Efficacy and safety of fosravuconazole L-lysine ethanolate, a novel oral triazole antifungal agent, for the treatment of onychomycosis: A multicenter, double-blind, randomized phase III study

Abstract

Fosravuconazole L-lysine ethanolate (F-RVCZ) is a prodrug of ravuconazole, a novel triazole antifungal agent, exerting broad and potent antifungal activity. The efficacy and safety of F-RVCZ, compared with a placebo, were investigated in a multicenter, double-blind, randomized study of Japanese onychomycosis patients with 25% or more clinical involvement of the target toenail. Subjects (n = 153) were randomly assigned to receive F-RVCZ (100 mg RVCZ, n = 101) or placebo (n = 52) p.o. once daily for 12 weeks. The primary end-point was the rate of complete cure (clinical cure [0% clinical involvement of the target toenail] plus mycological cure [negative potassium hydroxide examination]) at week 48 (36-week post-treatment visit). Secondary end-points were changes over time in the efficacy and mycological effect of F-RVCZ. Safety was also evaluated. The complete cure rate at week 48 was significantly higher with F-RVCZ (59.4%, 60/101) than the placebo (5.8%, 3/52) in the full analysis set (P < 0.001). The mycological cure rate at week 48 was also significantly higher with F-RVCZ (82.0%, 73/89) than the placebo (20.0%, 10/50, P < 0.001). Regarding safety, adverse events were observed in 83.2% (84/101) and 80.8% (42/52), and adverse drug reactions (ADR) in 23.8% (24/101) and 3.8% (2/52) of F-RVCZ and placebo subjects, respectively. ADR were mild to moderate in severity, with none being serious. F-RVCZ (equivalent to 100 mg ravuconazole) administrated once daily for 12 weeks was more effective than placebo and tolerable in patients with onychomycosis, suggesting it to be a promising drug for onychomycosis treatment.

Keywords: fosravuconazole; onychomycosis; oral antifungal agents; randomized controlled trial; ravuconazole.

Figure 1

Disposition of subjects. FAS, full analysis set; PPS, per‐protocol set; SAF, safety analysis set. Completed study drug administration, subjects who completed the treatment period (12 weeks) and entered the observation period (from weeks 12 to 48 after initiation of study drug administration). Completed study, subjects who completed the observation period.

Figure 2

Changes in complete cure rate of toenail onychomycosis. Changes in the proportion of subjects who achieved complete cure are shown. (a) The complete cure rate in the full analysis set population receiving fosravuconazole gradually increased over time. P = 0.003 at week 36, and P < 0.001 at week 48 (fosravuconazole, n = 101; placebo, n = 52). (b) A similar tendency was observed in the per‐protocol set population. P = 0.002 at week 36, and P < 0.001 at week 48 (fosravuconazole, n = 89; placebo, n = 50). *P < 0.05.

Figure 3

Healing process of toenail onychomycosis with 12‐week fosravuconazole treatment in representative subjects (baseline and at weeks 12, 24, 36 and 48). Toenail onychomycosis gradually improved in subjects with baseline nail involvement ratios of 67.5% (upper) and 58.7% (lower), leading to complete cure by week 48.

Figure 4

Changes in the distribution of efficacy ratings against toenail onychomycosis. Significant differences were observed from week 24 onward (P < 0.001 at weeks 24, 36 and 48; full analysis set).

Figure 5

Changes in the percent decrease in the area of nail involvement of toenail onychomycosis. The mean changes in the percent decrease in the area of nail involvement are shown. P = 0.013 at week 12, and P < 0.001 at weeks 24, 36 and 48 (full analysis set population at week 48: fosravuconazole, n = 89; placebo, n = 50). *P < 0.05.

Figure 6

Changes in the mycological cure rate of toenail onychomycosis. Changes in the proportion of subjects who achieved mycological cure are shown. P = 0.002 at week 24 and P < 0.001 at weeks 36 and 48 (full analysis set population at week 48: fosravuconazole, n = 89; placebo, n = 50). *P < 0.05.