The broad-spectrum triazole isavuconazole was as effective as voriconazole in patients with suspected invasive mold disease and caused significantly fewer drug-related adverse events, particularly those of the skin, eyes, and hepatobiliary system, a randomized double-blind study of 516 adults has shown.
The findings suggest that the newer agent “could allow safer therapy” for the primary treatment of invasive aspergillosis and other mold disease than standard therapy with voriconazole, researchers for the phase III, industry-sponsored SECURE trial say in a report published in the Lancet.
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Aspergillosis histology shows the presence of conidial heads.
The researchers assessed the safety and efficacy of isavuconazole versus voriconazole in patients with invasive mold infection. Patients were recruited from 102 centers across 26 countries over a 7-year period and were randomized to receive either drug.
In the study group of 516 adults with suspected invasive mold infection who received at least one dose of either antifungal drug, isavuconazole proved to be noninferior to voriconazole, by the primary endpoint of all-cause mortality at 6 weeks.
All-cause mortality at 6 weeks in this intention-to-treat group, of whom more than 80% had hematologic malignant disease, was 19% in the isavuconazole group (48 of 258) and 20% (52 of 258) in the voriconazole group.
This primary endpoint was chosen because “it provides the most objective and reproducible effect of therapy, and approximates best the attributable mortality, because deaths due to competing causes occur increasingly after 6 weeks,” Dr. Johan A. Maertensof the UZ Leuven (Belgium), and his associates wrote.
Secondary endpoints included overall response at the end of treatment among patients who were determined by an independent review committee to have proven or probable invasive mold disease – the study’s modified intention-to-treat population – as well as all-cause mortality at day 42 and day 84.
All-cause mortality in this modified intention-to-treat group, as well as in the group of patients found to have proven or probable invasive aspergillosis, specifically, supported the study’s primary findings (Lancet 2016 Feb:387:760-9).
Nearly all patients in the study had at least one treatment-emergent adverse event, and the proportion with serious treatment-emergent adverse events was similar between the treatment groups. However, patients treated with isavuconazole had a significantly lower frequency of hepatobiliary disorders, eye disorders, and skin or subcutaneous disorders.
And overall, significantly fewer patients reported drug-related adverse events with isavuconazole (42% of patients) than with voriconazole (60% of patients). Discontinuation from adverse events, moreover, was significantly less common among isavuconazole-treated patients.
Of the 516 patients in the intention-to-treat group, approximately 53% were confirmed to have proven or probable invasive mold disease, and more than 80% of the mycologically documented cases were Aspergillus infections. Enrollment of patients with possible invasive mold disease at the start “reflects the real-life strategy of early initiation of antifungal treatment,” the investigators say.
Isavuconazonium sulfate was approved in 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis.
Voriconazole is the current gold standard for the primary treatment of invasive aspergillosis and is recommended for some other mold infections as well, but it is not active against mucormycosis and has “highly variable nonlinear pharmacokinetics in adults,” which has triggered recommendations for drug monitoring, Dr. Maertens and his associates say.
Therapeutic monitoring aimed at individualizing dosage regimes in order to improve response and prevent adverse events became the standard of care in some institutions during the study period (2007-2013). The study used the labeled dose of voriconazole, however, and did not address the efficacy of either drug with therapeutic drug monitoring.
The study also excluded patients with AIDS, abnormal liver or renal function, and those receiving antifungal prophylaxis with a mold-active triazole – factors that may limit generalizability of the findings, the investigators note.
Funding for the study was provided by Astellas Pharma Global Development and Basilea Pharmaceutica International.
Dr. Maertens disclosed receiving grants and fees from Bio-Rad, personal fees and nonfinancial support from Astellas and Basilea, and grants, fees and support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer during the study.