Ibrexafungerp (DB12471): A Comprehensive Monograph on a First-in-Class Triterpenoid Antifungal

Executive Summary

Ibrexafungerp represents a significant advancement in antifungal therapy, being the first approved agent in a novel class, the triterpenoids, in over two decades.[1] Marketed under the brand name Brexafemme®, it is a semi-synthetic derivative of the natural product enfumafungin, developed to address the growing challenges of fungal infections, particularly those caused by resistant pathogens.[1] It is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute vulvovaginal candidiasis (VVC) and for the reduction in the incidence of recurrent VVC (RVVC) in adult and post-menarchal pediatric females.[3]

The pharmacological distinction of ibrexafungerp lies in its mechanism of action. It inhibits the fungal enzyme β-(1,3)-D-glucan synthase, a critical component for cell wall synthesis, similar to the echinocandin class of antifungals.[3] However, its unique triterpenoid structure allows it to bind to a site on the enzyme that is distinct from that of the echinocandins.[3] This structural and mechanistic nuance is of profound clinical importance, as it confers potent activity against a broad spectrum of fungal pathogens, including many strains that have developed resistance to both azoles and echinocandins.[8] Its spectrum includes most

Candida species, including the multidrug-resistant Candida auris, and Aspergillus species.[13]

Perhaps the most transformative feature of ibrexafungerp is its oral bioavailability, which overcomes the principal limitation of the highly effective but parenteral-only echinocandins.[3] This allows for convenient oral administration in outpatient settings and presents the potential for a "mechanism-consistent" oral step-down therapy for patients with severe invasive fungal infections initially treated with intravenous echinocandins.[16] Its pharmacokinetic profile is characterized by a long half-life of approximately 20 hours, extensive tissue distribution, and notably high penetration into vaginal tissue, where concentrations can be up to nine-fold higher than in plasma.[3] This targeted distribution, combined with sustained activity in the acidic vaginal milieu, provides a strong pharmacological basis for its efficacy in VVC.[17]

Clinically, ibrexafungerp has demonstrated efficacy comparable to fluconazole in the acute treatment of VVC, but with a significantly more durable response and a lower rate of relapse.[17] It is the only oral agent approved by the FDA for the prevention of RVVC.[17] The safety profile is generally favorable, with the most common adverse events being mild-to-moderate gastrointestinal effects.[5] However, its use is governed by a critical safety concern: a boxed warning for embryo-fetal toxicity, rendering it absolutely contraindicated in pregnancy and requiring stringent contraceptive measures in females of reproductive potential.[5]

Beyond its current indications, ibrexafungerp is being aggressively investigated for life-threatening invasive fungal infections, holding Fast Track and Orphan Drug designations from the FDA for these conditions.[13] Ongoing clinical trials are evaluating its role as salvage therapy for refractory infections, as a treatment for invasive candidiasis caused by

C. auris, and as part of combination regimens for invasive aspergillosis.[13] Ibrexafungerp is therefore positioned not merely as another treatment for vaginal yeast infections, but as a foundational molecule of a new therapeutic platform with the potential to reshape treatment paradigms for some of the most difficult-to-treat fungal diseases.

Drug Profile and Chemical Characteristics

A comprehensive understanding of a novel therapeutic agent begins with a precise characterization of its identity, chemical structure, and physicochemical properties. These foundational elements dictate its pharmacological behavior, formulation, and classification within the broader therapeutic landscape.

Identification and Nomenclature

Ibrexafungerp is identified by a variety of names and codes that reflect its developmental history and regulatory status. Establishing these identifiers is crucial for accurate cross-referencing in scientific literature, clinical practice, and pharmaceutical databases.

• Generic Name: Ibrexafungerp [3]
• Pronunciation: /aɪˌbrɛksəˈfʌndʒɜːrp/ (eye-BREKS-ə-FUN-jurp) [11]
• Brand Name: Brexafemme® [3]
• Developmental Codes: The compound has been known by several codes throughout its development pipeline, including SCY-078, MK-3118, and GSK5458448. The code MK-3118 reflects its origin at Merck & Co, while SCY-078 was used by its primary developer, SCYNEXIS, Inc..[3]
• Drug Type & Modality: It is classified as a Small Molecule therapeutic.[3]
• Database Identifiers: For unambiguous identification across global databases, the following codes are assigned:
• DrugBank ID: DB12471 [3]
• CAS Number: 1207753-03-4 (for the free base); 1965291-08-0 (for the citrate salt) [11]
• PubChem CID: 46871657 [4]
• UNII (Unique Ingredient Identifier): A92JFM5XNU [4]
• KEGG (Kyoto Encyclopedia of Genes and Genomes) ID: D11544 [4]
• ChEMBL ID: ChEMBL4297513 [4]
• ATC (Anatomical Therapeutic Chemical) Code: J02AX07 (WHO) [11]

Chemical Structure and Physicochemical Properties

The unique structure of ibrexafungerp is the basis for its novel mechanism of action and favorable pharmacokinetic properties. It is a large, complex molecule derived from a natural fungal metabolite.

• Chemical Class: Ibrexafungerp is a semi-synthetic derivative of enfumafungin, classifying it as a Triterpenoid Antifungal.[1] The FDA considers it a first-in-class medication, establishing a new therapeutic category sometimes referred to as "fungerps" (Antifungal Triterpenoid).[8]
• IUPAC Name: Due to its complex, polycyclic nature, multiple systematic names exist depending on the nomenclature convention. A commonly cited IUPAC name is (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21--5,7,10,15-tetramethyl-7--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.[4]
• Molecular Formula: The chemical formula for the active free base is C44​H67​N5​O4​.[11] The marketed citrate salt has the formula C50​H75​N5​O11​.[15]
• Molar Mass: The molar mass of the free base is 730.051 g·mol−1.[11] The citrate salt has a molecular weight of 922.18 g/mol.[15]
• Physical Properties: Ibrexafungerp is described as a White to Off-white Solid.[1] It is soluble in dimethyl sulfoxide (DMSO), a property relevant for preparing solutions for in vitro assays.[1] Predicted physicochemical properties include a boiling point of 815.9°C and a density of 1.22 g/cm³.[1]
• Structural Identifiers: For computational and chemical informatics purposes, the following identifiers are used:
• 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 [4]
• InChIKey: BODYFEUFKHPRCK-ZCZMVWJSSA-N [4]

The development of ibrexafungerp from its natural precursor, enfumafungin, is a notable success in medicinal chemistry. The entire class of glucan synthase inhibitors, represented by the highly effective echinocandins, has been hampered by a single, major clinical drawback: a lack of oral bioavailability, restricting their use to parenteral administration.[8] The advancement of ibrexafungerp demonstrates a successful strategic circumvention of this limitation. Through synthetic modifications to the distinct triterpenoid glycoside backbone of enfumafungin, researchers were able to engineer a molecule that retains the potent mechanism of action while gaining the crucial property of oral absorption.[8] The result is the first orally active glucan synthase inhibitor, a milestone that not only provides a new therapeutic agent but also validates the triterpenoid scaffold as a viable platform for future development of oral antifungals targeting the fungal cell wall.[3]

Furthermore, the existence of both a free base and a citrate salt form, each with distinct identifiers, is a critical detail for pharmaceutical science.[11] The approved product, Brexafemme, is formulated with ibrexafungerp citrate, where each 150 mg tablet of the active drug is equivalent to 189.5 mg of the salt.[18] The selection of a salt form is a deliberate step in drug development aimed at optimizing physicochemical properties such as chemical stability, solubility, and dissolution rate, all of which are critical for ensuring consistent and reliable absorption from an oral solid dosage form. The use of the citrate salt in the final marketed product indicates that it provided superior formulation characteristics compared to the free base, representing a key step in translating the active pharmacological molecule into a clinically effective and commercially viable medicine.

Property	Value	Source(s)
Generic Name	Ibrexafungerp	3
Brand Name	Brexafemme®	11
Drug Type	Small Molecule, Triterpenoid Antifungal	3
Developmental Codes	SCY-078, MK-3118, GSK5458448	3
DrugBank ID	DB12471	3
CAS Number (Free Base)	1207753-03-4	11
CAS Number (Citrate Salt)	1965291-08-0	11
PubChem CID	46871657	11
UNII	A92JFM5XNU	11
ATC Code	J02AX07	11
Molecular Formula (Free Base)	C44​H67​N5​O4​	11
Molar Mass (Free Base)	730.051 g·mol−1	11
Molecular Formula (Citrate Salt)	C50​H75​N5​O11​	15
Molar Mass (Citrate Salt)	922.18 g·mol−1	26
Appearance	White to Off-white Solid	1

Pharmacology and Mechanism of Action

The therapeutic efficacy of ibrexafungerp is rooted in its potent and specific interaction with a fungal target that is absent in human cells. Its mechanism, while sharing a target with an existing class of antifungals, possesses unique characteristics that confer a distinct and advantageous resistance profile.

Inhibition of β-(1,3)-D-Glucan Synthase

The primary molecular target of ibrexafungerp is the enzyme β-(1,3)-D-glucan synthase.[3] This enzyme complex is responsible for catalyzing the synthesis of β-(1,3)-D-glucan from UDP-glucose precursors.[24] β-(1,3)-D-glucan is the most abundant structural polymer in the cell walls of most pathogenic fungi, comprising up to 60% of the wall's dry weight and serving as the core scaffold to which other cell wall components are covalently linked.[8]

Ibrexafungerp acts as a non-competitive inhibitor of this enzyme.[8] By blocking the production of β-(1,3)-D-glucan, the drug severely compromises the structural integrity of the fungal cell wall.[7] The weakened wall is unable to withstand the internal osmotic pressure of the cell, leading to increased permeability, leakage of cellular contents, cell lysis, and ultimately, fungal cell death.[8] This terminal effect on the fungal cell defines its activity as fungicidal against susceptible organisms, particularly

Candida species.[8] Against

Aspergillus species, its effect is primarily fungistatic, meaning it inhibits growth and replication without directly killing the organism.[8]

A cornerstone of ibrexafungerp's favorable safety profile is the selective nature of its target. The β-(1,3)-D-glucan synthase enzyme is essential for fungi but is not present in mammalian cells.[3] This lack of a human homologue limits the potential for on-target toxicity, contributing to a wide therapeutic index and a lower likelihood of mechanism-related adverse effects such as renal or hepatic damage.[3]

Comparative Mechanistic Analysis: Ibrexafungerp vs. Echinocandins

While ibrexafungerp shares its target enzyme with the echinocandin class of antifungals (e.g., caspofungin, micafungin), a critical distinction exists in their molecular interaction with the enzyme complex. Echinocandins are large cyclic lipopeptides, whereas ibrexafungerp is a structurally distinct triterpenoid.[8] This fundamental difference in chemical structure translates to a different mode of binding.

The β-(1,3)-D-glucan synthase complex consists of a catalytic subunit, encoded by FKS genes (e.g., FKS1, FKS2), and a regulatory subunit.[3] Echinocandins are known to bind to a specific domain on the FKS1 subunit.[3] In contrast, ibrexafungerp and its parent compound, enfumafungin, bind at an alternate site.[3] While this site partially overlaps with the echinocandin-binding region, it is non-identical.[3]

This distinction in binding sites is not merely a pharmacological detail; it is the molecular foundation for ibrexafungerp's ability to circumvent a primary mechanism of antifungal resistance. Acquired resistance to echinocandins is most commonly mediated by specific point mutations within two "hot spot" regions of the FKS genes.[10] Because ibrexafungerp interacts with the enzyme differently, many of these resistance-conferring

FKS mutations have a minimal effect on its binding and inhibitory activity.[9] This results in a lack of complete cross-resistance, allowing ibrexafungerp to retain potent activity against a significant number of echinocandin-resistant fungal isolates.[3] This represents a highly strategic approach to drug design. Rather than the challenging pursuit of entirely novel cellular targets, which are limited due to the conserved biology between fungi and humans, ibrexafungerp's development demonstrates the power of creating new chemical classes that engage known, validated targets in novel ways. This approach effectively bypasses established resistance pathways and can restore clinical utility against pathogens that have evolved to evade existing therapies, offering a valuable blueprint for future anti-infective research.

Antimicrobial Spectrum and Potency

Ibrexafungerp exhibits a broad spectrum of potent in vitro activity against a wide array of clinically significant fungal pathogens.[10]

• Candida Species: It is highly active against the most common Candida species, including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis.[18] Its fungicidal action against this genus is a key attribute.[8]
• Resistant Pathogens: A defining feature of ibrexafungerp is its robust activity against multidrug-resistant (MDR) fungi, an area of critical unmet medical need.
• It consistently demonstrates activity against azole-resistant and echinocandin-resistant Candida strains.[11]
• It is notably active against the emerging global threat Candida auris. This species is frequently resistant to multiple antifungal classes, making infections difficult to treat. Ibrexafungerp shows consistent activity, with reported 50% minimum inhibitory concentrations (MIC50) in the range of 0.5 to 1 µg/mL.[13]
• Aspergillus Species: The drug is active in vitro against medically important molds, including Aspergillus fumigatus, A. flavus, A. niger, and A. terreus.[13] As previously noted, this activity is generally fungistatic.[8] This distinction has direct clinical implications: for invasive candidiasis, it could serve as a definitive, eradicating therapy, whereas for invasive aspergillosis, its role is more likely to be as part of a combination regimen. The ongoing SCYNERGIA trial, which evaluates ibrexafungerp with voriconazole, is a clinical exploration of this principle, aiming to leverage a synergistic effect by targeting the fungus via two distinct mechanisms.[13]
• Other Pathogens: The spectrum of activity extends to other fungi, including Pneumocystis spp., various dimorphic fungi, and some members of the order Mucorales.[10] However, it is reported to lack clinically significant activity against Fusarium species.[14]
• Activity in Physiological Conditions: A pharmacologically advantageous property, particularly for its VVC indication, is the stability of its antifungal activity across different pH levels. In contrast to azole antifungals, which exhibit significantly reduced potency in acidic environments, ibrexafungerp's activity is not adversely affected and may even be enhanced at a pH of 4.5. This is highly relevant as the normal vaginal milieu is acidic, meaning the drug can function optimally at the site of infection.[12]

Pharmacokinetics and Pharmacodynamics

The clinical utility of an antimicrobial agent is determined not only by its mechanism of action but also by its ability to reach and maintain effective concentrations at the site of infection without causing undue toxicity. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ibrexafungerp are key to its efficacy, particularly its advantages as an oral agent.

Absorption, Distribution, Metabolism, and Excretion (ADME)

The ADME profile of ibrexafungerp defines its movement through the body and underpins its dosing regimen and clinical applications.

• Absorption: Ibrexafungerp is orally bioavailable, a key feature that distinguishes it from the echinocandins.[3] Following the approved oral dosage for VVC (300 mg twice daily for one day), it reaches a mean peak plasma concentration (Cmax) of 435 ng/mL.[3] The time to reach this peak concentration (Tmax) is between 4 and 6 hours.[3] The total drug exposure over 24 hours, measured as the area under the concentration-time curve (AUC0-24), is 6832 h*ng/mL.[3] While administration with a high-fat meal can increase Cmax and AUC by approximately 32% and 38%, respectively, this effect is not considered clinically significant enough to mandate that the drug be taken with food.[18] Animal studies have estimated the absolute oral bioavailability to be approximately 50%.[18]
• Distribution: Ibrexafungerp distributes extensively into tissues, as indicated by its large apparent volume of distribution at steady state (Vdss​​), which is approximately 600 L.[3] In the bloodstream, it is highly bound to plasma proteins (99.5-99.8%), predominantly albumin.[3] This high degree of protein binding often limits the distribution of drugs, but ibrexafungerp demonstrates excellent tissue penetration. This is most critical for its primary indication, VVC. Preclinical animal models have shown that ibrexafungerp concentrates in vaginal tissue, achieving levels up to nine times higher than those observed in plasma.[3] This preferential distribution ensures that high, therapeutic concentrations of the drug are delivered directly to the site of infection. Furthermore, studies have shown that it also achieves high concentrations in other key organs susceptible to fungal invasion, such as the kidneys, liver, lungs, and bone marrow, where levels can be 25 to 50 times higher than in plasma.[31]
• Metabolism: Ibrexafungerp is cleared primarily via hepatic metabolism.[18] The principal metabolic pathway involves hydroxylation, a reaction catalyzed by the cytochrome P450 enzyme CYP3A4. Following this initial step, the resulting hydroxylated metabolite undergoes phase II conjugation, either through glucuronidation or sulfation, to form more water-soluble compounds that can be readily excreted.[3]
• Excretion: The primary route of elimination for ibrexafungerp and its metabolites is through the feces via biliary excretion.[18] In human mass balance studies using a radiolabeled dose, a mean of 90% of the radioactivity was recovered in the feces over time. A substantial portion of this, 51% of the total dose, was excreted as the unchanged parent drug, indicating that a significant amount of absorbed drug is cleared without being metabolized.[3] In stark contrast, only 1% of the administered dose was recovered in the urine.[3] The elimination half-life ( t1/2​) of ibrexafungerp is approximately 20 hours, which supports a once- or twice-daily dosing schedule.[3] Total plasma clearance values have been reported to be in the range of 53.6 to 56.1 L/h.[3]

The pharmacokinetic profile of ibrexafungerp reveals a sophisticated interplay of properties that make it particularly well-suited for its indications. The combination of high penetration into vaginal tissue and its sustained antifungal activity in the physiologically acidic environment of the vagina creates a powerful, localized therapeutic effect.[3] This is more than just a matter of bioavailability; it is a targeted pharmacological profile where the drug is delivered at high concentrations to the precise site of infection and functions optimally within the specific biochemical conditions of that site. This "right drug, right place, right conditions" synergy likely underlies the high rates of mycological cure and, more importantly, the durable clinical response and low relapse rates seen in clinical trials when compared to agents like fluconazole.[17]

Furthermore, the near-complete reliance on fecal elimination and negligible renal clearance is a significant clinical advantage.[3] This pharmacokinetic characteristic strongly implies that dosage adjustments for patients with renal impairment will not be necessary. This simplifies prescribing protocols and enhances the drug's utility in complex patient populations, such as the elderly or those with comorbidities like chronic kidney disease, who are often at higher risk for both renal dysfunction and invasive fungal infections.

Pharmacodynamics

The pharmacodynamics of ibrexafungerp describe the relationship between drug concentration and its antifungal effect.

• Concentration-Dependent Activity: Ibrexafungerp exhibits concentration-dependent fungicidal activity against Candida species.[11] This means that higher drug concentrations result in a more rapid and extensive killing of the fungal cells.
• PK/PD Index: The key pharmacokinetic/pharmacodynamic index that correlates with the efficacy of ibrexafungerp is the ratio of the free (unbound) drug area-under-the-curve to the minimum inhibitory concentration (fAUC/MIC).[31] This index integrates total drug exposure over time with the potency of the drug against a specific pathogen. Studies have determined that for a 1-log10 reduction in colony-forming units (a measure of fungal killing) of Candida isolates, the target fAUC/MIC ratio is in the range of 0.91 to 1.42.[31] Pharmacokinetic data from Phase 1 studies in healthy volunteers confirm that the standard approved dosing regimens achieve plasma concentrations that result in fAUC/MIC ratios well within this therapeutic target range for most clinically relevant Candida species.[31]

Parameter	Value	Source(s)
Time to Peak Concentration (Tmax)	4–6 hours	3
Peak Plasma Concentration (Cmax)	435 ng/mL (at 300 mg BID)	3
Area Under the Curve (AUC0-24)	6832 h*ng/mL (at 300 mg BID)	3
Volume of Distribution (Vdss​​)	~600 L	3
Plasma Protein Binding	99.5–99.8% (primarily to albumin)	3
Elimination Half-Life (t1/2​)	~20 hours	3
Metabolism	Hepatic; CYP3A4-mediated hydroxylation followed by conjugation	3
Primary Route of Elimination	Fecal (~90% of dose)	3
Urinary Excretion	~1% of dose	3
Clearance	53.6–56.1 L/h	3

Clinical Efficacy and Therapeutic Applications

The clinical development program for ibrexafungerp has established its efficacy in its approved indications and is actively exploring its potential in treating severe, life-threatening invasive fungal infections. The results of these trials underscore its value as a novel therapeutic option.

Approved Indication: Treatment of Vulvovaginal Candidiasis (VVC)

The initial FDA approval of ibrexafungerp was for the treatment of acute VVC, a condition affecting an estimated 75% of women at least once in their lifetime.[11] Efficacy was established in two pivotal Phase 3 trials.

• Pivotal Phase 3 Trials (VANISH 303 & VANISH 306): These were large, multicenter, randomized, double-blind, placebo-controlled studies designed to assess the superiority of ibrexafungerp in adult and post-menarchal pediatric females (age 12 and older) with VVC.[14] The treatment regimen consisted of a single-day course of ibrexafungerp 300 mg (administered as two 150 mg tablets) given twice, approximately 12 hours apart.[5]
• Efficacy Outcomes: In both studies, ibrexafungerp demonstrated a statistically significant and clinically meaningful improvement over placebo. The primary endpoint was the clinical cure rate (complete resolution of all signs and symptoms) at the test-of-cure (TOC) visit on Day 10.
• In the VANISH 303 trial (NCT03734991), the clinical cure rate was 50.5% in the ibrexafungerp group compared to 28.6% in the placebo group (p=0.001).[7]
• In the VANISH 306 trial (NCT03987620), the clinical cure rate was 63.3% for ibrexafungerp versus 44.0% for placebo.[7]
• Secondary endpoints, including mycological eradication (negative fungal culture) and improvement in symptoms, were also significantly higher in the ibrexafungerp arms.[17] A key finding was the durability of the response; at the follow-up visit on Day 25, a significantly greater proportion of patients treated with ibrexafungerp remained symptom-free compared to those who received placebo, indicating a sustained clinical benefit.[17]
• Phase 2 Comparator Trial (DOVE): To position ibrexafungerp relative to the existing standard of care, the Phase 2 DOVE trial (NCT03253094) included an active comparator arm with a single 150 mg oral dose of fluconazole.[14]
• Results: At the Day 10 TOC visit, the clinical cure rates were comparable between the two active treatments, with 51.9% for the ibrexafungerp 300 mg BID regimen versus 58.3% for fluconazole.[17] While these initial results might suggest simple non-inferiority, the follow-up data revealed a more nuanced and significant advantage for ibrexafungerp. At the Day 25 visit, 70.4% of patients in the ibrexafungerp group were completely free of signs and symptoms, compared to only 50.0% in the fluconazole group.[17] Furthermore, there was a dramatic difference in the need for additional antifungal rescue medication during the study period: only 3.7% of ibrexafungerp-treated patients required it, versus 29.2% of fluconazole-treated patients.[20] This divergence in outcomes over time suggests that while both drugs can achieve initial symptom control, ibrexafungerp provides a more definitive and durable cure. This superior sustained response is likely attributable to its fungicidal mechanism of action and its high, persistent concentrations in vaginal tissue, leading to more thorough eradication of the fungal pathogen and reducing the likelihood of early relapse. This positions ibrexafungerp not just as an alternative for azole-resistant cases, but potentially as a superior first-line option for patients who are prone to relapse or who desire a more robust and lasting resolution of their infection.

Approved Indication: Reduction in the Incidence of Recurrent VVC (RVVC)

Following its approval for acute VVC, ibrexafungerp became the first and only oral antifungal agent to be FDA-approved for the prevention of RVVC, a chronic and debilitating condition.[17]

• Pivotal Phase 3 Trial (CANDLE): The CANDLE study (NCT04029116) was designed to evaluate the efficacy and safety of a monthly prophylactic regimen of ibrexafungerp.[6]
• Dosage: Patients received the same one-day treatment course (300 mg BID) once a month for a total of six months.[7]
• Efficacy Outcomes: The trial met its primary endpoint, demonstrating that the monthly ibrexafungerp regimen was significantly more effective than placebo at preventing recurrences. Over the 24-week treatment period, 65.4% of patients in the ibrexafungerp arm remained free of any culture-proven, presumed, or suspected VVC episode, compared to 53.1% of patients in the placebo arm (p=0.02).[6] This protective effect was shown to be durable, as the statistically significant advantage over placebo was maintained through a three-month follow-up period after treatment cessation.[6]

Investigational Use in Invasive and Refractory Infections

Recognizing its potent, broad-spectrum activity and unique oral formulation, the clinical development of ibrexafungerp has strategically pivoted to focus on severe, hospital-based invasive fungal infections, where there is a profound unmet medical need.[11] Ibrexafungerp has been granted Qualified Infectious Disease Product (QIDP), Fast Track, and Orphan Drug designations by the FDA for invasive candidiasis and invasive aspergillosis, facilitating its development for these life-threatening conditions.[13]

• FURI Trial (NCT03059992): This ongoing Phase 3, open-label, single-arm study is evaluating ibrexafungerp as a salvage therapy for patients with a variety of invasive and/or severe fungal diseases who are either refractory to or intolerant of standard-of-care antifungal treatments.[13] An interim analysis of the first 41 patients, assessed by an independent data review committee, showed a promising overall complete or partial response rate of 56%. Efficacy was observed across infections caused by various pathogens, including difficult-to-treat species like C. glabrata and C. krusei.[14]
• MARIO Trial: This global Phase 3 study is investigating oral ibrexafungerp as a step-down therapy for patients with invasive candidiasis (including candidemia) who have been stabilized on initial intravenous echinocandin therapy.[13] The design of this trial is particularly innovative as it tests a "mechanism-consistent" therapeutic strategy. Currently, the standard of care involves stepping down from an IV glucan synthase inhibitor (an echinocandin) to an oral agent from a different class (an azole), which introduces different resistance profiles and drug interaction concerns. The MARIO trial explores the possibility of transitioning patients to an oral agent that maintains the same mechanism of action, potentially offering a seamless IV-to-oral switch that could facilitate earlier hospital discharge, reduce healthcare costs, and improve patient convenience without compromising therapeutic efficacy.[16]
• CARES Trial (NCT03363841): This Phase 3 open-label study is specifically designed to evaluate the efficacy and safety of ibrexafungerp in patients with candidiasis caused by the multidrug-resistant pathogen Candida auris.[13] This trial directly addresses one of the most urgent fungal threats identified by public health organizations worldwide.
• SCYNERGIA Trial (NCT03672292): This Phase 2 study evaluated the safety and efficacy of adding ibrexafungerp to voriconazole for the treatment of invasive pulmonary aspergillosis, exploring its potential role in combination therapy for severe mold infections.[13]

Trial Name (Acronym)	NCT Number	Phase	Indication	Design	Interventions	Key Efficacy Outcome(s)
VANISH 303	NCT03734991	3	Treatment of VVC	Randomized, Placebo-Controlled	Ibrexafungerp 300 mg BID for 1 day vs. Placebo	Clinical Cure at Day 10: 50.5% vs. 28.6% (p=0.001)
VANISH 306	NCT03987620	3	Treatment of VVC	Randomized, Placebo-Controlled	Ibrexafungerp 300 mg BID for 1 day vs. Placebo	Clinical Cure at Day 10: 63.3% vs. 44.0%
DOVE	NCT03253094	2	Treatment of VVC	Randomized, Active-Controlled	Ibrexafungerp 300 mg BID for 1 day vs. Fluconazole 150 mg single dose	Clinical Cure at Day 10: 51.9% vs. 58.3% (comparable) Symptom-Free at Day 25: 70.4% vs. 50.0% (superior)
CANDLE	NCT04029116	3	Reduction in RVVC	Randomized, Placebo-Controlled	Ibrexafungerp 300 mg BID for 1 day, monthly for 6 months vs. Placebo	Recurrence-Free at Week 24: 65.4% vs. 53.1% (p=0.02)
Sources: 6

Safety, Tolerability, and Risk Profile

The clinical utility of any therapeutic agent is a balance between its efficacy and its safety. Ibrexafungerp has been shown to be generally well-tolerated in clinical trials, with a predictable and manageable side effect profile, but its use is governed by a significant contraindication related to pregnancy.

Adverse Drug Reactions

Across the clinical development program, ibrexafungerp has demonstrated a favorable safety profile. The majority of reported adverse events (AEs) have been mild to moderate in severity and transient in nature.[1]

• Most Common Adverse Events: The safety profile is predominantly characterized by gastrointestinal disturbances. In the pivotal trials for VVC, the most frequently reported AEs (occurring in ≥2% of patients) were:
• Diarrhea (16.7%)
• Nausea (11.9%)
• Abdominal pain (including upper/lower abdominal pain and discomfort) (11.4%)
• Dizziness (including postural dizziness) (3.3%)
• Vomiting (2.0%) [5]
• Less Common Adverse Events: Other AEs reported in less than 2% of patients include dysmenorrhea (menstrual cramps), flatulence, back pain, transient elevations in liver transaminases, vaginal bleeding, and rash or hypersensitivity reactions.[5]
• Discontinuation Rate: The tolerability of the drug is underscored by a very low rate of treatment discontinuation due to adverse events. In the pooled analysis of the VVC trials, only 2 out of 545 patients (0.4%) stopped treatment due to AEs (one for vomiting, one for dizziness).[5]

Contraindications and Boxed Warning: Embryo-Fetal Toxicity

The most significant safety concern associated with ibrexafungerp is its potential for harm to a developing fetus. This risk has led to a strict contraindication and a prominent boxed warning on its label.

• Absolute Contraindication: Ibrexafungerp is absolutely contraindicated for use during pregnancy.[5]
• Boxed Warning: The FDA-approved labeling includes a boxed warning that explicitly states the risk of embryo-fetal toxicity.[7]
• Preclinical Evidence: This contraindication is based on findings from animal reproduction studies. When ibrexafungerp was administered orally to pregnant rabbits during the period of organogenesis, it was associated with fetal malformations, including rare but severe defects such as absent limbs (forelimb or hindpaw), absent ear pinna, and thoracogastroschisis (a congenital defect of the chest and abdominal wall). These effects were observed at systemic exposures approximately five times the recommended human dose (RHD) based on AUC comparisons.[5] Similar studies conducted in pregnant rats did not show evidence of fetal toxicity or malformations at comparable exposures.[5]
• Risk Management and Mitigation: Due to this potential risk, a stringent risk mitigation strategy is required for its use in females of reproductive potential.
• Pregnancy Testing: Pregnancy status must be verified with a negative test before initiating treatment with ibrexafungerp.[5] For patients on the monthly regimen for RVVC prevention, it is recommended that pregnancy status be reassessed prior to each monthly dose.[42]
• Contraception Counseling: Patients must be counseled on the risk and advised to use an effective method of contraception during treatment and for at least 4 days after the final dose.[5]

This absolute contraindication is the single greatest factor shaping the therapeutic niche of ibrexafungerp for VVC, a condition most prevalent in women of childbearing age. It places a significant logistical and counseling burden on prescribers and may limit its use to specific patient populations, such as post-menopausal women or those who can reliably adhere to strict contraceptive measures. This safety profile leaves a substantial unmet medical need for a safe and effective oral antifungal for VVC that can be used during pregnancy, highlighting a key area for future drug development.

Drug-Drug Interactions (DDIs)

The potential for drug-drug interactions with ibrexafungerp is primarily related to its role as both a substrate and an inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, a major pathway for drug metabolism.[3]

• Ibrexafungerp as a Substrate of CYP3A4:
• Co-administration with CYP3A4 Inhibitors: Strong or moderate inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, fluconazole) can decrease the metabolism of ibrexafungerp, leading to increased plasma concentrations and a potential for increased adverse reactions. When co-administered with a strong or moderate CYP3A4 inhibitor, the dose of ibrexafungerp should be reduced by half, to 150 mg twice in one day.[3]
• Co-administration with CYP3A4 Inducers: Strong or moderate inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, bosentan) can accelerate the metabolism of ibrexafungerp, leading to significantly lower plasma concentrations and a risk of therapeutic failure. Therefore, concomitant administration with strong or moderate CYP3A4 inducers should be avoided.[3]
• Ibrexafungerp as an Inhibitor: Ibrexafungerp itself is an inhibitor of CYP3A4 as well as the drug transporters P-glycoprotein (P-gp) and OATP1B3.[5] This means it has the potential to increase the plasma concentrations of other drugs that are substrates of these pathways. Dedicated Phase 1 DDI studies have been conducted to formally evaluate these effects, for example, with pravastatin and dabigatran.[8]

The DDI profile, while requiring clinical vigilance, is centered on the well-characterized and predictable CYP3A4 pathway. The clear and specific management guidelines provided in the drug's labeling—dose reduction with inhibitors and avoidance with inducers—provide clinicians with an actionable risk management plan. This makes its DDI profile manageable in patients on multiple medications, provided a thorough medication review is conducted.

Hepatotoxicity and Overdose

• Hepatotoxicity: Ibrexafungerp has not been associated with significant liver injury. In the large registration trials for VVC, the incidence of transient, asymptomatic elevations in liver transaminases was less than 1% and was not significantly different from the rate observed with placebo (0.7% vs. 0.4%).[7] While two cases of marked but ultimately resolving ALT elevations were noted in healthy volunteers during Phase 1 studies, there have been no reports of clinically apparent liver injury with jaundice since its approval.[7] Based on the available data, it is assigned a LiverTox Likelihood Score of "E," indicating it is an unlikely cause of clinically apparent liver injury.[7]
• Overdose: There is no specific antidote for an overdose of ibrexafungerp. Clinical trial experience includes patients who have taken more than the recommended dose without experiencing severe adverse effects, suggesting a wide therapeutic index.[3] In the event of an overdose, management should consist of standard symptomatic and supportive measures.[3]

Interacting Drug / Class	Example Drugs	Effect on Ibrexafungerp	Clinical Recommendation	Source(s)
Strong/Moderate CYP3A4 Inhibitors	Itraconazole, Clarithromycin, Fluconazole, Aprepitant, Amiodarone	Increased plasma concentration of ibrexafungerp (↑ risk of AEs)	Reduce ibrexafungerp dosage to 150 mg twice daily for one day.	3
Strong/Moderate CYP3A4 Inducers	Rifampin, Carbamazepine, Phenytoin, Bosentan, Apalutamide, Efavirenz	Decreased plasma concentration of ibrexafungerp (↓ efficacy)	Avoid concomitant administration.	3
Ibrexafungerp as an Inhibitor	Substrates of CYP3A4, P-gp, OATP1B3	Potential to increase concentrations of co-administered substrates.	Monitor for adverse effects of co-administered drugs.	5

Strategic Analysis and Future Outlook

Ibrexafungerp's entry into the therapeutic market is not just the launch of a new product but the introduction of a new class of antifungal agents. Its development history, regulatory journey, and strategic positioning provide insight into its current and future role in combating fungal diseases.

Development, Regulatory, and Commercial History

The development of ibrexafungerp has involved multiple pharmaceutical entities, reflecting the long and complex path of bringing a novel compound to market.

• Origin and Development: The compound originated in the discovery pipeline of Merck & Co (as MK-3118) and was subsequently acquired and advanced through clinical development by SCYNEXIS, Inc. (as SCY-078).[23] Jiangsu Hansoh Pharmaceutical has also been involved in its development.[23]
• U.S. FDA Regulatory Timeline:
• New Drug Application (NDA) Submission: SCYNEXIS submitted the NDA for the treatment of VVC on October 14, 2020.[48]
• Initial Approval (VVC): The FDA approved Brexafemme on June 1, 2021, for the treatment of acute VVC. This marked the first approval of a new antifungal class in over 20 years and the first oral non-azole agent for this indication.[2]
• Second Indication Approval (RVVC): On November 30, 2022, the FDA expanded the approval to include the reduction in the incidence of RVVC, making it the only oral therapy with this indication.[6]
• European Medicines Agency (EMA) Status: While not yet approved for marketing in the European Union, ibrexafungerp has achieved important regulatory milestones. On November 12, 2021, it received a positive opinion for Orphan Designation for the treatment of invasive candidiasis.[4] Additionally, a paediatric investigation plan (PIP) has been agreed upon with the agency, a necessary step for eventual marketing authorization in Europe.[4]
• Commercial Strategy and Partnership: Following the initial launch of Brexafemme, SCYNEXIS announced a significant strategic shift in late 2022. The company decided to out-license the commercial rights for the VVC/RVVC indications to a larger partner to maximize its market potential, while refocusing its internal resources on the development of ibrexafungerp for severe, hospital-based invasive fungal infections, where the potential for long-term return on investment is higher.[36] Subsequently, GSK acquired an exclusive license for the global development and commercialization of ibrexafungerp for all indications, with exceptions for certain regions like greater China.[52]

Therapeutic Niche and Clinical Positioning

Ibrexafungerp occupies a distinct and valuable niche in the current antifungal armamentarium, with its positioning expected to evolve as data from ongoing trials become available.

• Current Niche (VVC/RVVC): In the outpatient setting, ibrexafungerp is positioned as a crucial second-line or specialized first-line oral therapy for VVC and as a unique prophylactic agent for RVVC. Its primary patient populations include:
• Individuals with infections caused by azole-resistant Candida species, such as C. glabrata or resistant C. albicans, where fluconazole is ineffective.[17]
• Patients who cannot take azoles due to allergies, intolerance, or significant drug-drug interactions (e.g., with statins, certain antidepressants).[17]
• Patients who experience early relapse after fluconazole treatment, for whom the superior sustained clinical response of ibrexafungerp offers a more definitive cure.[17]
• As the only FDA-approved oral agent for preventing RVVC, it is the standard of care for this specific indication.[17]
• Future Niche (Invasive/Refractory Infections): The true long-term value of ibrexafungerp likely lies in the hospital setting, addressing severe infections.
• Oral Step-Down Therapy: Its most compelling potential role is as the first oral glucan synthase inhibitor for step-down therapy in patients with invasive candidiasis. This would allow for a seamless transition from IV echinocandins, maintaining a consistent mechanism of action and potentially enabling earlier and safer hospital discharge.[16]
• Salvage Therapy: For patients with invasive fungal infections who have failed or are intolerant to standard therapies, ibrexafungerp offers a novel mechanistic option, as demonstrated in the FURI trial.[14]
• Treatment for MDR Pathogens: It is a critical new weapon against highly resistant pathogens, particularly C. auris and echinocandin-resistant Candida species, for which therapeutic options are dangerously limited.[13]

Unmet Needs and Future Development

The development of ibrexafungerp is a direct response to the urgent global health threat posed by the rise of antifungal resistance.[3] Its novel mechanism and broad spectrum address several key unmet needs. Future development is focused on maximizing its potential in the most vulnerable patient populations.

• Ongoing research continues to explore its utility in combination with other antifungal classes, such as the use with voriconazole for aspergillosis, to potentially achieve synergistic effects and overcome resistance.[13]
• Its potential as a prophylactic agent in high-risk, immunocompromised patient populations (e.g., transplant recipients, patients with hematologic malignancies) is a logical area for future investigation.[54]
• The development of an intravenous formulation, which has completed Phase 1 trials, will provide maximum flexibility for clinicians, allowing for IV initiation of therapy in critically ill patients followed by a transition to the oral form for consolidation and outpatient treatment.[11]

Concluding Remarks

Ibrexafungerp is a landmark achievement in modern antifungal therapy. As the first member of the novel triterpenoid class, it breaks a two-decade-long drought in the approval of new oral antifungal classes. Its unique mechanism of action—inhibiting the validated target β-(1,3)-D-glucan synthase at a site distinct from echinocandins—provides a powerful tool against a broad spectrum of pathogens, including those resistant to existing drug classes. The combination of oral bioavailability, a favorable pharmacokinetic profile with excellent tissue penetration, and potent fungicidal activity against Candida establishes it as a highly valuable therapeutic agent.

For VVC and RVVC, it offers a durable cure and a unique prophylactic option, particularly for patients with azole-refractory disease or those who cannot tolerate standard therapies. However, its clinical utility in this large patient population is fundamentally constrained by its absolute contraindication in pregnancy, a significant limitation for a condition most common in women of childbearing age. Furthermore, its high acquisition cost relative to generic fluconazole presents a barrier to widespread first-line use.[33]

The long-term strategic importance of ibrexafungerp will likely be defined by its success in the hospital setting. Its potential as the first oral step-down therapy that maintains the glucan synthase inhibitor mechanism of action could revolutionize the management of invasive candidiasis, while its activity against formidable pathogens like C. auris addresses a critical and growing unmet medical need. Ultimately, ibrexafungerp is more than just a new drug; it is the foundation of a new therapeutic platform. Its successful development and strategic deployment will depend on the outcomes of ongoing pivotal trials and the ability of its commercial partners to position it effectively, ensuring its use in the patient populations where its unique benefits can justify its costs and its risks can be safely managed. It stands as a testament to innovative medicinal chemistry and a crucial new asset in the global fight against fungal diseases.

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