"There's a fungus among us" became an amusing slogan in the 1950s, thanks to television comedy, and the phrase inspired countless newspaper food-section editors stumped for headlines on stories about mushrooms. But fungal infections are anything but humorous to victims and physicians who treat them.
The challenge found itself in the spotlight last week with Vicuron Pharmaceuticals Inc.'s misfortune at the hands of the FDA, which gave a thumbs down on the company's new drug application for anidulafungin, ruling that the intravenous compound could not get a label for esophageal candidiasis - the throat infection otherwise known as thrush.
CEO George Horner told investors during a conference call that the firm "did not expect and are disappointed" by the agency's response, and Wall Street apparently felt the same. Vicuron's stock fell more than 40 percent on the news.
The brighter side is that the FDA also told Vicuron that it could get approval of anidulafungin for invasive candidiasis and candidemia - much more serious indications - after finishing a Phase III trial, which is due to complete by the end of this year.
Relapse rate is at the center of the FDA's concern, apparently. The relapse rate in the already completed Phase III trial was 35.6 percent in anidulafungin patients vs. 10.5 percent in those given fluconazole.
Timothy Henkel, chief medical officer for Vicuron, said the firm had "consulted with a number of external experts, who felt the follow-up response or relapse rate had very little clinical relevance." The FDA disagreed.
Gregory Wade, analyst with Pacific Growth Equities, told BioWorld Financial Watch "there is no explanation [for the relapse disparity], but the difference is believed to be real." In actual clinical practice, Wade pointed out in a research note, patients would get an oral therapy because of the high likelihood of relapse.
Aside from the candidiasis/candidemia trial, another route to approval might be research with anidulafungin in candidal patients refractory to other therapies, the agency told Vicuron. Horner said the existing package contains some such patients, but he would not say how many.
Wade was skeptical of that route.
"There are two aspects to it," he said. "Is the number of patients sufficient to meet the agency's requirement for approving the drug for patients with no existing options? How many patients would be appropriate? And if the company doesn't have enough, how long would it take to get them?"
Those questions make up only the first half of the dilemma, Wade said. "The second part of that is, what would the label look like for the drug?" Likely answer: not very comprehensive.
In-licensed from Eli Lilly and Co. about five years ago, anidulafungin belongs to a class known as echinocandins and works by way of 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 power against resistant organisms than the azoles, such as fluconazole.
Merck & Co. Inc. won approval in early 2001 for the first echinocandin, Cancidas (caspofungin acetate) to treat life-threatening Aspergillosis infections. The agency also cleared the drug in a supplemental label for invasive candidiasis and esophageal candidiasis. On the horizon is Fujisawa Healthcare Inc.'s Mycamine (micafungin sodium), an echinocandin for which the company submitted an NDA in April, seeking a label against esophageal candidiasis.
Henkel noted the agency gave Merck the nod for esophageal candidiasis using data from a significantly smaller trial than Vicuron's, 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 esophageal-candidiasis indication was not sought first, as in Vicuron's case.
"I honestly think our drug is best-in-class," Dov Goldstein, vice president and chief financial officer of Vicuron, told BioWorld Financial Watch. Goldstein also is a medical doctor. Wade said the same, crediting a number of factors: lack of drug-to-drug interactions, its ability to be pushed to higher doses, quickly achieved steady-state concentration, 24-hour half-life and superior tissue penetration.
"Anidulafungin will be the echinocandin [and antifungal] of choice" for serious fungal infections, predicted Wade, who owns Vicuron stock.
Wade does not believe it was a mistake in the first place to try for approval by the esophageal-candidiasis route. That was the most advanced indication when the drug was in-licensed from Lilly, and the condition is caused by Candida albicans, the bug that causes most serious fungal infections. What's more, esophageal candidiasis is a relatively simple clinical setting with clear, measurable endpoints.
Still, it didn't work. Vicuron now is faced with finding a way through the FDA's requirements. A meeting with the agency was expected within 60 days, and the company's next step after that is anybody's guess, Wade said.
"It's all a lot of speculation at this point," he said. "The company only has a letter, which in their assessment indicates a strong willingness of the agency [to work toward approval]. Perhaps the data they have already will get them over the hurdle, but there's really no way to know."