By Lisa Seachrist
SILVER SPRING, Md. - An FDA advisory panel declined to recommend Magainin Pharmaceuticals Inc.'s pexiganan acetate topical cream for the treatment of diabetic foot ulcers.
The Anti-Infective Drugs Advisory Committee voted 7 to 4 against recommending the drug for approval, citing a lack of efficacy data and questions about which patients would be candidates for treatment with the drug. Several panel members suggested Magainin test the drug against a placebo.
The company was unavailable for comment Thursday afternoon.
Pexiganan is a synthetic cationic peptide, known as a magainin, comprised of 22 amino acids. The Plymouth Meeting, Pa.-based company derived the compound from the naturally occurring compound found in the African clawed frog. All animals, including humans, produce some kind of magainin, typically in the skin, lungs, oral mucosa, tongue and intestine.
Positively charged magainins work by creating pores in the negatively charged membranes of bacteria and fungi, and causing the organisms to lyse. The compounds are effective against Gram-positive and Gram-negative bacteria, as well as some fungi. In addition, the company found that microorganisms don't develop resistance to the products.
Approximately 16 million Americans have diabetes, and 15 percent of them will suffer from foot ulcers. Every year in the U.S., about 54,000 diabetics in the U.S. undergo lower-extremity amputations.
Foot ulcers are considered complicated skin infections. In diabetics, they can be caused from reduced blood flow to the lower extremities or from peripheral neuropathy, which causes a loss of feeling in feet. If the ulcer is caused by a lack of blood flow, vascular surgery effectively deals with the ulcer. Neuropathic ulcers, which are caused by pressure that patients can't feel and adjust for, require aggressive wound debridement - surgical removal of dead, infected skin - and taking pressure off the feet.
Once neuropathic ulcers become infected, it can prolong healing, leaving the patient at risk for infections of the bone and soft tissue, which can lead to amputations. Magainin decided to test pexiganan against the broad spectrum oral antibiotic agent ofloxacin. When the company designed the pivotal trials, no therapy, oral or topical, had been approved for the treatment of diabetic foot ulcers. Although ofloxacin has not been approved by the FDA specifically for diabetic foot ulcers, some physicians use it for the indication.
The company presented data from two pivotal trials, in which patients with neuropathic ulcers had their wounds debrided and received both ointment and pills to take. Half of the patients received pexiganan cream and placebo pills, while the other half received ofloxacin pills and placebo cream.
After the participating physicians performed debridement on the patients' ulcers, patients took therapies for 14 to 28 days, according to the advice of their physicians. The company showed that, at the end of treatment, between 85 and 91 percent of patients using only pexiganan had their infections improve or resolve; between 89 and 91 percent of patients using only ofloxacin had their infections improve or resolve.
However, the FDA's analysis of the data found it did not reach the accepted definition of equivalence, based upon statistical measure. In fact, Li Ming Dong, statistical reviewer for the agency pointed out that the data favored ofloxacin in wound healing.
"It may simply be a lack of power in the study, that the difference isn't statistically significant," Dong said.
The panel found no evidence pexiganan had safety issues. Instead, the panel focused on the fact that the data didn't meet the definition of equivalence and that that it was unclear which patients would be candidates for the drug.
No Evidence Of Benefit, Says Panel Member
Julie Parsonnet, associate professor of medicine and of health research and policy at Stanford University School of Medicine, in Palo Alto, Calif., said that, for many patients, surgical debridement may be an adequate treatment for the condition.
"I don't think we have any evidence that there is a benefit [from the drug]," Parsonnet said. "I'm not convinced that, once they have done the debridement, there was any more infection. Surgical debridement could be the control for a placebo test of this agent."
When the company initially designed the protocol for the pivotal studies, it determined that because infected diabetic foot ulcers can lead to amputations, performing a placebo-controlled study, rather than an active-agent control would not be ethical.
Barbara Murray, director of the division of infectious disease at the University of Texas Medical School, in Houston, said she believes the company showed pexiganan was efficacious enough to recommend for marketing.
"It's close to being equivalent to the standard of care," Murray said.
The agency usually chooses to follow the advice of its advisory committees, but is not bound to do so.
Magainin and its partner, London-based SmithKline Beecham plc, have given pexiganan a new trade name, Locilex, which was changed from Cytolex at the request of the FDA.