Ibrexafungerp Citrate
[CAS# 1965291-08-0]

Identification

• Classification: Pharmaceutical intermediate
• Name: Ibrexafungerp Citrate
• Synonyms: (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid;2-hydroxypropane-1,2,3-tricarboxylic acid
• Molecular Formula: C₅₀H₇₅N₅O₁₁
• Molecular Weight: 922.16
• CAS Registry Number: 1965291-08-0
• SMILES: C[C@H](C(C)C)[C@]1(CC[C@@]2([C@H]3CC[C@H]4[C@]5(COC[C@]4(C3=CC[C@]2([C@@H]1C(=O)O)C)C[C@H]([C@@H]5OC[C@@](C)(C(C)(C)C)N)N6C(=NC=N6)C7=CC=NC=C7)C)C)C.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

Safety Data

• Hazard Symbols: GHS07;GHS08 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P280-P305+P351+P338

Discovory and Applicatios

Ibrexafungerp citrate is the citrate salt form of ibrexafungerp, a first-in-class antifungal agent belonging to the triterpenoid glucan synthase inhibitor class. It is a semi-synthetic derivative of enfumafungin, a natural product isolated from Hormonema species, and represents a new oral treatment option for fungal infections caused primarily by Candida and Aspergillus species. Unlike echinocandins, which also inhibit β-1,3-D-glucan synthase but are only available intravenously, ibrexafungerp provides an effective oral therapy with broad antifungal activity.

The development of ibrexafungerp was driven by the need for orally bioavailable glucan synthase inhibitors, particularly in the face of increasing resistance to azoles and polyenes and the limitations of current echinocandins. Ibrexafungerp retains the core mechanism of action of echinocandins—noncompetitive inhibition of the β-1,3-D-glucan synthase enzyme—leading to the disruption of the fungal cell wall and ultimately cell lysis. However, its triterpenoid structure allows for improved oral absorption and distribution into tissues, enabling systemic activity when administered orally.

Ibrexafungerp exhibits fungicidal activity against most *Candida* species, including strains resistant to fluconazole and echinocandins, and fungistatic activity against Aspergillus species. Its structure permits a strong binding affinity to the target enzyme while maintaining stability in acidic and enzymatic environments within the gastrointestinal tract. This pharmacological advantage enables oral administration without compromising efficacy, a significant development in antifungal therapy.

The citrate salt form enhances the solubility and stability of ibrexafungerp, contributing to consistent bioavailability. Once administered, the drug is rapidly absorbed, with peak plasma concentrations achieved within a few hours. It has a long terminal half-life that supports once- or twice-daily dosing regimens. Ibrexafungerp is metabolized primarily via hepatic mechanisms, and its elimination is mainly through the fecal route, with limited renal excretion. These properties reduce the need for dose adjustment in patients with renal impairment.

Clinically, ibrexafungerp citrate has been approved for the treatment of vulvovaginal candidiasis (VVC) in adult and postmenarchal pediatric females. It is also under investigation for broader indications, including invasive candidiasis, candidemia, and refractory fungal infections. Its efficacy in clinical trials has shown it to be noninferior or superior to fluconazole in cases of uncomplicated VVC and effective against multidrug-resistant Candida auris, a high-priority pathogen due to its resistance profile and associated outbreaks in healthcare settings.

Another significant application of ibrexafungerp is in treating infections in immunocompromised patients, including those with hematologic malignancies or undergoing organ transplants, where invasive fungal infections pose a high mortality risk. The potential for oral step-down therapy following initial intravenous treatment with other antifungals is also being explored, which would simplify treatment logistics and reduce hospital stays.

Ibrexafungerp citrate is generally well tolerated, with the most common adverse effects being mild gastrointestinal symptoms such as diarrhea and nausea. It does not exhibit significant drug-drug interactions, particularly with cytochrome P450 enzymes, which are a major concern with azole antifungals. This favorable interaction profile broadens its use among patients receiving multiple concomitant medications.

In summary, ibrexafungerp citrate represents a major advance in antifungal pharmacotherapy, introducing the first orally available glucan synthase inhibitor with a broad spectrum of activity and a favorable pharmacokinetic and safety profile. It addresses critical unmet needs in the treatment of fungal infections, especially for resistant strains and in settings where intravenous therapy is not feasible or desirable.

References

2017. De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance. Antimicrobial Agents and Chemotherapy, 61(9).
DOI: 10.1128/aac.00833-17

2022. Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: a global phase 3, randomised, placebo-controlled superiority study (VANISH 306). BJOG: An International Journal of Obstetrics and Gynaecology, 129(3).
DOI: 10.1111/1471-0528.16972

2024. Fungerps: discovery of the glucan synthase inhibitor enfumafungin and development of a new class of antifungal triterpene glycosides. Natural Product Reports, 41(12).
DOI: 10.1039/d4np00044g