A Phase 3, multicenter, randomized, placebo-controlled trial of monthly oral ibrexafungerp to reduce the incidence of recurrent vulvovaginal candidiasis.

BACKGROUND Recurrent vulvovaginal candidiasis develops in 5-9% of people assigned female at birth and has a serious impact on quality of life. Oral ibrexafungerp is a first-in-class, non-azole, triterpenoid antifungal approved in the United States for the treatment of postmenarchal females with acute vulvovaginal candidiasis and for the reduction in the incidence of recurrent vulvovaginal candidiasis. OBJECTIVE (S): This Phase 3 study (CANDLE) describes the efficacy and safety of monthly oral ibrexafungerp vs placebo for reducing the incidence of recurrent vulvovaginal candidiasis. STUDY DESIGN Participants with a history of recurrent vulvovaginal candidiasis experiencing an acute infection episode (confirmed by positive potassium hydroxide test) received 3 doses of oral fluconazole (150 mg once-daily every 3 days). Those who had a culture-confirmed vulvovaginal candidiasis from the screening sample, achieved significant resolution of signs and symptoms (composite Vulvovaginal Signs and Symptoms score ≤2) following fluconazole treatment, and continued to meet all study eligibility criteria entered a maintenance phase. In the maintenance phase, eligible participants were randomized (1:1) to oral ibrexafungerp (300 mg twice-daily for one day) or placebo, which was repeated once every 4 weeks for a total of 6 treatments (until Week 20). Efficacy was assessed by the percentage of participants with no mycologically-proven recurrence and the percentage of participants with clinical success (a participant with a Test-of-Cure [Week 24] evaluation and no recurrence; mycologically-proven, presumed, or suspected) by Test-of-Cure (4 weeks after last study drug dose). Safety and tolerability assessments included incidence of adverse events and treatment discontinuations. Participants were further assessed for recurrence during a 12-week follow-up phase. RESULTS In the intent-to-treat population, 70.8% (n=92/130) of participants who received ibrexafungerp and 58.5% (n=76/130) who received placebo had no mycologically-proven recurrence by Test-of-Cure (relative risk: 1.22; 95% confidence interval: 1.032, 1.430; P=0.019). The proportion of participants who achieved clinical success by Test-of-Cure was 65.4% (n=85/130) with ibrexafungerp and 53.1% (n=69/130) with placebo (relative risk: 1.24; 95% confidence interval: 1.034, 1.486; P=0.020). The benefit of ibrexafungerp over placebo was sustained over the 4 months following last study drug dose for both the no mycologically-proven recurrence (65.4% [n=85/130] vs 53.8% [n=70/130]; relative risk: 1.22; 95% confidence interval: 1.021, 1.456; P=0.029) and clinical success (57.7% [n=75/130] vs 46.2% [n=60/130]; relative risk: 1.26; 95% confidence interval: 1.017, 1.555; P=0.034) endpoints. Overall, 64.6% (n=84/130) of participants who received ibrexafungerp and 58.5% (n=76/130) of participants who received placebo experienced ≥1 treatment-emergent adverse event. Treatment-related adverse events occurred in 14.6% (n=19/130) of participants in the ibrexafungerp group and 6.9% (n=9/130) of participants in the placebo group. No adverse events in the ibrexafungerp group led to treatment or study discontinuation. The most common adverse events reported in both the ibrexafungerp and placebo groups were headache, bacterial vaginosis, and diarrhea; these events were mostly mild in severity. CONCLUSION Once-monthly oral ibrexafungerp was effective and well-tolerated in participants with recurrent vulvovaginal candidiasis.