October 11, 2014

PHILADELPHIA — Two analyses of the SECURE trials demonstrated comparable outcomes for isavuconazole and voriconazole in patients with invasive mold disease.

Dimitrios Kontoyiannis, MD, of the division of internal medicine at the University of Texas MD Anderson Cancer Center in Houston, described isavuconazole as water-soluble, broad-spectrum triazole antifungal available in IV and oral formulations for treatment of invasive fungal disease. The current phase 3 analysis included a pre-specified subset of patients with proven or probable invasive aspergillosis who were treated with at least one dose of isavuconazole.

Participants were randomly assigned isavuconazole or voriconazole for up to 84 days, according to Kontoyiannis. Patients in the study drug group received 200 mg IV three times daily for 2 days, followed by 200 mg IV or orally once daily, while those in the voriconazole group received 6 mg/kg IV twice a day on day 1, 4 mg/kg IV twice a day on day 2, then either 4 mg/kg IV twice a day or 200 mg orally twice a day.

“Treatment duration is an important parameter,” Kontoyiannis said. “Both IV and total duration of treatment in the two arms were comparable, with an almost identical mean and standard deviation of mean.”

All-cause mortality at day 42 served as the primary endpoint. The researchers also assessed patients for overall success at the end of treatment and for safety outcomes. A blinded independent review committee also assessed the findings.

Kontoyiannis reported on findings for 123 patients in the study drug group and 108 patients in the voriconazole group.

All-cause mortality rates were 19% in the isavuconazole group and 22% for voriconazole.

“There did not appear to be any particular signal demonstrating that isavuconazole is any better than voriconazole or vice versa in terms of the primary endpoint,” Kontoyiannis said. “All-cause mortality based on pathogen and patient characteristics was also comparable.”

The overall success of the drug at the end of treatment was 35% for isavuconazole and 39% for voriconazole.

Serious adverse events occurred in 58% of patients in the study drug group and 66% of those receiving voriconazole. Drug-related adverse event rates were 39% and 62% in favor of isavuconazole, with serious adverse event rates occurring in 13% of patients receiving the study drug and 12% of those receiving voriconazole. Kontoyiannis noted that eye disorders were significantly more common in the voriconazole group (15% vs. 29%).

“Differences in drug-related adverse events between isavuconazole and voriconazole were statistically significant,” Kontoyiannis said.

“This is the first study of these two broad-spectrum drugs,” he concluded.

Treatment in neutropenic patients

Thomas Patterson, MD, of the University of Texas Health Science Center in San Antonio, Texas, presented findings from an analysis of the SECURE study in patients with or without neutropenia. “Neutropenia is an important predictor of mortality in patients with invasive fungal disease,” Patterson said.

The dosing regimens were the same as the findings presented by Kontoyiannis, as was the primary endpoint.

This analysis included 163 neutropenic patients in the isavuconazole group and 175 patients in the voriconazole group. For non-neutropenics, there were 95 patients in the study drug group and 83 patients in the voriconazole group.

Crude all-cause mortality rates at 42 days in the intent-to-treat analysis were 21% for both drugs among patients with neutropenia. For non-neutropenics, the 42-day all-cause mortality rates were 15% for the study drug and 18% for voriconazole.

Results of a modified intent-to-treat analysis of neutropenics indicated a 25% mortality rate for isavuconazole and 23% for voriconazole. For non-neutropenics, those rates were 11% in the study drug arm and 23% in the voriconazole arm.

“Neutropenic patients have higher mortality than non-neutropenics in that setting,” Patterson said.

Drug-related adverse events occurred in 43% of neutropenics receiving isavuconazole and 58% of those receiving voriconazole. For non-neutropenics, drug-related adverse event rates favored isavuconazole, 42% vs. 64%. Similar outcomes were reported in the intent-to-treat analysis. Patterson also noted that eye-related adverse events occurred more frequently in the voriconazole arm.

“It makes a big difference in how we approach patients in the neutropenic setting,” he said. “Both of these drugs work in similar ways. We would love them to work better. We really have to aggressively and persistently treat our neutropenic patients. It seems to be promising in patients with neutropenia whether it resolves or not.”

For more information:

Kontoyiannis D. Abstract #1211. Presented at: IDWeek 2014. Oct. 8-12; Philadelphia.

Patterson T. Abstract #1210. Presented at: IDWeek 2014. Oct. 8-12; Philadelphia.

Disclosure: Kontoyiannis reports associations with companies including Astellas, Merck and Pfizer. Patterson reports associations with Astellas.