News from the FDA that Vicuron Pharmaceuticals Inc.'s new drug application for anidulafungin does not support a label for esophageal candidiasis sent the company's stock reeling Monday.
But the agency also told Vicuron that it could get approval of the drug for invasive candidiasis and candidemia after finishing a Phase III trial, which is due to complete by the end of this year.
Vicuron's shares (NASDAQ:MICU) lost $8.86 Monday, or 40.5 percent of its value, to close at $13.04.
The NDA was filed more than a year ago. Because Vicuron had been in regular contact with the FDA, CEO George Horner said, company officials "did not expect and are disappointed" by the agency's response. (See BioWorld Today, April 29, 2003.)
Apparently, the main sticking point for the FDA was relapse rate. Timothy Henkel, chief medical officer of King of Prussia, Pa.-based Vicuron, told investors during a conference call that the firm had "consulted with a number of external experts, who felt the follow-up response or relapse rate had very little clinical relevance. Clearly, the FDA has disagreed with us on that point."
The candidiasis/candidemia trial, which the agency named as one potential route to approval, is expected to complete by the end of this year. Another route might be research with anidulafungin in candidal patients refractory to other therapies, the FDA told Vicuron. Horner said a number of such patients are included in the package the FDA already has, but he would not say how many.
Anidulafungin, in-licensed from Indianapolis-based Eli Lilly and Co. about five years ago, belongs to a class known as echinocandins, which boast a mechanism of action different from the available classes of antifungals. In vitro work has shown the drug combines the potency and killing effects of polyenes, such as amphotericin B, with more "oomph" against resistant organisms than the azoles, such as fluconazole.
In January 2001, Whitehouse Station, N.J.-based Merck & Co. Inc. nailed down the first FDA approval of a drug in the echinocandin class: Cancidas (caspofungin acetate) for life-threatening infections, which the agency also cleared for esophageal candidiasis using data from a significantly smaller trial, with what Henkel described as "less robust" numbers around the primary endpoint.
"Obviously, we didn't expect the FDA's response to include a request for additional clinical data [on anidulafungin]," he said. But for Cancidas the specific esophageal candidiasis indication label was supplemental to the original (for invasive aspergillosis), which likely made a difference in the data required.
The agency's mention of the candidiasis/candidemia trial as a potential avenue for approval of Vicuron's drug probably didn't mean "any concern about the potency of the drug," Henkel said. "I think this has more to do with a disease they consider less serious than invasive candidiasis," i.e., esophageal candidiasis - an infection of the esophagus found in immuno-compromised patients such as those with AIDS, and caused by an overgrowth of Candida, the fungus normally found in the mouth, gastrointestinal tract and vagina, as well as on skin.
Dov Goldstein, vice president and chief financial officer of Vicuron (and a medical doctor), noted that esophageal candidiasis, sometimes called thrush, "has a high morbidity. It's very painful, and you can get anorexia, but it can't kill you. It's not athlete's foot, but it's not as serious as invasive candidiasis," which has a 38 percent mortality rate.
Goldstein told BioWorld Today the option of studying anidulafungin in resistant patients is "more ambiguous" than using the data from the candidiasis/candidemia trial.
"We haven't really discussed this much," he said, adding that research thus far has amounted to an 18-patient study with the drug in patients resistant to fluconazole. "Very few of the azole-refractory patients were in the first submissions," he said.
Another up-and-comer in the echinocandin class is Deerfield, Ill.-based Fujisawa Healthcare Inc.'s Mycamine (micafungin sodium), for which the company submitted an NDA late last month, seeking a label against esophageal candidiasis. The company is a subsidiary of Fujisawa Pharmaceutical Co. Ltd., based in Osaka, Japan.
"I honestly think our drug is best in class," Goldstein said, comparing it to the Merck compound, since "we know less about micafungin." Over Cancidas, anidulafungin is "intrinsically more potent" - 10 times as powerful - against Candida and Aspergillus, working with better tissue penetration, he said.
Importantly, too, "we have a route of elimination that is almost exclusively [based on] chemical degradation," not depending on the liver, Goldstein said.
In its pipeline Vicuron also has the semi-synthetic glycopeptide antibiotic, dalbavancin, an injectable, hospital-based treatment that can be administered once weekly. Dalbavancin belongs to the same class as vancomycin, against which it is being compared in a Phase III trial begun last fall when two larger pivotal Phase III trials already were in progress. (See BioWorld Today, Oct. 9, 2003.)
The latest Phase III, enrolling 150 patients, is designed to test the efficacy of dalbavancin compared to vancomycin for adult patients with skin and soft-tissue infections that are suspected or confirmed to be caused by methicillin-resistant Staphylococcus aureus.
Vicuron said earlier this month that it has enrolled all three Phase III trials, with a total of 1,500 patients, and expects to disclose data in the second half of this year, filing an NDA by the end of the year.
Gregory Wade, analyst with Pacific Growth Equities in San Francisco, wrote in a research note that Vicuron's pursuit of marketing clearance for anidulafungin by way of the esophageal candidiasis indication is appropriate, but Wade downgraded the stock to "equal weight" from "over weight," based on "a current lack of visibility into the timeline to overcome the [FDA's] concerns."
Vicuron was formed when Versicor Inc. and Biosearch Italia SpA, of Milan, Italy, merged in 2002 in a transaction valued at $225 million. (See BioWorld Today, Aug. 1, 2002.)