Pharmaceutical combinations for use in the treatment of fungal infections

Abstract

The present invention provides combinations comprising (a) a compound of formula (I) wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and (b) a triazole-based antifungal agent or a pharmaceutically acceptable salt thereof, as well as methods of using the combinations in the prevention and treatment of fungal infections.

Description

[0001] Pharmaceutical Combinations for Use in the Treatment of Fungal Infections

[0002] The present invention relates to pharmaceutical combinations comprising two therapeutic agents as described herein and methods of using the combinations of the invention in the treatment of fungal infections.

[0003] The compound of formula (la) described below, referred to as GR-2397, VL-2397 and ASP2397 in the scientific literature, is a first-in-class antifungal, derived from a natural product, and has demonstrated fungicidal activity against clinically important molds such as Aspergillus spp., including azole-resistant strains. Safety and tolerability have been demonstrated in a previously completed phase 1 study with single and multiple ascending intravenous (i.v.) doses (NCT02956499, Shaw).

[0004] Azole-based antifungals agents are the most used antifungal agents and are active against a wide range of fungal infections and diseases. All contain either an imidazole or triazole ring. Imidazole antifungal agents were discovered first with chlormidazole being the first compound in the azole class to be marketed for the treatment of fungal infections in 1958. The first generation imidazoles in addition to chlormidazole include clotrimazole, miconazole (both 1969) and econazole (1974). Ketoconazole (1981) is considered to be a second-generation imidazole antifungal and was the first azole orally available to treat systemic fungal infections. The triazole class represent the newest class of azole antifungals and are considered superior to the imidazole class by having more suitable solubility, greater selectivity for the target fungal enzyme versus the human enzyme, and a better safety and broader spectrum of action. Terconazole was the first triazole to be marketed, with fluconazole and itraconazole additionally being first generation triazoles. Second generation triazoles were introduced to improve pharmacokinetics, safety and spectrum and include voriconazole, posaconazole, ravuconazole (including the prodrug fosfavuconazole), as well as albaconazole, efinaconazole, and isavuconazole. All azole drugs share a common mechanism of action and act by targeting the fungal cell membrane, in particular the synthesis of ergosterol by inhibiting lanosterol 14-a-demethylase (or CYP51), a fungal cytochrome P450-dependent enzyme responsible for the transformation of lanosterol in 14-demethyl lanosterol in the ergosterol biosynthetic pathway (Teixeira et al.).

[0005] Isavuconazole, marketed under the trade name CRESEMBA®, is an intravenous and oral antifungal drug belonging to the triazole class of antifungal agents and is approved for the treatment of invasive aspergillosis and mucormycosis. It is administered to patients as the prodrug isavuconazonium (isavuconazonium sulfate). Isavuconazole is described in WO 1999 / 45008 and isavuconazonium is described in WO 2001 / 32652 as well as in numerous publications such as Maertens et al. Nakamura et al. (c) describes an experiment in which the compound of formula (la) and posaconazole were tested in an A. fiimigatus mouse infection model. No additive, synergistic or antagonistic effect on efficacy was observed.

[0006] There is an ongoing need for new effective treatment options for patients suffering from fungal infections and in particular invasive fungal diseases. As demonstrated in the Examples below it has now surprisingly been found that the combination of the compound of formula (la) and triazole antifungals, and in particular isavuconazole, exhibits synergistic activity against fungal pathogens.

[0007] Summary of the invention

[0008] In a first aspect the present invention provides a pharmaceutical combination comprising

[0009] (a) a compound of formula (I) wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and

[0010] (b) a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole.

[0011] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole- based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole.

[0012] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said subject is undergoing or will undergo administration of a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) as a combination therapy with the triazole-based antifungal agent.

[0013] In a further aspect the invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole for use in the prevention or treatment of a fungal infection in a subject.

[0014] In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole for the prevention or treatment of a fungal infection in a subject.

[0015] In a further aspect the invention provides a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a fungal infection in a subject.

[0016] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, in the preparation of single-agent medicaments for use in combination, or as a combined medicament, for the prevention or treatment of a fungal infection in a subject.

[0017] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament for use in combination with a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, or in the preparation of a combined medicament with a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, for the prevention or treatment of a fungal infection in a subject.

[0018] In a further aspect the invention provides use of a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a fungal infection in a subject.

[0019] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole- based antifungal agent, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0020] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said subject is undergoing or will undergo administration of a triazole-based antifungal agent as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0021] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the triazole-based antifungal agent, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a combination therapy with the triazole-based antifungal agent, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0022] In a further aspect the invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a triazole-based antifungal agent for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0023] In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0024] In a further aspect the invention provides a triazole-based antifungal agent for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0025] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent, in the preparation of single-agent medicaments for use in combination or as a combined medicament for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0026] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament for use in combination with a triazole-based antifungal agent, or in the preparation of a combined medicament with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0027] In a further aspect the invention provides use of a triazole-based antifungal agent in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

[0028] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole- based antifungal agent, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger, or Aspergillus flavus.

[0029] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said subject is undergoing or will undergo administration of a triazole-based antifungal agent as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus. In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a triazole-based antifungal agent, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a combination therapy with the triazole-based antifungal agent, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus , Aspergillus niger, or Aspergillus flavus.

[0030] In a further aspect the invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a triazole-based antifungal agent for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus.

[0031] In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus , Aspergillus niger, or Aspergillus flavus.

[0032] In a further aspect the invention provides a triazole-based antifungal agent for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is selected from Aspergillus ierreus. Aspergillus niger, and Aspergillus flavus.

[0033] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent, in the preparation of single-agent medicaments for use in combination or as a combined medicament for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger, or Aspergillus flavus.

[0034] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament for use in combination with a triazole-based antifungal agent, or in the preparation of a combined medicament with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus, Aspergillus niger, or Aspergillus flavus.

[0035] In a further aspect the invention provides use of a triazole-based antifungal agent in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus , Aspergillus niger. or Aspergillus flavus.

[0036] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole- based antifungal agent, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0037] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said subject is undergoing or will undergo administration of a triazole-based antifungal agent as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0038] In a further aspect the invention provides a method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the triazole-based antifungal agent, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a combination therapy with the triazole-based antifungal agent, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0039] In a further aspect the invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a triazole-based antifungal agent for use in the prevention or treatment of a fungal infection in a subject, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0040] In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the fungal infection is refractory to the compound of formula (I) or the pathogen causing the fungal infection is resistant to the compound of formula (I). In a further aspect the invention provides a triazole-based antifungal agent for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a fungal infection in a subject, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0041] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent, in the preparation of single-agent medicaments for use in combination or as a combined medicament for the prevention or treatment of a fungal infection in a subject, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0042] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament for use in combination with a triazole-based antifungal agent, or in the preparation of a combined medicament with a triazole-based antifungal agent, for the prevention or treatment of a fungal infection in a subject, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0043] In a further aspect the invention provides use of a triazole-based antifungal agent in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a fungal infection in a subject, wherein the pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0044] In a further aspect the invention provides a method of synergistically increasing the efficacy of a triazole-based antifungal agent in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0045] In a further aspect the invention provides a method of synergistically increasing the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering a triazole-based antifungal agent in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of synergistically increasing the efficacy of a triazole-based antifungal agent in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0046] In a further aspect the invention provides a triazole-based antifungal agent for use in a method of synergistically increasing the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0047] In a further aspect the invention provides use of a triazole-based antifungal agent in the preparation of a single-agent medicament or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for synergistically increasing the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering the triazole-based antifungal agent in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0048] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament or in the preparation of a combined medicament with a triazole-based antifungal agent for synergistically increasing the efficacy of a triazole-based antifungal agent in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0049] In a further aspect the invention provides a method of reducing the dose of a triazole-based antifungal agent needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0050] In a further aspect the invention provides a method of reducing the dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole-based antifungal agent thereof to the subject.

[0051] In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of reducing the dose of a triazole-based antifungal agent needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0052] In a further aspect the invention provides a triazole-based antifungal agent for use in a method of reducing the dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0053] In a further aspect the invention provides use of a triazole-based antifungal agent in the preparation of a single-agent medicament or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof, for reducing the dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the triazole-based antifungal agent in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0054] In a further aspect the invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a single-agent medicament or in the preparation of a combined medicament with a triazole-based antifungal agent for reducing the dose of a triazole-based antifungal agent needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

[0055] In a further aspect the invention provides a kit comprising a plurality of separate containers, wherein at least one container contains a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one different container contains a triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole. In a further aspect the invention provides a unit dosage form comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole and opelconazole.

[0056] In a further aspect the invention provides an in vitro method of contacting a fungal pathogen with a compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent.

[0057] Additional aspects and embodiments of the invention are described in more detail below.

[0058] Figures

[0059] Figure 1 shows the survival results in an invasive pulmonary aspergillosis (IP A) mouse model. Solid diamonds represent treatment with placebo, transparent diamonds represent the compound of formula (la) administered at a dose of 2 mg / kg bid 24 hours after infection, crosses represent isavuconazonium sulfate administered at a dose of 110 mg / kg fid 24 hours after infection, transparent triangles represent the combination treatment of formula (la) administered at a dose of 2 mg / kg bid and isavuconazonium sulfate administered at a dose of 110 mg / kg fid 24 hours after infection, and solid triangles represent the uninfected control.

[0060] Detailed description of the invention

[0061] Definitions

[0062] Certain terms used herein are described below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0063] The term "about" means a variation of no more than 10% of the relevant figure. In some embodiments the term “about” means a variation of no more than 5% of the relevant figure.

[0064] The term "combination", "therapeutic combination", or "pharmaceutical combination" are interchangeable terms and refer to either a fixed combination or a non-fixed combination of the therapeutic agents.

[0065] The terms "fixed combination", "fixed dose", "single formulation" and "combined medicament" as used herein refers to a single dosage form formulated to deliver both therapeutic agents to a subject. The single dosage form is designed to deliver an amount of each of the therapeutic agents that is jointly therapeutically effective for the treatment of a fungal infection, along with any pharmaceutically acceptable carriers or excipients.

[0066] The terms "non-fixed combination,", "kit", "separate formulations", "single-agent medicaments" and "single-agent dosage forms" means that the therapeutic agents are formulated as separate dosage forms to allow each therapeutic agent to be delivered independently to a subject. The separate dosage forms are designed to deliver an amount of each of the therapeutic agents that is jointly therapeutically effective for the treatment of a fungal infection, along with any pharmaceutically acceptable carriers or excipients.

[0067] The term "patient" refers to a human presenting themselves for therapeutic treatment.

[0068] The term "pharmaceutically acceptable" as used herein refers to items such as compounds, materials, compositions and / or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject, in particular a patient, without excessive toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0069] The term "pharmaceutically effective amount," "therapeutically effective amount," or "clinically effective amount" is an amount sufficient to provide an observable or clinically significant improvement over the baseline clinically observable signs and symptoms of the fungal infection treated, e.g., commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. The skilled person will understand that the therapeutically effective amount of a therapeutic agent for use in combination therapy may be lower than the amount required to provide an equivalent therapeutic effect when using the agent as a monotherapy.

[0070] The term "pharmaceutical composition" is defined herein to refer to a solid or liquid formulation containing at least one therapeutic agent to be administered to a subject, optionally with one or more pharmaceutically acceptable excipients, in order to treat a particular fungal infection affecting the subject.

[0071] The term "prevent", "preventing" or "prevention" as used herein comprises a reduction in the risk of acquiring or developing at least one symptom associated with or caused by the fungal infection being prevented. Hence, the term comprises prophylaxis of fungal infections. Prophylaxis of fungal infections includes administration to subjects who are at risk of acquiring a fungal infection, e.g., subjects who are immunocompromised, e.g., due to inherited immune deficiency, due to the presence of a disease which weakens the immune system, such as human immunodeficiency virus (HIV), or because the patient has received or is receiving immunotherapy, e.g., in connection with organ transplant, or because the patient has received or is receiving treatment for a disease such as cancer, e.g., acute leukemia, or autoimmune disease.

[0072] The term "subject" refers to a mammal and preferably refers to a patient.

[0073] The term "treatment," as used herein in the context of treating a fungal infection in a subject pertains generally to treatment and therapy in which some desired therapeutic effect is achieved, for example one or more of the following: the inhibition of the progress of the infection, a reduction in the rate of progress, a halt in the rate of progress, a prevention of the progression of the infection, alleviation of symptoms of the infection, amelioration of infection, and cure of the infection. For example, treatment can be the diminishment of at least one or several symptoms of a fungal infection or complete eradication of the fungal infection (which is usually the goal of the treatment). Within the meaning of the present disclosure, the term "treat" also denotes to arrest, delay the onset (i.e. the period prior to clinical manifestation of an infection) and / or reduce the risk of developing or worsening of a fungal infection. Treatment of fungal infections includes administration to subjects with a proven fungal infection as well as administration to subjects displaying potential symptoms of a fungal infection which have not been proven as a fungal infection. Accordingly, “treatment” includes empiric treatment, i.e. administration to subjects with neutropenic fever (defined as a single oral temperature greater than or equal to 101°F (38.3°C) or a temperature greater than or equal to 100.4°F (38°C) for at least an hour, with an absolute neutrophilic count (ANC) of less than 1500 cells / microliter, Punnapuzha et al.) without a known cause; pre-emptive treatment, i.e. antifungal treatment based on clinical or radiological indicators of invasive fungal disease; and targeted treatment, i.e. antifungal treatment in patients with probable or proven fungal disease.

[0074] The terms "fungal infection" and "fungal disease" have their customary meanings in the art; i.e. the term "fungal infection" refers to the invasion and multiplication of pathogenic fungi in a subject and the term "fungal disease" refers to the clinical symptoms caused by a fungal infection, i.e. any deviation from or interruption of the normal structure or function of any part, organ, or system of the body. Reference to prevention or treatment of a fungal infection encompasses prevention or treatment of a fungal disease.

[0075] The term "refractory" is synonymous with "unresponsive", and generally means the failure or non- improvement of a prior treatment of a subject with the therapeutic agent in question. A fungal infection which is refractory to a particular triazole-based antifungal means that a patient has received prior treatment with that triazole-based antifungal agent but the treatment has failed to eradicate the fungal infection. For the avoidance of doubt, where a range is provided the range includes the stated upper limit and lower limit of the range.

[0076] Compounds of formula (I)

[0077] The compound of formula (I) has the structure shown above and is described for example in U.S. Patent No. 8,241,872, U.S. Patent No. 8,598,115, Shaw, Nakamura et al. (a), Nakamura et al. (b) and Nakamura et al.(c).

[0078] The compound of formula (I) complexed with an Al ion is referred to herein as the compound of formula (la) and has the CAS registry number 2088622-19-7. The chemical structure of the compound of formula (la) is shown below. coie%

[0079] I

[0080] H

[0081] N

[0082] H I!: ti

[0083] 11 z ■O'

[0084] It

[0085] \

[0086] (la)

[0087] As described herein, the compound of formula (I) as well as (la), (lb) and (Ic) also encompass pharmaceutically acceptable salts thereof.

[0088] Fungal activity is also present when the compound of formula (I) is complexed with an Fe or Ga ion, as described in U.S. Patent No. 8,598,115 and Nakamura et al. (a) (denoted AS2488053 when complexed with an Fe ion, referred to herein as the compound of formula (lb) and AS2529132 when complexed with a Ga ion, referred to herein as the compound of formula (Ic)).

[0089] The compound of formula (I) is preferably the compound of formula (la). In some embodiments the compound of formula (la) is the free base (containing M(III)). In some embodiments the compound of formula (la) is a pharmaceutically acceptable salt thereof.

[0090] The compound of formula (I) was originally isolated from the fungus strain MF-347833 of genus Acremonitim. which was isolated from leaf litter collected in the Endau Rompin national park, Johore, Malaysia. As stated in U.S. Patent No. 8,241,872 and U.S. Patent No. 8,598,115, this strain has been deposited in the International Patent Organism Depositary National Institute of Advanced Industrial Science and Technology (Address: AIST Tsukuba Central 6, 1-1, Higashi 1-chome Tukuba- shi, Ibaraki-ken 305-8566 Japan) as FERM BP-10916 (deposit date: Oct. 10, 2007) (Shaw). The compound of formula (I) can be prepared following the methods described in U.S. Patent No. 8,241,872 and U.S. Patent No. 8,598,115. The compound of formula (I) can also be prepared by following the protocol described in Nakamura et al. (a), summarized below.

[0091] A broth culture of Acremonium sp. MF-347833 is prepared as follows: A loopful of a slant culture of MF-347833 is used to inoculate 30 mL of sterilized culture of seed medium (cornstarch 2%, glycerol 1%, sucrose 1%, pharma media 1%, gluten meal 1% and Tween 80 0.2%) and cultured at 25 °C for 4 days with shaking on a rotary shaker (220 r.p.m.). The seed culture (3.2 mL) is aseptically inoculated into 160 mL of the same sterilized seed medium in each of three 500-mL Erlenmeyer flasks and is then cultured at 25 °C for 3 days with shaking on a rotary shaker (220 r.p.m.). These cultures (480 mL) are aseptically inoculated into a 30 L jar fermenter containing 20 L of sterile production medium (glycerol 5%, soluble starch (Nacalai Tesque, Kyoto, Japan) 7%, yeast extract (Wako Pure Chemical Industries, Osaka, Japan) 1.5%, B-cyclodextrin 1%, KNOs 1%, DL-methionine 1.3%, CaCOs 0.5%, A1K(SO4)2*12H2O 0.3%, Adekanol LG-109 0.1% and Silicone KM-70 0.05%). The culture is incubated at 25°C for 6 days with aeration at 20 L.min"1and agitation at 200 r.p.m.

[0092] The compound of formula (la) (complexed with an Al ion) may be obtained as follows: An equal volume of acetone is added to a 20 L broth culture o£ Acremonium sp. MF-347833 and fdtered to obtain the culture extract that is diluted with an equal volume of water and applied to a Diaion SP 850 column (5 L, Mitsubishi Chemical Corporation, Tokyo, Japan). The column is eluted with 40% acetone, and the eluate (32.5 L) is diluted with two volumes of water and applied to a Daisogel SP- 120-ODS-B column (15 / 30 pm, 8 1; OSAKA SODA Co., LTD, Osaka, Japan) and eluted with 30% CHUN. The eluate of 4 L (the latter half of 8.8 L) is then diluted with an equal volume of water and applied to a Daisogel SP-120-ODS-B column (1 L OSAKA SODA Co., Ltd) and eluted with MeOH and acetone. The eluate is concentrated under reduced pressure, lyophilized and crystallized using MeOH, ethyl acetate and N-hexane to obtain the compound of formula (I) complexed with an Al ion.

[0093] The compound of formula (lb) (complexed with a Fe ion) or compound of formula (Ic) (complexed with a Ga ion) may be prepared by first making the compound of formula (I) without a complexing ion as follows: An equal volume of acetone is added to a culture broth of Acremonium sp. MF- 347833 which is then filtered to obtain the culture extract. The filtrate is diluted twofold with water and applied to a Diaion SP 850 column (400 mL; Mitsubishi Chemical Corporation) and then eluted with 30% acetone. The eluate (1.9 L) is diluted with water (2. 1 L) water, applied to a Daisogel SP- 120-ODS-B column (15 / 30 pm; size, 350 mL; DAISO) and eluted with 25% CHUN (340 mL). The eluate is diluted with an equal volume of water and applied to an OASIS HLB cartridge (6 g, Waters, Tokyo, Japan), and eluted with MeOH (150 mL). The eluate is concentrated under reduced pressure, and acetone added to the concentrate to obtain a precipitate that is dried to a yellow powder (100 mg). A small volume of MeOH is used to dissolve the precipitate, and the solution is loaded onto a preparative HPLC (Symmetry 7-pm C18 column, 19* 300 mm; Waters) and eluted at 7mL.min1with 27% CH3CN containing 0.05% TFA. The peak that elutes at ~22 min is collected, mixed with an equal volume of water and applied to an OASIS HUB cartridge (size: 500 mg). Water (50 mb) is passed through the cartridge and then eluted using MeOH (50 mb). This eluate is concentrated under reduced pressure, and acetone added to the concentrate to obtain a precipitate that is dried to yield a white powder. The compound of formula (I) without complexing ion is dissolved in MeOH (0.2 mb) and water (0.2 mb), mixed with an aqueous solution (0.6 mb) of FeChe6H2O (5 mg) and stirred for 2.25 h at room temperature. Water is added, and the solution applied to an OASIS HUB cartridge (30 mg, Waters). Water (3 mb) is passed through the cartridge, and the desired compound is eluted from the cartridge with MeOH (2 mb). The resulting eluate is concentrated under reduced pressure and dried to obtain the compound of formula (lb) as an orange powder. Similarly, the compound of formula (Ic) can be obtained as a white powder by replacing FeChe6H2O for Ga2(SO4)3*nH2O

[0094] In some embodiments the compound of formula (I) is used as the free base (complexed with M(III)). In other embodiments the compound of formula (I) is used as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compound of formula (I) may be acid addition salts. Salts are formed e.g., with organic or inorganic acids from compounds of formula (I). Pharmaceutically acceptable salts are within the common general knowledge of the person skilled in the art (see e.g., U.S. Patent No. 8,598,115). Pharmaceutically acceptable salts may include more than one molecule or ion of the corresponding acid.

[0095] All embodiments (unless indicated otherwise) include all possible solvates and complexes (including hydrates) thereof as well as any polymorphs and amorphous solids of the compound of formula (I) and its pharmaceutically acceptable salts.

[0096] Azole-based antifungal agents

[0097] All triazole-based antifungal agents have a 1,2,4-triazole ring within their chemical structure. Their common mechanism of action is inhibition of the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14- alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function. Mammalian cell demethylation is less sensitive to triazole inhibition (Cresemba® prescribing information, FDA). In some embodiments the triazole-based antifungal agent is selected from isavuconazole (e.g., as isavuconazole free base or isavuconazonium), voriconazole, posaconazole, fluconazole, itraconazole, and opelconazole. In some embodiments the triazole-based antifungal agent is selected from isavuconazole (e.g., as isavuconazole free base or isavuconazonium), voriconazole and posaconazole. In some embodiments the triazole-based antifungal agent is selected from isavuconazole (e.g., as isavuconazole free base or isavuconazonium) and voriconazole. In some embodiments the triazole- based antifungal agent is not posaconazole.

[0098] In some embodiments the triazole-based antifungal agent is isavuconazole (e.g., as isavuconazole free base or isavuconazonium).

[0099] In some embodiments the triazole-based antifungal agent is isavuconazole free base.

[0100] In some embodiments the triazole-based antifungal agent is isavuconazonium.

[0101] In some embodiments the triazole-based antifungal agent is voriconazole.

[0102] In some embodiments the triazole-based antifungal agent is posaconazole.

[0103] In some embodiments the triazole-based antifungal agent is fluconazole.

[0104] In some embodiments the triazole-based antifungal agent is itraconazole.

[0105] In some embodiments the triazole-based antifungal agent is opelconazole.

[0106] The triazole-based antifungal agent is preferably isavuconazole, e.g., as isavuconazole free base or isavuconazonium, such as isavuconazonium sulfate.

[0107] Isavuconazole as the free base has the following chemical structure:

[0108] The chemical abstracts registry number is 241479-67-4.

[0109] Isavuconazonium has the following chemical structure: wherein X- is a pharmaceutically acceptable anion, usually sulfate.

[0110] The chemical abstracts registry number of isavuconazonium is 742049-41-8.

[0111] The chemical abstracts registry number of isavuconazonium sulfate is 946075-13-4.

[0112] Reference herein to "isavuconazole" refers to isavuconazole free base and isavuconazonium, wherein X- is a pharmaceutically acceptable anion, usually sulfate.

[0113] Voriconazole has the following chemical structure:

[0114] The chemical abstracts registry number of voriconazole is 137234-62-9.

[0115] Posaconazole has the following chemical structure:

[0116] The chemical abstracts registry number of posaconazole is 171228-49-2.

[0117] Fluconazole has the following chemical structure:

[0118] The chemical abstracts registry number is 86386-73-4.

[0119] Itraconazole has the following chemical structure:

[0120] The chemical abstracts registry number is 84625-61-6.

[0121] Opelconazole has the following chemical structure:

[0122] The chemical abstracts registry number is 1931946-73-4.

[0123] Isavuconazole (as isavuconazonium sulfate) is marketed under the brand name CRESEMBA®.

[0124] Voriconazole is marketed under the brand name VFEND®. Posaconazole is marketed under the brand name NOXAFIL®. Fluconazole is marketed under the brand name DIFLUCAN®. Itraconazole is marketed in the United States under the brand name SPORANOX®.

[0125] Fungal infections

[0126] In some embodiments the combinations described herein are for preventing a fungal infection. In some embodiments the combinations described herein are for prophylaxis of a fungal infection. In some embodiments the combinations described herein are for treating a fungal infection. In some embodiments the subject will already be displaying symptoms of the fungal infection and / or will have been diagnosed as having the fungal infection by a medical practitioner. In some embodiments the combinations described herein are for empiric treatment of a fungal infection. In some embodiments the combinations described herein are for pre-emptive treatment of a fungal infection. In some embodiments the combinations described herein are for targeted treatment of a fungal infection.

[0127] The fungal infection to be prevented or treated by the combinations described herein is caused by pathogenic fungi. Pathogenic fungi which may be treated by the combinations described herein in view of the reported spectrum of activity of the respective therapeutic agents include the genus Candida (examples include C. glabrata, C. kefyr, C. guilliermondii, C. parapsilosis, and C. auris), the genus Cryptococcus (an example is C. neoformans), the genus Trichosporon (an example is T. asahii), the genus Aspergillus (examples include A. fumigatus., A. flavus, A. terreus, A. lentulus, A. udagawae, A. nidulans, A. versicolor and A. niger), the genus Fusarium (an example is F. solani), the genus Mucor (examples include M. circinelloides, M, ramosissimus, M. indicus, M. rasemosus, and M. piriformis), the genus Rhizopus (an example is Rhizopus arrhizus), the genus Blastomyces, the genus Rhodotorula, the genus Exophiala (including Exophiala dermatitidis), the genus Paecilomyces (including Paecilomyces variotii), the genus Sporothrix (including Sporothrix schenckii), the genus Altenaria, the genus Curvularia, the genus Exserohilum, the genus Histoplasma, the genus Emergomyces, the genus Microsporum, the genus Coccidioides, the genus Penicillium, the genus Pichia, the genus Rhinocladiella, the genus Cladophialophora, the genus Dipodascus, the genus Epidermophyton, the genus Fonsecaea, the genus Scedosporium, the genus Apophysomyces, the genus Saksenaea, the genus Ochronis, the genus Paracoccidioides, and the genus Syncephalastrum.

[0128] In some embodiments the fungal infection to be prevented or treated is one caused by a pathogen treatable by the compound of formula (la) or by isavuconazole as single agents, in view of their reported spectra of activities. These include fungi from the genus Aspergillus (e.g., Aspergillus fumigatus, Aspergillus terreus, Aspergillus lentulus, Aspergillus udagawae, Aspergillus niger, Aspergillus nidulans, Aspergillus flavus, Aspergillus versicolor, Aspergillus calidoustus, Aspergillus clavatus, Aspergillus glaucus, Aspergillus oryzae, Aspergillus sydowii and Aspergillus ustus) and from the genus Mucor (e.g.. M. circinelloides, M, ramosissimus, M. indicus, M. rasemosus, M. piriformis, Rhizopus spp., Absidia spp., Cunninghamella spp. Lichtheimia spp. and Rhizomucor spp.) as well as Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, Candida kefyr, Candida guilliermondii, Candida auris, Candida parapsilosis, Fusarium solani, Fusarium oxysporum, Trichosporon spp., Trichophyton spp., Microsporum spp., Penicillium spp., Pichia spp., Rhinocladiella spp., Cryptococcus neoformans, Cryptococcus gattii, Exophiala dermatitidis, Paecilomyces variotii, Sporothrix spp., Blastomyces spp., Histoplasma spp., Emergomyces spp., Coccidioides spp., Cladophialophora spp., Dipodascus spp., Epidermophyton spp., Exophialia spp., Fonsecaea spp., Scedosporium spp. Rhodotorula spp. Apophysomyces spp., Saksenaea spp., Verruconis gallopava, Paracoccidioides spp., and Syncephalastrum spp. as well as fungi from the genera Altenaria, Curvularia, and Exserohilum.

[0129] In some embodiments the fungal infection to be prevented or treated is caused by a fungal pathogen selected from the genera Aspergillus, Candida, Fusarium and Mucor. In some embodiments the fungal infection is caused by a fungal pathogen selected from the genera Aspergillus and Candida. In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus. In some embodiments the fungal pathogen causing the fungal infection is selected from A. fumigatus, A. flavus, A. terreus and A. niger. In some embodiments the fungal infection is caused by a fungal pathogen selected from the genus Candida. In some embodiments the fungal infection is caused by a fungal pathogen selected from the genus Fusarium. In some embodiments the fungal infection is caused by a fungal pathogen selected from the genus Mucor. In some embodiments the fungal infection is invasive aspergillosis. In some embodiments the fungal infection is invasive candidiasis. In some embodiments the fungal infection is fusariosis. In some embodiments the fungal infection is mucormycosis.

[0130] In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal infection is caused by a fungal pathogen from the genus Aspergillus. In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal pathogen causing the fungal infection is A. fumigatus, A. flavus, A. terreus, or A. niger. In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal pathogen causing the fungal infection is A. fumigatus. In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal pathogen causing the fungal infection is A. flavus. In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal pathogen causing the fungal infection is A. terreus. In some embodiments the triazole-based antifungal agent is isavuconazole and the fungal pathogen causing the fungal infection is A. niger.

[0131] In some embodiments the triazole-based antifungal agent is voriconazole and the fungal infection is caused by a fungal pathogen from the genus Aspergillus. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. fumigatus, A. flavus, A. terreus, or A. niger. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. flavus, A. terreus, or A. niger. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. fumigatus. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. flavus. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. terreus. In some embodiments the triazole-based antifungal agent is voriconazole and the fungal pathogen causing the fungal infection is A. niger.

[0132] In some embodiments the triazole-based antifungal agent is posaconazole and the fungal infection is caused by a fungal pathogen from the genus Aspergillus. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. fumigatus, A. flavus, A. terreus, or A. niger. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. flavus, A. terreus, or A. niger. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. fumigatus. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. flavus. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. terreus. In some embodiments the triazole-based antifungal agent is posaconazole and the fungal pathogen causing the fungal infection is A. niger.

[0133] In some embodiments the fungal infection to be prevented or treated is a fungal disease. In some embodiments the fungal infection to be prevented or treated is an invasive fungal disease. In some embodiments, the fungal infection to be prevented or treated is a systemic fungal disease.

[0134] In some embodiments the fungal infection to be prevented or treated is refractory to the triazole-based antifungal agent being used. In some embodiments the fungal infection to be prevented or treated is refractory to isavuconazole. In some embodiments the fungal infection to be prevented or treated is refractory to voriconazole. In some embodiments the fungal infection to be prevented or treated is refractory to posaconazole.

[0135] In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to the triazole-based antifungal agent being used. In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to isavuconazole. In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to voriconazole. In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to posaconazole.

[0136] In some embodiments the fungal infection is refractory to the compound of formula (I). In some embodiments the fungal infection is refractory to the compound of formula (I) and to the triazole- based antifungal agent being used, when not used in combination.

[0137] In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to the compound of formula (I). In some embodiments the fungal infection is caused by a fungal pathogen from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is refractory to the triazole-based antifungal agent being used and to the compound of formula (I), when not used in combination. In some embodiments the fungal pathogen causing the fungal infection is resistant to the compound of formula (I). In some embodiments the fungal pathogen causing the fungal infection is resistant to the triazole-based antifungal agent being used. In some embodiments the fungal pathogen causing the fungal infection is resistant to isavuconazole. In some embodiments the fungal pathogen causing the fungal infection is resistant to voriconazole. In some embodiments the fungal pathogen causing the fungal infection to be treated is resistant to posaconazole.

[0138] In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. terreus, or A. niger) and is resistant to the compound of formula (I). In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. terreus, or A. niger) and is resistant to the compound of formula (I) and to the compound of formula (I), when not used in combination.

[0139] In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is resistant to the triazole-based antifungal agent being used. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is resistant to isavuconazole. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is resistant to voriconazole. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g,., A. fumigatus, A. flavus, A. terreus, or A. niger) and is resistant to posaconazole.

[0140] A fungal pathogen which is resistant to a triazole-based antifungal agent means that there is a high likelihood of therapeutic failure using a standard dosing regimen of that triazole-based antifungal agent. Whether or not the likelihood of therapeutic failure is high can be assessed by a relevant medical practitioner.

[0141] Whether or not a fungal pathogen or fungal infection is resistant to a triazole-based antifungal agent may be determined by reference to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint (“breakpoint”) value for that fungal pathogen (EUCAST Breakpoint tables for interpretation of MICs for antifungal agents, Version 13.1, valid from 2023-06-29). See also below for specific resistance breakpoint values. If the fungal pathogen has an MIC which is higher than the resistance breakpoint for the triazole-based antifungal agent then the fungal pathogen may be considered resistant. If there is no EUCAST breakpoint value available then reference may be made to the EUCAST epidemiological cut-off value (ECOFF), Data from the EUCAST MIC distribution website, November 2023. http: / / www.eucast.org. If the fungal pathogen has an MIC which is higher than the EUCAST ECOFF value for the triazole-based antifungal agent then the fungal pathogen may be considered resistant. If there is no EUCAST ECOFF value available then reference may be made to the Clinical and Laboratory Standards Institute (CLSI) ECOFF value, CLSI, Epidemiological Cutoff Values for Antifungal Susceptibility Testing. 4th ed. CLSI supplement M57S, Clinical and Laboratory Standards Institute; 2022. If the fungal pathogen has an MIC which is higher than the CLSI ECOFF value for the triazole-based antifungal agent then the fungal pathogen may be considered resistant.

[0142] In some embodiments the fungal pathogen causing the fungal infection is susceptible to the triazole- based antifungal agent being used. In some embodiments the fungal pathogen causing the fungal infection is susceptible to isavuconazole. In some embodiments the fungal pathogen causing the fungal infection is susceptible to voriconazole. In some embodiments the fungal pathogen causing the fungal infection is susceptible to posaconazole.

[0143] In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is susceptible to the triazole-based antifungal agent being used. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is susceptible to isavuconazole. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is susceptible to voriconazole. In some embodiments the fungal pathogen causing the fungal infection is from the genus Aspergillus (e.g., A. fumigatus, A. flavus, A. ierreus. or A. niger) and is susceptible to posaconazole.

[0144] Whether or not a fungal pathogen or fungal infection is susceptible to a triazole-based antifungal agent may be determined by reference to the EUCAST breakpoint value for that fungal pathogen (EUCAST Breakpoint tables for interpretation of MICs for antifungal agents, Version 13.1, valid from 2023-06-29). See also below for specific susceptibility breakpoint values. If the fungal pathogen has an MIC which is lower than or equal to the resistance breakpoint for the triazole-based antifungal agent then the fungal pathogen may be considered susceptible. If there is no EUCAST breakpoint value available then reference may be made to the ECOFF, Data from the EUCAST MIC distribution website, November 2023. http: / / www.eucast.org. If the fungal pathogen has an MIC which is lower than or equal to the EUCAST ECOFF value for the triazole-based antifungal agent then the fungal pathogen may be considered susceptible. If there is no EUCAST ECOFF value available then reference may be made to the CLSI ECOFF value, CLSI, Epidemiological Cutoff Values for Antifungal Susceptibility Testing. 4th ed. CLSI supplement M57S, Clinical and Laboratory Standards Institute; 2022. If the fungal pathogen has an MIC which is lower than or equal to the CLSI ECOFF value for the triazole-based antifungal agent then the fungal pathogen may be considered susceptible.

[0145] For determination of resistance and / or susceptibility the MIC of the fungal pathogen should be measured according to the guidelines provided by EUCAST or CLSI respectively. In some embodiments determining whether a fungal pathogen is resistant or susceptible to a triazole-based antifungal agent includes determining the MIC of the triazole-based antifungal agent for the fungal pathogen, e.g., by obtaining the MIC of a clinical isolate taken from the subject.

[0146] In some embodiments the methods described herein include a step of diagnosing whether the fungal pathogen can be optimally treatable by the combinations described herein. A sample containing the fungal pathogen may be taken from the subject and the susceptibility of the fungal pathogen to the respective combination may be determined, e.g., by contacting in vitro the fungal pathogen with a compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent using standard techniques. The results of the analysis would then assist a physician decide whether to treat a subject with the combinations provided herein.

[0147] In some embodiments administration of the combination reduces the dose of a triazole-based antifungal agent needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen. In other words, a lower dose of the triazole-based antifungal agent is needed when administered in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof to achieve the same reduction of colony forming units when administered alone. Likewise, in some embodiments administration of the combination reduces the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen. In other words, a lower dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is needed when administered in combination with the triazole-based fungal agent to achieve the same reduction of colony forming units when administered alone.

[0148] The reduction in colony forming units can be determined by taking a sample from the subject prior to treatment and after treatment with the combination and comparing the reduction in colony forming units to the reduction in colony forming units before and after treatment in a subject infected with the same fungal pathogen with one of the therapeutic agents alone. Measurement of the number of colony forming units can be performed according to standard techniques known by a person skilled in the art, e.g., by spreading a sample on an agar plate, allowing to dry and manually counting the number of colonies. Such comparisons will generally be performed on animal infection models or in clinical trials. In some embodiments the combinations described herein are used to prevent or treat a fungal infection caused by a fungal pathogen against which the compound of formula (I) and / or the triazole-based antifungal agent is known to be active as described below. In some embodiments the combinations described herein are used to prevent or treat a fungal infection for which the triazole-based antifungal agent has been approved by the FDA and / or by the EMA as described below.

[0149] Compound of formula (I)

[0150] In vitro the compound of formula (la) has been shown to be active against Aspergillus fumigaius. Aspergillus ierreus. Aspergillus lentulus, Aspergillus udagawae. Aspergillus niger. Aspergillus nidulans. Aspergillus flavus. Aspergillus versicolor, Candida glabrata, Candida kefyr. Candida guilliermondii, Candida auris, Candida parapsilosis. Fusarium solani, Trichosporon asahii. Cryptococcus neoformans. Exophiala dermaiiiidis. Paecilomyces varioiii. Sporothrix schenckii. Blastomyces spp., Histoplasma spp., Emergomyces spp. as well as fungi from the genera Alienaria. Curvularia. and Exserohilum (Shaw, Nakamura et al. (a) and Nakamura et al.(b), Nakamura et al. (c)), internal information).

[0151] In vivo the compound of formula (la) has been shown to be active in murine models of invasive pulmonary aspergillosis including azole susceptible, azole-refractory and azole resistant A. fumigatus models, and also in disseminated aspergillosis models. The compound of formula (la) has also been shown to be active in disseminated models of invasive candidiasis caused by both wild-type and multi drug-resistant C. glabrata (Shaw, Nakamura et al. (c)).

[0152] The compound of formula (la) has also been the subject of a phase 2 clinical trial (NCT03327727) entitled "A Phase 2 Study of VL-2397 Compared to Standard First-Line Treatment for Invasive Aspergillosis in Adults with Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, or Allogeneic Hematopoietic Cell Transplant Recipients".

[0153] Isavuconazole

[0154] In the United States isavuconazole is indicated for the treatment of invasive aspergillosis and invasive mucormycosis (FDA isavuconazole Labeling-Package Insert, 2022). In the European Union isavuconazole is indicated for the treatment of invasive aspergillosis and mucormycosis in patients for whom amphotericin B is inappropriate (EMA, Annex I, Summary of Product Characteristics, Cresemba, 2023).

[0155] In addition, isavuconazole appears to have in vitro activity against all Candida species, with activity against most Candida species comparable to that of voriconazole and posaconazole. It has also shown in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. It appears to have potent in vitro activity against the most common Aspergillus species as well as hyaline molds, such as Paecilomyces lilacinus and Scedosporium apiospermum. Additionally, isavuconazole has activity against many dermatophytes. In vitro studies with isavuconazole show that this drug is active against many genera of Mucoraceae, although the MICs vary widely within any given genera (Micel et al.).

[0156] The isavuconazole EUCAST breakpoints are as follows (S = susceptible; R = resistant): Aspergillus flavus S ≤1 mg / L, R >2 mg / L; Aspergillus fumigatus S ≤1 mg / L, R >2 mg / L; Aspergillus nidulans S ≤0.25 mg / L, R >0.25 mg / L; Aspergillus terreus S ≤1 mg / L, R >1 mg / L.

[0157] Voriconazole

[0158] In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition, voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents. In vitro activity of voriconazole against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 pg / mL. In vitro activity of voriconazole against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp. (EMA, Annex I, Summary of Product Characteristics, VLEND, 2023).

[0159] Clinical efficacy of voriconazole defined as partial or complete response, has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including .S'. apiospermum, S. proliflcans; and Fusarium spp. Other treated fungal infections by voriconazole (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including ?, marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections. (EMA, Annex I, Summary of Product Characteristics, VLEND, 2023).

[0160] The voriconazole EUCAST breakpoints are as follows (S = susceptible; R = resistant): Candida albicans S ≤0.06 mg / L, R >0.25 mg / L; Candida dubliniensis S ≤0.06 mg / L, R >0.25 mg / L; Candida parapsilosis S ≤0.125 mg / L, R >0.25 mg / L; Candida tropicalis S ≤0.125 mg / L, R >0.25 mg / L (EMA, Annex I, Summary of Product Characteristics, VFEND, 2023).

[0161] Posaconazole

[0162] In the United States posaconazole is indicated for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections, oropharyngeal candidiasis and oropharyngeal candidiasis refractory to itraconazole and / or fluconazole (FDA posaconazole Labelling-Package Insert, 2022).

[0163] Posaconazole is indicated in the European Union for treatment of invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products; fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products; and oropharyngeal candidiasis as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor. Posaconazole is also indicated in the European Union for prophylaxis of invasive fungal infections in the following patients: patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high- risk of developing invasive fungal infections; and hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high-risk of developing invasive fungal infections (EMA, Annex I, Summary of Product Characteristics, Noxafil, 2023).

[0164] Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fiimigaius. A. flavus, A. ierreus. A. nidtdans. A. niger. A. ustus\ Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudoiropicaUs)'. Coccidioides immitis, Fonsecaea pedrosoi. and species of Fusarium, Rhizomucor. Mucor. and Rhizopus. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor. and Rhizopus; however, the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents (EMA, Annex I, Summary of Product Characteristics, Noxafil, 2023).

[0165] The posaconazole EUCAST breakpoints are as follows (S = susceptible; R = resistant): Candida albicans; S ≤0.06 mg / L, R >0.06 mg / L; Candida tropicalis; S ≤0.06 mg / L, R >0.06 mg / L; Candida parapsilosis; S ≤0.06 mg / L, R >0.06 mg / L; Candida dubliniensis; S ≤0.06 mg / L, R > 0.06 mg / L (EMA, Annex I, Summary of Product Characteristics, Noxafd, 2023)

[0166] Fluconazole

[0167] In the United States fluconazole is indicated for the treatment of vaginal candidiasis (vaginal yeast infections due to Candida); oropharyngeal and esophageal candidiasis (the indicates and usage statements also mention that fluconazole was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia); and Cryptococcal meningitis. Fluconazole is also indicated under prophylaxis to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and / or radiation therapy (FDA Fluconazole Labelling-Package Insert, 2023).

[0168] Fluconazole is indicated in the European Union for the treatment of cryptococcal meningitis; coccidioidomycosis; invasive candidiasis, mucosal candidiasis including oropharyngeal candidiasis, oesophageal candidiasis, candiduria and chronic mucocutaneous candidiasis; chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are insufficient; vaginal candidiasis, acute or recurrent when local therapy is not appropriate; candidal balanitis when local therapy is not appropriate; dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections when systemic therapy is indicated; and tinea unguinium (onychomycosis) when other agents are not considered appropriate. Fluconazole is also indicated for the prophylaxis of: relapse of cryptococcal meningitis in patients with high risk of recurrence; relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at high risk of experiencing relapse; to reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year); and prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with hematological malignancies receiving chemotherapy or patients receiving hematopoietic stem cell transplantation (EMA, Annex III, Summary of Product Characteristics, Labelling and Package Leaflet, Diflucan, 2012).

[0169] Fluconazole has also been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections; Candida albicans, Candida glabrata (many isolates are intermediately susceptible), Candida parapsilosis, Candida tropicalis, and Cryptococcus neoformans (FDA Fluconazole Labelling-Package Insert, 2023).

[0170] The fluconazole EUCAST breakpoints are as follows (S = susceptible; R = resistant): Candida albicans; S ≤2 mg / L, R >4 mg / L; Candida parapsilosis; S ≤2 mg / L, R >4 mg / L; Candida tropicalis; S ≤2 mg / L, R > 4 mg / L, non-species related breakpoints (for use only for organisms that do not have specific breakpoints): S ≤2 mg / L, R > 4 mg / L (EMA, Annex III, Summary of Product Characteristics, Labelling and Package Leaflet, Diflucan, 2012).

[0171] Itraconazole

[0172] In the United States itraconazole as capsules is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: blastomycosis, pulmonary and extrapulmonary; histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis; and aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Itraconazole as capsules is also indicated for the treatment of the following fungal infections in non-immunocompromised patients for onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and onychomycosis of the fingernail due to dermatophytes (tinea unguium). Itraconazole as oral solution is indicated for the treatment of oropharyngeal and oesophageal candidiasis (FDA itraconazole Labelling-Package Insert, 2023).

[0173] Opelconazole

[0174] Opelconazole is currently undergoing a clinical phase 2 study to evaluate its safety and tolerability for the prevention of fungal Aspergillus infections in the lung in participants who have received a lung transplant (NCT05037851). It is disclosed for example, in WO 2016 / 087878.

[0175] Administration

[0176] The compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are administered to a subject as a combination therapy. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner as well as use of each type of therapeutic agent in a sequential manner (e.g., according to different administration routes), either at approximately the same time or at different times, e.g., according to different dosage regimens, examples of which are described herein. When the therapeutic agents are administered sequentially the dosing schedules will be such that there is intentionally a therapeutic interaction between the therapeutic agents within the subject’s body and / or that a therapeutic effect resulting from the first therapeutic agent is present when the second therapeutic agent is administered.

[0177] For example, in some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent may be administered simultaneously (e.g., as fixed combination), consecutively, within one hour of each other, within 12 hours, or within 24 hours etc. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are administered to a subject on the same day. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are each administered according to a recurring treatment schedule and the two treatment schedules overlap. In such a situation, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at least once before and after the triazole-based antifungal agent and / or vice versa. Usually, the recurring treatment schedule for the two agents will start on the same day. Usually, a recurring treatment schedule will comprise at least daily administration, optionally with a loading dose (see below).

[0178] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are each administered to the subject according to treatment schedules which overlap by at least one week, e.g., by at least two weeks, e.g., by at least three weeks, e.g., by at least four weeks. In the period of overlap the subject will be receiving recurring doses of both the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent.

[0179] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are each administered to the subject daily, wherein the patient receives both the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent on at least one day, e.g., on at least 3 days, e.g., on at least 7 days, e.g., on at least 14 days, e.g., on at least 28 days. In some embodiments the patient receives both the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent daily and on the same day, e.g., for at least 7 consecutive days, e.g., at least 14 consecutive days, e.g., for at least 21 consecutive days, e.g., for at least 28 consecutive days, and may be continued as long as deemed necessary e.g., up to 180 days, e.g., up to 90 days, e.g., up to 48 days.

[0180] The administration of the pharmaceutical combinations described herein may result not only in a beneficial effect, e.g., a synergistic effect, such as with regard to reducing, alleviating, delaying progression of or inhibiting the symptoms of the fungal infection, but may also result in further beneficial effects, e.g., fewer side-effects or a more durable therapeutic effect, compared with a monotherapy applying only one of the pharmaceutically therapeutic agents used in the combinations described herein. It may also be the case that lower doses of the therapeutic agents of the combinations described herein can be used, for example, such that the dosages may not only often be smaller, but also may be applied less frequently, or can be used in order to diminish the incidence of side-effects observed with one of the combination partners alone. It may also be the case that the combination can be used to treat a fungal infection which is refractory and / or resistant to one of the therapeutic agents in the combination, e.g., use of the combination results in a higher efficacy against the fungal pathogen (which is refractory and / or resistant to one of the single agents) compared to when the other therapeutic agent (to which the fungal pathogen is not refractory and / or resistant) is used alone.

[0181] In some embodiments, the combination provided herein may display a synergistic effect. The term "synergistic effect" as used herein, refers to action of the two agents, namely the compound of formula (I) or a pharmaceutically acceptable salt thereof and a triazole-based antifungal agent, to produce a therapeutic effect, e.g., a reduction in the severity of the fungal infection or symptoms thereof, which is greater than the addition of the same therapeutic effect of each drug administered on its own. Generally, in determining a synergistic interaction between two therapeutic agents, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w / w ratio ranges and doses to subjects (e.g., patients) in need of treatment. For humans, the complexity and cost of carrying out clinical studies on patients may render impractical the use of this form of testing as a primary model for synergy. However, the observation of synergy in certain experiments, in vitro or in vivo can be predictive of the effect in other species, and animal models may be used to further quantify a synergistic effect. The results of such studies can also be used to predict effective dose ratio ranges and the absolute doses and plasma concentrations, e.g., as illustrated in the Examples below. In some embodiments synergy is determined in vitro by measuring the fractional inhibitory concentration index and using that value as a determinator of synergy, as described in the Examples.

[0182] Further embodiments, provide a synergistic pharmaceutical combination for administration to a subject comprising the pharmaceutical combination as described herein, where the dose range of each component corresponds to the synergistic ranges, e.g., as indicated in a suitable infection model or clinical study.

[0183] Compound of formula (I)

[0184] In the phase 2 clinical trial entitled A Phase 2 Study of the ASP2397 Compared to Standard First-Line Treatment for Invasive Aspergillosis in Adults with Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, or Allogeneic Hematopoietic Cell Transplant Recipients) (NCT03327727) 600 mg compound of formula (la) was administered by i.v. infusion every day for 28 days (4 weeks), followed by 2 weeks of standard treatment (voriconazole, isavuconazole, or liposomal-amphotericin B). Active comparator consisted of standard treatments of voriconazole, isavuconazole, or liposomal amphotericin B administered every day for 42 days (6 weeks). For the avoidance of any doubt, the administration of compound of formula (la) followed by standard treatment is not regarded as a combination therapy of the compound of formula (la) with the standard treatment. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 500 mg to 700 mg of the compound of formula (la).

[0185] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la).

[0186] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of at least 300 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of at least 500 mg of the compound of formula (la).

[0187] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of no more than 1200 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of no more than 900 mg of the compound of formula (la).

[0188] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la). In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0189] The compound of formula (I) or a pharmaceutically acceptable salt thereof will usually be for daily administration for a duration to be determined by a physician, e.g., for at least 7 days, e.g., up to 28 days, but in some cases may be longer, e.g., up to 180 days, e.g., up to 90 days, e.g., up to 48 days.

[0190] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of about 600 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days, and may be continued as long as deemed necessary e.g., up to 180 days, e.g., up to 90 days, e.g., up to 48 days.

[0191] In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a daily dose which is the mole equivalent of about 900 mg of the compound of formula (la), e.g., for at least 7 days, e.g., up to 28 days, and may be continued as long as deemed necessary e.g., up to 180 days, e.g., up to 90 days, e.g., up to 48 days.

[0192] In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 600 mg of the compound of formula (la) once daily.

[0193] In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 900 mg the compound of formula (la) once daily.

[0194] In some embodiments the dosage regimen of the compound of formula (I) or a pharmaceutically acceptable salt thereof includes a loading dose. The loading dose will usually be several of the daily (maintenance) doses administered at regular intervals during e.g., the first 24 to 48 hours from the start of administration. In some embodiments the loading dose is administered during the first 24 hours from the start of administration and is 2 to 3 of the daily (maintenance) doses administered at regular intervals, e.g., 1 dose every 12 hours (2 doses in 24 hours) or 1 dose every 8 hours (3 doses in 24 hours). In some embodiments the loading dose is administered during the first 48 hours from the start of administration and is 4 to 6 of the daily (maintenance) doses administered at regular intervals, e.g., 1 dose every 12 hours (4 doses in 48 hours) or 1 dose every 8 hours (6 doses in 48 hours).

[0195] In some embodiments a loading dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered with the same frequency and for the same duration of the loading dose of the respective triazole-based antifungal agent. For example, when the triazole-based antifungal agent is isavuconazole (e.g., as isavuconazole free base or isavuconazonium) a loading dose of the compound of formula (I) may be administered to the patient with a frequency according to the approved loading dose of isavuconazole, namely every 8 hours for 6 doses (48 hours), which is then followed by a maintenance dosing schedule. In other embodiments the loading dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof and triazole based fungal agent is administered with the same frequency and for the same duration of the loading dose but for a shorter duration or administered less frequently compared to the approved loading dose of the triazole based fungal agent, e.g., the duration may be up to 50% less and / or the frequency may be up to 50% less versus the approved loading dose.

[0196] For example, when the triazole-based antifungal agent is isavuconazole (e.g., as isavuconazole free base or isavuconazonium) a loading dose of the compound of formula (I) and isavuconazole may be administered to the patient every 8 hours for 3 doses (24 hours), which is then followed by a maintenance dosing schedule, or may be administered to the patient every 12 hours for 4 doses (48 hours), which is then followed by a maintenance dosing schedule.

[0197] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0198] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0199] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0200] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0201] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0202] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0203] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0204] In some embodiments the compound of formula (I) is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily. In some embodiments the compound of formula (I) is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0205] The doses described above for the compound of formula (I) or a pharmaceutically acceptable salt thereof apply to adult human subjects. If administration is to pediatric subjects or animal subjects, the dose should be reduced appropriately.

[0206] Isavuconazole

[0207] According to the FDA isavuconazole Labelling-Package Insert, 2022 and EMA, Annex I, Summary of Product Characteristics, Cresemba, 2023, isavuconazole is administered as a loading dose of 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole free base) every 8 hours for 6 doses (48 hours) via oral or intravenous administration, followed by a maintenance dose of 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole free base) once daily via oral or intravenous administration starting 12 to 24 hours after the last loading dose.

[0208] Accordingly, in some embodiments isavuconazole (as isavuconazole free base or isavuconazonium sulfate) is administered to a patient as per the approved dosage regimen, namely as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily (referred to below as the "approved dose" below).

[0209] In some embodiments the dose of isavuconazole (as isavuconazole free base or isavuconazonium sulfate) administered to patients may be less than the approved dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the loading dose and maintenance doses may be 50% to 100% of the above approved dose for single-agent administration, e.g., 75% to 100% of the approved dose for single-agent administration. For example, the loading dose and maintenance doses may be no lower than 50% of the above approved dose for single-agent administration, e.g., no lower than 75% of the approved dose for single-agent administration.

[0210] In some embodiments isavuconazole as free base or isavuconazonium sulfate is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0211] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0212] In some embodiments isavuconazole as free base or isavuconazonium sulfate is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la).

[0213] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0214] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0215] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la). In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0216] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily.

[0217] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily.

[0218] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0219] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily.

[0220] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily.

[0221] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily. In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily.

[0222] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily.

[0223] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0224] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la) once daily.

[0225] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la) once daily.

[0226] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 600 mg of the compound of formula (la) once daily.

[0227] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily.

[0228] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily.

[0229] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily. In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily.

[0230] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily.

[0231] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0232] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily.

[0233] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily.

[0234] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily.

[0235] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily.

[0236] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la) once daily.

[0237] In some embodiments isavuconazole free base or isavuconazonium sulfate is administered to a patient as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (24 hours) followed by a maintenance dose equivalent to 200 mg of isavuconazole free base once daily and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of about 900 mg of the compound of formula (la) once daily. The pharmaceutical combinations described herein may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0238] Embodiments Al to A54 in Table A provide further embodiments of methods of administration of the indicated combinations in which the dosing schedule of both therapeutic agents begin on the same day, as well as further embodiments of the pharmaceutical combinations per se. Embodiments Al to

[0239] A54 may represent administration to a patient as fixed combinations or single-agent medicaments.

[0240] Likewise, embodiments Al to A54 may represent the pharmaceutical combinations as fixed combinations or single-agent dosage forms.

[0241] *Formula (I) or a pharmaceutically acceptable salt thereof / isavuconazole free base or isavuconazonium; **mole equivalent of the given amount of the compound of formula (la); ***single dose daily, optionally with a loading dose wherein the first 48 hours of the dosing schedule includes 6 doses of the given dose and a single dose daily thereafter or wherein the first 24 hours of the dosing schedule includes 3 doses of the given dose and a single dose daily thereafter and may be continued for a long as deemed necessary, e.g., up to 180 days; ****mole equivalent of the given amount of isavuconazole free base;

[0242] *****single daily dose, optionally with a loading dose wherein the first 48 hours of the dosing schedule includes 6 doses of the given dose and a single dose daily thereafter or wherein the first 24 hours of the dosing schedule includes 3 doses of the given dose and a single dose daily thereafter and may be continued for a long as deemed necessary, e.g., up to 180 days.

[0243] The above doses for isavuconazole and compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0244] Voriconazole

[0245] According to the FDA voriconazole Labelling-Package Insert, 2022 voriconazole is administered for the treatment of invasive aspergillosis as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 4 mg / kg every

[0246] 12 hours or oral administration of 200 mg every 12 hours.

[0247] For the treatment of Candidemia in non-neutropenics and other deep tissue Candida infections voriconazole is administered as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3 to 4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours.

[0248] For the treatment of Scedosporiosis and Fusariosis voriconazole is administered as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 4mg / kg every 12 hours or oral administration of 200 mg every 12 hours.

[0249] For the treatment of oesophageal candidiasis voriconazole is administered as an oral maintenance does of 200 mg every 12 hours (loading doses and intravenous maintenance doses have not been evaluated). According to the EMA, Annex I, Summary of Product Characteristics, VFEND, 2023, voriconazole is administered as an intravenous loading dose of 6 mg / kg every 12 hours for 24 hours, followed by an intravenous maintenance dose of 4 mg / kg twice daily or an oral maintenance dose of 200 mg twice daily. Treatment duration should be as short as possible depending on the patient’s clinical and mycological response.

[0250] Accordingly, in some embodiments voriconazole is administered to patients as per the approved dosage regimen, namely as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours (referred to as the "approved dose" below).

[0251] In some embodiments the dose of voriconazole administered to patients may be less than the approved dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the loading dose and maintenance doses may be 50% to 100% of the approved dose for single-agent administration, e.g., 75% to 100% of the approved dose for single- agent administration. For example, the loading dose and maintenance doses may be no lower than 50% of the approved dose for single-agent administration, e.g., no lower than 75% of the approved dose for single-agent administration.

[0252] In some embodiments voriconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0253] In some embodiments voriconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0254] In some embodiments voriconazole is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0255] In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0256] In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0257] In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0258] In some embodiments voriconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la).

[0259] In some embodiments voriconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la).

[0260] In some embodiments voriconazole is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0261] In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la). In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la).

[0262] In some embodiments voriconazole is administered to a patient as an intravenous infusion loading dose of 6 mg / kg every 12 hours for the first 24 hours, followed by a maintenance dose as intravenous infusion of 3-4 mg / kg every 12 hours or oral administration of 200 mg every 12 hours and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0263] The pharmaceutical combinations described above may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0264] The above doses for voriconazole and compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0265] Posaconazole

[0266] According to the FDA posaconazole Labelling-Package Insert, 2022 posaconazole is administered for the treatment of invasive aspergillosis as a loading dose of 300 mg intravenously twice a day on the first day and as a maintenance dose of 300 mg injection intravenously once a day thereafter. The recommended total duration of therapy is 6 to 12 weeks. As a delayed release tablet posaconazole is administered for the treatment of invasive aspergillosis as a loading dose of 300 mg (three 100 mg delayed-re lease tablets) twice a day on the first day, and as a maintenance dose of 300 mg (three 100 mg delayed-release tablets) once a day thereafter. The recommended total duration of therapy is 6 to 12 weeks. Switching between the intravenous and delayed-release tablets is acceptable and a loading dose is not required when switching between formulations.

[0267] Posaconazole is administered for prophylaxis of invasive Aspergillus and Candida infections as a loading dose of 300 mg injection intravenously twice a day on the first day and as a maintenance dose of 300 mg injection intravenously once a day thereafter. The recommended total duration of therapy is based on recovery from neutropenia or immunosuppression. As a delayed release tablet posaconazole is administered for the prophylaxis of invasive Aspergillus and Candida infections as a loading dose of 300 mg twice a day on the first day, and as a maintenance dose of 300 mg once a day thereafter. The recommended duration of therapy is based on recovery from neutropenia or immunosuppression. As an oral suspension posaconazole is administered for prophylaxis of invasive Aspergillus and Candida infections as a dose of 200 mg three times a day with duration of therapy based on recovery from neutropenia or immunosuppression.

[0268] Posaconazole is administered for oropharyngeal candidiasis as an oral suspension with a loading dose of 100 mg twice a day on the first day, and as a maintenance dose of 100 mg once a day for 13 days.

[0269] Posaconazole is administered for oropharyngeal candidiasis refractory to itraconazole and / or fluconazole as an oral suspension 400 mg twice a day with duration of therapy based on the severity of the patient’s underlying disease and clinical response.

[0270] According to the EMA, Annex I, Summary of Product Characteristics, Noxafil (posaconazole), 2023, for the treatment of refractory invasive fungal infections and patients with invasive fungal infections intolerant to 1st line therapy the dose of oral suspension of posaconazole is 200 mg four times a day. Alternatively, patients who can tolerate food or a nutritional supplement may take 400 mg oral suspension twice a day during or immediately following a meal or nutritional supplement. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.

[0271] For the treatment of oropharyngeal candidiasis the loading dose of oral suspension of posaconazole is 200 mg once a day on the first day, then 100 mg once a day for 13 days.

[0272] For the prophylaxis of invasive fungal infections the dose of oral suspension of posaconazole is 200 mg three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukaemia or myelodysplastic syndromes, prophylaxis with oral suspension should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm3.

[0273] For the treatment of invasive aspergillosis the tablet or infusion dose of posaconazole is 300 mg twice a day on the first day then 300 mg once a day thereafter. The recommended duration of therapy is 6 to 12 weeks.

[0274] For the treatment of refractory invasive fungal infections and patients with invasive fungal infections intolerant to 1stline therapy the tablet or infusion dose of posaconazole is 300 mg twice a day on the first day then 300 mg once a day thereafter. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response. For the prophylaxis of invasive fungal infections the tablet or infusion dose of posaconazole is 300 mg twice a day on the first day then 300 mg once a day thereafter. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response. For patients with acute myelogenous leukaemia or myelodysplastic syndromes, prophylaxis administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm3.

[0275] Accordingly, in some embodiments posaconazole is administered to patients as per the approved dosage regimens, which for the treatment of invasive fungal infections is 300 mg twice a day on the first day then 300 mg once a day thereafter (referred to as the "approved dose" below).

[0276] In some embodiments the dose of posaconazole administered to patients may be less than the approved dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the loading dose and maintenance doses may be 50% to 100% of the above approved dose for single-agent administration, e.g., 75% to 100% of the approved dose for single-agent administration. For example, the loading dose and maintenance doses may be no lower than 50% of the above approved dose for single-agent administration, e.g., no lower than 75% of the approved dose for single-agent administration.

[0277] In some embodiments posaconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0278] In some embodiments posaconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0279] In some embodiments posaconazole is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0280] In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0281] In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0282] In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0283] In some embodiments posaconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la).

[0284] In some embodiments posaconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la).

[0285] In some embodiments posaconazole is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0286] In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la).

[0287] In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 800 mg to 1000 mg of the compound of formula (la). In some embodiments posaconazole is administered to a patient at a dose which is 300 mg twice a day on the first day then 300 mg once a day thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 900 mg of the compound of formula (la).

[0288] The pharmaceutical combinations described above may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0289] The above doses for posaconazole and compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0290] Fluconazole

[0291] According to the FDA Fluconazole Labelling-Package Insert, 2023 the recommended dose of fluconazole for the treatment of vaginal candidiasis is 150 mg as a single oral dose.

[0292] For the treatment of oropharyngeal candidiasis the recommended dosage of fluconazole is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis is said to generally resolve within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

[0293] For the treatment of oesophageal candidiasis the recommended dosage of fluconazole tablets is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg / day may be used, based on medical judgment of the patient’s response to therapy. Patients with oesophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.

[0294] For the treatment of systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy are said not to have been established. In open, non-comparative studies of small numbers of patients, doses of up to 400 mg daily of fluconazole have been used.

[0295] For the treatment of Candida urinary tract infections and peritonitis, daily doses of fluconazole of 50 to 200 mg have been used in open, non-comparative studies of small numbers of patients. The recommended dosage of fluconazole for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole tablets for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.

[0296] The recommended daily dosage of fluconazole for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils cells / mm3) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells / mm3.

[0297] According to the EMA, Annex III, Summary of Product Characteristics, Labelling and Package Leaflet, Diflucan (fluconazole), 2012, for the treatment of cryptococcal meningitis the loading dose of fluconazole is 400 mg on day 1, with subsequent doses of 200 mg to 400 mg daily (in life-threatening infections the daily dose can be increased to 800 mg). The duration of treatment is usually at least 6 to 8 weeks. Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with high risk of recurrence is 200 mg daily, continued indefinitely.

[0298] For the treatment of coccidioidomycosis the dose of fluconazole is 200 mg to 400 mg with duration of treatment 11 months up to 24 months or longer depending on the patient. 800 mg daily may be considered for some infections and especially for meningeal disease.

[0299] For the treatment of invasive candidiasis the loading dose of fluconazole is 800 mg on day 1, with subsequent doses of 400 mg daily. In general, the recommended duration of therapy for candidemia is for 2 weeks after first negative blood culture result and resolution of signs and symptoms attributable to candidemia.

[0300] For the treatment of mucosal candidiasis (oropharyngeal candidiasis) the loading dose of fluconazole is 200 mg to 400 mg on day 1 with subsequent doses of 100 mg to 200 mg daily with duration of treatment 7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function.

[0301] For the treatment of mucosal candidiasis (oesophageal candidiasis) the loading dose of fluconazole is 200 mg to 400 mg on day 1 with subsequent doses of 100 mg to 200 mg daily with duration of treatment 14 to 30 days (until oesophageal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function.

[0302] For the treatment of mucosal candidiasis (candiduria) the dose of fluconazole is 200 mg to 400 mg daily with duration of treatment 7 to 21 days. Longer periods may be used in patients with severely compromised immune function.

[0303] For the treatment of mucosal candidiasis (chronic atrophic candidiasis) the dose of fluconazole is 50 mg daily for 14 days.

[0304] For the treatment of mucosal candidiasis (chronic mucocutaneous candidiasis) the dose of fluconazole is 50 mg to 100 daily with duration of treatment up to 28 days. Longer periods may be used depending on both the severity of infection of underlying immune compromisation and infection.

[0305] For the prevention of relapse of mucosal candidiasis in patients infected with HIV who are high risk of experiencing relapse (oropharyngeal candidiasis and oesophageal candidiasis) the dose of fluconazole is lOOmg to 200 mg daily or 200 mg three times per week, in both cases for an indefinite period for patients with chronic immune suppression.

[0306] For treatment of genital candidiasis (acute vaginal candidiasis and candidal balanitis) the dose of fluconazole is 150 mg as a single dose. For the treatment and prophylaxis of recurrent vaginal candidiasis (4 or more episodes a year) the dose is 150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by 150 mg once weekly maintenance dose, with a maintenance dose duration of 6 months.

[0307] For the prophylaxis of candidal infections in patients with prolonged neutropenia the dose of fluconazole is 200 mg to 400 mg, with treatment starting several days before anticipated onset of neutropenia and should continue for 7 days after recovery from neutropenia after the neutrophil count rises above 1000 cells per mm3.

[0308] Accordingly, in some embodiments fluconazole is administered to patients as per the approved dosage regimens, which for the treatment of invasive fungal infections is 800 mg on day 1, with subsequent doses of 400 mg daily thereafter (referred to as the "approved dose" below).

[0309] In some embodiments the dose of fluconazole administered to patients may be less than the approved dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the loading dose and maintenance doses may be 50% to 100% of the above approved dose for single-agent administration, e.g., 75% to 100% of the approved dose for single-agent administration. For example, the loading dose and maintenance doses may be no lower than 50% of the above approved dose for single-agent administration, e.g., no lower than 75% of the approved dose for single-agent administration.

[0310] In some embodiments fluconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0311] In some embodiments fluconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0312] In some embodiments fluconazole is administered to a patient at a dose which is the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0313] In some embodiments fluconazole is administered to a patient at a dose of 800 mg on day 1, with subsequent doses of 400 mg daily thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0314] In some embodiments fluconazole is administered to a patient at a dose of 800 mg on day 1, with subsequent doses of 400 mg daily thereafter and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0315] In some embodiments fluconazole is administered to a patient at a dose of 800 mg on day 1, with subsequent doses of 400 mg daily thereafter the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la). The pharmaceutical combinations described above may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0316] The above doses for fluconazole and the compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0317] Itraconazole

[0318] According to the FDA itraconazole Labelling -Package Insert, 2023 for the treatment of blastomycosis and histoplasmosis the recommended dose of itraconazole is 200 mg once daily. If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100- mg increments to a maximum of 400 mg daily.

[0319] For the treatment of aspergillosis a daily dose of itraconazole of 200 to 400 mg is recommended. In the treatment in life-threatening situations a loading dose of 200 mg three times daily (600 mg / day) should be given during the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

[0320] For the treatment of onychomycosis (toenails with or without fingernail involvement) the recommended dose of itraconazole is 200 mg once daily for 12 consecutive weeks. For the treatment of onychomycosis (fingernails only) the recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg b.i.d. (400 mg / day) for 1 week. The pulses are separated by a 3-week period.

[0321] For the treatment of oropharyngeal candidiasis the recommended dose of itraconazole is 200 mg daily for 1 to 2 weeks. For patients with oropharyngeal candidiasis unresponsive / refractory to treatment with fluconazole tablets, the recommended dose is 100 mg (b.i.d.).

[0322] For the treatment of oesophageal candidiasis the recommended dose of itraconazole is 100 mg daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg per day may be used based on medical judgment of the patient’s response to therapy

[0323] Accordingly, in some embodiments itraconazole is administered to patients as per the approved dosage regimens, which for the treatment of aspergillosis is a daily dose of 200 to 400 mg (referred to as the "approved dose" below).

[0324] In some embodiments the dose of itraconazole administered to patients may be less than the approved dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the dose may be 50% to 100% of the above approved dose for single-agent administration, e.g., 75% to 100% of the approved dose for single-agent administration. For example, the dose may be no lower than 50% of the above approved dose for single-agent administration, e.g., no lower than 75% of the approved dose for single-agent administration.

[0325] In some embodiments itraconazole is administered to a patient at a dose which is 50% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0326] In some embodiments itraconazole is administered to a patient at a dose which is 75% to 100% of the above approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0327] In some embodiments itraconazole is administered to a patient at a dose which is the approved dose for single-agent administration and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0328] In some embodiments itraconazole is administered to a patient at a dose which is a daily dose of 200 to 400 mg and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0329] In some embodiments itraconazole is administered to a patient at a dose which a daily dose of 200 to 400 mg and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la).

[0330] In some embodiments itraconazole is administered to a patient at a dose which is a daily dose of 200 to 400 mg and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0331] The pharmaceutical combinations described above may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0332] The above doses for fluconazole and the compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0333] Opelconazole

[0334] Opelconazole is currently undergoing a phase 2 study entitled “A Safety Study of PC945 (Opelconazole) Prophylaxis or Pre-emptive Therapy Against Pulmonary Aspergillosis in Lung Transplant Recipients” (NCT05037851). According to the study patients receive 14.8 mg opelconazole administered twice daily for 12 weeks.

[0335] Accordingly, in some embodiments opelconazole is administered to patients as per the phase 2 dosage regimen, which is a twice daily dose of 14.8 mg (referred to as the "phase 2 dose" below).

[0336] In some embodiments the dose of opelconazole administered to patients may be less than the phase 2 dose in view of the combined administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the dose may be 50% to 100% of the above phase 2 dose for single-agent administration, e.g., 75% to 100% of the phase 2 dose for single-agent administration. For example, the dose may be no lower than 50% of the above phase 2 dose for single-agent administration, e.g., no lower than 75% of the phase 2 dose for single-agent administration.

[0337] In some embodiments opelconazole is administered to a patient at a dose which is a twice daily dose of 10 to 15 mg (e.g., about 14.8 mg) and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 1200 mg of the compound of formula (la).

[0338] In some embodiments opelconazole is administered to a patient at a dose which a twice daily dose of 10 to 15 mg (e.g., about 14.8 mg) and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of 300 mg to 900 mg of the compound of formula (la). In some embodiments opelconazole is administered to a patient at a dose which is a twice daily dose of 10 to 15 mg (e.g., about 14.8 mg) and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient at a dose which is the mole equivalent of about 600 mg of the compound of formula (la).

[0339] The pharmaceutical combinations described above may be provided with amounts of the two therapeutic agents to facilitate administration to patients at the above-described doses, either as a fixed combination or single-agent medicaments.

[0340] The above doses for opelconazole and compound of formula (I) apply to adult patients. Doses should be adjusted appropriately for pediatric patients and other populations (e.g., pediatric, elderly, renal impairment, hepatic impairment) or animals.

[0341] Formulations

[0342] The compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent (e.g., isavuconazole) may be provided as a combined medicament or as a single- agent medicaments. Separate formulations have a number of advantages, for example, to allow different dosing schedules, different dosages and / or different routes of administration for each therapeutic agent. On the other hand, separate formulations have advantages such as ease of administration. For example, if both agents are administered intravenously then the administration time (and time spent in a hospital) would be less when administered as a fixed combination.

[0343] The therapeutic agents described herein may be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or oral administration, e.g., in the form of oral solid dosage forms, e.g., granules, pellets, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard and soft gelatin or hydroxypropylmethylcellulose (HPMC) capsules, coated as applicable, orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular, or subcutaneous, intrathecal, intradermal or epidural administration, to mammals, especially humans, e.g., in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. In some cases, the pharmaceutical compositions may comprise the therapeutic agents alone or, preferably, together with one or more pharmaceutically acceptable excipients.

[0344] The therapeutic agents described herein can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms, e.g., granules, pellets, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules or orally disintegrating tablets. Fillers e.g., lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders e.g., cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, glidants e.g., talcum, stearic acid or its salts, flowing agents e.g., fumed silica, can be used as such excipients for formulating and manufacturing of oral solid dosage forms, such as granules, pellets, powders, tablets, fdm or sugar coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft gelatin capsules are e.g., vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitable excipients for the manufacture of oral solutions, lipid emulsions or suspensions are e.g., water, alcohols, polyols, saccharose, invert sugar, glucose etc.

[0345] Suitable excipients for parenteral formulations are e.g., water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

[0346] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules such as compounds of formula (I) it can be advantageous to include solubilizers in the formulation, for example surfactants, polymeric surfactants, polymers, complexing agents and / or co-solvents, which may significantly increase the solubility of the compounds in water. Examples of solubilizers include polyethylene glycol, propylene glycol, ethanol, glycerol and cyclodextrins (e.g., sulfobutyl ether-[3-cyclodextrins).

[0347] Formulations of the compound of formula (I) or a pharmaceutically acceptable salt thereof as a single- agent medicament may be prepared as described above (and as described e.g., in U.S. Patent No. 8,598,115). The compound of formula (la) was formulated for i.v. administration in the phase 1 and 2 clinical trials and it is currently not proven that an oral formulation of the compound of formula (la) would be sufficiently bioavailable for optimal treatment of a fungal infection (Shaw). Accordingly, the compound of formula (I) or a pharmaceutically acceptable salt is preferably formulated for intravenous administration, and, in view of its strong lipophilicity, the compound of formula (I) is preferably formulated with the solubilizers listed above (such as polyethylene glycol, propylene glycol, ethanol, glycerol and / or a cyclodextrin). These considerations apply both to formulations of the compound of formula (I) as a single-agent medicament and formulations of the compound of formula (I) as a combined medicament, i.e. a combined medicament of the compound of formula (I) and the triazole-based antifungal agent is preferably formulated for intravenous administration as described above.

[0348] In some embodiments the triazole-based antifungal agent is formulated as a single-agent medicament as commercially available, e.g., as described below.

[0349] Isavuconazole for injection as available commercially is formulated as a lyophilized powder of isavuconazonium sulfate with mannitol and sulfuric acid (for pH adjustment). Isavuconazole capsules are formulated as isavuconazonium sulfate with magnesium citrate (anhydrous), microcrystalline cellulose, talc, silica (colloidal anhydrous) and stearic acid (EMA, Annex I, Summary of Product Characteristics, Cresemba, 2023). Formulations of isavuconazole free base are described in WO 2009 / 024590.

[0350] In some embodiments the compound of formula (la) is formulated with isavuconazole free base as a fixed combination for intravenous administration.

[0351] Voriconazole for infusion is formulated as a lyophilized powder with sulfobutylether beta cyclodextrin sodium. Voriconazole tablets are formulated with the following inactive ingredients: lactose monohydrate, pregilatinised starch, croscarmellose sodium, povidone, and magnesium stearate. Voriconazole powder for oral suspension is formulated with the following inactive ingredients: sucrose, silica (colloidal anhydrous), titanium dioxide (E 171), xanthan gum, sodium citrate, citric acid anhydrous, sodium benzoate (E211) and natural orange flavor. EMA, (Annex I, Summary of Product Characteristics, VFEND, 2023).

[0352] Posaconazole for injection is formulated with the following inactive ingredients: Betadex sulfobutyl ether sodium (SBECD), edetate disodium, hydrochloric acid and sodium hydroxide for pH adjustment and water for injection. Posaconazole delayed-release tablets are formulated with the following inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol / PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, silicon dioxide, talc, and titanium dioxide. Posaconazole oral suspension is formulated with the following inactive ingredients: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. Posaconazole powdermix for delayed-release oral suspension (for pediatric patients) is formulated with the following inactive ingredients: hypromellose acetate succinate. The mixing liquid contains: anhydrous citric acid, antifoam Af emulsion, berry citrus sweet flavor, carboxymethylcellulose sodium, carrageenan calcium sulfate trisodium phosphate, glycerin, methylparaben, microcrystalline cellulose, potassium sorbate, propylparaben, purified water, sodium citrate, sodium phosphate monobasic monohydrate, sodium saccharin, sorbitol solution, and xanthan gum. (FDA posaconazole Labelling -Package Insert, 2022).

[0353] According to the FDA Fluconazole Labelling -Package Insert, 2023 fluconazole tablets contain 50 mg, 100 mg, 150 mg, or 200 mg of fluconazole and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate. Fluconazole for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted suspension contains 10 mg or 40 mg of fluconazole. According to the EMA Annex III, Summary of Product Characteristics, Labelling and Package Leaflet, 2012, fluconazole is additionally available as a solution for infusion containing 50 mg, 100 mg, 200, mg or 400 mg fluconazole and the following excipients: sodium chloride, water for injection, sodium hydroxide (for pH adjustment).

[0354] Itraconazole capsules (hard gelatin capsules) are formulated with hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. Itraconazole oral solution is formulated with hydroxypropyl-[3-cyclodextrin, hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor (FDA itraconazole Labelling-Package Insert, 2023).

[0355] Opelconazole may be formulated as described in WO 2016 / 087878.

[0356] Kits

[0357] Also provided are pharmaceutical products such as kits which may include a container with the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent (e.g., isavuconazole), which can be provided in amounts sufficient for administration, e.g., in pharmaceutically effective amounts. The kits can thus include multiple containers that each include pharmaceutically effective amounts of the therapeutic agents. Optionally, instruments and / or devices necessary for administering the pharmaceutical composition(s) can also be included in the kits. Furthermore, the kits can include additional components, such as instructions or administration schedules, for preventing or treating a fungal infection in a subject with the combinations described herein. Accordingly, a pharmaceutical product such as a kit for use in preventing or treating a fungal infection in a subject is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole are provided as single-agent medicaments. In some embodiments, the kit further comprises instructions for simultaneous, separate or sequential administration thereof for use in preventing or treating a fungal infection in a subject. In some embodiments the fungal infection is susceptible to treatment with a triazole-based antifungal agent, in a subject. In some embodiments the fungal infection is resistant and / or refractory to the triazole-based antifungal agent.

[0358] Also provided is a pharmaceutical product such as a kit for use in preventing or treating a fungal infection, which fungal infection is susceptible to treatment with a triazole-based antifungal agent, in a subject, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the triazole-based antifungal agent are provided as single-agent medicaments. In some embodiments, the kit further comprises instructions for simultaneous, separate or sequential administration thereof for use in preventing or treating a fungal infection in a subject.

[0359] All aspects and embodiments of the invention described herein may be combined in any combination where possible.

[0360] A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0361] Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail and should not be construed as limiting the invention in any way.

[0362] Examples

[0363] In vitro experiments

[0364] Methodology

[0365] Antifungal Agents

[0366] The following antimicrobial agents were tested in as a 7x11 checkerboard study against isolates at the respective specified concentration:

[0367] 1. Isavuconazole (7 dilutions; 0; 0.12 - 8 mg / L) 2. Posaconazole (7 dilutions; 0; 0.06 - 4 mg / L)

[0368] 3. Voriconazole (7 dilutions; 0; 0.12 - 8 mg / L)

[0369] 4. Compound of formula (la) (11 dilutions; 0; 0.03 - 32 mg / L)

[0370] The compound of formula (la) was solvated in DMSO to a 3.2 mg / mL concentration and diluted in RPMI medium 100-fold to a top concentration of 32 mg / L and final DMSO concentration of 1%. Isavuconazole (active moiety) was solvated in DMSO to a 1.6 mg / mL concentration and diluted in RPMI medium. Posaconazole and voriconazole were initially solvated in DMSO to a concentration of 1600 mg / L. Posaconazole was further diluted (1 : 1) in DMSO to a starting concentration of 800 mg / L. These stocks were used to generate the top concentration tested. These stocks were serially diluted (1: 1) in DMSO to generate the concentrations needed for the lower dilutions. Then 0.3 mL of each DMSO dilution (including the top dilutions of 1600 mg / L voriconazole and 800 mg / L posaconazole) was added to 29.7 mL of RPMI resulting in a hundred-fold dilution.

[0371] Strains

[0372] The checkerboard study with compound of formula (la) and isavuconazole, posaconazole and voriconazole respectively was performed against 15 Aspergillus isolates (including isavuconazole resistant isolates) as listed in Tables 1, 5 and 7. Strains other than ATCC strains were sourced from JMI Laboratories.

[0373] Broth Microdilution Reference Method

[0374] All isolates were tested by the broth microdilution method as described by Clinical and Laboratory Standards Institute (CLSI) M38 document. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid buffer) and 0.2% glucose and inoculated with 0.4 to 5 X 104cells / mL for molds. MIC endpoints were read as 100% inhibition after 48 hours of incubation.

[0375] Drug combination interactions were calculated algebraically by determining the fractional inhibitory concentration (FIC) index. The minimal FIC value was used for evaluating synergy (FIC ≤0.5) and the maximal FIC value was used for evaluating antagonism (FIC >4).

[0376] Quality Control

[0377] Quality Control (QC) strains, Aspergillus flavus ATCC 204304 and Aspergillus fumigatus MYA- 3626, were tested concomitantly with testing of clinical isolates. Inoculum density was monitored by colony counts. QC ranges and interpretative criteria followed the CLSI M38 (2017) and M38M5 IS (2022) documents. Results

[0378] The checkerboard method is used for testing the activity of antimicrobial drugs combinations and to evaluate the nature of their interactions being either synergistic, additive, antagonist or indifferent. A routine checkerboard 96-well microplate format, based on the broth microdilution method, is a two- dimensional drug microdilution assay where two antimicrobial drugs are tested in double serial dilutions, and the concentration of each drug is tested both alone and in combination (Garcia). Checkerboards allow for the quantification of the activities of both the individual drug and their combination. The nature of the interaction between the two drugs is then calculated algebraically by determining the fractional inhibitory concentration (FIC). The sum of the FICs (^FIC) is calculated as follows: A is calculated as the MIC of drug A in the combination divided by the MIC of drug A alone, and FICB equals the MIC of drug B in the combination divided by the MIC of drug B alone. The interpretation of ^FIC (FIC index) is as follows: synergy (S), ≤0.5; indifference (I), >0.5-≤4.0; antagonism (AN), ≥4.0. An indeterminate category will be defined for when the result for one agent when tested alone demonstrates an off scale (≤ or ≥) MIC result.

[0379] Broth microdilution checkerboard method was used to investigate the nature of the interaction between the investigational compound and isavuconazole, posaconazole and voriconazole respectively against 15 Aspergillus isolates, including isavuconazole resistant strains.

[0380] Table 1 shows that the compound of formula (la) combination with isavuconazole displayed no antagonism but synergy in 12 out of the 15 Aspergillus isolates tested. The FIC index was low ranging from ≤0.08 to 0.5. The combination was synergistic on all 6 strains of Aspergillus flavus, 2 out of 3 Aspergillus fumigatus, 3 out of 4 Aspergillus niger and 1 out of 2 Aspergillus terreus. Of note, synergy was observed for the 4 out of 4 isavuconazole resistant isolates. Indifference was observed for ■Aspergillus fumigatus (ATCC MYA-3626) and Aspergillus terreus (AT2) and for Aspergillus niger (AN1).

[0381] Table 2 shows the distribution shift to lower MICs for isavuconazole against the 15 Aspergillus isolates in the presence of combinations of the compound of formula (la) at fixed concentrations (11 dilutions ranging from 0.03 to 32 mg / L, as well as with no compound of formula (la)). The 15 Aspergillus species displayed an MIC90 >8 mg / L for isavuconazole alone and >32 mg / L for the compound of formula (la) alone. Of note, an MIC90 >8 mg / L for isavuconazole is much higher than the EUCAST ECOFFs of all Aspergillus species tested: Aspergillus fumigatus (2 mg / L) (EUCAST, 2023-11-10), Aspergillus terreus (1 mg / L) (EUCAST, 2023-11-10), Aspergillus flavus (2 mg / L) (EUCAST, 2023-11-10); Aspergillus niger (4 mg / L) (EUCAST, 2023-11-10). In contrast, all combinations, even at the lowest fixed concentration of the compound of formula (la) displayed lower MICs, compared to the MICs of the single agent isavuconazole. At a fixed concentration of 8 mg / L of the compound of formula (la), the combination with isavuconazole resulted in a low MIC,,, of 1 mg / L, lower or equal to all Aspergillus species ECOFFs values.

[0382] Table 3 shows a similar distribution shift to lower MICs for compound of formula (la) against the 15 Aspergillus isolates in the presence of combinations of isavuconazole at fixed concentrations (7 dilutions ranging from 0.03 to 2 mg / L as well as no isavuconazole) with compound of formula (la).

[0383] Table 4 shows that isavuconazole MICs are lowered to or below the epidemiological cutoff value (ECV) for most of the A. flavus isolates tested in the presence of the compound of formula (la) at concentrations of 0.25 to 2 mg / L, despite MICs of 32 mg / L.

[0384] Table 5 shows that synergy between the compound of formula 1(a) and posaconazole was observed for 6 of the 14 isolates where FICmin values could be calculated. The FIC values of 1 isolate (AT2) could not be determined due to off-scale low MIC values observed for both agents. For 3 isolates (AFL3, ATCC 204304 and AN3), a posaconazole MIC of 0.06 mg / L was observed. For these isolates it was not possible for synergy to be demonstrated due to the MIC testing range. One isolate (AN1) was categorized as “Indifferent”. However, if a formula (Ia)-alone MIC of 64 mg / L was assumed for this isolate, synergistic activity would be observed. Among the 6 Aspergillus flavus isolates tested, formula (la) alone activity was >8 mg / L. Synergy was demonstrated among 3 of these 6 isolates. Synergy could not be determined for combinations among all these isolates, due to limitations of the MIC ranges tested.

[0385] Table 6 shows the distribution shift to lower MICs for the compound of formula (la) against the 15 Aspergillus isolates in the presence of posaconazole at fixed concentrations (7 dilutions ranging from 0.06 mg / mLto 4 mg / L, as well as with no posaconazole).

[0386] Table 7 shows that synergy between the compound of formula (la) and voriconazole was observed for 3 of the 15 isolates where FICmin values could be calculated. Two isolates (AFL5 and AN4) were categorized as “Indifferent”. However, if a formula (Ia)-alone MIC of 64 mg / L was assumed synergistic activity would be observed. Among the 6 Aspergillus flavus isolates tested, formula (la)- alone activity was >8 mg / L. Synergy was demonstrated among 1 of these 6 isolates. An additional isolate would likely have demonstrated synergy if combinations included formula (la) at higher concentrations. Among the 3 Aspergillus fumigatus isolates tested, the activity of formula (la) alone ranged from 0.12 to 0.5 mg / L. Synergy was not demonstrated among any of these 3 isolates. Among the 4 Aspergillus nigri isolates tested, the activity of formula (la) alone ranged from 4 to >8 mg / L. Synergy was demonstrated among 1 of these 4 isolates and an additional isolate would likely have demonstrated synergy if combinations included formula (la) at higher concentrations. Formula (la) alone MIC values of >8 mg / L and 0.12 mg / L were observed for the 2 Aspergillus terrei isolates tested.

[0387] Synergy was demonstrated among 1 of these 2 isolates.

[0388] Table 8 shows the distribution shift to lower MICs for the compound of formula (la) against the 15 Aspergillus isolates in the presence of voriconazole at fixed concentrations (7 dilutions ranging from 0.12 mg / mLto 8 mg / L, as well as with no posaconazole).

[0389] Table 2. Distribution of isavuconazole MICs in combination with the compound of formula (la) at fixed concentrations. ECV = epidemiological cutoff value; NWT = non-wildtype; WT = wildtype

[0390] The compound of formula (la) showed synergy when tested in combination with isavuconazole against Aspergillus isolates. Synergy was observed in 12 of the 15 (80%) isolates tested. Also, at least one example of synergy was observed within each of the 4 different Aspergillus sections tested including Flavi, Fumigati, Nigri, and Terrei.

[0391] The compound of formula (la) also often showed synergy when tested in combination with posaconazole and voriconazole against Aspergillus isolates. For posaconazole, at least one example of synergy was observed within each of the 4 different Aspergillus sections tested including Flavi, Fumigati, Nigri, and Terrei. Similarly, for voriconazole synergy was observed for at least one isolate for the 4 Aspergillus sections tested except Fumigati. In general, synergy was more commonly observed in combinations among Aspergillus flavus or Aspergillus niger isolates. These species are also the ones for which the compound of formula (la) alone has lower activity.

[0392] In vivo efficacy study: mouse model of IP A - combination of formula (la) with isavuconazole

[0393] Nasal infection model

[0394] Male ICR mice, 20-25 g, were used in this study.

[0395] Neutropenia was induced in mice by administering cyclophosphamide (200 mg / kg, via intraperitoneal [IP] injection) and cortisone acetate (500 mg / kg via subcutaneous injection [SC]) on days -2 and +3 relative to infection. According to the literature this treatment regimen results in ~10 days of leukopenia with a total white blood cell count dropping from ~13,0000 / cm3to almost no detectable leukocytes as determined by the Unopette® system (BD, New Jersey) (Luo).

[0396] The animals were given free access to water and a standard laboratory diet. To prevent bacterial infection, mice were given enrofloxacin (Baytril®) (50 pg / mL) added to the drinking water from Day -3 to Day 0. Ceftazidime (5 pg / dose / 0.2 mb) replaced enrofloxacin treatment on Day 0 and was administered daily SC from Day 0 until Day +8. Isavuconazonium sulfate was used in this study (ISAV). All drug treatments were initiated 24 h post infection and continued for 7 consecutive days, and were given SC twice daily (bid) for the compound of formula (la) and by oral gavage (po) three times daily (tid) for ISAV.

[0397] The mice were challenged with A. fumigatus AF293 in an inhalation chamber by aerosolizing 12 mb of a 1 x 109mb suspension of conidia with a small particle nebulizer driven by compressed air (Sheppard). A standard exposure time of one hour was used for all experiments. Immediately after infection, a subset of mice was sacrificed. Their lungs were removed, homogenized, and quantitatively cultured to determine the number of conidia delivered to the mouse. This exposure reproducibly delivers 1-5 x 103conidia per mouse and produces infection in 100% of animals with 70- 100% mortality by two weeks (Gebremariam 2018, Gebremariam 2022).

[0398] The results are shown in Figure 1 and Tables 9 and 10 below. IV infection model

[0399] Immunosuppression is induced in mice by administering cyclophosphamide (200 mg / kg, via IP injection) and 5 -fluorouracil (5 mg / mouse via IV injection) one day prior to infecting the mice via tail vein (hematogenous infection) (Wiederhold).

[0400] The animals are given free access to water and a standard laboratory diet. To prevent bacterial infection, mice are given enrofloxacin (Baytril®) (50 pg / mL) added to the drinking water from Day - 3 to Day 0. Ceftazidime (5 pg / dose / 0.2 mL) replaces enrofloxacin treatment on Day 0 and is administered daily SC from Day 0 until Day +8. All drug treatments are initiated 16 h or 24 h post infection and continued for 7 consecutive days, and are given SC twice daily (bid) for the compound of formula (la) and by oral gavage (po) three times daily (tid) for ISAV.

[0401] Immunosuppressed animals are challenged with A. fumigatus via IV injection in the tail vein at 5 x 105conidia per mouse (Wiederhold). Immediately after infection, a subset of mice is sacrificed. Their lungs are removed, homogenized, and quantitatively cultured to determine the number of conidia delivered to the mouse.

[0402] References

[0403] Garcia., Clinical Microbiology Procedures Handbook. 3rd ed. American Society of Microbiology (2014) Synergism testing: broth microdilution checkerboard and broth macrodilution methods 140 162.

[0404] Ghannoum et al., Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance, Clin Microbiol Rev. (1999) 12(4): 501-517.

[0405] Luo G, Gebremariam T, Lee H, Edwards IE, Jr., Kovanda L, Ibrahim AS. Isavuconazole therapy protects immunosuppressed mice from mucormycosis. Antimicrob Agents Chemother;58:2450-3.

[0406] Gebremariam T, Alkhazraji S, Alqarihi A, et al. APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis. Antimicrobial Agents and Chemotherapy 2018:AAC.01713-18.

[0407] Gebremariam T, Gu Y, Alkhazraji S, Youssef E, Shaw KJ, Ibrahim AS. The Combination Treatment of Fosmanogepix and Liposomal Amphotericin B Is Superior to Monotherapy in Treating Experimental Invasive Mold Infections. Antimicrob Agents Chemother 2022;66:e0038022. Maertens et al., Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial, Lancet 2016 20;387(10020):760-9.

[0408] Miceli et al., Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent, Clinical Infectious Diseases (2015) 61(10): 1558-65.

[0409] Nakamura et al. (a), ASP2397: a novel antifungal agent produced by Acremonium persicinum MF- 347833, The Journal of Antibiotics (2017) 70: 45-51.

[0410] Nakamura et al.(b), Discovery of a new antifungal agent ASP2397 using a silkworm model of Aspergillus fumigatus infection, The Journal of Antibiotics (2017) 70: 41-44.

[0411] Nakamura et al.(c), ASP2397 Is a Novel Natural Compound That Exhibits Rapid and Potent Fungicidal Activity against Aspergillus Species through a Specific Transporter, Antimicrobial Agents and Chemotherapy (2019) 63(10): e02689-18.

[0412] Punnapuzha et al. [Updated 2023 Mar 30], In: StatPearls [Internet], Treasure Island (FL): StatPearls Publishing; 2023 Jan (Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK541102 / ).

[0413] Teixeira et al., New Antifungal Agents with Azole Moieties, Pharmaceuticals (2022), 15, 1427

[0414] Shaw, GR-2397: Review of the Novel Siderophore-like Antifungal Agent for the Treatment of Invasive Aspergillosis. Journal of Fungi (Basel) (2022) 8: 909.

[0415] Sheppard DC, Rieg G, Chiang LY, Filler SG, Edwards JE, Jr., Ibrahim AS. Novel inhalational murine model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2004;48: 1908-11.

[0416] Wiederhold NP, Najvar EK, Jaramillo R, Olivo M, Catano G, Patterson TF. Rezafimgin is efficacious against invasive aspergillosis caused by azole-resistant Aspergillus fumigatus harboring the TR34 / L98H mutation (AAR-638). ASM Microbe; 2019 June 20-24; San Francisco. The following paragraphs describe particular embodiments of the invention.

[0417] PI1. A pharmaceutical combination comprising (a) a compound of formula (I) wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and (b) isavuconazole.

[0418] PI2. The pharmaceutical combination according to paragraph PI 1, wherein the compound of formula (I) is a compound of formula (la)

[0419] PI3. The pharmaceutical combination according to paragraph PI1 or paragraph PI2, wherein the compound of formula (I) and isavuconazole are formulated as a fixed combination for intravenous administration.

[0420] PI4. The pharmaceutical combination according to paragraph PI3, wherein isavuconazole is isavuconazole free base.

[0421] PI5. The pharmaceutical combination according to paragraph PI 1 or paragraph PI2, wherein the compound of formula (I) and isavuconazole are formulated as single-agent medicaments for intravenous administration. PI6. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI1 and isavuconazole, for use in the prevention or treatment of a fungal infection in a subject.

[0422] PI7. The pharmaceutical combination for use according to paragraph PI6, wherein the compound of formula (I) is a compound of formula (la) as defined in paragraph PI2.

[0423] PIS. The pharmaceutical combination for use according to paragraph PI6 or paragraph PI7, wherein the fungal infection is caused by a fungal pathogen from the genus Aspergillus.

[0424] PI9. The pharmaceutical combination for use according to paragraph PIS, wherein the fungal pathogen causing the fungal infection is Aspergillus fumigatus, Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus.

[0425] PI10. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI9, wherein the fungal infection is invasive aspergillosis.

[0426] Pil l. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 10, wherein the fungal pathogen causing the fungal infection is susceptible to isavuconazole.

[0427] PI12. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 10, wherein the fungal pathogen causing the fungal infection is resistant to isavuconazole or the fungal infection is refractory to isavuconazole.

[0428] PI13. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) and wherein the subject is an adult human.

[0429] PI14. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human. PI15. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0430] PI16. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0431] PI17. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0432] PI18. The pharmaceutical combination for use according to any one of paragraphs PI76 to PI 17, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

[0433] PI19. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 17, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

[0434] PI20. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 17, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human. PI21. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI 17, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (12 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

[0435] PI22. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at least once before and at least once after isavuconazole has been administered to the subject and / or vice versa.

[0436] PI23. The pharmaceutical combination for use according to any one of paragraphs PI6 to PI22, wherein the compound of formula (I) is administered intravenously.

[0437] PI24. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI 1 , for use in combination with isavuconazole, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PI 6 to PI23 where applicable may be appended to this paragraph.

[0438] PI25. Isavuconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI 1, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PI 6 to PI23 where applicable may be appended to this paragraph.

[0439] PI26. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI1 in combination with isavuconazole. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph.

[0440] PI27. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PH, wherein said subject is undergoing or will undergo administration of isavuconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph. PI28. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of isavuconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI 1 as a combination therapy with isavuconazole. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph.

[0441] PI29. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI1 and isavuconazole, in the preparation of single-agent medicaments for use in combination, or as a combined medicament, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph.

[0442] PI30. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI1 in the preparation of a single-agent medicament for use in combination with isavuconazole, or in the preparation of a combined medicament with isavuconazole, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph.

[0443] PI31. Use of isavuconazole in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PI 1 , for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PI6 to PI23 where applicable may be appended to this paragraph.

[0444] PV1. A pharmaceutical combination comprising (a) a compound of formula (I), wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and (b) voriconazole.

[0445] PV2. The pharmaceutical combination according to paragraph PV1, wherein the compound of formula (I) is a compound of formula (la)

[0446] PV3. The pharmaceutical combination according to paragraph PV1 or paragraph PV2, wherein the compound of formula (I) and voriconazole are formulated as a fixed combination for intravenous administration.

[0447] PV4. The pharmaceutical combination according to paragraph PV1 or paragraph PV2, wherein the compound of formula (I) and voriconazole are formulated as single-agent medicaments for intravenous administration.

[0448] PV5. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV 1 and voriconazole, for use in the prevention or treatment of a fungal infection in a subject.

[0449] PV6. The pharmaceutical combination for use according to paragraph PV5, wherein the compound of formula (I) is a compound of formula (la) as defined in paragraph PV2.

[0450] PV7. The pharmaceutical combination for use according to paragraph PV5 or PV6, wherein the fungal pathogen causing the fungal infection is from the genus from the genus Aspergillus.

[0451] PV8. The pharmaceutical combination for use according to paragraph PV7, wherein the fungal pathogen causing the fungal infection is Aspergillus fumigatus, Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus.

[0452] PV9. The pharmaceutical combination for use according to paragraph PV7, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger, or Aspergillus flavus. PV10. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV9, wherein the fungal infection is invasive aspergillosis.

[0453] PV 11. The pharmaceutical combination for use according to any one of paragraphs PV 5 to PV 10, wherein the fungal pathogen causing the fungal infection is susceptible to voriconazole.

[0454] PV12. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV10, wherein the fungal pathogen causing the fungal infection is resistant to voriconazole or the fungal infection is refractory to voriconazole.

[0455] PV13. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) and wherein the subject is an adult human.

[0456] PV14. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0457] PV15. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0458] PV16. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human. PV17. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0459] PV18. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at least once before and at least once after voriconazole has been administered to the subject and / or vice versa.

[0460] PV19. The pharmaceutical combination for use according to any one of paragraphs PV5 to PV18, wherein the compound of formula (I) is administered intravenously.

[0461] PV20. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV1, for use in combination with voriconazole for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0462] PV21. Voriconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV 1 for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0463] PV22. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with voriconazole. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0464] PV23. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV1, wherein said subject is undergoing or will undergo administration of voriconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph. PV24. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of voriconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV1 as a combination therapy with voriconazole. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0465] PV25. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV 1 and voriconazole, in the preparation of single-agent medicaments for use in combination, or as a combined medicament, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0466] PV26. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV 1 in the preparation of a single-agent medicament for use in combination with voriconazole, in the preparation of a combined medicament with voriconazole, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0467] PV27. Use of voriconazole in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PV1, for the prevention or treatment of a fungal infection in a subject. Any one or more of the features defined in paragraphs PV5 to PV19 where applicable may be appended to this paragraph.

[0468] PPI. A pharmaceutical combination comprising a compound of formula (I) wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and posaconazole, for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus , Aspergillus niger. or Aspergillus flavus.

[0469] PP2. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PPI, and posaconazole, for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I).

[0470] PP3. The pharmaceutical combination for use according to paragraph PP 1 or paragraph PP2, wherein the compound of formula (I) is a compound of formula (la)

[0471] (la).

[0472] PP4. The pharmaceutical combination for use according to paragraph PP2 or paragraph PP3 as dependent on paragraph PP2, wherein the fungal infection is caused by a fungus from the genus Aspergillus.

[0473] PP5. The pharmaceutical combination for use according to paragraph PP4, wherein the fungal pathogen causing the fungal infection is Aspergillus fimigaius. Aspergillus terreus, Aspergillus niger, or Aspergillus flavus.

[0474] PP6. The pharmaceutical combination for use according to paragraph PP5, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus, Aspergillus niger, and Aspergillus flavus.

[0475] PP7. The pharmaceutical combination for use according to any one of paragraphs PPI to PP6, wherein the fungal infection is invasive aspergillosis.

[0476] PP8. The pharmaceutical combination for use according to any one of paragraphs PP 1 to PP7, wherein fungal pathogen causing the fungal infection is susceptible to posaconazole. PP9. The pharmaceutical combination for use according to any one of paragraphs PP 1 to PP7, wherein the fungal pathogen causing the fungal infection is resistant to posaconazole or the fungal infection is refractory to posaconazole.

[0477] PP10. The pharmaceutical combination for use according to any one of paragraphs PPI to PP9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) and wherein the subject is an adult human.

[0478] Pl l. The pharmaceutical combination for use according to any one of paragraphs PPI to PP9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0479] PP12. The pharmaceutical combination for use according to any one of paragraphs PPI to PP9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0480] PP13. The pharmaceutical combination for use according to any one of paragraphs PPI to PP9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

[0481] PP14. The pharmaceutical combination for use according to any one of paragraphs PPI to PP9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human. PP15. The pharmaceutical combination for use according to any one of paragraphs PPI to PP14, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at least once before and at least once after posaconazole has been administered to the subject and / or vice versa.

[0482] PPI 6. The pharmaceutical combination for use according to any one of paragraphs PPI to PPI 5, wherein the compound of formula (I) is administered intravenously.

[0483] PPI 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 , for use in combination with posaconazole for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus terreus, Aspergillus niger, or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0484] PP 18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 , for use in combination with posaconazole for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0485] PPI 9. Posaconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ter reus. Aspergillus niger. or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0486] PP20. Posaconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0487] PP21. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with posaconazole, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0488] PP22. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with posaconazole, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0489] PP23. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PPI, wherein said subject is undergoing or will undergo administration of posaconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger, or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0490] PP24. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PPI, wherein said subject is undergoing or will undergo administration of posaconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0491] PP25. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of posaconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 as a combination therapy with posaconazole, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger, or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph. PP26. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of posaconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 as a combination therapy with posaconazole, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PP31 to PPI 6 where applicable may be appended to this paragraph.

[0492] PP27. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 and posaconazole, in the preparation of single-agent medicaments for use in combination, or as a combined medicament, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ter reus. Aspergillus niger. or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0493] PP28. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 and posaconazole, in the preparation of single-agent medicaments for use in combination, or as a combined medicament, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0494] PP29. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 in the preparation of a single-agent medicament for use in combination with posaconazole, in the preparation of a combined medicament with posaconazole, fluconazole, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ter reus. Aspergillus niger, or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0495] PP30. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PP 1 in the preparation of a single-agent medicament for use in combination with posaconazole, in the preparation of a combined medicament with posaconazole, fluconazole, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph. PP31. Use of posaconazole in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PPI, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ierreus. Aspergillus niger. or Aspergillus flavus. Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

[0496] PP32. Use of posaconazole in the preparation of a single-agent medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, or in the preparation of a combined medicament with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in paragraph PPI, for the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I) or the fungal infection is refractory to the compound of formula (I). Any one or more of the features defined in paragraphs PPI to PPI 6 where applicable may be appended to this paragraph.

Claims

Claims1. A pharmaceutical combination comprising (a) a compound of formula (I)wherein M(III) is an ion selected from Al, Fe and Ga; or a pharmaceutically acceptable salt thereof, and(b) a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole.

2. The pharmaceutical combination according to claim 1, wherein the triazole-based antifungal agent is isavuconazole.

3. The pharmaceutical combination according to claim 1, wherein the triazole-based antifungal agent is voriconazole.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of formula (I) is a compound of formula (la)(la).

5. The pharmaceutical combination according to claim 4, wherein the triazole-based antifungal agent is isavuconazole and wherein the compound of formula (la) and isavuconazole are formulated as a fixed combination for intravenous administration.

6. The pharmaceutical combination according to claim 5, wherein isavuconazole is isavuconazole free base.

7. The pharmaceutical combination according to claim 4, wherein the triazole-based antifungal agent is isavuconazole and wherein the compound of formula (la) and isavuconazole are formulated as single-agent medicaments for intravenous administration.

8. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, for use in the prevention or treatment of a fungal infection in a subject.

9. The pharmaceutical combination for use according to claim 8, wherein the triazole-based antifungal agent is isavuconazole.

10. The pharmaceutical combination for use according to claim 8, wherein the triazole-based antifungal agent is voriconazole.

11. The pharmaceutical combination for use according to any one of claims 8 to 10, wherein the compound of formula (I) is a compound of formula (la).

12. The pharmaceutical combination for use according to any one of claims 8 to 11, wherein the fungal infection is caused by a fungal pathogen from the genus Aspergillus.

13. The pharmaceutical combination for use according to claim 12, wherein the fungal pathogen causing the fungal infection is Aspergillus fimigaius. Aspergillus terreus, Aspergillus niger, or Aspergillus flavus.

14. The pharmaceutical combination for use according to claim 12, wherein the triazole-based antifungal agent is voriconazole and wherein the fungal pathogen causing the fungal infection is Aspergillus terreus , Aspergillus niger. or Aspergillus flavus.

15. The pharmaceutical combination for use according to any one of claims 8 to 14, wherein the fungal infection is invasive aspergillosis.

16. The pharmaceutical combination for use according to any one of claims 8 to 15, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

17. The pharmaceutical combination for use according to any one of claims 8 to 15, wherein the fungal infection is refractory to or the fungal pathogen causing the fungal infection is resistant to treatment with the triazole-based antifungal agent.

18. The pharmaceutical combination for use according to any one of claims 8 to 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject at a dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) and wherein the subject is an adult human.

19. The pharmaceutical combination for use according to any one of claims 8 to 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 6 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

20. The pharmaceutical combination for use according to any one of claims 8 to 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 8 hours for 3 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

21. The pharmaceutical combination for use according to any one of claims 8 to 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) every 12 hours for 4 doses (48 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

22. The pharmaceutical combination for use according to any one of claims 8 to 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject as a loading dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la)every 12 hours for 2 doses (24 hours) followed by a maintenance dose which is the mole equivalent of 600 mg to 1200 mg of the compound of formula (la) once daily and wherein the subject is an adult human.

23. The pharmaceutical combination for use according to any one of claims 9, 11 to 13 and 15 to 22, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 6 doses (48 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

24. The pharmaceutical combination for use according to any one of claims 9, 11 to 13 and 15 to 22, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 8 hours for 3 doses (24 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

25. The pharmaceutical combination for use according to any one of claims 9, 11 to 13 and 15 to 22, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 4 doses (48 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

26. The pharmaceutical combination for use according to any one of claims 9, 11 to 13 and 15 to 22, wherein isavuconazole is administered to a subject as a loading dose equivalent to 200 mg of isavuconazole free base every 12 hours for 2 doses (12 hours) followed by a maintenance dose of equivalent to 200 mg of isavuconazole free base once daily and wherein the subject is an adult human.

27. The pharmaceutical combination for use according to any one of claims 8 to 26, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at least once before and at least once after the triazole-based antifungal agent has been administered to the subject and / or vice versa.

28. The pharmaceutical combination for use according to any one of claims 8 to 27, wherein the compound of formula (I) is administered intravenously.

29. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and a triazole-based antifungal agent, for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is Aspergillus ter reus. Aspergillus niger. or Aspergillus flavus.

30. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and a triazole-based antifungal agent, for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is resistant to the compound of formula (I), or the fungal infection is refractory to the compound of formula (I).

31. The pharmaceutical combination for use according to claim 29 or claim 30, wherein the triazole-based antifungal agent is posaconazole.

32. A pharmaceutical combination comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, and (b) a triazole-based antifungal agent, for use in the prevention or treatment of a fungal infection in a subject, wherein the fungal pathogen causing the fungal infection is susceptible to treatment with the triazole-based antifungal agent.

33. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for use in a method of synergistically increasing the efficacy of a triazole-based antifungal agent in the prevention or treatment of a fungal infection in a subject, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a triazole-based antifungal agent to the subject.

34. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for use in a method of reducing the dose of a triazole-based antifungal agent needed to achieve a reduction in colony forming units of a fungal pathogen in a subject infected with the fungal pathogen, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the triazole-based antifungal agent to the subject.

35. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 for use in combination with a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole for the prevention or treatment of a fungal infection in a subject.

36. A triazole-based antifungal agent, selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, for the prevention or treatment of a fungal infection in a subject.

37. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 in combination with a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole.

38. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein said subject is undergoing or will undergo administration of a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole as a combination therapy with the compound of formula (I) or a pharmaceutically acceptable salt thereof.

39. A method for preventing or treating a fungal infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a triazole-based antifungal agent selected from isavuconazole, voriconazole, fluconazole, itraconazole, and opelconazole, wherein said subject is undergoing or will undergo administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 as a combination therapy with the triazole-based antifungal agent.

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