UltraVIOLET: Oteseconazole turns in satisfactory results for recurrent yeast infection
In the treatment and prevention of recurrent yeast infection or vulvovaginal candidiasis (RVVC), oteseconazole performs similarly to standard-of-care fluconazole but better as compared with placebo, as shown in the results of the phase III ultraviolet study.
“Oteseconazole administered as oral doses of 600 mg on day 1 (four 150-mg doses) and 450 mg on day 2 (three 150-mg doses) at the start of the 2-week induction phase was … noninferior to fluconazole in the treatment of the presenting acute VVC episode and, when followed by 150 mg oteseconazole once weekly for the initial 11 weeks of the maintenance phase, was statistically superior to placebo in prevention of recurrence of acute VVC episodes in these participants with a history of RVVC,” according to the investigators.
UltraVIOLET included 219 women and postmenarcheal girls (mean age 35 years, 59 percent White, mean body mass index 29.1 kg/m2) with a history of RVVC enrolled across 38 sites in the US. Of these, 147 received oteseconazole in the induction and maintenance phases, while 72 received fluconazole (three sequential 150-mg oral doses, given once every 72 hours) in the induction phase and placebo in the maintenance phase. All patients were followed for an additional 37 weeks.
The primary outcome of the proportion of patients with ≥1 culture-verified acute VVC episode through 50 weeks during the maintenance phase was significantly lower with oteseconazole than with placebo (5.1 percent vs 42.2 percent; p<0.001). [Am J Obstet Gynecol 2022;doi:10.1016/j.ajog.2022.07.023]
For secondary efficacy endpoints, 93.2 percent of patients on oteseconazole vs 95.8 percent on fluconazole achieved resolution at the week 2 test-of-cure visit during the induction phase. Oteseconazole also proved better than placebo in terms of the number of patients with ≥1 positive culture for Candida species infection (23.6 percent vs 79.7 percent; p<0.001) and the difference in time to recurrence (hazard ratio, 0.06, 95 percent confidence interval, 0.02–0.18; p<0.001) during the maintenance phase.
Overall, treatment-emergent adverse event (TEAE) rates were comparable in the treatment groups: 54 percent among patients who received oteseconazole in the induction and maintenance phases as compared with 64 percent among those who received fluconazole in the induction phase and placebo in the maintenance phase.
Commonly reported TEAEs included urinary tract infection, bacterial vaginosis, headache, nausea, diarrhoea, upper respiratory tract infection, and pyrexia. Most of these events were mild or moderate in severity, with only 3.4 percent of TEAEs graded as severe or higher in the oteseconazole/oteseconazole group vs 4.2 percent in fluconazole/placebo group.
Broad antifungal activity spectrum
UltraVIOLET, according to the investigators, has shown that oteseconazole is efficacious and well tolerated in participants with a history of RVVC, “extending clinical findings generated in two prior global, phase III, multicentre, randomized, double-blind, placebo-controlled [VIOLET] studies (NCT03562156 and NCT03561701).
“Because this study was conducted with more than 37 weeks of follow-up during the maintenance phase, results suggest that oteseconazole may have long-term efficacy against acute VVC infection in patients with RVVC,” they added.
Guidelines for RVVC treatment from the Infectious Diseases Society of America recommend 10–14 days of oral fluconazole (or a topical agent) followed by 6 months of 150-mg fluconazole once weekly. However, this pattern of use poses risks of liver toxicity, drug-drug interactions, and a US Food and Drug Administration (FDA) pregnancy warning of potential birth defects in infants. [Antimicrob Agents Chemother 2014;58:7121-7127; tinyurl.com/2bnm3znq; N Engl J Med 2004;351:876-883; J Low Genit Tract Dis 2020;24:48-52]
“Repeated use of fluconazole to treat recurrences increases the risk of resistant isolates developing… Additionally, treatment failure is common in nonalbicans Candida infections, as some strains are intrinsically resistant or show low susceptibility to currently available antifungal agents,” the investigators pointed out. [Obstet Gynecol 2012;120:1407-1414; Antimicrob Agents Chemother 2014;58:7121-7127; J Low Genit Tract Dis 2020;24:48-52; Adv Infect Dis 2013;3:238-242]
On the other hand, oteseconazole demonstrated broad antifungal activity spectrum in the current study. The drug worked against all Candida species isolated in the ultraVIOLET population—including C albicans, C glabrata, C parapsilosis, and C tropicalis—at lower concentrations than fluconazole (range, ≤0.0005 to >0.25 μg/mL vs <0.06 to 32 μg/mL).
Based on oteseconazole’s efficacy, duration of efficacy, and favourable safety profile, together with its broad spectrum of antifungal activity against many Candida species, including fluconazole-resistant strains, the investigators believe that the drug represent a novel option to treat and prevent recurrent episodes of VVC.
A novel oral selective inhibitor of fungal lanosterol demethylase (CYP51), an enzyme required for fungal growth, oteseconazole has received the US FDA’s approval for reducing the incidence of RVVC in women who are not of reproductive potential. This approval is based on the positive results from three phase III trials of the drug – the two global, pivotal VIOLET studies and the current US-focused ultraVIOLET study – which comprised 875 patients enrolled from 232 sites across 11 countries. [tinyurl.com/2dbj333a]