mk-3118 and Candidiasis--Vulvovaginal

Vulvovaginal candidiasis (VVC) is experienced by an estimated 75% of women at least once in their lifetime and is recurrent, defined as three or more infections per year (RVVC) in 5-9%. Candida albicans is the most common causative agent, but up to 19% of infections may be related to non-albicans species. Available treatment options for VVC have consisted of oral and topical azoles (except for topical nystatin, a polyene). Oral polyenes are not absorbed and therefore not effective for VVC. Fluconazole is the only oral medication FDA approved for VVC. None of these treatments are FDA approved for RVVC. Ibrexafungerp, a triterpenoid fungicidal agent, was FDA approved in 2021, becoming the first oral non-azole agent for VVC. Ibrexafungerp reaches concentrations up to 9-fold higher in vaginal tissues versus plasma. In Phase 2 clinical trials, ibrexafungerp had a clinical cure rate comparable to fluconazole at day 10, but significantly better at day 25. In Phase 3 clinical trials, ibrexafungerp had both a higher clinical and mycologic cure rate versus placebo at both days 10 and 25. In December 2022, Ibrexafungerp received FDA approval for once monthly dosing to decrease the incidence of RVVC. This approval was based on data from the CANDLE STUDY, which showed 65.4% resolution of symptoms and culture negative success through week 24, compared to 53.1% of placebo. Ibrexafungerp provides an alternative oral option for treatment of acute, severe VVC. It is the only FDA approved antifungal for RVVC. Currently, the population likely to benefit from this drug are those with azole allergy, non-albicans or azole resistant albicans species, or other azole contraindications such as drug interactions (like statins or tricyclics). Side effects are mostly gastrointestinal and mild in nature. Ibrexafungerp, like fluconazole, should be used with caution in women who are or may become pregnant.

Topics: Antifungal Agents; Azoles; Candida albicans; Candidiasis, Vulvovaginal; Female; Fluconazole; Humans; Polyenes; Pregnancy; Triterpenes

On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as vaginal yeast infection. Ibrexafungerp is the first drug approved in a novel antifungal class in more than two decades, and the Food and Drug Administration's decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. The decision was also based on substantial preclinical and clinical work in both the pharmacokinetics and pharmacodynamics of ibrexafungerp. This paper reviews that research and looks ahead to explore how this novel antifungal agent may be used in the future to address the expanding problem of drug-resistant mycotic infections.

Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes; United States

Worldwide, effective management of vulvovaginal candidiasis (VVC) continues to serve as a major therapeutic goal with numerous unmet drug treatment challenges. After 3 decades of azole drug dominance, with few recent new antifungal agents and little progress in VVC management, the first-in-class oral triterpenoid glucan synthase inhibitor agent ibrexafungerp has emerged in the treatment of acute VVC. After reviewing existing treatment standards and unmet needs, the pharmacology, pharmacokinetics, antimicrobial activity and clinical efficacy of ibrexafungerp are reviewed in this article together with phase III clinical trial results and drug safety. The projected role and status of ibrexafungerp are reviewed together with perspectives of its future development and role in the treatment of VVC.

Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes

Ibrexafungerp (BREXAFEMME

Topics: Antifungal Agents; Candidiasis, Invasive; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Invasive Fungal Infections; Male; Pulmonary Aspergillosis; Triterpenes

Vulvovaginal candidiasis (VVC) is a common fungal infection caused by predominantly. Ibrexafungerp is an orally active, semi-synthetic triterpenoid glucan synthase inhibitor under development for treatment and prevention of VVC. We present the chemistry, mechanism of action, pharmacology, microbiology, and results from clinical studies with ibrexafungerp in women with VVC.. Ibrexafungerp addresses several unmet needs with existing antifungal drugs as a first in a new class of antifungal agents with a novel mechanism of action demonstrating no antifungal cross resistance with azoles, and fungicidal activity against

Topics: Animals; Antifungal Agents; Candida; Candidiasis, Vulvovaginal; Drug Administration Schedule; Drug Interactions; Drug Resistance, Fungal; Female; Glycosides; Humans; Triterpenes

Current treatment of vulvovaginal candidiasis (VVC) is largely limited to azole therapy. Ibrexafungerp is a first-in-class triterpenoid antifungal with broad-spectrum anti-Candida fungicidal activity. The objective of this study was to evaluate the efficacy and safety of ibrexafungerp compared with placebo in patients with acute VVC.. Patients were randomly assigned 2:1 to receive ibrexafungerp (300 mg twice for 1 day) or placebo. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms [VSS] = 0) at test-of-cure (day 11 ± 3). Secondary endpoints included the percentage of patients with mycological eradication, overall success (clinical cure and mycological eradication), clinical improvement (VSS ≤ 1) at test-of-cure, and symptom resolution at follow-up (day 25 ± 4).. Patients receiving ibrexafungerp had significantly higher rates of clinical cure (50.5% [95/188] vs 28.6% [28/98]; P = .001), mycological eradication (49.5% [93/188] vs 19.4% [19/98]; P < .001), and overall success (36.0% [64/178] vs 12.6% [12/95]; P < .001) compared with placebo. Symptom resolution was sustained and further increased with ibrexafungerp compared with placebo (59.6% [112/188] vs 44.9% [44/98]; P = .009) at follow-up. Post hoc analysis showed similar rates of clinical cure and clinical improvement at test-of-cure for Black patients (54.8% [40/73] and 63.4% [47/73], respectively) and patients with a body mass index >35 (54.5% [24/44] and 68.2% [30/44], respectively) compared with overall rates. Ibrexafungerp was well tolerated. Adverse events were primarily gastrointestinal and mild in severity.. Ibrexafungerp provides a promising safe and efficacious oral treatment that mechanistically differs from current azole treatment options for acute VVC.

Topics: Antifungal Agents; Azoles; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes

Vulvovaginal candidiasis affects approximately 75% of women in their lifetime. Approved treatment options are limited to oral or topical azoles. Ibrexafungerp, a novel, first-in-class oral triterpenoid glucan synthase inhibitor, has demonstrated broad fungicidal Candida activity and a favorable tolerability profile. The primary objective of this dose-finding study was to identify the optimal dose of oral ibrexafungerp in patients with acute vulvovaginal candidiasis.. Patients with vulvovaginal signs and symptoms score ≥7 were randomized equally to 6 treatments groups: 5 treatment doses of oral ibrexafungerp or oral fluconazole 150 mg. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms) at the test-of-cure visit (day 10).. Overall, 186 patients were randomized into the 6 treatment groups. Results, using the modified intent-to-treat population (baseline positive culture), are reported for ibrexafungerp 300 mg twice daily (BID) for 1 day (n = 27), which was the dose selected for phase 3 studies, and fluconazole 150 mg for 1 day (n = 24). At day 10, the clinical cure rates for ibrexafungerp and fluconazole were 51.9% and 58.3%, respectively; at day 25, patients with no signs or symptoms were 70.4% and 50.0%, respectively. During the study ibrexafungerp patients required less antifungal rescue medications compared with fluconazole (3.7% vs 29.2%, respectively). Ibrexafungerp was well tolerated, with the most common treatment-related adverse events being mild gastrointestinal events.. Ibrexafungerp is a well-tolerated novel antifungal with comparable efficacy to fluconazole in the treatment of acute vulvovaginal candidiasis.. NCT03253094.

Topics: Administration, Oral; Antifungal Agents; Candidiasis, Vulvovaginal; Female; Fluconazole; Glycosides; Humans; Triterpenes

To evaluate the efficacy and safety of ibrexafungerp versus placebo for acute vulvovaginal candidiasis (VVC) treatment.. Global phase 3, randomised, placebo-controlled superiority study.. Study sites in the USA (n = 19) and Bulgaria (n = 18).. Female patients aged ≥12 years with acute VVC and a vulvovaginal signs and symptoms (VSS) score ≥4 at baseline.. Patients were randomly assigned 2:1 to ibrexafungerp (300 mg twice for 1 day) or placebo.. The primary endpoint was the percentage of patients with a clinical cure (VSS = 0) at the test-of-cure visit (day 11 ± 3). Secondary endpoints included percentages of patients with mycological eradication, clinical cure and mycological eradication (overall success), clinical improvement (VSS ≤1) at test-of-cure visit, and complete resolution of symptoms at follow-up visit (day 25 ± 4).. At the test-of-cure visit, patients receiving ibrexafungerp had significantly higher rates of clinical cure (63.3% [119/188] versus 44.0% [37/84]; P = 0.007), mycological eradication (58.5% [110/188] versus 29.8% [25/84]; P < 0.001), overall success (46.1% [82/188] versus 28.4% [23/84]; P = 0.022) and clinical improvement (72.3% [136/188] versus 54.8% [46/84]; P = 0.01) versus those receiving placebo. Symptom resolution was sustained and further increased with ibrexafungerp (73.9%) versus placebo (52.4%) at follow-up (P = 0.001). Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mild to moderate in severity.. Ibrexafungerp demonstrated statistical superiority over placebo for the primary and secondary endpoints. Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute VVC.. Ibrexafungerp is statistically superior to placebo for the treatment of vulvovaginal candidiasis.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Antifungal Agents; Candidiasis, Vulvovaginal; Double-Blind Method; Female; Glycosides; Humans; Middle Aged; Treatment Outcome; Triterpenes; Young Adult

The pharmacology, microbiology, pharmacokinetics, pharmacodynamics, efficacy, safety, and role of ibrexafungerp in the treatment of fungal infections are reviewed.. Ibrexafungerp is the first triterpenoid antifungal. Similarly to echinocandins, it inhibits the synthesis of 1,3-β-d-glucan. However, it binds to a different site on the enzyme than echinocandins, resulting in limited cross-resistance. Ibrexafungerp exerts concentration-dependent fungicidal activity against Candida species and retains in vitro activity against most fluconazole-resistant strains. It is also active against Aspergillus species. Ibrexafungerp has been shown to be safe and effective in the treatment of vulvovaginal candidiasis caused by Candida albicans in phase 2 and phase 3 clinical trials. It is approved for vulvovaginal candidiasis in adult and postmenarchal pediatric females and is given as two 150-mg tablets orally, administered 12 hours apart. Ibrexafungerp is contraindicated in pregnancy. The most commonly reported adverse reactions were diarrhea, nausea, abdominal pain, dizziness, and vomiting. Ibrexafungerp should be avoided with strong or moderate CYP3A inducers, and the dose should be reduced with strong CYP3A inhibitors. Ibrexafungerp may be useful for patients who are not able to receive fluconazole or prefer oral therapy for the treatment of vulvovaginal candidiasis. However, it is more expensive than the 150-mg tablet of generic fluconazole, which is the current standard of care for vulvovaginal candidiasis. Clinical trials are ongoing for recurrent and complicated vulvovaginal candidiasis as well as invasive candidiasis and pulmonary aspergillosis.. Ibrexafungerp is an alternative to fluconazole for the treatment of vulvovaginal candidiasis in nonpregnant females. It has the potential to be useful for recurrent and complicated vulvovaginal candidiasis as well as certain invasive fungal infections.

Topics: Adult; Antifungal Agents; Candidiasis, Vulvovaginal; Child; Echinocandins; Female; Fluconazole; Humans; Pregnancy; Triterpenes

Topics: Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes

Topics: Candidiasis, Vulvovaginal; Glycosides; Humans; Triterpenes

Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Drug Approval; Female; Glycosides; Humans; Randomized Controlled Trials as Topic; Triterpenes; United States; United States Food and Drug Administration

The vaginal environment with candidiasis has a pH of 3.8 to 4.5 and this has a negative effect on the activity of antifungals. Ibrexafungerp was evaluated against 187

Topics: Antifungal Agents; Candida; Candidiasis, Vulvovaginal; Drug Resistance, Fungal; Female; Fluconazole; Glycosides; Humans; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Pichia; Triterpenes