Isavuconazole Has Lowest Hepatotoxicity Signal Among Azoles in FAERS

Isavuconazole had the lowest hepatotoxicity reporting signal among 5 azole antifungals in the FDA Adverse Event Reporting System (FAERS), significantly lower than voriconazole and posaconazole.¹ Varshini Thiruvadi, MD, of the University of Illinois College of Medicine Peoria, presented the pharmacovigilance analysis at IDWeek 2026, held October 21-24 in Washington, DC. Three additional posters at the meeting reported activity of olorofim, manogepix, and rezafungin against molds with azole resistance or limited treatment options.^2-4

Azoles anchor treatment of invasive fungal infections, but all carry a risk of drug-induced liver injury, and comparative postmarketing data including isavuconazole (Cresemba; Astellas Pharma) have been limited.¹ Rising azole resistance in Aspergillus species adds pressure for agents with new mechanisms.⁴

FAERS Hepatotoxicity Signals for Isavuconazole, Voriconazole, and Other Azoles

The investigators searched FAERS reports from 1984 to 2026, identifying 73,145 reports and 7320 hepatobiliary events across isavuconazole, voriconazole, fluconazole, itraconazole, and posaconazole.¹ All 5 drugs met every prespecified signal criterion, and isolated laboratory abnormalities were excluded.¹ The full database contained more than 33 million adverse event reports, including 287,056 hepatobiliary events.¹

Isavuconazole had a reporting odds ratio (ROR) of 10.90 (95% CI, 9.75-12.18), compared with 15.09 (95% CI, 14.46-15.76; P < .001) for voriconazole and 14.49 (95% CI, 13.48-15.57; P < .001) for posaconazole.¹ Differences from fluconazole (ROR, 11.73; P = .226) and itraconazole (ROR, 11.16; P = .719) were not significant.¹ Signals for fluconazole and itraconazole fell between those of isavuconazole and the 2 higher-signal agents.¹

More than 97% of hepatobiliary reports were classified as serious for every agent.¹ Case fatality ranged from 15.3% with itraconazole to 22.3% with fluconazole, with isavuconazole at 19.8%. The authors noted spontaneous reports lack a denominator of exposed patients, so the analysis shows a reporting signal rather than incidence or causation.¹

"Azoles are the backbone of treatment for invasive fungal infections, but they all carry a risk of drug-induced liver injury," Thiruvadi said in a recorded presentation accompanying the poster. "There's very little real-world data comparing all of them side-by-side, especially including isavuconazole."

"First, all azoles need liver function monitoring, whichever one you choose," Thiruvadi said. "Second, isavuconazole had the lowest signal of the group, significantly lower than voriconazole and posaconazole. That supports considering it in patients at higher hepatic risk."

Olorofim, Manogepix, and Rezafungin Activity Against Resistant Molds

Olorofim (F2G), a first-in-class oral orotomide, inhibits fungal dihydroorotate dehydrogenase and blocks pyrimidine biosynthesis.² In long-term follow-up of the phase 2b Study 32 (NCT03583164), 76 of 202 treated patients met inclusion criteria, most often excluded because they continued olorofim through compassionate access.² In the follow-up cohort, 67.1% had proven infections and 67.1% had high or moderate immunosuppression.²

Of 52 patients whose invasive fungal infection resolved, 46 (88.5%) remained infection free over a mean of 955 days after the last dose.² Six (11.5%) had pulmonary recurrences at a median of 343 days, and none of 12 resolved bone infections recurred. Recurrence was more frequent among patients with at least 1 later immunosuppressive event, such as transplant or chemotherapy, than among those without (25% vs 7.5%).²

Manogepix, the active moiety of fosmanogepix (Basilea Pharmaceutica), targets the fungal Gwt1 enzyme, and fosmanogepix is in phase 3 trials for invasive candidiasis and invasive mold infections.³ Among 740 US Aspergillus isolates collected from 2017 to 2024, 16 carried CYP51 alterations. Of these, 15 were non-wild-type to itraconazole and 5 to voriconazole, yet manogepix minimum effective concentrations stayed between 0.008 and 0.06 mg/L.³

Rezafungin (Rezzayo; Melinta Therapeutics), a once-weekly echinocandin in phase 2 trials for chronic pulmonary aspergillosis, retained activity against 1115 Aspergillus isolates from 25 countries.⁴ The collection included 55 isolates (4.9%) non-wild-type to itraconazole or voriconazole. Among isolates with CYP51 alterations, rezafungin minimum effective concentrations (MEC50/90) were 0.015/0.03 mg/L vs voriconazole MIC50/90 of 2/more than 8 mg/L.⁴

References

1. Thiruvadi V, Ravichandran R, Kagzi Y, et al. Hepatotoxicity signals across azole antifungals: is isavuconazole safer? A pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS). Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-31.

2. Thompson GR III, Maertens JA, Spec A, et al. Long-term follow-up of Study 32 (S32LTFU): a retrospective observational study of olorofim as treatment of invasive fungal infections in patients lacking suitable alternative treatment options. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-4.

3. Winkler ML, Edeker S, Klauer A, et al. Activity of manogepix against Aspergillus spp. isolates with CYP51 alterations. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-17.

4. Winkler ML, Edeker S, Klauer AL, et al. Activity of rezafungin against Aspergillus spp. that are non-wild-type to azole antifungal agents. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-20.