Ibrexafungerp: A Novel Antifungal Agent That Is Easier to Pronounce Than Spell

The first antifungal medication, amphotericin B deoxycholate, was approved in 1958 for the treatment of fungal infections. It wasn’t until 15 years later that flucytosine was introduced and 15 years after that when azole antifungals were brought to market in the 1990s.¹ Echinocandins, introduced in the 2000s, provided broad-spectrum antifungal coverage with minimal toxicity compared with the preceding agents. Since that time, the FDA has approved no new classes of antifungal agents. Although the current antifungals used in clinical practice provide sufficient coverage against a plethora of fungal species, resistant species and strains are evolving rapidly. The multidrug-resistant fungus Candida auris is a specific species of Candida that is emerging as a serious global health threat; it has high rates of resistance to azoles and amphotericin B, correlating to poor clinical outcomes.²

Ibrexafungerp (Brexafemme) is a first-in-class triterpenoid approved by the FDA on June 1, 2021, for the treatment of vulvovaginal candidiasis (VVC) in adult and postmenarchal pediatric females.³ In this article we review the agent’s mechanism of action, pharmacokinetic properties, safety and efficacy, and place in therapy.

About That Name

Ibrexafungerp has a unique name that can be understood by breaking it down. “Ibrexa” is the fantasy prefix, “fung” refers to the mechanism of action targeting (1,3)-β-D-glucan synthase (similar to caspofungin), and “erp” is derived from triterpenoid. In 2019, the United States Adopted Names Council approved the use of the “-fungerp” stem for this new class of triterpenoid antifungals.⁴

Pharmacology and Microbiology

Similar to echinocandins, ibrexafungerp is an inhibitor of (1,3)-β-D-glucan synthase; however, it is structurally different and interacts with the enzyme in a different way. Due to this difference there is limited potential for cross-resistance with echinocandins, which has been confirmed in in vitro studies, as ibrexafungerp was shown to retain activity against echinocandin-resistant strains of Candida species (spp).^5,6

Ibrexafungerp is active against Candida spp (including C auris), Aspergillus spp, and Pneumocystis, and inactive against Cryptococcus spp, Mucorales, and Fusarium spp. It is also active against some other less common molds.⁷ Ibrexafungerp has demonstrated activity against biofilms produced by Candida spp, with similar activity to that of echinocandins but significantly higher than that of fluconazole (P < .001).⁸

Pharmacokinetics

Unlike the echinocandins, ibrexafungerp is highly bioavailable and can be given both intravenously and orally. Ibrexafungerp is available as 150-mg oral tablets and administered at 300 mg given 12 hours apart for 2 doses, which completes the regimen in a single day.³ Plasma concentrations peak around 4 to 6 hours after oral administration. Administration with a high-fat meal increased the maximum concentration and area under the curve by around 32% and 38% compared with fasting, respectively, but this is not considered clinically significant. Ibrexafungerp can be taken with or without food.3 Protein binding is 99.6% to 99.8% and the mean steady state volume of distribution is approximately 600 L.³ Tissue to blood ratios for several organs have been estimated in a single-dose pharmacokinetic analysis in rats, which found extensive distribution in vaginal tissue; the lung, kidney, liver, and spleen; bone marrow; muscle; and skin, but minimal distribution in central nervous system tissue and the spinal cord.⁹ Ibrexafungerp is hepatically cleared and mainly eliminated in the feces and bile (~90%), with approximately 1.5% urinary elimination. Dose adjustments are not required for renal or hepatic impairment. The half-life is approximately 20 hours, supporting the single-day dosing.³ Currently, no data exist on crushing or breaking the oral tablets.

Drug-Drug Interactions

Ibrexafungerp is extensively metabolized by the cytochrome P450 pathway and is affected by drugs that induce or inhibit this pathway. Because it is a substrate of cytochrome P3A4 (CYP3A4), coadministration of the drug with strong CYP3A4 inhibitors increases its concentration and a 50% dose reduction is recommended.³ Avoid coadministration with moderate to strong CYP3A4 inducers, such as rifampin, which may reduce concentrations of ibrexafungerp. Ibrexafungerp is also a CYP3A4, P-gp, and OATP1B3 transporter inhibitor, but the clinical significance of this is not of concern for the short duration of treatment for VVC.³ Concomitant use with pantoprazole for 5 days resulted in decreased ibrexafungerp exposure by 25%, though this was not considered clinically significant at the current approved dose.³

Phase 3 Clinical Trials

Two phase 3 clinical studies evaluated the safety and efficacy of ibrexafungerp compared with placebo for the treatment of VVC. VANISH 303 and VANISH 306 (NCT03734991 and NCT03987620) were randomized, double-blind, placebo-controlled trials that included nonpregnant postmenarchal patients aged 12 and older with a diagnosis of symptomatic acute VVC.³ More than 90% of patients with baseline cultures were culture positive with C albicans. The investigators in both trials evaluated clinical cure, defined by the complete resolution of signs and symptoms, at test of cure at 8 to 14 days post treatment. According to the data, patients receiving ibrexafungerp showed complete response rates compared with those receiving placebo of 50% vs 28% (P = .001) in VANISH 303, and 63.5% vs 44.9% (P = .009) in VANISH 306. Adverse effects among patients were minimal and mainly gastrointestinal in nature.³

Several other ongoing phase 2 and 3 clinical trials are being conducted to evaluate the role of ibrexafungerp in patients with recurrent VVC (CANDLE, NCT04029116), invasive aspergillosis (SCYNERGIA, NCT03672292), refractory invasive fungal infections (FURI, NCT02244606), and invasive infections due to C auris (CARES, NCT03363841). Highlighting the CARES study in particular, investigators evaluated the safety and efficacy of ibrexafungerp 750 mg twice daily for 2 days, then 750 mg once daily for up to 90 days in hospitalized patients with documented candidiasis or candidemia caused by C auris. Interim results have demonstrated a complete or partial response in 8 of 10 patients (80%).¹⁰ FURI has also shown positive results thus far, with investigators reporting that 46 of 74 patients (62%) experienced complete or partial responses and 18 of 74 (24%) had stable disease at the time of analysis.¹⁰

Adverse Effects, Warnings, and Precautions

Based on data from clinical trials in patients with VVC, the adverse effect profile of single-day ibrexafungerp is generally favorable. Gastrointestinal adverse effects were the most common, including diarrhea (16.7%), abdominal pain (11.4%), nausea (11.9%), dizziness (3.3%), and vomiting (2.0%).³ A press release for the FURI and CARES studies stated that ibrexafungerp was well tolerated overall and that investigators had identified no safety signals warranting changes to the studies.¹⁰ In contrast to many azole antifungals, ibrexafungerp does not cause QTc prolongation.³

The use of ibrexafungerp is contraindicated in pregnancy, as data from animal studies have shown a potential for fetal harm. During treatment with the agent, the use of effective contraception is advised. Concentrations in breast milk are unknown.

Resistance Data

Investigators in in vitro studies have evaluated the potential for resistance to ibrexafungerp, finding an association with mutations in the FKS2 gene. The clinical relevance of this is not yet known, but it has been established that ibrexafungerp retains activity against most echinocandin- and fluconazole-resistant strains of Candida spp.^3,5,6

Place in Therapy

Although fluconazole is an inexpensive, well-tolerated, single-dose agent that is effective in the majority of VVC cases, ibrexafungerp is an option for patients who either fail fluconazole therapy or may be unable to receive it. Ibrexafungerp is available orally and has a favorable adverse effect profile.

Beyond VVC, ibrexafungerp has the potential to advance the care of patients with invasive fungal infections, including those caused by resistant Candida spp. Clinical data evaluating inpatient use in more invasive and resistantinfections are pending. There is currently insufficient data to support the use of ibrexafungerp in patients with these infections, and clinicians should note that the dosing regimens under study are different from the approved VVC regimen. The drug interactions that are not clinically relevant with a single-day dosing regimen may warrant caution or necessitate dose modification for other uses.

Geena Kludjian, PharmD, is an infectious diseases clinical pharmacy specialist at Cooper University Hospital in Camden, New Jersey.

Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS, is a clinical professor at Temple University (TU) School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital in Philadelphia, Pennsylvania. He also is director of the PGY2 Residency in Infectious Diseases Pharmacy at TU.

References

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3. ^{Brexafemme. Package insert. SCYNEXIS, Inc; 2021. Accessed June 22, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214900s000lbl.pdf}
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7. ^{Jallow S, Govender NP. Ibrexafungerp: a first-in-class oral triterpenoid glucan synthase inhibitor. J Fungi (Basel). 2021;7(3):163. doi:10.3390/jof7030163}
8. ^{Marcos-Zambrano LJ, Gómez-Perosanz M, Escribano P, Bouza E, Guinea J. The novel oral glucan synthase inhibitor SCY-078 shows in vitro activity against sessile and planktonic Candida spp. J Antimicrob Chemother. 2017;72(7):1969-1976. doi:10.1093/jac/dkx010}
9. ^{Wring S, Borroto-Esoda K, Solon E, Angulo D. SCY-078, a novel fungicidal agent, demonstrates distribution to tissues associated with fungal infections during mass balance studies with intravenous and oral [14C]SCY-078 in albino and pigmented rats. Antimicrob Agents Chemother. 2019;63(2):e02119-18. doi:10.1128/AAC.02119-18}
10. ^{SCYNEXIS announces positive results from interim analyses of ongoing phase 3 studies (FURI and CARES), demonstrating oral ibrexafungerp’s ability to treat severe fungal infections in the hospital setting. Press release. SCYNEXIS. March 2, 2021. Accessed June 22, 2021. https://www.scynexis.com/news-media/press-releases/detail/233/scynexis-announces-positive-results-from-interim-analyses}