By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A randomized clinical trial compared one day of oral ibrexafungerp with placebo for female patients with vulvovaginal candidiasis (VVC). It found ibrexafungerp to be safe and effective, with mild diarrhea the most common adverse event. Ibrexafungerp differs mechanistically from azoles and appears to be a promising new treatment for VVC.
SOURCE: Schwebke JR, Sobel R, Gersten JK, et al. Ibrexafungerp versus placebo for vulvovaginal candidiasis treatment: A phase 3, randomized, controlled superiority trial (VANISH 303). Clin Infect Dis 2022;74:1979-1985.
Approximately 75% of women will experience an episode of vulvovaginal candidiasis (VVC) in their lifetime, with 40% to 45% having two or more episodes. The azole class of antifungals has been the mainstay of treatment. However, options are limited for patients unable to tolerate azoles or for azole-resistant strains of Candida. Thus, new oral treatments are needed, especially with limited drug-drug interactions and a low risk of toxicity in women of childbearing age.
Ibrexafungerp is the first triterpenoid class antifungal. Preclinical studies showed ibrexafungerp levels to be two- to nine-fold higher in vaginal tissue than in plasma and activity that is not affected by low (≤ 4.5) vaginal pH. Therefore, Schwebke and colleagues sought to determine the safety and effectiveness of ibrexafungerp in female patients with VVC.
The study, called VANISH 303, was a randomized, controlled, superiority clinical trial that compared oral ibrexafungerp (300 mg BID × 1 day) to placebo in female patients 12 years and older diagnosed with VVC or having a positive microscopic examination with 10% potassium hydroxide (KOH) that showed yeast forms. Patients were excluded who had received systemic and/or vaginal antifungal treatment within 28 days of study enrollment, were pregnant or lactating, had human immunodeficiency virus, or had active vaginal or cervical cancer.
Patients were randomized 2:1 to receive ibrexafungerp or matching placebo. Vulvovaginal samples were obtained at baseline, at test of cure (TOC) visit (day 11 ± 3), and at follow-up visit (day 25 ± 4).The primary endpoint was the percentage of patients with a clinical cure at the TOC visit.
There were 376 patients randomized, of whom 247 received ibrexafungerp and 124 received placebo. The demographics were similar between the two groups, including the severity of VVC and having diabetes. The mean age was 33.5 ± 10.3 years in the ibrexafungerp group and 36.0 ± 12.4 years in the placebo group.
Most of the Candida species in the ibrexafungerp group were C. albicans (n = 173), with some C. glabrata (n = 11), C. tropicalis (n = 4), and C. dubliniensis (n = 2). The clinical cure rate at TOC was 50.5% (95/188 patients) in those who received ibrexafungerp vs. 28.6% (28/98) in the placebo recipients (relative risk [RR], 1.71; 95% confidence interval [CI], 1.205-2.431; P = 0.001).
Furthermore, a higher percentage of patients who received ibrexafungerp had complete resolution of symptoms at day 25 compared to placebo, regardless of clinical cure at TOC (59.6% [112/188 patients] vs. 44.9% [44/98 patients], respectively; P = 0.009). Post-hoc analyses found clinical improvement and clinical cure with ibrexafungerp at TOC were similar in Black patients and in patients with a body mass index > 35.
More patients who received ibrexafungerp reported an adverse event (AE) (39.7% [98/247 patients]) compared to those who received placebo (16.9% [21/124 patients]). Most of the AEs were gastrointestinal symptoms and mild and included nausea, diarrhea, and abdominal pain. Pregnancies were reported in two women in the ibrexafungerp group, both of whom had live births with no complications.
COMMENTARY
Similar to echinocandins, ibrexafungerp targets the fungal enzyme glucan synthase. This causes a decrease in (1, 3)-β-D-glucan polymers, leading to weakness in the fungal cell wall. Ibrexafungerp is fungicidal against many Candida isolates, including those resistant to azoles and echinocandins. It also has fewer off-target effects than azoles since human cells lack glucan synthase.
The study by Schwebke and colleagues showed oral ibrexafungerp to be a safe and effective therapy for VVC. Another recent study showed similar results comparing ibrexafungerp to oral fluconazole.1 An interesting finding from the Schwebke et al study was the large placebo effect, which suggests a significant proportion of VVC cases resolve without treatment over time. Further research on this finding seems warranted and should be considered in future clinical trials. Indeed, complications are unlikely from delayed treatment for VVC, and patients can be given rescue therapy as needed.
There were a few limitations to the study. First, the use of a placebo group negates the ability to directly compare ibrexafungerp to other active therapies (e.g., fluconazole), but this is addressed in the study. Second, the small number of non-albicans Candida isolates means the use of ibrexafungerp against these pathogens remains somewhat unclear. Finally, the mean age of the patients in the ibrexafungerp group (33.5 years) makes it uncertain whether the drug will have similar efficacy in other age groups.
Adding a new oral option for VVC to our armamentarium is an exciting notion. The U.S. Food and Drug Administration approved ibrexafungerp for VVC in June 2021. What role, if any, ibrexafungerp will have in treating other fungal infections remains to be elucidated.
REFERENCE
- Nyirjesy P, Schwebke JR, Angulo DA, et al. Phase 2 randomized study of oral ibrexafungerp versus fluconazole in vulvovaginal candidiasis. Clin Infect Dis 2022;74:2129-2135.
