Isavuconazole Comparable to Voriconazole for Aspergillosis Treatment

Diana Phillips

December 18, 2015

The antifungal drug isavuconazole is as effective as voriconazole for the treatment of invasive mold disease and causes significantly fewer drug-related adverse events, according to the results of a large, randomized controlled trial published online December 9 in the Lancet.

The novel triazole agent with broad-spectrum antifungal activity was approved by the US Food and Drug Administration in March and by the European Commission in October for the treatment of adult patients with invasive aspergillosis and for the treatment of adult patients with mucormycosis for whom amphotericin B is not warranted.

The safety and efficacy of the drug were assessed in the phase 3, double-blind SECURE trial. For this investigation, 516 patients with suspected invasive mold disease who were recruited between March 7, 2007, and March 28, 2013, from 102 centers across 26 countries were randomly assigned to receive oral formulations of either isavuconazole or voriconazole.

The primary efficacy endpoint of the noninferiority study was all-cause mortality from the first dose of study drug to day 42 in the intention-to-treat (ITT) population, according to lead investigator Johan A. Maertens, MD, from the Department of Hematology, Universitaire Ziekenhuizen Leuven, KU Leuven, Belgium, and colleagues. "The ITT population was chosen because it is representative of a population of patients requiring antifungal therapy in a real-world setting," they explain.

Secondary endpoints included overall response at end of treatment in the modified ITT (mITT) population; all-cause mortality from first dose of study drug to day 84; overall, clinical, mycological, and radiological responses on day 42, day 84, and end of treatment; and safety and tolerability, assessed by monitoring adverse events and clinical findings.

Compared with voriconazole, which had an all-cause mortality from first dose to day 42 of 20% (52 patients) in the ITT population, the all-cause mortality of isavuconazole during this period was 19% (48 patients) in the ITT population, thus meeting the study's primary objective of demonstrating noninferiority, the authors report. All-cause mortality across the mITT and mycological ITT subpopulations supported this conclusion, they note.

The secondary endpoint of overall response at end of treatment in the mITT population was similar for isavuconazole and voriconazole, as were the clinical, mycological, and radiological responses at end of treatment (as assessed by the data review committee) and the mortality from first dose of study drug to day 84 in both the ITT population and the mITT population, the authors report.

The safety and tolerability analyses showed that most patients in both groups most commonly experienced treatment-emergent adverse events, including gastrointestinal disorders and infections/infestations. The proportions of patients with treatment-emergent adverse events by system organ class were similar overall; however, patients in the isavuconazole group experienced fewer hepatobiliary, eye, and skin or subcutaneous tissue disorders.

Significantly fewer patients in the isavuconazole group (n = 109) reported drug-related adverse events than those in the voriconazole group (n = 155). "Additionally, fewer isavuconazole-treated patients experienced drug-related treatment-emergent adverse events within the following system organ classes: hepatobiliary disorders, laboratory investigations, eye disorders, and psychiatric disorders," the authors write, also noting that permanent drug discontinuation as a result of drug-related adverse events was less common in the isavuconazole group.

"The most important differentiating feature between isavuconazole and voriconazole in the current study was the tolerability and safety profile of isavuconazole, which could allow safer therapy," the authors write. "Voriconazole therapy is characterised by a narrow therapeutic window and an established association between elevated concentrations and neurotoxic, hepatic, and visual adverse events." Although these adverse events are usually reversible, they often lead to premature discontinuation of the drug, the authors write.

In an accompanying comment, Monica A. Slavin, MD, and Karin A. Thursky, MD, both from the Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, Australia, list the advantages of isavuconazole over voriconazole, including its broader spectrum of activity, once-daily dosing after the loading dose, linear pharmacokinetics, and less interpatient variability in exposure, water solubility, and fewer CYP enzyme-mediated drug–drug interactions.

The commentators point out some of the study's limitations, including the fact that most of the patients were undergoing treatment for hematological malignant disease, and none were receiving mold-active triazole prophylaxis, which is a common practice in at-risk patients. They also write that, although the findings of this trial "represent important progress in widening therapeutic options for mould infections" and isavuconazole is "a welcome addition" to available treatment strategies, "much remains to be done to prevent and reduce mortality from mould infections in this vulnerable group of [hematology and cancer] patients."

Funding for this study was provided by Astellas Pharma Global Development and Basilea Pharmaceutica International. Dr Maertens disclosed receiving grants and personal fees from Bio-Rad, personal fees and nonfinancial support from Astellas and Basilea, and grants, personal fees, and nonfinancial support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer, Inc. during the conduct of the study. Full conflict-of-interest information is available in the article. Dr Slaving reports receiving grants from Merck, Gilead, and Pfizer. Dr Thursky has disclosed no relevant financial relationships.

Lancet. Published online December 9, 2015. Article abstract, Comment extract


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