Antifungal agents with enhanced activity in acidic pH
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Publication Number
US-11534433-B2
Publication Date
2022-12-27
Expiration Date
Abstract
Enfumafungin derivative triterpenoid antifungal compounds are used to treat or prevent fungal infections occurring in or under acidic conditions where the pH is lower than about 7, due to their unexpected, enhanced efficacy under such conditions. The enfumafungin derivative triterpenoids (or pharmaceutically acceptable salts or hydrates thereof) are inhibitors of (1,3)-β-D-glucan synthesis and are useful in the treatment or prevention of yeast or mold infections that occur in anatomic areas having a low pH, such as the vaginal cavity, or under acidic local environment conditions such of those seen in fungal abscesses, empyema, or upper gastrointestinal tract infections.
Core Innovation
The invention relates to enfumafungin-derivative triterpenoid antifungal compounds, including compounds having Formula (I) and Formula (II) embodiments, with a specific compound having a Formula (IIa) embodiment. The disclosed compounds include SCY-078 and pharmaceutically acceptable salt or hydrate forms, including citrate and phosphate salt forms.
The invention addresses enhanced antifungal activity in acidic pH conditions where (1,3)-β-D-glucan synthesis is inhibited. It is described that the compounds exhibit unexpectedly enhanced antifungal potency under acidic pH conditions, including conditions where pH is lower than about 5, such as vaginal pH about 4 to 4.5.
The invention further relates to treating or preventing vulvovaginal candidiasis (VVC) infection in a subject, including in anatomical areas or conditions with pH lower than about 5. The disclosed use cases include treating and preventing VVC, including recurrent VVC, and the document also discusses infection in low-pH anatomical environments such as vulvovaginal candidiasis and upper gastrointestinal tract infections.
The document supports the claimed approach with rationale versus prior art and with experimental and clinical support, including in vitro potency comparisons showing SCY-078 potency improvement at pH 4.5 versus pH 7 and loss of potency for comparator azoles. It also describes mouse exposure to vaginal tissue/secretions after oral dosing and phase 2 clinical study results in moderate/severe acute VVC, including recurrence and clinical/mycological cure endpoints and safety observations, as well as pharmaceutical compositions and administration concepts including oral tablet dosage forms and salt embodiments.
Claims Coverage
The provided claim set includes three independent claims, each centered on administering a compound with a Formula (IIa) embodiment for VVC in the presence of acidic conditions (pH lower than about 5). Across the independent claims, the coverage is focused on treating VVC, preventing VVC, and orally administering a citrate salt form of the Formula (IIa) compound.
Treating VVC at acidic pH with Formula (IIa) compound at 150 to 600 mg/day
A method of treating vulvovaginal candidiasis (VVC) infection in a subject by administering a compound of Formula (IIa) or a pharmaceutically acceptable salt or hydrate thereof at a total daily dose of 150 to 600 mg, wherein the VVC infection occurs in a condition or an anatomic area in which the pH is lower than about 5.
Preventing VVC at acidic pH with Formula (IIa) compound at 150 to 600 mg/day
A method of preventing vulvovaginal candidiasis (VVC) infection in a subject by administering a compound of Formula (IIa) or a pharmaceutically acceptable salt or hydrate thereof at a total daily dose of 150 to 600 mg, wherein the VVC infection occurs in a condition or an anatomic area in which the pH is lower than about 5.
Oral citrate salt of Formula (IIa) for treating VVC at 150 to 600 mg/day
A method of treating vulvovaginal candidiasis (VVC) infection in a subject by orally administering a citrate salt of a compound of Formula (IIa), wherein the citrate salt of the compound is administered at a total daily dose of 150 to 600 mg of the compound.
Overall, the independent claims cover VVC treatment and prevention using a Formula (IIa) compound or pharmaceutically acceptable salt/hydrate at a total daily dose of 150 to 600 mg/day in conditions where pH is lower than about 5, with an additional independent claim specifically requiring oral administration of the citrate salt form for treating VVC at 150 to 600 mg/day.
Stated Advantages
Unexpectedly enhanced antifungal potency under acidic pH conditions where pH is lower than about 5 (including vaginal pH about 4 to 4.5).
Inhibition of (1,3)-β-D-glucan synthesis.
Reduced antifungal potency of comparator azoles under low pH conditions is discussed, supporting effectiveness under acidic conditions.
Phase 2 clinical study results include recurrence and clinical/mycological cure endpoints with safety observations.
Documented Applications
Treating vulvovaginal candidiasis (VVC) infection in a subject, including where the infection occurs in a condition or anatomic area in which the pH is lower than about 5.
Preventing vulvovaginal candidiasis (VVC) infection in a subject, including where the infection occurs in a condition or anatomic area in which the pH is lower than about 5.
Treating VVC using an oral citrate salt of a compound of Formula (IIa).
The document discusses low-pH anatomical environments such as vulvovaginal candidiasis (VVC) and upper gastrointestinal tract infections.
The document discusses recurrent VVC (rVVC) as an explicit targeted condition in the claim set.
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