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Posaconazole Study Shows Significant Reduction in Serious Fungal Infections in High-Risk Neutropenic Patients

ATLANTA, Dec. 12 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE:SGP) today reported results of a new prophylaxis clinical study demonstrating that NOXAFIL(R) (posaconazole) Oral Suspension, a new broad-spectrum triazole antifungal, significantly reduced the incidence of serious invasive fungal infections (IFIs), the incidence of aspergillosis and overall mortality compared to standard azole antifungals (fluconazole and itraconazole), during treatment in high-risk neutropenic patients undergoing intensive chemotherapy. Additionally, in this study involving 602 patients, a significant survival benefit was seen in patients receiving NOXAFIL. In the study, NOXAFIL demonstrated a safety profile similar to fluconazole, with both drugs being well tolerated.

These results comparing prophylaxis with NOXAFIL to standard azoles for the prevention of IFIs in patients with a new diagnosis or first relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who were neutropenic due to intensive chemotherapy were presented for the first time at the 47th annual meeting of the American Society of Hematology (ASH) in Atlanta.

NOXAFIL was approved in the European Union (EU) in October 2005 for the treatment of certain serious IFIs in adult patients who are intolerant of or with disease that is refractory to certain commonly used antifungal agents. It recently was launched in Germany. An application for NOXAFIL to treat refractory IFIs received an approvable letter from the U.S. Food and Drug Administration (FDA) in June 2005.

"There is medical need worldwide for potent new broad-spectrum agents to prevent life-threatening fungal infections, especially in high-risk patients such as those with severe and prolonged neutropenia. These infections are increasingly caused by moulds that are both difficult to diagnose and treat," said lead study investigator Oliver Cornely, M.D., University of Cologne, Germany, who presented the data. "The results of this study demonstrated that NOXAFIL prophylaxis was associated with significant overall and IFI-related survival in these patients compared to standard azole prophylaxis."

Based on the results of this prophylaxis study and those of a previously reported study of NOXAFIL prophylaxis,(1) Schering-Plough plans to file new drug applications with regulatory authorities in the United States and Europe seeking marketing approval of NOXAFIL prophylaxis in high-risk patient populations.

Patients with leukemia undergoing chemotherapy are at high risk for IFIs due to myelosuppression, with incidence rates up to 24 percent.(2,3) Mortality rates in these patients due to candidiasis and aspergillosis range from 40 percent to 50 percent.(4,5)

"NOXAFIL has achieved successful clinical outcomes in this prophylaxis study, demonstrating potent activity against a wide range of fungal infections, including those caused by both yeasts and moulds," said study investigator John Perfect, M.D., Duke University Hospital, Durham, North Carolina, USA.

Clinical Study and Results
Patients in this randomized, evaluator-blinded, active controlled, multicenter study received NOXAFIL Oral Suspension 200 mg three times daily (n=304) or oral standard azoles, either fluconazole oral suspension 400 mg once daily (n=240) or itraconazole oral solution 200 mg twice daily (n=58), with each cycle of chemotherapy until complete remission or for up to a maximum of 12 weeks. The primary efficacy end point of the study was the comparison of the incidence of proven and probable IFIs during the treatment phase (7 days after last dose) as adjudicated by a blinded expert panel based on EORTC/MSG criteria.(6) The incidence of aspergillosis during treatment and the incidence of IFIs 100 days after randomization also were compared.

In the study, the number of proven and probable IFIs during treatment was significantly lower with NOXAFIL prophylaxis vs. the standard azoles (7 vs. 25; p=0.0009). NOXAFIL also significantly reduced the number of Aspergillus infections during treatment (2 vs. 20; p=0.0001) as well as all invasive fungal infections within 100 days post-randomization (14 vs. 33; p=0.0031).

The overall all-cause mortality was 49 (16 percent) vs. 67 (22 percent) (p=0.048) for patients in the NOXAFIL and standard azoles arms, respectively. Analysis of time to death (all cause mortality) within 100 days post-randomization demonstrated a significant survival benefit for NOXAFIL (p=0.035).

Safety and tolerability were comparable for NOXAFIL and fluconazole, with the incidence of treatment-related adverse events and rate of patient discontinuations being similar in the study. The most common adverse events in both treatment groups were gastrointestinal in nature.

Clinical studies have demonstrated that NOXAFIL Oral Suspension is generally safe and well tolerated. The most frequently reported adverse reactions reported in healthy volunteers and patients in a treatment setting who received NOXAFIL were headache (8 percent) and nausea (6 percent). Treatment-related serious adverse events reported in patients with invasive fungal infections (1 percent each) included altered concentration of other medicinal products, increased hepatic enzymes, nausea, rash and vomiting. NOXAFIL co-administration with ergot alkaloids, CYP3A4 substrates known to prolong the QTc interval and HMG-CoA reductase inhibitors is contraindicated. NOXAFIL also should be used with caution in patients with pro-arrhythmic conditions and severe hepatic impairment. The safety and efficacy of NOXAFIL in patients below the age of 18 years have not been established.

1 Ullmann AJ et al. Posaconazole vs. Fluconazole for Prophylaxis of Invasive Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Graft-Versus-Host Disease, Trends In Medical Mycology (TIMM) meeting, Berlin, October 2005.
2 Rotstein C et al. Clin Infect Dis. 1999;28:331-340.
3 Winston DJ et al. Ann Intern Med. 1993;118:495-503.
4 Viscoli C et al. Clin Infect Dis. 1999;28:1071-1079
5 Lin SJ et al. Clin Infect Dis. 2001;32:358-366.
6 European Organisation for Research and Treatment of Cancer/Mycoses Study Group

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