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

VITAL and FungiScope Mucormycosis Investigators

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331 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)828-837
Number of pages10
JournalThe Lancet Infectious Diseases
Volume16
Issue number7
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Funding Information:
Isavuconazonium sulfate was co-developed by Astellas Pharma US, and Basilea Pharmaceutica International. The VITAL study was supported by Astellas Pharma US. Independent of the present analysis, the FungiScope Registry is supported by Astellas, Basilea Pharmaceutica, Gilead Sciences, MSD/Merck, and Pfizer Pharma GmbH. Independent Data and Safety Monitoring Board members were Ben de Pauw, John Wingard, and Emmanuel Quinaux. We acknowledge the contributions of the medical monitor of the VITAL trial, Neddie Zadeikis (Astellas Pharma Global Development during the conduct of the study), in the design and conduct of the study. Editorial assistance was provided by Debra Brocksmith, Radhika Bhatia, and Suzanne Douthwaite of Envision Scientific Solutions, funded by Astellas Pharma Global Development. The authors are grateful for the contributions of the investigators and study centre staff who did the studies and the patients who participated in the VITAL trial and FungiScope Registry.

Funding Information:
FMM reports grants, personal fees, and non-financial support from Astellas and Merck, and grants and personal fees from WHISCON, during the conduct of the study. Additionally, FMM has a patent (Diagnosis and Treatment of Invasive Aspergillosis, Application 61/698,155) pending from Brigham and Women's Hospital. LO-Z reports personal fees from Astellas during the conduct of the study, personal fees from Merck, and grants and personal fees from Astellas and Pfizer, outside the submitted work. OAC reports grants from 3M, Bayer, Celgene, Genzyme, GSK, Miltenyi, Quintiles, and Viropharma; personal fees from Da Volterra, Daiichi Sankyo, F2G, Sanofi Pasteur, Summit, Vical, and Vifor; and grants and personal fees from Actelion, Astellas, Basilea, Cubist, Gilead Sciences, Merck/MSD, Optimer, and Pfizer, outside the submitted work. KMM reports grants and personal fees from Astellas, outside the submitted work. JRP reports support from Astellas at the time of the study, and grants and consulting fees from Amplyx, Arno, Astellas, Cidara, F2G, Merck, Scynexis, Viamet, Vical, and Tokoyama, outside of the submitted work. GRT was a member of the data review committee for the SECURE study (Astellas) and reports grants from Astellas and Merck, outside the submitted work. WJH reports personal fees from Astellas, Basilea, and Gilead Sciences; and grants and personal fees from Merck/MSD and Pfizer, outside the submitted work. RH reports personal fees from Astellas, Basilea, Gilead Sciences, MSD, and Schering-Plough; and grants and personal fees from Pfizer during the conduct of the study. NK reports personal fees from Astellas and Pfizer, and grants and personal fees from Merck, outside the submitted work. GK reports lectures fees from Astellas Russian Federation, and lectures fees and travel grants from Pfizer Russian Federation, and MSD Russian Federation, outside the submitted work. JAM reports personal fees and non-financial support from Basilea, and grants, personal fees, and non-financial support from Astellas, Gilead Sciences, Merck Sharpe and Dohme, and Pfizer. PGP reports grants and personal fees from Astellas, during the conduct of the study; grants from Gilead, Merck, Scynexis, and T2 Biosystems; and personal fees from Viamet, outside the submitted work. ZR reports grants and personal fees from Astellas, outside the submitted work. SS reports personal fees from MSD Sharp and Dohme, Pfizer, and Gilead Sciences and grants and personal fees from Astellas, during the conduct of the study; and personal fees from Amgen and BTG International, outside the submitted work. JJV reports grants from Astellas during the conduct of the study; grants, personal fees, and non-financial support from Astellas, Gilead Sciences, Merck/MSD, and Pfizer, outside the submitted work. J-AHY reports that the University of Minnesota was paid by Astellas on a per participant basis for the participants that were enrolled on this clinical trial, during the conduct of the study. PC reports grants from Astellas during the conduct of the study. SSK received principal investigator fees for enrolling patients, and received honorarium for talks for Pfizer and MSD outside the submitted work. MJGTV reports grants from Astellas, Gilead Sciences, Merck/MSD, and Pfizer during the conduct of the study; grants from 3M; personal fees from Merck/MSD, Berlin Chemie, and Pfizer; and grants and personal fees from Astellas, DaVolterra, and Gilead Sciences, outside the submitted work. ME and AK are employees of Basilea Pharmaceutica International. MI, ML, CS, RMM, and BZ are employees of Astellas Pharma Global Development. GJA, JMB, DNF, SRM, IO, GR, RS, and SJ declare no competing interests.

Publisher Copyright:
© 2016 Elsevier Ltd.

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