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Publication Number
US-11110102-B2
Publication Date
2021-09-07
Expiration Date
Abstract
The present invention relates to the use of enfumafungin derivative triterpenoid antifungal compounds in combination with other antifungal agents such azoles, polyenes, lipopeptides, and allylamides to treat fungal diseases. More particularly, the invention relates to antifungal combinations of enfumafungin derivative triterpenoids which are inhibitors of (1,3)-β-D-glucan synthesis, in combination with other antifungal agents such as mold-active agents that have activity against molds, including but not limited to voriconazole, isavuconazole, posaconazole, itraconazole and amphotericin B, for the treatment and/or prevention of infections caused by molds.
Core Innovation
The invention relates to antifungal combination therapy for an Aspergillus infection in a subject in need thereof. It includes administering a first therapeutic agent that is a compound of Formula (II) or Formula (IIa), or a pharmaceutically acceptable salt thereof, together with isavuconazole. The disclosed approach provides oral administration and defines the dosing amounts and dosing frequency and duration.
The invention is directed to treating and/or preventing pulmonary aspergillosis, including invasive pulmonary aspergillosis, by combining a (1,3)-β-D-glucan synthase inhibition antifungal compound with mold-active second antifungals such as isavuconazole. The document further characterizes the antifungal combination as improving clinical outcomes compared with administration of a single agent.
The disclosed rationale includes activity against azole-resistant Aspergillus and a low drug-drug interaction risk, and it reports interaction outcomes described as synergistic or no antagonism. The document supports the combination concept with in vitro checkerboard synergy testing (FICI) and in vivo neutropenic rabbit studies using endpoints including survival, pulmonary infarct scores, and serum galactomannan for the combination versus monotherapy.
Claims Coverage
The independent claims cover treating and preventing pulmonary aspergillosis, including invasive pulmonary aspergillosis, using an oral pharmaceutical combination of a Formula (II) or Formula (IIa) compound, or pharmaceutically acceptable salt, with isavuconazole. The inventive concept is implemented across five independent claims.
Oral combination therapy with Formula (II) compound and isavuconazole
A method of treating an Aspergillus infection in a subject comprising administering orally a first therapeutic agent that is a compound of Formula (II) or a pharmaceutically acceptable salt and a second therapeutic agent that is isavuconazole, with defined oral dose ranges and administration at least once or twice per day for at least one week.
Oral combination therapy with Formula (IIa) compound and isavuconazole for treating Aspergillus infection
A method of treating an Aspergillus infection in a subject comprising administering orally a first therapeutic agent that is a compound of Formula (IIa) or a pharmaceutically acceptable salt and a second therapeutic agent that is isavuconazole, with defined oral dose ranges and administration at least once or twice per day for at least one week.
Prophylaxis for pulmonary aspergillosis using Formula (IIa) compound and isavuconazole
A method of preventing pulmonary aspergillosis in a subject in need thereof comprising administering orally a first therapeutic agent that is a compound of Formula (IIa) or a pharmaceutically acceptable salt and a second therapeutic agent that is isavuconazole, with defined oral dose ranges and administration at least once or twice per day for at least one week.
Survival-improving treatment with Formula (IIa) compound and isavuconazole
A method of treating an Aspergillus infection in a subject comprising administering a first therapeutic agent that is a compound of Formula (IIa) or a pharmaceutically acceptable salt and a second therapeutic agent that is isavuconazole, where each therapeutic agent is administered in an amount effective to increase survival compared to survival from administering either agent alone.
Pharmaceutical combination defined by higher survival in a subject population
A method of treating an Aspergillus infection in a subject comprising administering a pharmaceutical combination of a first therapeutic agent that is a compound of Formula (IIa) or a pharmaceutically acceptable salt and a second therapeutic agent that is isavuconazole, wherein the combination results in a survival rate higher than the survival rate of a second population receiving either therapeutic agent alone.
Across the independent claims, the core inventive coverage is the administration of a pharmaceutical combination containing a compound of Formula (II) or Formula (IIa), or a pharmaceutically acceptable salt, together with isavuconazole, orally and with defined dosing regimens. Claim coverage further includes prevention of pulmonary aspergillosis and treatment outcomes defined by increased survival relative to monotherapy, including embodiments directed to invasive pulmonary aspergillosis.
Stated Advantages
Improved survival compared to administration of either the first therapeutic agent or the second therapeutic agent alone.
Reduced pulmonary infarct scores.
Reduced serum galactomannan (galactomannan antigen).
Synergistic interaction and/or no antagonism as determined by checkerboard synergy testing (FICI).
Activity against azole-resistant Aspergillus and low drug-drug interaction risk.
Documented Applications
Treatment of an Aspergillus infection in a subject, including treating invasive pulmonary aspergillosis.
Prevention of pulmonary aspergillosis in a subject in need thereof.
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