ligand Pharmaceuticals presented data from two Phase III trials — one conducted in North America and one conducted internationally. The international study was halted early, with only 82 patients enrolled, when an interim analysis in August 1998 showed that patients applying Panretin two times a day enjoyed a 42 percent response rate, compared to 7 percent who received a placebo vehicle gel.
The North American study included 268 patients equally split between Panretin and placebo. Patients applied the gel two to four times a day. After a 12-week blinded period, 35 percent of patients treated with Panretin showed a response, while only 18 percent of placebo patients responded.
Responses in both studies were defined using AIDS Clinical Group Criteria, which measure height, area and color of lesions.
Side effects of Panretin included redness, rash, and pain which, the sponsor noted, could be managed by a reduction in number of times the drug was applied each day or by temporarily discontinuing the treatment.
In the North American study, after the 12-week blinded phase, patients were given the option to move to an open-label phase of the study, where the response rate rose to 49 percent.
"Duration of response was difficult to determine, because so few patients failed to respond," said Richard Yocum, senior medical director of clinical research for Ligand.
The FDA, however, questioned the true response rate in these patients, and conducted a post hoc analysis of benefit by evaluating pre- and post-therapy photographs of index lesions to determine the "beneficial response" from treatment. The company, however, strenuously objected to the analysis.
"Photographs may not fully capture the character of these lesions," Yocum said. "Such an analysis is not appropriate, not protocol-specified and didn't correspond to the patients' or physicians' assessment. The photographs were never meant to be primary data in this study, only supportive data."
The agency argued that the photographs demonstrate Panretin is not cosmetically beneficial in approximately 50 percent of all responders, because the drug caused redness and rash.
Patient representative and panel member Michael Marco found the agency's presentation of the photos persuasive in deciding that the side effects of the redness and pain far outweighed "the potential for a 35 percent response rate."
Panretin Shouldn't Be First-Line Therapy, Panel Says
Panel members agreed with the company that Panretin should be made available to patients, but were not convinced the company satisfied criteria for the therapy to be named as a first-line therapy.
"There may be other things somebody would want to do first," said panel member James Krook, an oncologist in Duluth, Minn. "I have problems with calling this a first-line therapy." Robinson, however, said the change in wording is unlikely to alter the manner in which the drug is used.
The FDA isn't bound by the decisions of its advisory panels, but usually follows their advice.
Ligand developed Panretin in a joint venture with Allergan Inc., of Irvine, Calif. Their company, called Allergan Ligand Retinoid Therapeutics (ALRT), conducted the international clinical trial which was concluded early and was run largely by Allergan.
Late last year, Ligand bought out the joint venture. Under the terms of the deal, Ligand will pay Allergan 15 percent of North American sales revenues from topical Panretin and 10 percent of the sales revenue from overseas, if Panretin gains marketing approval. (See BioWorld Today, Sept. 26, 1997, p. 1.)
Ligand halted trading of its shares while the panel was evaluating Panretin, and resumed trading later in the afternoon. The company's stock (NASDAQ:LGND) closed at $10.625, down $0.625. n