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GLASGOW, Scotland and KING OF PRUSSIA, Pa. -- Vicuron Pharmaceuticals announced today that positive results from a large Phase II study highlighting anidulafungin, its lead product candidate, as a potential therapy for invasive candidiasis (IC)/candidemia, the most common hospital-based fungal infections, were presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).
Excellent efficacy of a loading dose of 200 or 150 mg intravenous anidulafungin, followed by a daily dose of 100 or 75 mg intravenous anidulafungin, respectively, was observed at the end of therapy (EOT) and at the follow-up visit two weeks later. Anidulafungin was well tolerated at all doses tested in the trial.
"We are extremely encouraged that anidulafungin demonstrated high efficacy in these difficult-to-treat, often life-threatening infections," said Timothy J. Henkel, MD, PhD, Vicuron's chief medical officer and one of the co-authors of the study. "Higher global response rates (ranging from 81 percent to 88 percent) were observed with anidulafungin in this Phase II trial, compared with rates (ranging from 56 percent to 81 percent) reported historically in previous invasive candidiasis/candidemia clinical trials of other antifungal agents, including fluconazole, amphotericin B and caspofungin."
Results from the Phase II trial, the top-line results of which were previously reported, were used to select an optimal dosing regimen for a randomized, controlled, double-blind Phase III trial using a 200 mg loading dose of IV anidulafungin, followed by a 100 mg daily maintenance dose of IV anidulafungin in invasive candidiasis/candidemia. This trial is now underway in the U.S., Canada and Europe. The standard-of-care comparator in the trial is IV fluconazole.
Due to its broad spectrum of antifungal activity, anidulafungin is being developed as a therapy for a variety of serious fungal infections. Last month, Vicuron filed a New Drug Application (NDA) with the U.S. Food and Drug Administration and plans to file for marketing clearance in Europe in the second half of 2003. Also, interim safety data from an ongoing Phase III trial of anidulafungin in combination with a liposomal amphotericin for the treatment of invasive aspergillosis was included as part of the NDA submission.
Anidulafungin is a member of the novel echinocandin class of antifungal drugs. Echinocandins are the first new class of antifungal agents introduced in more than 40 years. In vitro and clinical studies of anidulafungin have demonstrated that the drug is highly active against Candida and other fungal pathogens.
"We believe anidulafungin has considerable potential to become an important part of the antifungal armamentarium due in large part to its potential efficacy in invasive candidiasis/candidemia and we're encouraged to see such high rates of response, which compare favorably to those reported historically with other agents currently used for these types of infections," said George F. Horner III, president and CEO of Vicuron. "Anidulafungin is further distinguished by its quicker achievement of steady state, strong in vitro potency, ability to be given at high doses and favorable drug interaction profile. These attributes should enable us to position it competitively within the echinocandin class."
The market opportunity for antifungals to treat serious hospital-based fungal infections is large and growing, due to the aging population and the increased incidence and prevalence of immunocompromised patients. By the year 2008, the worldwide market for echinocandins is estimated to be $1.8 billion, according to Datamonitor.
A randomized, open-label dose-ranging study of the safety and efficacy of IV anidulafungin was conducted in the U.S. in 120 adult patients with documented IC, including candidemia (i.e., Candida infection in the blood) or histologic or culture evidence of infection in a normally sterile site, and expected survival >72 hours. The most common species of Candida observed at baseline was C. albicans, however it represented only half of all isolates, followed by C. glabrata. Among all species of Candida observed, per pathogen responses were similar.
Three experimental arms of the trial were compared: a loading dose of 100 mg of IV anidulafungin on day 1, followed by 50mg IV daily (100/50 mg); 150/75 mg; and 200/100 mg. Duration of treatment was 2 weeks beyond cure or improvement, up to 42 days.
Adverse events (AEs) attributable to anidulafungin were infrequent. Higher doses of anidulafungin were as well tolerated as the lowest doses of the drug. For example, AEs, serious AEs, and laboratory values were similar for each dose of anidulafungin tested.
Efficacy was evaluated at two time-points: EOT and at the follow-up visit two weeks later. The primary efficacy endpoint was global response at follow-up. A successful global response was defined as a successful clinical and microbiological outcome.
End-of-therapy outcomes in evaluable patients demonstrated an 89 percent global response rate (25/28 patients) with a loading dose of 200 mg followed by a 100 mg maintenance dose per day; 90 percent (27/30 patients) with an analogous regimen of 150 mg followed by 75 mg per day; and 84 percent (21/25 patients) with 100 mg followed by 50 mg. Outcomes in evaluable patients at the two-week follow-up visit demonstrated an 83 percent global response rate (20/24 patients) with a loading dose of 200 mg followed by a 100 mg maintenance dose per day; 85 percent (22/26 patients) with an analogous regimen of 150 mg followed by 75 mg per day; and 72 percent (13/18 patients) with 100 mg followed by 50 mg.
Anidulafungin is a naturally occurring molecule that has been significantly improved through chemical modification. In vitro studies have demonstrated that anidulafungin combines both the potency and killing effects of the polyene class (e.g., amphotericin B) without the resistance problems found with the azole class (e.g., fluconazole). Anidulafungin is a broad-spectrum agent, and has been demonstrated to be highly potent in vitro against the fungi responsible for serious systemic infections. Preclinical studies have shown that five-minute exposure to anidulafungin in vitro kills more than 99 percent of Candida, including fluconazole-resistant strains. Anidulafungin has no cross-resistance with azoles or amphotericin, and in the laboratory it has proven very difficult to develop resistance to anidulafungin. Anidulafungin also was well tolerated in the Phase I study when given in combination with cyclosporine, the leading chronic immunosuppressive drug.
Source: Vicuron Pharmaceuticals