FDA has completed their review of the rationale document titled, “Isavuconazole Breakpoints for Aspergillus fumigatus” submitted by the Clinical and Laboratory Standards Institute (CLSI) to the public docket FDA-2017-N-5925-0038 in January 2025.¹

Isavuconazonium sulfate is a prodrug of isavuconazole, an azole antifungal drug.  Isavuconazonium sulfate oral capsules and powder for intravenous injection were approved on March 6, 2015, for the treatment of invasive aspergillosis and invasive mucormycosis.  In adult patients, both formulations are administered at 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for 6 doses and then at 372 mg daily.²

FDA has not provided susceptibility test interpretive criteria, also known as breakpoints, for isavuconazonium sulfate (hereafter isavuconazole). In January 2023, CLSI set minimum inhibitory concentration (MIC) breakpoints for isavuconazole against A. fumigatus sensu stricto (Table 1).³   Disk diffusion breakpoints have not been established. The breakpoints are based on isavuconazole dosages listed above.

Table 1. CLSI Isavuconazole Breakpoints against A. fumigatus sensu stricto^a

S= susceptible; I=intermediate; R=resistant

^a Breakpoints were derived from a collection of sequence-confirmed isolates of A. fumigatus sensu stricto and are not applicable to other members of the A. fumigatus section Fumigati.

In evaluating isavuconazole breakpoints for A. fumigatus sensu stricto, FDA has considered MIC distribution data, correlation between MIC and Cyp51 gene mutations (Cyp51 is an enzyme needed for ergosterol synthesis and is the target of azoles), the epidemiological cutoff value (ECV), pharmacokinetic-pharmacodynamic (PK/PD) data, and clinical outcome data.

The isavuconazole MIC₉₀ value based on testing of 3632 sensu stricto clinical isolates of A. fumigatus described in the CLSI rationale document is 1 mcg/mL. The CLSI ECV for isavuconazole against A. fumigatus is 1 mcg/mL.⁴ Notably, CYP51A gene sequencing indicates that some isolates with CYP51A variants may have MICs ≤ 1 mcg/mL.¹

Pharmacokinetic/pharmacodynamic data supporting the breakpoints include one in vitro and three animal studies. ^5,6,7,8 The breakpoints are primarily based on probability of target attainment (PTA) analyses using a target derived from an immunocompetent mouse model and the approved isavuconazole dosing regimen. PTA was ≥90% for MICs ≤1 mcg/mL, approximately 75% for MIC = 2 mcg/mL, and <20% for MIC = 4 mcg/mL. However, the use of an immunocompetent mouse model may not accurately represent the immunocompromised patient population typically affected by invasive aspergillosis. The other three models (neutropenic mouse, neutropenic rabbit, and in vitro model) presented additional limitations including the use of galactomannan as an outcome measure and inconsistent correlations between the targets derived with each model. Overall, nonclinical PK/PD data suggest that the proposed breakpoints may be acceptable, although supporting information is limited.

Clinical data included a pooled analysis of 25 subjects with A. fumigatus infections included in two clinical trials,⁹ a phase 3 randomized trial comparing isavuconazole with voriconazole¹⁰, and an open label, non-comparator trial where isavuconazole was used in patients with renal impairment.¹¹ Out of 25 A. fumigatus isolates, 21 had MICs less than or equal to the proposed susceptible breakpoint of 1 mcg/mL; 42-day all-cause mortality in this group was 9.5% (2/21).  While available clinical data do not allow identifying an MIC threshold associated with favorable clinical outcomes, the data suggest that the use of isavuconazole for invasive A. fumigatus infections with MIC up to 1 mcg/mL resulted in overall favorable clinical outcomes.

In conclusion, FDA considers that while the available data are limited, the totality of data supports the recognition of the CLSI MIC breakpoints for isavuconazole against A. fumigatus sensu stricto, i.e., a susceptible breakpoint of ≤1 mcg/mL, an intermediate breakpoint of 2 mcg/mL, and a resistant breakpoint of ≥4 mcg/mL. FDA agrees with CLSI that having an intermediate category is important to mitigate the inherent variability of testing methods.

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¹ https://www.regulations.gov/comment/FDA-2017-N-5925-0038
² CRESEMBA (isavuconazonium sulfate) prescribing information, revised 3/2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/207500s016,207501s016lbl.pdf
³ https://clsi.org/media/zg5naqnf/2023_january_afsc_2_meeting_summary_minutes.pdf
⁴ Clinical and Laboratory Standards Institute (CLSI). Epidemiologic cutoff values for antifungal susceptibility testing; CLSI document M57S, Fourth Edition August 2022
⁵ Box, H., et al., Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother, 2016. 60(1): p. 278-87.
⁶ Seyedmousavi, S., et al., Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis. J Antimicrob Chemother, 2013. 68(2): p. 385-93.
⁷ Lepak, A.J., et al., Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob Agents Chemother, 2013. 57(12): p. 6284-9.
⁸ Kovanda, L.L., et al., Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints. J Antimicrob Chemother, 2016. 71(7): p. 1885-91.
⁹ Andes, D.R., et al., Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials. Antimicrob Agents Chemother, 2019. 63(1).
¹⁰ Maertens, J.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(10020): p. 760-9.
¹¹ Perfect, J.R., et al., Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial. Mycoses, 2018. 61(7): p. 420-429.