Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

Abstract

SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and Cmax. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices Cmax/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases.

Lack of Impact by SCY‐078, a First‐in‐Class Oral Fungicidal Glucan Synthase Inhibitor, on the Pharmacokinetics of Rosiglitazone, a Substrate for CYP450 2C8, Supports the Low Risk for Clinically Relevant Metabolic Drug‐Drug Interactions

“…Administration of a 1250‐mg loading dose of SCY‐078 (day 1) resulted in a geometric mean (CV%) AUC 0‐24h of 11.64 (38.8) μg·hr/mL, consistent with the target antifungal exposure evaluated in phase 2 studies and the efficacy target was based on in vivo murine models for invasive fungal infections with Candida species is 11.2 μg·h 2 /mL . Values for C max of 0.783 (36.2) μg/mL, plasma concentration at 24 hours post‐dose (C 24h ) of 0.294 (49.7) μg/mL, and median T max of 6.0 hours.…”

“…SCY‐078, an enfumafungin derivative, represents the first compound of the triterpenoid class of β 1,3‐glucan synthesis inhibitors in development for the treatment of fungal infections . SCY‐078 was documented to have potent in vitro activity against Candida and Aspergillus species clinical isolates, and retained activity against azole‐resistant, most echinocandin‐resistant, and multidrug‐resistant strains of Candida species .…”

“…SCY‐078 recently met primary end points in two phase 2 clinical studies in invasive candidiasis and vulvovaginal candidiasis, which evaluated a 1250‐mg loading dose on day 1 followed by once‐daily doses of 750 mg. A loading dose strategy was employed to achieve a therapeutically relevant antifungal concentration in plasma on the first day of treatment, as early target attainment has been correlated with improved patient outcomes . Thus, this novel antifungal agent represents a new class of non‐azole, orally bioavailable treatment for Candida and Aspergillus species infections, having the potential to treat multidrug‐resistant fungal isolates …”

“…4,5 SCY-078, an enfumafungin derivative, represents the first compound of the triterpenoid class of β 1,3-glucan synthesis inhibitors in development for the treatment of fungal infections. 6 SCY-078 was documented to have potent in vitro activity against Candida and Aspergillus species clinical isolates, and retained activity against azole-resistant, most echinocandin-resistant, and multidrug-resistant strains of Candida species. 7-10 SCY-078 recently met primary end points in two phase 2 clinical studies in invasive candidiasis and vulvovaginal candidiasis, 11,12 which evaluated a 1250-mg loading dose on day 1 followed by once-daily doses of 750 mg. A loading dose strategy was employed to achieve a therapeutically relevant antifungal concentration in plasma on the first day of treatment, as early target attainment has been correlated with improved patient outcomes.…”

Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases

“…The oral availability and the activity against drug resistant pathogens have made enfumafungin an excellent lead for next generation antifungal therapeutics. Merck and Scynexis generated series of enfumafungin derivatives, and identified ibrexafungerp that has advanced to phase 2 clinical trials as oral formulations with indications for invasive and vulvovaginal candidiasis, and as a step‐down therapy from intravenous echinocandins in patients with invasive candidiasis (Wring et al ., , b). Such an experimental drug would offer a major advantage over the echinocandin class of antifungals because of its oral availability and its effectiveness against emerging echinocandin‐resistant strains.…”