SILVER SPRING, MdThe Oncologic Drugs Advisory Committee (ODAC) has recommended that the FDA approve Ligand Pharmaceuticals Panretin gel 0.1% (alitretinoin) for the treatment of cutaneous lesions in patients with AIDS-related Kaposis sarcoma (KS).
The committee voted 8-to-1 to support the NDA for the 9-cis-retinoic acid. The lone dissenting vote was cast by AIDS activist Michael Marco, the panels patient representative. Mr. Marco questioned the value of the drug to KS patients. To replace a disfiguring lesion with a large red mark that lasts up to 6 weeks with pain that lasts for a few weeks, I just dont think its worth it, he said.
However, six KS patients treated experimentally with Panretin gel voiced strong support for the drug, four in person and two by letter. They stressed the psychological benefits of getting rid of their visible KS skin blemishes. I have my body back, one told the committee.
The two randomized, placebo-controlled studies presented by Ligand were designated 31 and 503. Both were blinded for the first 12 weeks, with patients then allowed to receive open-label Panretin gel.
Study 31 involved 268 KS patients at 35 centers in the United States and Canada. Study 503 enrolled 134 of an intended 270 KS patients at 22 sites in the United States, Europe, and Australia. It was terminated early after an interim data analysis of 82 patients showed that those receiving Panretin were six times more likely to respond than were controls.
Response was measured in several ways. Researchers in both studies and the FDA used the criteria set by the AIDS Clinical Trials Group (ACTG) for topical therapy to assess the cutaneous lesions, with very similar results. In study 31, Ligand reported 47 responders (35%) in the Panretin group vs 24 (18%) in the placebo arm. The FDA designated 46 Panretin-treated patients (34%) and 22 controls (16%) as responders. Both the company and the FDA called one Panretin patient a complete responder.
For study 503, Ligand presented data from the 82-patient interim analysis, which had 36 patients in the Panretin group and 46 patients as controls. The company claimed 15 responders (41.7%), including one complete responder, in the drug arm and 3 (6.5%) responders in the placebo group. The FDA found 14 responders (39%), all partial responders, in the treatment group and 3 (6.5%) responders among controls.
Other means used to assess response provided a greater diversity of opinion between Ligand and the FDA. In study 31, the company reported that a physicians global assessment of all treated lesions provided a response rate of 19% for the Panretin group vs 4% for those on placebo. In study 503, a physicians subjective assessment gave a 47% response rate for Panretin patients vs 11% in the placebo arm.
The FDA used photographs of lesions to retrospectively assess response. It reported a 15% response rate for the Panretin arm during the blinded phase of study 31 vs 4% for controls, and, in study 503, a 19% response for Panretin vs 2.2% for placebo.
Several ODAC members questioned the reliability of the 10-year old ACTG criteria for assessing topical treatments for KS-related skin lesions. Even though the ACTG criteria seem to be reproducible, it also appears that they are not really useful in this clinical setting, said Richard L. Schilsky, MD, of the University of Chicago Cancer Research Center.
Safety data showed more adverse reactions among patients in study 31 than in study 503. For example, for application site adverse events, in study 31, 75% of treatment and 12% of placebo patients suffered rash vs 14% and 2%, respectively, in study 503. In study 31, 34% of Panretin users and 7% of controls experienced pain vs 0% and 4%, respectively, in study 503. Pain was effectively managed with dose reduction or treatment interruption, said Steven D. Reich, MD, a senior vice president for Ligand.
There are no data to suggest unusual adverse events, he said. There were no photosensitivity reactions to Panretin gel, and once the drug was discontinued, there were no adverse withdrawal effects.