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Efficacy and safety of isavuconazole against deep-seated mycoses: A phase 3, randomized, open-label study in Japan

Open AccessPublished:November 01, 2022DOI:https://doi.org/10.1016/j.jiac.2022.10.010

      Abstract

      Objectives

      Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses.

      Patients and methods

      In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT).

      Results

      A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole.

      Conclusions

      Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.

      Keywords

      Abbreviations

      CPA
      chronic pulmonary aspergillosis
      DRC
      Data Review Committee
      EMA
      European Medicines Agency
      EORTC/MSG
      European Organization for Research and Treatment of Cancer/Mycoses Study Group
      EOT
      end of treatment
      FDA
      Food and Drug Administration
      IA
      invasive aspergillosis
      ITT
      intention-to-treat
      MIC
      minimum inhibitory concentration
      mITT
      modified intention-to-treat
      SOC
      system organ class
      TDM
      therapeutic drug monitoring
      TEAE
      treatment-emergent adverse event

      1. Introduction

      Invasive deep-seated mycoses are often problematic due to their rapid progression and fatal outcomes. Chronic mycoses, which progress gradually with a course of repeated remission and recurrence, are also associated with poor outcomes [
      • Lowes D.
      • Al-Shair K.
      • Newton P.J.
      • et al.
      Predictors of mortality in chronic pulmonary aspergillosis.
      ]. Voriconazole, which is one of the first-line treatments for aspergillosis, is associated with numerous adverse drug reactions, including liver and eye disorders. In addition, plasma levels of voriconazole can fluctuate markedly due to factors including a non-linear pharmacokinetic profile, CYP2C19 polymorphism [
      • Purkins L.
      • Wood N.
      • Ghahramani P.
      • et al.
      Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens.
      ,
      • Lee S.
      • Kim B.H.
      • Nam W.S.
      • et al.
      Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers.
      ], and drug interactions. Because of these issues, therapeutic drug monitoring (TDM) is recommended [
      Committee of Practice Guidelines for TDM of Antimicrobial Agents
      Revised guidelines for therapeutic drug monitoring of antimicrobials.
      ]. Moreover, the β-cyclodextrin present in the injectable formulation restricts their use in patients with renal impairment.
      Isavuconazole is a triazole antifungal agent with a broad antifungal spectrum [
      • Miceli M.H.
      • Kauffman C.A.
      Isavuconazole: a new broad-spectrum triazole antifungal agent.
      ]. Isavuconazole is available as injectable and oral formulations (with 98% oral bioavailability) [
      • Schmitt-Hoffmann A.
      • Roos B.
      • Heep M.
      • et al.
      Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers.
      ], both of which have generally linear pharmacokinetics. Since CYP2C9, CYP2C19, CYP2D6, and glucuronosyltransferases, polymorphisms of which affect pharmacokinetics [
      EMA
      Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products.
      ,
      FDA
      Clinical Pharmacogenomics: Premarket evaluation in early-phase clinical studies and recommendations for labeling.
      ], are not involved in the metabolism of isavuconazole, no evidence seems to suggest that TDM is required. The injectable formulation lacks β-cyclodextrin and can therefore be administered to patients with renal impairment without dose adjustment [
      • Falci D.R.
      • Pasqualotto A.C.
      Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections.
      ]. In pivotal phase III studies (SECURE and VITAL studies) [
      • Maertens J.A.
      • Raad II,
      • Marr K.A.
      • et al.
      Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
      ,
      • Marty F.M.
      • Ostrosky-Zeichner L.
      • Cornely O.A.
      • et al.
      Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
      ], isavuconazole was shown to be effective against invasive aspergillosis ( IA ) and mucormycosis, which supported Food and Drug Administration (FDA) and European Medicines Agency (EMA) marketing authorizations. The European Conference on Infections in Leukaemia and European Confederation of Medical Mycology guidelines recommend isavuconazole for use as first-line treatment for IA and primary treatment for mucormycosis [
      • Tissot F.
      • Agrawal S.
      • Pagano L.
      • et al.
      ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients.
      ,
      • Ullmann A.J.
      • Aguado J.M.
      • Arikan-Akdagli S.
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      ,
      • Cornely O.A.
      • Alastruey-Izquierdo A.
      • Arenz D.
      • et al.
      Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of medical Mycology in cooperation with the mycoses study group education and research consortium.
      ]. Furthermore, the VITAL study suggested that isavuconazole is effective in cryptococcosis [
      • Thompson III, G.R.
      • Rendon A.
      • Ribeiro dos Santos R.
      • et al.
      Isavuconazole treatment of cryptococcosis and dimorphic mycoses.
      ], but the drug does not have an FDA or EMA indication for this.
      Since there is no evidence to support the use of isavuconazole in Japan, a phase 3 clinical study was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses. Patients with chronic pulmonary aspergillosis (CPA) were mainly enrolled in the study because of the relatively high prevalence of tuberculosis in Japan [
      • Kimura Y.
      • Sasaki Y.
      • Suzuki J.
      • et al.
      Prognostic factors of chronic pulmonary aspergillosis: a retrospective cohort of 264 patients from Japan.
      ]. This is the first prospective, large-scale trial demonstrating the effect of isavuconazole in patients with CPA. Patients with cryptococcosis, IA, and mucormycosis were also enrolled, though in small numbers, and the results are presented together in this report.

      2. Patients and methods

      2.1 Study design and participants

      This was a randomized, multi-center, open-label study (ClinicalTrials.gov registration number NCT03471988) in Japanese patients with deep-seated mycoses conducted from April 2018 to April 2021 at 39 sites in Japan.
      Participants with aspergillosis were assigned to Cohort A, and participants with cryptococcosis or mucormycosis were assigned to Cohort B. For Cohort A, voriconazole was established as an active comparator. In Cohort B, no comparator was used due to limited sample sizes, and all participants were administered isavuconazole.
      The inclusion criteria required participants to be Japanese men or women at least 20 years old and met the diagnostic criteria for CPA, IA, cryptococcosis, or mucormycosis. The diagnostic criteria for CPA were established in reference to the Japanese Guidelines for the Diagnosis and Management of Deep-seated Mycoses (hereafter called “the Japanese Guidelines”) [
      ,
      • Kohno S.
      • Tamura K.
      • Niki Y.
      • et al.
      Executive summary of Japanese Domestic guidelines for management of deep-seated mycosis 2014.
      ], and participants who met the criteria for proven or probable were eligible. For other mycoses, the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) were used [
      • Donnelly J.P.
      • Chen S.C.
      • Kauffman C.A.
      • et al.
      Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group education and research consortium.
      ], and participants who met the criteria for proven, probable, or possible for IA, proven or probable for cryptococcosis, and proven for mucormycosis were eligible. Participants enrolled with possible IA that did not meet the criteria for proven or probable within 7 days of the start of treatment were discontinued from treatment. Such participants who met the criteria for proven mucormycosis based on tests within 7 days of the start of treatment were switched to Cohort B. The main exclusion criteria were hepatic dysfunction (i.e., total bilirubin ≥3 times the upper limit of normal, alanine transaminase or aspartate transaminase ≥5 times the upper limit of normal, hepatic cirrhosis, or chronic hepatic failure) or moderate to severe renal impairment.
      The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice. The study was approved in advance by the institutional review board of each study site. All participants gave their written, informed consent before starting the study.

      2.2 Procedures

      Based on a participant recruitment survey of clinical studies of antifungal agents conducted in Japan, target sample sizes of 90 patients with aspergillosis in Cohort A and 10 patients with cryptococcosis and 3 patients with mucormycosis in Cohort B were selected. Participants in Cohort A were randomized using a third-party Interactive Web Response System to assign them to receive isavuconazole or voriconazole in a 2:1 allocation. Randomization was performed using a block size of six and three and was stratified by disease name (CPA, IA) and weight (≤40 kg, > 40 kg). All participants in Cohort B were assigned to the isavuconazole group.
      Participants assigned to isavuconazole received, intravenously or orally, 6 loading doses of 200 mg of isavuconazole once every about 8 h and then, 12–24 h after the last loading dose, 200 mg of isavuconazole once a day as maintenance doses. For voriconazole, participants received 2 loading doses of 6 mg/kg (intravenously) or 300 mg (orally) of voriconazole once every about 12 h and then, 12–24 h after the last loading dose, 4 mg/kg (intravenously) or 200 mg (orally) of voriconazole 2 times a day as maintenance doses. Voriconazole dosages were adjusted according to the package inserts, with TDM performed during the treatment period as necessary. Switching from intravenous to oral administration was allowed, but not vice versa. The maximum treatment period was 84 days.
      Clinical symptoms were assessed at screening, Days 3, 7, 14, 28, 42, 63, and 84 of treatment, and the end of treatment (EOT), and radiological examinations (CT or MRI), mycological tests (culture, cytology, or histological tests), and serological tests (galactomannan antigen, β-D-glucan, Aspergillus antibody, glucuronoxylomannan antigen) were performed at screening, Days 42 and 84 of treatment, and at EOT. The fungi isolated and identified at the study sites before and after the start of treatment were re-identified by morphological and biochemical characterization test or genetic analysis [
      • Yamaguchi H.
      • Yoshida A.
      • Suzuki H.
      • et al.
      Medical important fungi: a guide to identification.
      ] at a central laboratory, where sensitivity to different antifungal agents was determined using broth microdilution according to standardized Clinical and Laboratory Standards Institute procedures [
      Clinical and Laboratory Standards Institute
      Reference method for Broth Dilution antifungal susceptibility testing of yeasts.
      ,
      Clinical and Laboratory Standards Institute
      Reference method for Broth Dilution antifungal susceptibility testing of filamentous fungi. Approved standard.
      ].
      A Data Review Committee (DRC) consisting of infectious disease experts was established for the study. The DRC was independent of the sponsor and investigators. It evaluated diagnostic classifications on enrollment and clinical responses, radiological responses, mycological responses, overall responses, and causes of death on Days 42 and 84 and at EOT. The DRC was blinded to treatment assignment and performed these evaluations for Cohort A, which had a control.

      2.3 Outcomes

      The study endpoints were similar to endpoints used in phase III studies of isavuconazole (SECURE and VITAL studies) [
      • Maertens J.A.
      • Raad II,
      • Marr K.A.
      • et al.
      Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
      ,
      • Marty F.M.
      • Ostrosky-Zeichner L.
      • Cornely O.A.
      • et al.
      Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
      ,
      • Thompson III, G.R.
      • Rendon A.
      • Ribeiro dos Santos R.
      • et al.
      Isavuconazole treatment of cryptococcosis and dimorphic mycoses.
      ].
      Diagnostic classification and efficacy evaluation were performed by the blinded DRC. The efficacy endpoint was the DRC-assessed crude treatment success rate (overall response success rate on Days 42 and 84 and at EOT), which was classified as “success” or “failure”. The overall response was determined by the clinical, radiological, and mycological responses. For CPA and cryptococcosis, clinical and radiological responses were assessed on a 4-grade scale (improved, stable, progression, unevaluable). The overall response was assessed as “improved”, and treatment was considered to be a “success” if no assessment of progression or unevaluable was made in the clinical and radiological responses, and improvement was seen in one or both. For IA and mucormycosis, the overall response was assessed as “complete” or “partial”, and treatment was considered to be a “success” if all or some clinical symptoms and physical findings resolved, and there was resolution or apparent improvement in lesions on imaging. The response assessment criteria were established in reference to the EORTC/MSG [
      • Segal B.H.
      • Herbrecht R.
      • Stevens D.A.
      • et al.
      Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.
      ] and Japanese Guidelines [
      ,
      • Kohno S.
      • Tamura K.
      • Niki Y.
      • et al.
      Executive summary of Japanese Domestic guidelines for management of deep-seated mycosis 2014.
      ]. The efficacy analysis sets were the intention-to-treat (ITT) set, consisting of all participants assigned to treatment who received the study drug at least once, and the modified ITT (mITT) set, consisting of the ITT set participants with a proven or probable deep-seated mycosis as assessed by the DRC.
      Treatment-emergent adverse events (TEAEs) were defined as adverse events reported from the start of study treatment to 28 days after EOT. The safety endpoint was the proportion of participants with at least one TEAE, and the investigators also evaluated laboratory test values, vital signs, and 12-lead electrocardiography. The investigators assessed causal relationships between AEs and the study drugs on a 2-grade scale of related and unrelated. AEs classified as related were considered to be adverse drug reactions. The safety analysis set consisted of all participants assigned to treatment who received the study drug at least once.

      2.4 Statistical analyses

      In this study, no statistical hypothesis testing was performed, with the data evaluated by calculating descriptive statistics. The primary endpoint was the proportion of participants with at least one TEAE (safety). Efficacy was the secondary endpoint, including overall, clinical, radiological, and mycological responses in the mITT set. For overall response, the crude success rate and 95% confidence interval at the evaluation points (Days 42 and 84 and EOT) were calculated individually for each diagnosis name and each treatment group. When data were missing at an evaluation point, the assessment for that point was considered to be “failure.”

      3. Results

      3.1 Subjects

      Participants were recruited at 39 sites in Japan from April 2018 to January 2021. A total of 103 participants were enrolled in the study and received the study drug (ITT set). Of these participants, 90 were in Cohort A (60 in the isavuconazole group and 30 in the voriconazole group), and 13 were in Cohort B. One patient in the isavuconazole group who was enrolled with CPA was subsequently confirmed to have mucormycosis on testing performed within 7 days of the start of treatment and therefore switched to Cohort B. Seven participants found by the DRC not to meet the diagnostic criteria for deep-seated mycosis were treated as having no deep-seated mycosis and excluded from the mITT set (Fig. 1).
      Fig. 1
      Fig. 1Enrollment and study flow
      ISCZ: isavuconazole; VRCZ: voriconazole; ITT: intention-to-treat; mITT: modified intention-to-treat; CPA: chronic pulmonary aspergillosis; IA: invasive aspergillosis.
      † Excluding subjects migrated from Cohort A to Cohort B.
      ‡ Including subjects migrated from Cohort A to Cohort B.
      * Of the three IA patients treated with isavuconazole, two had pulmonary and one had sinus disease. Aspergillus fumigatus was isolated in one, but the pathogen was not isolated in the other two, who were diagnosed as probable.
      ** All 10 patients with cryptococcosis had pulmonary lesions.
      *** One of each of the three patients with mucormycosis had pulmonary, sinus, or thoracic abscess involvement. Cunninghamella bertholletiae was isolated in two of the three patients, and the remaining patient was diagnosed with mucormycosis by histopathology.
      In the ITT set, the median duration of treatment for CPA was 84.0 days in the isavuconazole group (52 participants) and 85.0 days in the voriconazole group (27 participants). The percentages of participants completing study treatment in the isavuconazole and voriconazole groups were 82.7% (43/52) and 85.2% (23/27). AEs were the most common reason for discontinuation in each group. The median duration of treatment for cryptococcosis (10 participants in the isavuconazole group only) was 84.5 days.
      The demographic characteristics and underlying diseases and conditions at baseline of the ITT set are shown in Table 1. The characteristics of the participants with CPA in the isavuconazole and voriconazole groups were generally balanced.
      Table 1Baseline characteristics of the subjects in the ITT set.
      CharacteristicChronic pulmonary aspergillosisCohort ACohort A/B combined
      ISCZ (N = 52)VRCZ (N = 27)ISCZ (N = 60)VRCZ (N = 30)ISCZ (N = 73)
      Age (y)
       Mean (range)66.0 (35–86)68.1 (41–88)65.9 (35–86)68.3 (41–88)66.4 (24–87)
       Median68.069.068.069.068.0
       ≤6520 (38.5%)10 (37.0%)24 (40.0%)12 (40.0%)26 (35.6%)
       >65 to ≤7523 (44.2%)9 (33.3%)24 (40.0%)9 (30.0%)29 (39.7%)
       >759 (17.3%)8 (29.6%)12 (20.0%)9 (30.0%)18 (24.7%)
      Sex
       Male46 (88.5%)23 (85.2%)52 (86.7%)26 (86.7%)59 (80.8%)
      Weight (kg)
       Mean (range)53.28 (31.0–81.4)50.38 (31.4–71.7)52.82 (31.0–81.4)51.68 (31.4–80.3)53.65 (31.0–81.4)
       Median52.9050.3051.6550.7052.70
       <408 (15.4%)5 (18.5%)10 (16.7%)5 (16.7%)13 (17.8%)
       ≥40 to < 5013 (25.0%)7 (25.9%)16 (26.7%)7 (23.3%)19 (26.0%)
       ≥5031 (59.6%)15 (55.6%)34 (56.7%)18 (60.0%)41 (56.2%)
      BMI (kg/m2)
       Mean (range)19.28 (12.9–25.4)18.52 (13.0–26.4)19.29 (12.9–25.4)18.85 (13.0–26.4)19.90 (12.9–33.7)
       Median19.3417.9919.2518.0619.92
      eGFR category (mL/min/1.73 m2)
       <606 (11.5%)7 (25.9%)6 (10.0%)8 (26.7%)8 (11.0%)
       ≥6046 (88.5%)20 (74.1%)54 (90.0%)22 (73.3%)65 (89.0%)
      Primary underlying disease and condition (>10% in one or more treatment groups)
       Pulmonary cavitation17 (32.7%)9 (33.3%)18 (30.0%)9 (30.0%)19 (26.0%)
       COPD16 (30.8%)7 (25.9%)17 (28.3%)8 (26.7%)18 (24.7%)
       History of pulmonary tuberculosis14 (26.9%)12 (44.4%)15 (25.0%)12 (40.0%)15 (20.5%)
       After thoracic operation11 (21.2%)4 (14.8%)11 (18.3%)4 (13.3%)12 (16.4%)
       Bronchiectasis9 (17.3%)5 (18.5%)11 (18.3%)5 (16.7%)11 (15.1%)
       Interstitial lung disease9 (17.3%)3 (11.1%)11 (18.3%)4 (13.3%)11 (15.1%)
      Data are n/N (%) values, unless otherwise indicated. Diagnosis was based on assessment by the DRC. Participants with chronic pulmonary aspergillosis or invasive aspergillosis were assigned to Cohort A, and participants with cryptococcosis or mucormycosis were assigned to Cohort B.
      BMI: body mass index; COPD: chronic obstructive pulmonary disease; eGFR: estimated glomerular filtration rate; ITT: intention-to-treat; ISCZ: isavuconazole; VRCZ: voriconazole.

      3.2 Efficacy

      The DRC-evaluated overall response success rates of CPA participants in the mITT set in the isavuconazole and voriconazole groups were 78.8% (41/52) and 63.0% (17/27) on Day 42, 84.6% (44/52) and 74.1% (20/27) on Day 84, and 82.7% (43/52) and 77.8% (21/27) at EOT, respectively (Table 2). The number of patients with proven and probable CPA was 23 and 29 in the isavuconazole group and 13 and 14 in the voriconazole group, respectively. At any evaluation point, response rates by diagnostic criteria were similar in both groups. The clinical, radiological, and mycological response rates in the isavuconazole group were comparable to or superior to those in the voriconazole group.
      Table 2DRC-assessed response in chronic pulmonary aspergillosis (mITT set).
      Day 42Day 84EOT
      ISCZVRCZISCZVRCZISCZVRCZ
      (N = 52)(N = 27)(N = 52)(N = 27)(N = 52)(N = 27)
      Overall response
       Success41 (78.8)17 (63.0)44 (84.6)20 (74.1)43 (82.7)21 (77.8)
       95% CI (%) of Success(65.3–88.9)(42.4–80.6)(71.9–93.1)(53.7–88.9)(69.7–91.8)(57.7–91.4)
       Improved41 (78.8)17 (63.0)44 (84.6)20 (74.1)43 (82.7)21 (77.8)
       Failure11 (21.2)10 (37.0)8 (15.4)7 (25.9)9 (17.3)6 (22.2)
       Stable1 (1.9)3 (11.1)1 (1.9)2 (7.4)3 (5.8)3 (11.1)
       Progression5 (9.6)4 (14.8)2 (3.8)2 (7.4)2 (3.8)2 (7.4)
       Unevaluable5 (9.6)3 (11.1)5 (9.6)3 (11.1)4 (7.7)1 (3.7)
      Clinical response
       Success36 (69.2)15 (55.6)38 (73.1)17 (63.0)37 (71.2)18 (66.7)
       95% CI (%) of Success(54.9–81.3)(35.3–74.5)(59.0–84.4)(42.4–80.6)(56.9–82.9)(46.0–83.5)
      Radiological response
       Success42 (80.8)17 (63.0)42 (80.8)19 (70.4)41 (78.8)20 (74.1)
       95% CI (%) of Success(67.5–90.4)(42.4–80.6)(67.5–90.4)(49.8–86.2)(65.3–88.9)(53.7–88.9)
      Mycological response
       Success9 (17.3)8 (30.8)14 (26.9)8 (30.8)14 (26.9)9 (34.6)
       95% CI (%) of Success(8.2–30.3)(14.3–51.8)(15.6–41.0)(14.3–51.8)(15.6–41.0)(17.2–55.7)
      Data are n (%) values, unless otherwise indicated. Diagnosis was based on assessment by the DRC. The mITT set was the ITT set participants with a proven or probable deep-seated mycosis.
      DRC: Data Review Committee; mITT: modified intention-to-treat; EOT: end of treatment; ISCZ: isavuconazole; VRCZ: voriconazole; CI: confidence interval.The 95% CI for the treatment group was based on a binomial distribution.
      All 10 cryptococcosis patients were diagnosed with pulmonary cryptococcosis, and none had disseminated cryptococcosis or cryptococcal encephalomeningitis. The DRC-assessed overall response success rate was 90.0% (9/10) at each evaluation point. One of three participants with IA and one of three participants with mucormycosis responded in the isavuconazole group (Supplementary Table 1).

      3.3 Safety

      The proportions of participants with CPA who had at least one TEAE or TEAEs resulting in discontinuation of study treatment were comparable between both groups. The incidence of adverse drug reactions was numerically lower in the isavuconazole group, at 61.5% (32/52), than in the voriconazole group, at 85.2% (23/27). Although the incidence of serious AEs was higher in the isavuconazole group than in the voriconazole group, most individual serious AEs occurred in only one participant. The overview of TEAEs in the participants with cryptococcosis did not show any trend of being significantly different from that in the isavuconazole group of participants with CPA (Table 3).
      Table 3Overview of treatment-emergent adverse events (safety analysis set).
      Chronic pulmonary aspergillosisCryptococcosisInvasive aspergillosisMucormycosisNo deep-seated mycosis
      ISCZVRCZISCZISCZVRCZISCZISCZVRCZ
      (N = 52)(N = 27)(N = 10)(N = 3)(N = 1)(N = 3)(N = 5)(N = 2)
      Treatment-emergent adverse events (TEAEs)47 (90.4)25 (92.6)9 (90.0)3 (100.0)1 (100.0)3 (100.0)5 (100.0)2 (100.0)
      Study drug-related TEAEs32 (61.5)23 (85.2)6 (60.0)2 (66.7)1 (100.0)2 (66.7)2 (40.0)0
      Serious TEAEs
      All individual serious TEAEs occurred in only one participant, except for infectious pleural effusion (unrelated) in the isavuconazole group (2 participants) in patients with chronic pulmonary aspergillosis.
      9 (17.3)3 (11.1)2 (20.0)2 (66.7)02 (66.7)2 (40.0)0
      Serious drug-related TEAEs4 (7.7)1 (3.7)0001 (33.3)00
      TEAEs leading to discontinuation of study drug8 (15.4)4 (14.8)1 (10.0)1 (33.3)001 (20.0)0
      Study drug-related TEAEs leading to discontinuation of study drug7 (13.5)4 (14.8)1 (10.0)1 (33.3)0000
      TEAEs leading to death1 (1.9)002 (66.7)02 (66.7)1 (20.0)0
       Pneumonitis1 (1.9)0000000
       Sinusitis/Basal ganglia infarction0001 (33.3)0000
       Idiopathic pneumonia syndrome0001 (33.3)0000
       Acute myocardial infarction/Aspiration pneumonia000001 (33.3)00
       Death000001 (33.3)00
       Pneumococcal infection0000001 (20.0)0
      Study drug-related TEAEs leading to death000001 (33.3)00
       Death000001 (33.3)00
      Data are n (%) values. Diagnosis was based on assessment by the DRC. Coded in MedDRA version 23.1. TEAEs leading to death (preferred terms) are listed.
      ISCZ: isavuconazole; VRCZ: voriconazole; DRC: Data Review Committee.
      a All individual serious TEAEs occurred in only one participant, except for infectious pleural effusion (unrelated) in the isavuconazole group (2 participants) in patients with chronic pulmonary aspergillosis.
      AEs resulting in death were observed only in the isavuconazole group, but most were related to co-occurring or progressive infections or underlying respiratory diseases, and all deaths occurred by Day 42. Therefore, for all but one of these events, a causal relationship with the study drug was ruled out. The AE “death” was a sudden death, and no reasonable cause of death could be determined because no autopsy was performed. The investigator assessed that a causal relationship with isavuconazole could not be completely ruled out.
      The numbers of participants with an adverse drug reaction having an incidence of at least 5% in either group are shown in Table 4. In particular, incidences in the system organ classes (SOCs) eye disorders and hepatobiliary disorders were lower in the isavuconazole group than in the voriconazole group. No specific events tended to occur more frequently in the isavuconazole group in any of the other diseases.
      Table 4Study drug-related treatment-emergent adverse events (safety analysis set).
      Chronic pulmonary aspergillosis
      ISCZVRCZ
      (N = 52)(N = 27)
      Hepatic function abnormal4 (7.7)7 (25.9)
      Liver function test increased4 (7.7)3 (11.1)
      Hot flush4 (7.7)0
      Nausea2 (3.8)2 (7.4)
      Photophobia07 (25.9)
      Visual impairment04 (14.8)
      Colour blindness02 (7.4)
      Dizziness02 (7.4)
      Hallucination, visual02 (7.4)
      Liver disorder02 (7.4)
      Vision blurred02 (7.4)
      Vomiting02 (7.4)
      Data are n (%) values. Coded in MedDRA version 23.1. Drug-related TEAEs (preferred terms) (incidence >5% in one or more treatment groups) in chronic pulmonary aspergillosis are listed. Diagnosis was based on assessment by the DRC.
      ISCZ: isavuconazole; VRCZ: voriconazole; DRC: Data Review Committee.

      3.4 Antifungal susceptibility

      The isavuconazole minimum inhibitory concentration (MIC) ranges for the Aspergillus strains isolated from CPA cases in the study (70 strains) were similar to those of voriconazole. All Cryptococcus strains isolated (5 strains) were Cryptococcus neoformans, and the isavuconazole MIC range tended to be comparable to or lower than the ranges of other antifungal agents (Table 5).
      Table 5Summary of MIC values for fungal isolates in the ITT set.
      SpeciesNumber of isolatesMIC50/MIC90 (MIC range) (μg/mL): CLSI standards
      ISCZVRCZITCZFLCZPSCZCPFG
      For caspofungin and micafungin, data are minimum effective concentration (MEC) values.
      MCFG
      For caspofungin and micafungin, data are minimum effective concentration (MEC) values.
      AMPH-B
      Aspergillus species700.5/10.5/10.5/1128/1280.12/0.50.25/0.250.004/0.0081/2
      (0.12, 2)(0.25, 2)(0.25, 32)(32, 128)(0.06, 32)(0.12, 2)(0.004, 0.015)(0.25, 4)
      Aspergillus fumigatus420.5/0.50.25/0.50.5/0.5128/1280.12/0.250.25/0.50.004/0.0080.5/1
      (0.25, 1)(0.25, 0.5)(0.25, 32)(32, 128)(0.06, 32)(0.12, 0.5)(0.004, 0.015)(0.25, 1)
      Aspergillus niger171/21/21/2128/1280.25/0.50.25/0.250.004/0.0080.25/1
      (0.5, 2)(0.5, 2)(0.5, 2)(32, 128)(0.25, 0.5)(0.12, 0.25)(0.004, 0.008)(0.25, 1)
      Aspergillus terreus7(0.25, 0.5)(0.25, 0.5)(0.25, 0.25)(64, 128)(0.06, 0.12)(0.12, 0.5)(0.004, 0.004)(2, 4)
      Aspergillus flavus2(0.5, 1)(1, 1)(0.5, 0.5)(128, 128)(0.25, 0.5)(0.12, 0.25)(0.008, 0.015)(0.5, 1)
      Aspergillus amoenus1(0.25, 0.25)(0.25, 0.25)(0.5, 0.5)(64, 64)(0.12, 0.12)(0.12, 0.12)(0.004, 0.004)(2, 2)
      Aspergillus NOS1(0.12, 0.12)(0.25, 0.25)(0.5, 0.5)(64, 64)(0.25, 0.25)(2, 2)(0.015, 0.015)(1, 1)
      Cryptococcus species5(0.03, 0.06)(0.03, 0.12)(0.03, 0.25)(1, 4)(0.03, 0.12)(16, 32)(16, 16)(0.25, 1)
      Mucorales5(2, 32)(16, 32)(1, 4)(128, 128)(0.5, 2)(32, 32)(16, 16)(0.12, 4)
      MIC: minimum inhibitory concentration; MIC50: minimum inhibitory concentration which inhibited 50% of the isolates; MIC90: minimum inhibitory concentration which inhibited 90% of the isolates; ITT: intention-to-treat; CLSI: clinical and laboratory standards institute; NOS: not otherwise specified.
      ISCZ: isavuconazole; VRCZ: voriconazole; ITCZ: itraconazole; FLCZ: fluconazole; PSCZ: posaconazole; CPFG: caspofungin; MCFG: micafungin; AMPH-B: amphotericin B.
      MIC50 and MIC90 were calculated only for the pathogen with ten or more isolates.
      a For caspofungin and micafungin, data are minimum effective concentration (MEC) values.

      4. Discussion

      This is the first large-scale, prospective trial to demonstrate the effect of isavuconazole in CPA patients, and its effect was compared with that of voriconazole, which is one of the first-line treatments for aspergillosis [
      • Ullmann A.J.
      • Aguado J.M.
      • Arikan-Akdagli S.
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      ,
      ,
      • Kohno S.
      • Tamura K.
      • Niki Y.
      • et al.
      Executive summary of Japanese Domestic guidelines for management of deep-seated mycosis 2014.
      ], in Japanese patients. The DRC-evaluated overall response success rate of participants with CPA was consistently higher in the isavuconazole group than in the voriconazole group at all evaluation points, beginning early in the treatment stage. As in the SECURE study [
      • Maertens J.A.
      • Raad II,
      • Marr K.A.
      • et al.
      Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
      ], the present study showed that isavuconazole was generally safe and well tolerated in participants with CPA. In particular, the lower incidence of adverse drug reactions in the SOCs hepatobiliary disorders and eye disorders, which are concerns with voriconazole treatment, in the isavuconazole group compared with the voriconazole group was similar to the trends seen in the SECURE study. Furthermore, isavuconazole is more convenient, with fewer treatment restrictions than voriconazole. Isavuconazole therefore shows promise as a new first-line treatment for CPA.
      The 10 participants with pulmonary cryptococcosis in this study received isavuconazole. The DRC-evaluated overall response success rate (90.0%, 9/10) was similar to the success rate in the 6 participants with pulmonary cryptococcosis (83.3%, 5/6) among the 9 participants with cryptococcosis in the VITAL study [
      • Thompson III, G.R.
      • Rendon A.
      • Ribeiro dos Santos R.
      • et al.
      Isavuconazole treatment of cryptococcosis and dimorphic mycoses.
      ]. The VITAL study also had a success rate of 80.0% (4/5) in the participants with cryptococcal encephalomeningitis. (Three of these participants had both pulmonary and encephalomeningeal lesions.) These efficacy findings are similar to those of fluconazole for pulmonary cryptococcosis and amphotericin B for cryptococcal encephalomeningitis [
      • Ikemoto H.
      • Watanabe K.
      • Mori T.
      • et al.
      [Clinical study of fluconazole on deep-seated fungal infections].
      ,
      • Hamill R.J.
      • Sobel J.D.
      • El-Sadr W.
      • et al.
      Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety.
      ], and, therefore, isavuconazole may be a useful new treatment option for cryptococcosis.
      Although the conclusions are speculative because there were only 3 participants each with IA and mucormycosis in the present study, the success rates for isavuconazole in these populations were each 33.3%, which is similar to the rates in the SECURE and VITAL studies [
      • Maertens J.A.
      • Raad II,
      • Marr K.A.
      • et al.
      Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
      ,
      • Marty F.M.
      • Ostrosky-Zeichner L.
      • Cornely O.A.
      • et al.
      Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
      ], with success rates of 35.0% (50/143) and 31.4% (11/35), respectively. IA and mucormycosis are serious, life-threatening diseases. Differentiating mucormycosis from aspergillosis rapidly is difficult and poses a therapeutic challenge [
      • Cornely O.A.
      • Alastruey-Izquierdo A.
      • Arenz D.
      • et al.
      Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of medical Mycology in cooperation with the mycoses study group education and research consortium.
      ], hence new therapeutic options indicated for both diseases are desired. Isavuconazole is available as intravenous and oral formulations that can be selected according to the patient's condition and the treatment course, and the intravenous formulation has no restrictions on administration to patients with renal impairment. Another advantage of this drug is that there is less concern about drug interactions than with other azole antifungals [
      • Falci D.R.
      • Pasqualotto A.C.
      Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections.
      ]. Isavuconazole has potential to meet the medical needs for both IA and mucormycosis in Japanese patients as well.
      In this study, no particular serious AE specific to isavuconazole was observed. Most of the serious AEs reported in the isavuconazole group were found to be causally unrelated to the study drug because they were related to diseases or symptoms present before the start of isavuconazole treatment. Overall, isavuconazole treatment did not likely increase the incidence of serious AEs. These findings were not considered to suggest that the safety of isavuconazole was inferior to that of voriconazole.
      The occurrence of fatal AEs related to infections and underlying diseases in patients with poor general conditions was similar to that in the SECURE and VITAL studies and, therefore, predictable. In the SECURE study, no between-group difference was seen in the incidence of AEs or adverse drug reactions that resulted in death. As for the reason why the incidence of AEs resulting in death was higher in the isavuconazole group than in the voriconazole group of the present study, since the demographics of the participants with CPA were generally balanced between the groups, it may be a coincidental imbalance, given that the numbers of participants evaluated in the study were small.

      4.1 Limitations

      The study has several limitations. First, statistical interpretation is hindered by the limited sample size. In this study, the maximum possible number of participants was recruited, as in the previous study of posaconazole conducted in Japan [
      • Kohno S.
      • Izumikawa K.
      • Yoshida M.
      • et al.
      [A randomized, active controlled, open-label, comparative study to assess the safety and efficacy of posaconazole in Japanese subjects with deep-seated fungal infection].
      ], and the results of Japanese patients exposed to isavuconazole were accumulated. Second, the possibility that bias was present in the safety and efficacy evaluations cannot be completely ruled out, because this was an open-label study. However, as in the SECURE and VITAL studies, bias in the efficacy evaluations was minimized through blinded assessments by an independent DRC.

      5. Conclusion

      Isavuconazole was shown to be effective, safe, and well tolerated in the treatment of Japanese patients with CPA and cryptococcosis. Since isavuconazole is not currently indicated for both diseases, this study provides new evidence. Isavuconazole shows promise as a new treatment option that fulfills medical needs unmet by the limited number of existing drugs used to treat fungal infections.

      Funding

      This work was supported by Asahi Kasei Pharma Corporation , Tokyo, Japan. Asahi Kasei Pharma Corporation was involved in the design of the study, the enrollment of patients, the collection, analysis, and interpretation of data, and contributed to the writing of the manuscript.

      Authorship statement

      All authors meet the ICMJE authorship criteria. S.K. served as the medical expert. S.K., K.I., T.M., M.Y., K.T., Y.M., and M.K. contributed to study design. K.I., K.O., S.T., K.A., H.M., Y.K., and J.S. led the clinical conduct as the Coordinating investigators. M.Y., K.T., and Y.M. served as the medical advisors. M.Y. and K.T. contributed to safety monitoring. K.K., F.O., H.K., S.K., and Y.N. participated in clinical assessment as members of the Data Review Committee. M.K. and M.M. contributed to study management and execution. S.K., K.I., T.T., T.M., M.K., M.M., and Y.N. were involved in primary manuscript writing. All authors contributed to the final version of the manuscript. K.I. had final responsibility for the decision to submit for publication.

      Data sharing statements

      Data sharing is not applicable.

      Declaration of competing interest

      K.I. has received financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants, consulting fees, and honoraria from Asahi Kasei Pharma Corporation, and honoraria from Pfizer, outside the submitted work. T.T. has received non-financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants from MSD, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Shionogi Pharma; honoraria from Sumitomo Dainippon Pharma, Pfizer, Kyorin Pharmaceutical, Fisher & Paykel Healthcare, and MSD; and participated on the advisory boards of GlaxoSmithKline, Roche Diagnostics, and Pfizer, outside the submitted work. T.M. has received non-financial support for the present manuscript from Asahi Kasei Pharma Corporation; grants from Asahi Kasei Pharma Corporation, Pfizer, MSD, Astellas Pharma, Otsuka Pharmaceutical, Taisho Pharmaceutical, Daiichi Sankyo, Teijin Pharma, Mitsubishi Tanabe Pharma, Shionogi Pharma, Kyowa Kirin, Chugai Pharmaceutical, and AbbVie; consulting fees from Asahi Kasei Pharma Corporation, Pfizer, and Kyorin Pharmaceutical; honoraria and support for attending meetings from Asahi Kasei Pharma Corporation, Pfizer, MSD, Astellas Pharma, Sumitomo Dainippon Pharma, Janssen Pharmaceutical, AstraZeneca, GlaxoSmithKline, Taisho Pharmaceutical, Daiichi Sankyo, Meiji Seika Pharma, Eli Lilly, Novartis Pharma, Boehringer Ingelheim, Shionogi Pharma, Takeda Pharmaceutical, Gilead Sciences, Insmed, and Sanofi; and drugs and medical writing services from Pfizer and MSD, outside the submitted work. K.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; K.K. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and MSD, outside the submitted work. K.A. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and Takeda Pharmaceutical, and honoraria from Pfizer and Janssen Pharmaceutical, outside the submitted work. H.M. has received consulting fees and honoraria from Asahi Kasei Pharma Corporation, outside the submitted work. F.O. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; F.O. has received consulting fees from Asahi Kasei Pharma Corporation, outside the submitted work. Y.K. has received grants from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, and Pfizer, and honoraria from Asahi Kasei Pharma Corporation, Sumitomo Dainippon Pharma, Pfizer, MSD, Astellas Pharma, and Janssen Pharmaceutical, outside the submitted work. H.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; H.K. has received honoraria from MSD, Sumitomo Dainippon Pharma, Astellas Pharma, Pfizer, and Shionogi Pharma, outside the submitted work. S.K. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; S.K. has received consulting fees from Asahi Kasei Pharma Corporation, and honoraria from MSD, Sumitomo Dainippon Pharma, Pfizer, Bristol-Myers Squibb, Eisai, Takeda Pharmaceutical, Janssen Pharmaceutical, Meiji Seika Pharma, Astellas Pharma, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Nippon Kayaku, SymBio Pharmaceuticals, and Nippon Shinyaku, outside the submitted work. M.K. is an employee and stockholder of Asahi Kasei Pharma Corporation; M.K. also has patent 2021-157676 pending with Asahi Kasei Pharma Corporation. M.M. is an employee of Asahi Kasei Pharma Corporation; M.M. also has patent 2021-157676 pending with Asahi Kasei Pharma Corporation. Y.N. was a member of the Data Review Committee for Asahi Kasei Pharma Corporation during the conduct of the study; Y.N. has received consulting fees from Asahi Kasei Pharma Corporation, outside the submitted work. All other authors: none to declare.

      Acknowledgements

      The authors would like to thank the investigators and clinical sites in Japan that participated in this study. The following is a list of the investigators:Taiga Miyazaki, Nagasaki University Hospital, Nagasaki; Yasushi Miyazaki, Nagasaki University Hospital, Nagasaki; Takahiro Takuma, Showa University Hospital, Tokyo; Yuta Hayashi, National Hospital Organization Higashinagoya National Hospital, Nagoya; Junko Suzuki, National Hospital Organization Tokyo National Hospital, Tokyo; Eri Hagiwara, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Hidetoshi Igari, Chiba University Hospital, Chiba; Koichi Yamada, Osaka City University Hospital, Osaka; Hideo Koh, Osaka City University Hospital, Osaka; Tadashi Kohyama, Teikyo University Hospital Mizonokuchi, Kawasaki; Kazuya Sato, Jichi Medical University Hospital, Shimotsuke; Yoshio Taguchi, Tenri Hospital, Tenri; Yasuo Mori, Kyushu University Hospital, Fukuoka; Hideki Nakasone, Jichi Medical University Saitama Medical Center, Saitama; Hiroshige Mikamo, Aichi Medical University Hospital, Nagakute; Yasuhiro Yamazaki, National Hospital Organization Asahikawa Medical Center, Asahikawa; Tadakatsu Tsuji, National Hospital Organization Asahikawa Medical Center, Asahikawa; Takeo Endo, National Hospital Organization Mito Medical Center, Higashiibaraki; Tatsuo Kato, National Hospital Organization Nagara Medical Center, Gifu; Susumu Sakamoto, Toho University Omori Medical Center, Tokyo; Masahiro Shirai, National Hospital Organization Tenryu Hospital, Hamamatsu; Hidenori Ibata, National Hospital Organization Mie Chuo Medical Center, Tsu; Yasunori Ueda, Kurashiki Central Hospital, Kurashiki; Hideki Asaoku, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima; Michihiro Hidaka, National Hospital Organization Kumamoto Medical Center, Kumamoto; Yuichi Fukuda, Sasebo City General Hospital, Sasebo; Eriko Morino, National Center for Global Health and Medicine, Tokyo; Jin Takasaki, National Center for Global Health and Medicine, Tokyo; Yuka Sasaki, Japan Anti-Tuberculosis Association Fukujuji Hospital, Kiyose; Yoshiaki Tanaka, Japan Anti-Tuberculosis Association Fukujuji Hospital, Kiyose; Kazunari Tsuyuguchi, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai; Kosaku Komiya, Oita University Hospital, Yufu; Tomo Mihara, National Hospital Organization Nagasaki Medical Center, Omura; Maki Hagihara, Yokohama City University Hospital, Yokohama; Yasushi Takamatsu, Fukuoka University Hospital, Fukuoka; Kensuke Kataoka, Tosei General Hospital, Seto; Yuki Mori, Toranomon Hospital, Tokyo; Takehiko Mori, Keio University Hospital, Tokyo; Shotaro Ide, Japan Community Health care Organization Isahaya General Hospital, Isahaya; Shinya Tomari, Japan Community Health care Organization Isahaya General Hospital, Isahaya; Kazuya Miyagi, University of the Ryukyus Hospital, Nakagami; Nobuaki Kobayashi, Yokohama City University Hospital, Yokohama; Daisuke Kurai, Kyorin University Hospital, Mitaka – all in Japan.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Lowes D.
        • Al-Shair K.
        • Newton P.J.
        • et al.
        Predictors of mortality in chronic pulmonary aspergillosis.
        Eur Respir J. 2017; 491601062https://doi.org/10.1183/13993003.01062-2016
        • Purkins L.
        • Wood N.
        • Ghahramani P.
        • et al.
        Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens.
        Antimicrob Agents Chemother. 2002; 46: 2546-2553https://doi.org/10.1128/AAC.46.8.2546-2553.2002
        • Lee S.
        • Kim B.H.
        • Nam W.S.
        • et al.
        Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers.
        J Clin Pharmacol. 2012; 52: 195-203https://doi.org/10.1177/0091270010395510
        • Committee of Practice Guidelines for TDM of Antimicrobial Agents
        Revised guidelines for therapeutic drug monitoring of antimicrobials.
        Japanese Society of Chemotherapy, The Japanese Society of Therapeutic Drug Monitoring, Tokyo2016 (Japanese)
        • Miceli M.H.
        • Kauffman C.A.
        Isavuconazole: a new broad-spectrum triazole antifungal agent.
        Clin Infect Dis. 2015; 61: 1558-1565https://doi.org/10.1093/cid/civ571
        • Schmitt-Hoffmann A.
        • Roos B.
        • Heep M.
        • et al.
        Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers.
        Antimicrob Agents Chemother. 2006; 50: 279-285https://doi.org/10.1128/AAC.50.1.279-285.2006
        • EMA
        Guideline on the use of pharmacogenetic methodologies in the pharmacokinetic evaluation of medicinal products.
        • FDA
        Clinical Pharmacogenomics: Premarket evaluation in early-phase clinical studies and recommendations for labeling.
        • Falci D.R.
        • Pasqualotto A.C.
        Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections.
        Infect Drug Resist. 2013; 6: 163-174https://doi.org/10.2147/IDR.S51340
        • Maertens J.A.
        • Raad II,
        • Marr K.A.
        • et al.
        Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.
        Lancet. 2016; 387: 760-769https://doi.org/10.1016/S0140-6736(15)01159-9
        • Marty F.M.
        • Ostrosky-Zeichner L.
        • Cornely O.A.
        • et al.
        Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.
        Lancet Infect Dis. 2016; 16: 828-837https://doi.org/10.1016/S1473-3099(16)00071-2
        • Tissot F.
        • Agrawal S.
        • Pagano L.
        • et al.
        ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients.
        Haematologica. 2017; 102: 433-444https://doi.org/10.3324/haematol.2016.152900
        • Ullmann A.J.
        • Aguado J.M.
        • Arikan-Akdagli S.
        • et al.
        Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
        Clin Microbiol Infect. 2018; 24: e1-e38https://doi.org/10.1016/j.cmi.2018.01.002
        • Cornely O.A.
        • Alastruey-Izquierdo A.
        • Arenz D.
        • et al.
        Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of medical Mycology in cooperation with the mycoses study group education and research consortium.
        Lancet Infect Dis. 2019; 19: e405-e421https://doi.org/10.1016/S1473-3099(19)30312-3
        • Thompson III, G.R.
        • Rendon A.
        • Ribeiro dos Santos R.
        • et al.
        Isavuconazole treatment of cryptococcosis and dimorphic mycoses.
        Clin Infect Dis. 2016; 63: 356-362https://doi.org/10.1093/cid/ciw305
        • Kimura Y.
        • Sasaki Y.
        • Suzuki J.
        • et al.
        Prognostic factors of chronic pulmonary aspergillosis: a retrospective cohort of 264 patients from Japan.
        PLoS One. 2021; 16e0249455https://doi.org/10.1371/journal.pone.0249455
      1. Guidelines for the diagnosis and management of deep-seated mycosis preparation committee. Japanese Domestic Guidelines for the Management of deep-seated mycosis 2014. Kyowa Kikaku, Tokyo2014 (Japanese)
        • Kohno S.
        • Tamura K.
        • Niki Y.
        • et al.
        Executive summary of Japanese Domestic guidelines for management of deep-seated mycosis 2014.
        Med Mycol J. 2016; 57: E117-E163https://doi.org/10.3314/mmj.16-00010
        • Donnelly J.P.
        • Chen S.C.
        • Kauffman C.A.
        • et al.
        Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group education and research consortium.
        Clin Infect Dis. 2020; 71: 1367-1376https://doi.org/10.1093/cid/ciz1008
        • Yamaguchi H.
        • Yoshida A.
        • Suzuki H.
        • et al.
        Medical important fungi: a guide to identification.
        fifth ed. Eiken Chemical, Tokyo2013 (Japanese)
        • Clinical and Laboratory Standards Institute
        Reference method for Broth Dilution antifungal susceptibility testing of yeasts.
        fourth ed. Approved standard. 2017 (M27-A4. Wayne, PA)
        • Clinical and Laboratory Standards Institute
        Reference method for Broth Dilution antifungal susceptibility testing of filamentous fungi. Approved standard.
        third ed. 2017 (M38-A3. Wayne, PA)
        • Segal B.H.
        • Herbrecht R.
        • Stevens D.A.
        • et al.
        Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.
        Clin Infect Dis. 2008; 47: 674-683https://doi.org/10.1086/590566
        • Ikemoto H.
        • Watanabe K.
        • Mori T.
        • et al.
        [Clinical study of fluconazole on deep-seated fungal infections].
        Jpn J Antibiot. 1989; 42 (Japanese): 63-116
        • Hamill R.J.
        • Sobel J.D.
        • El-Sadr W.
        • et al.
        Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety.
        Clin Infect Dis. 2010; 51: 225-232https://doi.org/10.1086/653606
        • Kohno S.
        • Izumikawa K.
        • Yoshida M.
        • et al.
        [A randomized, active controlled, open-label, comparative study to assess the safety and efficacy of posaconazole in Japanese subjects with deep-seated fungal infection].
        Med Mycol J. 2020; 61 (Japanese): 1-11