Articles
Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis

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Summary

Background

Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis.

Methods

In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353.

Findings

Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595).

Interpretation

Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated.

Funding

Astellas Pharma Global Development, Basilea Pharmaceutica International.

Introduction

Mucormycosis, an opportunistic invasive fungal disease, which is classically associated with diabetic ketoacidosis and iron overload1 is increasingly encountered in immunocompromised individuals, especially those receiving treatment for haematological malignancies or undergoing transplantation.2, 3 The outlook in these populations is particularly poor, with fatality rates of 52–91%.1, 2, 3, 4 Present guidelines recommend antifungal treatment, surgical debridement, and correction of underlying predisposing disorders.5 Although amphotericin B and posaconazole show in-vitro activity against Mucorales moulds, their clinical use is often restricted.6, 7 Nephrotoxicity remains a common adverse effect of amphotericin B,8 and posaconazole has mainly been studied in the salvage setting.9, 10

Isavuconazonium sulfate is a water-soluble prodrug, which is rapidly hydrolysed to the triazole isavuconazole after oral or intravenous administration. Isavuconazole has high oral bioavailability, linear pharmacokinetics, and is active against a broad range of clinically important fungi, including moulds of the order Mucorales. Isavuconazole inhibits ergosterol biosynthesis, which results in accumulation of toxic sterols and cell death.11

We present the results of a single-arm open-label trial of isavuconazole treatment of mucormycosis, and a case-control analysis. The primary objective of the open-label trial was to assess the efficacy of isavuconazole; the case-control analysis evaluated the mortality outcomes recorded with isavuconazole compared with amphotericin B.

Section snippets

Patients and study design

VITAL was a single-arm open-label trial done in 34 centres worldwide (appendix) that assessed the efficacy and safety of isavuconazole for the treatment of invasive aspergillosis in patients with renal impairment and for the treatment of rare invasive fungal diseases. The study prespecified a category for mucormycosis primary treatment, defined as 4 days or less of previous systemic antifungals. Patients were also eligible if they were intolerant or refractory to other antifungals. Patients

Results

From April 22, 2008, to Oct 6, 2008, six patients consented to participate in the VITAL study. Enrolment was suspended between Jan 23, 2009, and April 3, 2011, to conduct additional non-clinical safety studies and transfer sponsorship from Basilea Pharmaceutica International to Astellas Pharma Global Development. From April 20, 2011, to June 21, 2013, another 143 patients consented to participate in the study (figure 1). Of 37 patients with mucormycosis only, 32 had proven and five had probable

Discussion

The VITAL study showed that isavuconazole was active as primary or salvage (refractory or intolerant to other antifungals) treatment for mucormycosis, with overall end-of-treatment complete and partial response of 32% for primary treatment and 36% for treatment of mucormycosis refractory to other antifungals (table 3). These response rates are similar to those reported for liposomal amphotericin B.22 The stringent response criteria used in the VITAL study might underestimate the relevant

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    Additional VITAL and FungiScope Mucormycosis Investigators are listed in the appendix

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