Isavuconazole effective for primary treatment of invasive fungal disease

By Will Boggs MD

NEW YORK (Reuters Health) - Isavuconazole is as effective as voriconazole for treating invasive fungal disease and has fewer adverse effects, according to results from the SECURE trial.

"Voriconazole has been considered for over 13 years standard of care for the treatment of invasive aspergillosis," Dr. Andrew J. Ullmann, from KU Leuven, Leuven, Belgium, told Reuters Health by email. "Over time we had to learn that voriconazole has some considerable adverse events. The results of our trial demonstrate an improved safety profile with the new azole isavuconazole."

Isavuconazole is available orally and, as its prodrug isavuconazonium sulfate, for intravenous administration and has demonstrated potent activity in animal models of invasive aspergillosis, mucormycosis, invasive candidiasis, and cryptococcosis.

Dr. Ullmann and colleagues in the SECURE study compared isavuconazole and voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus spp or other filamentous fungi in their phase 3 noninferiority study of 516 patients (258 patients assigned to each treatment).

All-cause mortality from first dose of study drug to day 42, the primary efficacy endpoint, did not differ significantly with isavuconazole (19%) and voriconazole (20%), according to the December 9 online report in The Lancet.

Overall response at the end of treatment among patients with proven or probably invasive fungal disease (the modified intention-to-treat population) was also similar for isavuconazole (35%) and voriconazole (36%).

Mortality rates to day 84 were also similar for both treatments.

All but a few patients in both groups experienced at least one treatment-emergent adverse event, but significantly fewer patients in the isavuconazole group (42%) than in the voriconazole group (60%) reported events considered drug-related by the investigator. Fewer isavuconazole patients (8%) than voriconazole patients (14%) discontinued the drug due to drug-related adverse events.

"In the real world where confirmation of a precise filamentous fungal disease is not always possible, physicians need an agent that can be administered in our sick immunocompromised patient population which is safe and expresses broad spectrum activity," Dr. Ullmann said. "Isavuconazole takes on this clinical need with broad spectrum antifungal activity and an improved safety profile."

Dr. Ullmann added, "The prodrug is not dissolved in a solution with a cyclodextrin derivate. This makes the application of the agent in renally impaired patients possible."

Dr. Monica Slavin, from Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia, who coauthored an editorial related to this report, told Reuters Health by email, "Most surprising to me was that in the 15 years since the Herbrecht study of voriconazole versus amphotericin B, survival in the voriconazole/isavuconazole arms of the present study were no different to survival in the voriconazole arm of the Herbrecht study."

"Factors that one should consider when choosing between antifungals are toxicity (rate of LFT and renal toxicity), potential for drug interactions, particularly through the CYP450 enzymes, availability of IV formulation, and need for therapeutic drug monitoring," she explained.

"Isavuconazole is an alternative to voriconazole for treatment of invasive pulmonary aspergillosis," Dr. Slavin concluded. "The number of other mould infections was quite low, so its value in treating moulds, although promising, remains to be confirmed. Likewise its role in treating infections at sites other than lung, such as (central nervous system) and eye."

The editorial, cowritten with Dr. Karin A. Thursky, adds, "Although isavuconazole is a welcome addition to treatment options, much remains to be done to prevent and reduce mortality from mold infections in this vulnerable group of patients."

Astellas Pharma Global Development and Basilea Pharmaceutica International sponsored the trial, employed four of the 28 authors, and had various relationships with 20 of the other authors, including Dr. Ullmann.

SOURCE: https://bit.ly/1RSemxR and https://bit.ly/1lUmuly

Lancet 2015.