RU2805930C1 - Use of compounds in treating fungal infections - Google Patents

Abstract

FIELD: chemistry; pharmaceuticals.

SUBSTANCE: invention relates to the treatment of fungal infections. A method of treating a fungal infection being a mold infection caused by the following fungi: Aspergillus spp., Scedosporium spp., Fusarium spp. or Mucorales or a combination thereof is disclosed, the said method comprises administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the therapeutically effective amount of Compound 1 provides a stable area over a 24 hour period under the concentration-time curve (AUC0-24) of Compound 1A at subject exceeding 200 mcg⋅h/ml of Compound 1A, and administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a treatment regimen comprising daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for a period of at least 4 weeks, wherein the regimen treatment includes a loading dose of Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate and a maintenance dose of Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate, where the loading dose of Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate is 2,000 mg and where the maintenance the dose includes a single daily administration of 600 to 1,500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

EFFECT: use of the invention provides effective treatment of fungal infections caused by Aspergillus spp., Scedosporium spp., Fusarium spp. or Mucorales or a combination thereof.

32 cl, 3 tbl, 3 ex

Description

OTHER APPLICATIONS RELATED TO THIS APPLICATION

This application claims benefit from U.S. Provisional Patent Application No. 62/985,274, filed March 4, 2020, which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] Fungal infections are a leading cause of human health problems. The present invention generally relates to the treatment of fungal infections in humans.

PREREQUISITES FOR CREATION OF THE INVENTION

[0003] Invasive infections caused by fungi such as Aspergillus, Fusarium, Scedosporium and fungi of the order Mucorales are difficult to treat, resulting in high mortality, even when patients receive standard treatment. The incidence of fungi resistant to standard antifungal drugs, including drugs from the azole, echinocandin, and amphotericin B classes, is increasing. There remains a significant unmet medical need for new broad-spectrum antifungals to treat serious invasive fungal infections and reduce the existing high morbidity and mortality.

SUMMARY OF THE INVENTION

[0004] In one aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to the subject with the fungal infection a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the fungal infection in the subject is caused by Aspergillus, Fusarium, Scedosporium and fungi of the order Mucorales or other intractable fungal infections and/or fungal infections caused by rare fungi.

[0005] In one aspect, described herein is a method of treating a fungal infection in a subject, comprising administering to the subject with the fungal infection a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

Where

The subject's fungal infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp. , Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp. ., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or a combination thereof;

a therapeutically effective amount of Compound 1 provides a stable area over a 24 hour period under the concentration-time curve (AUC _0-24 ) of Compound 1A in a subject greater than approximately 150 μg×h/ml of Compound 1A:

and administering Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a treatment regimen comprising daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least about 4 weeks.

[0006] In some embodiments, a therapeutically effective amount of Compound 1 provides a stable 24-hour area under the concentration-time curve (AUC _0-24 ) of at least about 180 μg×h/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a stable area under the concentration-time curve (AUC _0-24 ) over a 24 hour period of at least about 200 μg×h/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a stable area under the concentration-time curve (AUC _0-24 ) over a 24 hour period of at least about 250 μg×h/mL of Compound 1A.

[0007] In some embodiments, the fungal infection is a mold infection (mold infection). In some embodiments, the mold infection is caused by the fungi Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp. or Mucorales or a combination thereof. In some embodiments, the mold infection is caused by A. flavus, A. niger, A. fumigatus, A. terreus, S. apiospermum, S. boydii, S. dehoogii, F. solani, P. lilacinus, P. variotii, or Rhizopus oryzae, or a combination of these. In some embodiments, the mold infection is caused by Aspergillus spp. In some embodiments, the mold infection is caused by A. fumigatus. In some embodiments, the A. fumigatus strain is a Cyp51 or Fks1 mutant strain. In some embodiments, the A. fumigatus strain is AF293, AF41, EMFR S678P, F11628, AF72, or F14532.

[0008] In some embodiments, the fungal infection is a yeast infection (yeast infection). In some embodiments, the yeast infection is caused by Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Wickerhamomyces (Pichia) spp., or a combination thereof. In some embodiments, the yeast infection is caused by G. clavatum, T. asahii, T. mucoides, T. mycotoxinivorans, M. furfur, R. mucilaginosa, or S. cerevisiae, or a combination thereof.

[0009] In some embodiments, the fungal infection is a dimorphic fungal infection (dimorphic fungal infection). In some embodiments, the dimorphic fungal infection is caused by Emergomyces spp., Talaromyces spp. or Emmonsia-like fungi or a combination thereof.

[0010] In some embodiments, the yeast infection is caused by T. marneffei.

[0011] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is infected with HIV/AIDS or has cancer. In some embodiments, the cancer is acute myeloid leukemia or acute lymphoid leukemia. In some embodiments, the subject is diagnosed with neutropenia. In some embodiments, the subject is diagnosed with lymphopenia. In some embodiments, the subject is undergoing or has undergone chemotherapy treatment for cancer. In some embodiments, the subject is or has been treated with corticosteroids. In some embodiments, the subject is or has been treated with a tumor necrosis factor (TNF) inhibitor. In some embodiments, the subject is an organ transplant recipient. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant. In some embodiments, the subject has been diagnosed with graft-versus-host disease.

[0012] In some embodiments, the fungal infection is superficial, locally invasive, or disseminated throughout the subject's body. In some embodiments, the fungal infection is a skin infection, a lung infection, a sinus infection, a central nervous system infection, a brain infection, an eye infection, a heart infection, a kidney infection, a gastrointestinal infection, a stomach infection, a pelvic infection, a blood infection or a combination thereof.

[0013] In another aspect, described herein is a method of treating a fungal disease or condition in a subject, comprising administering to the subject with the fungal disease or condition a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

Where

the fungal disease or condition in the subject is aspergillosis, fusarium, scedosporiasis or mucormycosis or a combination thereof;

a therapeutically effective amount of Compound 1 provides a stable area over a 24 hour period under the concentration-time curve (AUC _0-24 ) of Compound 1A in a subject greater than approximately 150 μg×h/ml of Compound 1A:

and administering Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject is a treatment regimen comprising daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least about 4 weeks.

[0014] In some embodiments, a therapeutically effective amount of Compound 1 provides a stable 24-hour area under the concentration-time curve (AUC _0-24 ) of at least about 200 μg×h/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a stable area under the concentration-time curve (AUC _0-24 ) over a 24 hour period of at least about 250 μg×h/mL of Compound 1A.

[0015] In some embodiments, the subject is immunocompromised.

[0016] In some embodiments, the subject is infected with HIV/AIDS or has cancer. In some embodiments, the cancer is acute myeloid leukemia or acute lymphoid leukemia. In some embodiments, the subject is diagnosed with neutropenia. In some embodiments, the subject is diagnosed with lymphopenia. In some embodiments, the subject is undergoing or has undergone chemotherapy treatment for cancer. In some embodiments, the subject is or has been treated with corticosteroids. In some embodiments, the subject is or has been treated with a tumor necrosis factor (TNF) inhibitor. In some embodiments, the subject is an organ transplant recipient. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant. In some embodiments, the subject has been diagnosed with graft-versus-host disease.

[0017] In some embodiments, the fungal disease or condition is allergic bronchopulmonary aspergillosis, aspergillus sinusitis, azole-resistant A. fumigatus, aspergilloma, pulmonary aspergillosis, invasive aspergillosis, cutaneous aspergillosis, fusarium, scedosporiasis, rhinocerebral mucormycosis, pulmonary mucormycosis, dys seminated mucormycosis , mucormycosis of the abdominal cavity, mucormycosis of the stomach, mucormycosis of the skin, or a combination thereof.

[0018] In some embodiments, the treatment regimen includes a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0019] In some embodiments, the treatment regimen includes a loading dose of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, of about 2000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is achieved by administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (IV) infusion. In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion over about 30 minutes to about 4 hours.

[0020] In some embodiments, each loading dose contains about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose comprises administering about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject via intravenous (IV) infusion, followed by a second administration of about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. subject by intravenous (IV) infusion over approximately 24 hours after the first infusion.

[0021] In some embodiments, the maintenance dose is administered once daily, beginning on the second day of treatment. In some embodiments, the maintenance dose includes once daily administration of from about 600 mg to about 1500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 4 hours of intravenous infusion, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 600 mg to about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 4 hours, beginning on the second, third, or fourth day of treatment . In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally to the subject beginning on the second, third, or fourth day of treatment.

[0022] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject orally once daily, beginning on the second, third, or fourth day of treatment.

[0023] In some embodiments, beginning on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours of intravenous infusion; or b) from about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[0024] In some embodiments, beginning on the second day of treatment, about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by intravenous infusion; and beginning on the fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous (IV) infusion over a period of about 30 minutes to about 3 hours; or b) from about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[0025] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an antifungal agent. In some embodiments, the antifungal agent is a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, and an echinocandin antifungal agent. In some embodiments, the antifungal agent is amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, sertaconazole, sulconazole, tioconazole . albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine or terbinafine, anidulafungin, caspofungin, micafungin, rezafungin, or a pharmaceutically acceptable salt of any of the above numerical antifungal agents.

[0026] In another aspect, described herein is a method of treating a fungal or mold infection in a subject, the method comprising administering to the subject with the fungal or mold infection a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt, solvate or hydrate thereof;

Where,

The subject's fungal infection is caused by Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp., Rhizopus, Mucor spp., Lichtheimia spp., Cunninghamella spp., Acremonium spp., Rasamsonia spp. , Scedosporium spp., Schizophyllum spp., Trichoderma spp., Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp., Magnusiomyces (Geotrichum) spp. ., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi, or a combination thereof;

a therapeutically effective amount of Compound 1 provides a stable area over a 24-hour period under the concentration-time curve (AUC _0-24 ) of Compound 1A in a subject of at least about 150 μg×h/ml of Compound 1A:

in this case, the subject has resistance, contraindications, intolerance or lack of clinical response to standard antifungal therapy; and

wherein administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject is a treatment regimen comprising daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for at least about 4 weeks.

[0027] In some embodiments, a therapeutically effective amount of Compound 1 provides a stable 24-hour area under the concentration-time curve (AUC _0-24 ) of at least 200 μg×h/mL of Compound 1A. In some embodiments, a therapeutically effective amount of Compound 1 provides a stable area under the concentration-time curve (AUC _0-24 ) over a 24 hour period of at least 250 μg×h/mL of Compound 1A.

[0028] In some embodiments, the standard antifungal therapy includes an azole antifungal, an allylamine antifungal, an echinocandin antifungal, or a polyene antifungal. In some embodiments, the standard antifungal therapy includes amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, sertaconazole, sulcona zol, tioconazole , albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine or terbinafine, anidulafungin, caspofungin, micafungin, rezafungin, or a pharmaceutically acceptable salt of any of the above antifungal agents .

[0029] In some embodiments, the fungal infection is a mold infection. In some embodiments, the mold infection is caused by the fungi Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp. or Mucorales or a combination thereof. In some embodiments, the mold infection is caused by A. flavus, A. niger, A. fumigatus, A. terreus, S. apiospermum, S. boydii, S. dehoogii, F. solani, P. lilacinus, P. variotii, or Rhizopus oryzae, or a combination of these. In some embodiments, the mold infection is caused by Aspergillus spp. In some embodiments, the mold infection is caused by A. fumigatus. In some embodiments, the A. fumigatus strain is a Cyp51 or Fks1 mutant strain. In some embodiments, the A. fumigatus strain is AF293, AF41, EMFR S678P, F11628, AF72, or F14532.

[0030] In some embodiments, the fungal infection is a yeast infection. In some embodiments, the yeast infection is caused by Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., or Wickerhamomyces (Pichia) spp. or a combination thereof. In some embodiments, the yeast infection is caused by G. clavatum, T. asahii, T. mucoides, T. mycotoxinivorans, M. furfur, R. mucilaginosa, or S. cerevisiae, or a combination thereof.

[0031] In some embodiments, the fungal infection is a dimorphic fungal infection. In some embodiments, the dimorphic fungal infection is caused by Emergomyces spp., Talaromyces spp. or Emmonsia-like fungi or a combination thereof.

[0032] In some embodiments, the yeast infection is caused by T. marneffei.

[0033] In some embodiments, the subject is infected with HIV/AIDS or has cancer. In some embodiments, the cancer is acute myeloid leukemia or acute lymphoid leukemia. In some embodiments, the subject is diagnosed with neutropenia. In some embodiments, the subject is diagnosed with lymphopenia. In some embodiments, the subject is undergoing or has undergone chemotherapy treatment for cancer. In some embodiments, the subject is or has been treated with corticosteroids. In some embodiments, the subject is or has been treated with a tumor necrosis factor (TNF) inhibitor. In some embodiments, the subject is an organ transplant recipient. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant. In some embodiments, the subject has been diagnosed with graft-versus-host disease.

[0034] In some embodiments, the fungal infection or mold infection is superficial, locally invasive, or disseminated throughout the subject's body. In some embodiments, the fungal infection is a skin infection, a lung infection, a sinus infection, a central nervous system infection, a brain infection, an eye infection, a heart infection, a kidney infection, a gastrointestinal infection, a stomach infection, a pelvic infection, a blood infection or a combination thereof.

[0035] In some embodiments, the fungal infection includes the fungal disease or condition of allergic bronchopulmonary aspergillosis, allergic sinusitis, azole-resistant A. fumigatus, aspergilloma, pulmonary aspergillosis, invasive aspergillosis, cutaneous aspergillosis, fusarium, scedosporiasis, rhinocerebral mucormycosis, mucormycosis lungs, disseminated mucormycosis, mucormycosis of the abdominal cavity and pelvis, gastric mucormycosis, skin mucormycosis or a combination of these.

[0036] In some embodiments, the treatment regimen includes a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0037] In some embodiments, the treatment regimen includes a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof of about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous infusion. In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion over about 30 minutes to about 4 hours. In some embodiments, each loading dose contains about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose comprises administering about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, to a subject via intravenous (IV) infusion, followed by a second administration of about 1000 mg of Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. subject by intravenous (IV) infusion over approximately 24 hours after the first infusion.

[0038] In some embodiments, the maintenance dose is administered once daily, beginning on the second day of treatment.

[0039] In some embodiments, the maintenance dose includes a single daily administration of from about 600 mg to about 1500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0040] In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 4 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 600 mg to about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over about 30 minutes to about 4 hours, beginning on the second, third, or fourth day of treatment.

[0041] In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally to the subject beginning on the second, third, or fourth day of treatment.

[0042] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject orally once daily, beginning on the second, third, or fourth day of treatment.

[0043] In some embodiments, beginning on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes up to approximately 3 hours; or b) about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[0044] In some embodiments, beginning on the second day of treatment, about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; and, beginning on the fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; or b) from about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[0045] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with an additional therapeutic agent.

[0046] In some embodiments, the treatment regimen includes daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for about 4 weeks to about 12 weeks. In some embodiments, the treatment regimen includes daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof for about 4 weeks to about 6 weeks.

[0047] In some embodiments, the treatment regimen increases the chances of survival of the subject, reduces the subject's galactomannan levels, reduces the subject's β-d-glucan levels, or reduces a combination of levels thereof.

[0048] Provided are articles of manufacture comprising packaging material, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof in the packaging material, and a label indicating that Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is used to treat a fungal infection or to prevent or relieve one or more symptoms of a fungal infection.

[0049] Other purposes, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given for illustrative purposes only, as various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0050] There is a growing need for new and versatile treatments for fungal infections in patients. The occurrence of drug-resistant strains of fungi is increasing, especially the common species Aspergillus spp., as well as rare and difficult-to-treat molds, including Fusarium species, Scedosporium spp. and fungi of the order Mucorales, increasing the need for new antifungal therapies.

[0051] Invasive infections caused by Aspergillus, Fusarium, Scedosporium and molds of the order Mucorales are particularly difficult to treat, resulting in high mortality rates (50-80%), even when patients receive standard treatment. The incidence of fungi resistant to standard antifungal drugs, including drugs from the azole and echinocandin classes and amphotericin B, is increasing. Thus, there remains a significant unmet medical need for a new broad-spectrum antifungal agent to treat serious invasive fungal infections and reduce the existing high morbidity and mortality.

[0052] Aspergillosis is an infection caused by Aspergillus (a type of mold), i.e. mold found indoors and outdoors. Most people inhale Aspergillus spores every day without getting sick. However, people with weakened immune systems or lung disease are at higher risk of developing health problems due to Aspergillus. Types of health problems caused by Aspergillus include allergic reactions, lung infections, and infections of other organs.

[0053] In people with a significantly weakened immune system, the fungus can be transferred from the lungs through the bloodstream to the brain or other organs, including the eyes, heart, kidneys and skin. This is usually a bad sign as the condition becomes more severe and the risk of mortality increases. However, sometimes a skin infection allows an earlier diagnosis and treatment to begin.

[0054] When disease does occur, it can appear in several forms. The types of diseases caused by Aspergillus vary from allergic diseases to life-threatening generalized infections. The severity of aspergillosis is determined by various factors, but one of the most important is the state of the human immune system.

[0055] Allergic bronchopulmonary aspergillosis (ABPA) is a condition caused by an allergy to Aspergillus spores. The disease is quite common in asthmatics; up to 2.5% of adult asthmatics may develop asthma at some point in their lives. ABPA is also common in patients with cystic fibrosis entering adolescence and adulthood. In the long term, ABPA can lead to permanent lung damage (fibrosis or bronchiectasis) if the disease is not treated.

[0056] Aspergilloma occurs when a fungus grows in a body cavity, such as the sinus cavity, or the cavity of a specific organ, such as the lung. Any lung disease that forms cavities, such as tuberculosis or sarcoidosis, can make a person vulnerable to developing aspergilloma in the lungs. The spores penetrate the cavity and germinate, forming a fungal ball inside the cavity. In some people, cavities in the lungs are formed by Aspergillus, but the fungal ball is not observed. The fungus produces toxic and allergic products that can cause illness in humans.

[0057] Chronic pulmonary aspergillosis occurs when an Aspergillus infection causes cavities to form in the lungs, and can be a long-term (3 months or more) condition. One or more fungal balls (aspergillomas) may also be present in the lungs.

[0058] Aspergillus disease can occur in the sinuses, leading to aspergillus sinusitis. As in the lungs, aspergillus can cause three diseases - allergic sinusitis, fungal ball or invasive aspergillosis. Surgical sinus drainage usually resolves the problem unless the aspergillus has invaded sinuses deep inside the skull. In the latter case, antifungal drug therapy is used in combination with surgery.

[0059] If patients have a damaged immune system, such as in the case of leukemia or bone marrow transplantation, Aspergillus sinusitis occurs in a more severe form. In these cases, sinusitis manifests itself in the form of invasive aspergillosis. Symptoms include fever, facial pain, nasal discharge and headaches. Diagnosis is made by finding the fungus in fluid or tissue from the sinuses and scanning it. In most cases, surgery is performed, as it is important to find out what exactly is wrong, and often surgery is what helps destroy the fungus. Treatment with antifungal drugs is necessary.

[0060] Azole-resistant Aspergillus fumigatus occurs when the fungus becomes resistant to certain azole antifungals used in treatment.

[0061] Invasive aspergillosis is the most severe form of aspergillosis and usually affects people with weakened immune systems. Persons with weakened immune systems include, but are not limited to, persons who have had an organ transplant or stem cell transplant, persons with long-standing neutropenia, persons receiving cancer chemotherapy, persons receiving high doses of corticosteroids, persons receiving broad-spectrum drugs, antibiotics, or receiving any other immunosuppressive therapy. Invasive aspergillosis most often begins in the lungs and then spreads through the bloodstream, affecting other organs such as the heart, brain, kidneys, liver, and skin, among others. Invasive aspergillosis can be fatal due to the development of severe life-threatening complications such as shock, delirium, massive bleeding from the lungs, inflammation of the trachea and bronchi, organ failure, intracranial bleeding, brain damage, meningitis and stroke. For patients with invasive aspergillosis, survival is higher the earlier the diagnosis is made. Unfortunately, there is no good single diagnostic test. Treatment is often started when the condition is first suspected. This condition is usually diagnosed clinically in a person with a low immune system defense, such as a bone marrow transplant, low white blood cell count after treatment for cancer, AIDS, or severe burns. There is also a rare hereditary disease in which a person's immune system is weakened (chronic granulomatous disease), which puts the patient at moderate risk.

[0062] In some embodiments, invasive aspergillosis occurs in patients with chronic obstructive pulmonary disease (COPD).

[0063] Invasive pulmonary aspergillosis (IPA) is an increasingly common opportunistic fungal infection, usually occurring in patients who are neutropenic and/or under the influence of corticosteroids. The lungs are affected in approximately 85% of cases of invasive aspergillosis. Factors that influence whether patients acquire this life-threatening infection include: severity of neutropenia, duration of neutropenia, neutrophil dysfunction (eg, chronic granulomatous disease, severe combined immunodeficiency (SCID), late stage AIDS, or chronic leukemia), dose of corticosteroids, and duration of treatment with such, other immunosuppressants such as methotrexate and anti-TNF inhibitors, inoculum (eg, but not limited to, exposure to dust, compost or moldy materials), previous or current lung disease (increasing risks), presence of genetic markers such as high level of IL-10 production, and severe systemic diseases (such as but not limited to liver dysfunction). Additional agents/medicines that may weaken the immune system include: cyclosporine, tacrolimus, sirolimus, everolimus, interleukin inhibitors, pomalidomide, omalizumab, azathioprine, lenalidomide, and thalidomide.

[0064] Interleukin inhibitors include, but are not limited to, rilonacept, canakinumab, anakinra, reslizumab, brodalumab, ustekinumab, benralizumab, mepolizumab, tocilizumab, ixekizumab, dupilumab, secukinumab, tildrakizumab, guselkumab, sarilumab, basiliximab, risankizumab, siltuximab, daclizumab and daclizumab .

[0065] Dermal aspergillosis occurs when Aspergillus enters the body through a break in the skin (for example, after surgery or a burn wound) and causes an infection, usually in people with weakened immune systems. In some embodiments, cutaneous aspergillosis can also occur if invasive aspergillosis spreads to the skin from another part of the body, such as the lungs.

[0066] Other forms of aspergillosis include chronic cavitary pulmonary aspergillosis, subacute invasive pulmonary aspergillosis, aspergillus nodules, and infections of the nail beds, eyes, skin, sinuses, or ear canals.

[0067] Scedosporiasis is an infection caused by fungi of the genus Scedosporium, which includes two hyphomycetes of emerging medical importance, Scedosporium apiospermum and Scedosporium prolificans.

[0068] Fusarium species cause a wide range of infections in humans, including superficial, locally invasive and disseminated infections. The clinical form of Fusarium depends largely on the host's immune status and route of entry, with superficial and localized disease occurring primarily in immunocompetent patients and invasive and disseminated disease affecting immunocompromised patients. Risk factors for severe fusarium infection include prolonged neutropenia and T-cell immunodeficiency, especially in hematopoietic stem cell transplant recipients with severe graft-versus-host disease. The most common presentation of disseminated fusarium is a combination of characteristic skin lesions and positive blood cultures with or without pulmonary or sinus involvement. The prognosis is poor and is largely determined by the degree of immunosuppression and the extent of infection, with nearly 100% mortality among patients with persistent neutropenia and disseminated disease. In some embodiments, infections are identified clinically (or suspected) based on a combination of clinical and laboratory data.

[0069] Fusarium species are widely distributed in soil, underground and above-ground plant parts, plant debris and other organic substrates and are present in water throughout the world as part of water structure biofilms. The wide distribution of Fusarium species can be explained by their ability to grow on a wide range of substrates and efficient mechanisms for their dispersal.

More than 50 species of Fusarium have been identified, including plant and animal pathogens, some of which cause human infections. Twelve Fusarium species are associated with human infection: Fusarium solani was the most common, followed by Fusarium oxysporum, Fusarium verticillioidis and Fusarium moniliforme. Other infective species include Fusarium dimerum, Fusarium proliferatum, Fusarium chlamidosporum, Fusarium sacchari, Fusarium nygamai, Fusarium napiforme, Fusarium anthophilum and Fusarium vasinfectum. Fusarium solani is also the most common causative agent of Fusarium keratitis and, together with F. oxysporum, is responsible for the majority of cases of onychomycosis caused by Fusarium species.

[0071] Among immunocompetent hosts, the most common infections are keratitis and onychomycosis. Immunocompromised patients at high risk for fusarium infection are those with prolonged and severe neutropenia and/or severe T-cell immunodeficiency (Boutati, E.I., et al. 1997. Blood 90:999-1008). Unlike infection in a normal population, fusarium in an immunocompromised population is usually invasive and disseminated.

[0072] The primary route of entry for Fusarium spp. - the respiratory tract, followed by the skin at the site of tissue destruction and possibly mucous membranes. Airborne Fusarium is thought to be transmitted by inhalation of airborne Fusarium conidia, as evidenced by the occurrence of sinusitis and/or pneumonia in the absence of dissemination. The role of the skin as a portal of entry is evidenced by the development of infection due to damage to the skin resulting from trauma (car accidents, etc.), burns or onychomycosis in normal hosts, as well as the development of cellulitis (usually in areas of tissue damage, such as toes and fingers), infections can remain localized or progress to disseminated infections in immunocompromised patients (Nucci, M., et al., 2003. Cancer 98:315-319).

[0073] A striking characteristic of fusarium, in contrast to aspergillosis, is the high frequency of positive blood cultures, mainly in the context of disseminated disease. Sometimes fungemia is the only manifestation of fusarium, usually in the absence of neutropenia, in patients with central venous catheters. Antifungal treatment and removal of the catheter lead to cure in most of these cases.

[0074] Disseminated disease is the most common and complex clinical form of fusarium in immunocompromised patients, accounting for approximately 70% of all cases of fusarium in this population. Patients at risk for disseminated fusarium include those with acute leukemia and prolonged and profound neutropenia.

[0075] The most common presentation of disseminated disease is a combination of skin lesions and positive blood cultures, with or without involvement of other body sites (sinuses, lungs, etc.).

[0076] Many different types of fungi can cause mucormycosis. These species belong to the large group of molds Mucorales. These forms include Rhizopus, Rhizomucor and Mucor. Each type causes similar symptoms.

[0077] These molds are common in the environment and do not usually cause infection. Mucormycosis usually occurs in the presence of one of the following factors: poorly controlled diabetes; an immune system weakened by medications (such as corticosteroids or drugs that suppress the immune system) or by leukemia or other diseases or conditions that reduce the number of white blood cells in the blood; deferoxamine, used to treat iron overload. Additional agents/medicines that may weaken the immune system include: cyclosporine, tacrolimus, sirolimus, everolimus, interleukin inhibitors, pomalidomide, omalizumab, azathioprine, lenalidomide, and thalidomide.

[0078] In some embodiments, mucormycoses can be classified into rhinocerebral, pulmonary and disseminated, abdominopelvic and gastric, and cutaneous or chronic subcutaneous diseases. Common features of rhinocerebral, pulmonary, and disseminated disease include blood vessel invasion, hemorrhagic necrosis, thrombosis, and rapid death.

[0079] Rhinocerebral mucormycosis is more often associated with uncontrolled diabetes mellitus and ketoacidosis than with malignancy or deferoxamine therapy. Inhaled spores first colonize the superior turbinates and paranasal sinuses and cause sinusitis. Depending on the underlying disease, in some embodiments the fungus rapidly invades the central nervous system, causing symptoms such as altered mental status, coma, and death within days.

[0080] Pulmonary mucormycosis is usually observed in patients with leukemia, lymphoma, solid organ or bone marrow transplantation, and diabetes, but is also sometimes observed in otherwise healthy subjects. Disease manifestations range from localized nodular lesions to cavitary lesions and dissemination; in the latter case, massive hemoptysis usually occurs. Overall mortality is lower with isolated lesions than with severe pulmonary and disseminated diseases.

[0081] In some embodiments, the gastrointestinal disease is a manifestation of mucormycosis and is primarily associated with malnutrition with predisposing factors, especially in children with amoebic colitis, typhoid fever, and pellagra. In the most severe cases, the disease can be characterized by ulceration of the mucous membrane and germination of blood vessels, followed by the formation of necrotic ulcers; this form of the disease ends in death.

[0082] In some embodiments, cutaneous mucormycosis is a primary disease due to disruption of the skin barrier or occurs as a result of hematogenous dissemination from other sites, and the outcome of the disease is strictly dependent on the condition of the patients. In some embodiments, primary cutaneous mucormycosis affects the subcutaneous tissue, as well as the fat, muscle, and fascial layers.

[0083] The need for improved treatment of invasive fungal diseases remains high, especially with the growing number of immunocompromised patients, such as patients with acute myeloid leukemia (AML), patients with non-Hodgkin's lymphoma, and solid organ transplant recipients, who are in the increased risk category. risk of developing fungal infections and treatment of which can be difficult. Candida and Aspergillus species are well known as the two main causes of fungal diseases in these patients, although other emerging fungi, such as rare molds (eg, Fusarium spp., Scedosporium spp., and Mucorales fungi), raise the need to find new and more effective control strategies. these infections. Existing antifungals may be inconvenient to use, often poorly tolerated, have drug-drug interactions (DDIs), may not be available as intravenous or oral formulations, or are becoming increasingly ineffective due to the emergence of drug-resistant fungal strains.

Connection 1

[0084] Many patients have limited or no antifungal treatment options due to confirmed/suspected resistance, contraindications, intolerance, or lack of clinical response to standard antifungal therapy (SOC). Under these conditions, Compound 1 has advantages over SOC antifungal therapy, necessitating preliminary investigation of Compound 1 for the treatment of invasive mold infections (IMI).

[0085] Compound 1, a prodrug that is rapidly converted in vivo by phosphatases to the microbiologically active Compound 1A, is a broad-spectrum antifungal agent for the treatment of invasive fungal infections by both intravenous and oral routes of administration. Compound 1 is a prodrug with a labile phosphate moiety/moiety. The phosphate moiety improves the solubility of the drug in water at higher pH ranges, but also has limited stability.

[0086] Compound 1A inhibits the fungal glycosylphosphatidylinositol (GPI)-membrane-anchored enzyme transporter protein 1 (GWT1), a highly conserved inositol acylase that catalyzes an early step in the GPI-anchored protein biosynthetic pathway. This inhibition has a pleiotropic effect on the fungal cell due to inhibition of cell wall mannoprotein localization, which promotes cell wall integrity, biofilm formation, germ tube formation, and fungal growth. Compound 1A does not inhibit phosphatidylinositol glycan-anchored biosynthesis protein class W (PIGW), which is the closest mammalian ortholog of the fungal protein GWT1, consistent with the potential for a significant therapeutic window for the target.

[0087] Compound 1A demonstrated broad in vitro antifungal activity against Candida spp., Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium spp. and some Mucorales fungi, including activity against azole- and echinocandin-resistant strains. In mice immunosuppressed to 5-fluorouracil and IMIs (Aspergillus fumigatus, Scedosporium prolificans and Fusarium solani), Compound 1 or 1A demonstrated a statistically significant improvement in survival rates and a reduction in the number of pulmonary fungal colonies. In cyclophosphamide and cortisone acetate immunosuppressed mice with IMIs (A. fumigatus, S. apiospermum, F. solani and Rhizopus spp.), Compound 1 demonstrated a statistically significant improvement in survival rates and a reduction in fungal load.

[0088] In addition, Compound 1A demonstrated antifungal activity against a wide range of clinical isolates of rare mold infections and rare yeast infections, including activity against a number of Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp. , Dematiaceous spp., Mucorales fungi, Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp. , Lacazia spp., Emmonsia spp., Wickerhamomyces (Pichia) spp., Emergomyces spp., Talaromyces spp., or Emmonsia-like fungi. These rare types of molds and yeasts do not usually pose a threat to healthy people, but can lead to invasive mold infections in immunocompromised people.

[0089] In some embodiments, Compound 1 or Compound 1A is used to treat various fungal infections caused by Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidioides, or a combination thereof.

[0090] In some embodiments, Compound 1 or Compound 1A is used to treat various mold infections, including rare infections. In some embodiments, mold (common or rare) infections are caused by the fungi Aspergillus spp., Mucorales, Hyalohyphomycete, Phaeohyphomycete, or a combination thereof.

[0091] Aspergillus spp. include A. flavus, A. niger, A. fumigatus, A. terreus.

[0092] Mucorales fungi include Rhizopus spp., Mucor spp., Lichtheimia spp., Cunninghamella spp.

[0093] Hyalohyphomycete fungi include species include Acremonium spp., Fusarium spp., Paecilomyces spp., Rasamsonia spp., Scedosporium spp., Schizophyllum spp., Trichoderma spp.

[0094] Phaeohyphomycete fungi include Alternaria spp., Cladophialophora spp., Cladosporium spp., Exophiala spp., Fonsecaea spp., Lomentospora spp., Phialophora spp., Scopulariopsis spp.

[0095] Scedosporium spp. include S. apiospermum, S. boydii, S. dehoogii.

[0096] Fusarium spp. include F. solani.

[0097] Rhizopus spp. include Rhizopus oryzae.

[0098] In some embodiments, Compound 1 or Compound 1A is used to treat infections caused by the fungi Aspergillus spp., Scedosporium spp., Fusarium spp., Paecilomyces spp., Purpureocillium spp., Dematiaceous spp. or Mucorales, or a combination thereof; including A. flavus, A. niger, A. fumigatus, A. terreus, S. apiospermum, S. boydii, S. dehoogii, F. solani, P. lilacinus, P. variotii and Rhizopus oryzae.

[0099] In some embodiments, Compound 1A is used to treat various yeast and rare yeast infections, including those caused by Magnusiomyces (Geotrichum) spp., Trichosporon spp., Malassezia spp., Saprochaete spp., Kodamaea spp., Rhodotorula spp., Saccharomyces spp., Pseudozyma spp., Sporobolomyces spp., Exophiala spp., Lacazia spp., Emmonsia spp., or Wickerhamomyces (Pichia) spp., or a combination thereof; including G. clavatum, T. asahii, T. mucoides, T. mycotoxinivorans, M. furfur, R. mucilaginosa or S. cerevisiae.

[00100] In some embodiments, Compound 1A is used to treat various additional fungal infections, including dimorphic fungal infections caused by Emergomyces spp., Talaromyces spp. or Emmonsia-like fungi, or a combination thereof; and including T. marneffei.

[00101] Pharmacokinetic-pharmacodynamic (PK-PD) studies in immunosuppressed mice with invasive A. fumigatus infections showed that the area under the concentration-time curve (AUC) divided by the ratio of the minimum effective concentration (MEC) is the driving force efficiency. The dosing regimen used in this study provided a steady-state AUC of ≥200 μg×h/mL associated with drug efficacy (as measured by colony counts and improved survival) in immunocompromised mice with invasive pulmonary aspergillosis (IPA). In addition, formal PK-PD studies have demonstrated that the dosing regimen carries a good probability of target (PTA) for the majority of isolates expected to be identified in this study.

[00102] Phase 1 clinical studies of Compound 1 examined the safety, tolerability, and pharmacokinetics of single and multiple escalating doses administered intravenously (IV) and orally (PO). To date, a total of 197 healthy volunteers and 21 patients with acute myeloid leukemia (AML) have received Compound 1 in 5 phase 1 studies. The duration of multi-dose regimens in these studies was 7, 14 and 42 days (6 weeks).

[00103] Compound 1 may have potential advantages over the current SOC standard for the treatment of invasive infections caused by Aspergillus spp. or rare mold fungi. Additionally, Compound 1 has a differentiated safety profile, is available as intravenous (IV) and oral (PO) formulations, and may have fewer DDIs than SOC treatments.

[00104] Patients with azole-resistant mold infections, including azole-resistant A. fumigatus and some rare molds (eg, Fusarium spp., Scedosporium spp., species of the order Mucorales), are usually prescribed intravenous treatment with polyenes. Polyenes have been associated with a risk of nephrotoxicity, electrolyte imbalances, and infusion reactions, which are limiting factors in patient care. Compound 1 has broad-spectrum antifungal activity, including azole-resistant molds, and may potentially be safer and easier to use than polyenes.

[00105] Compound 1 may provide an advantage over polyenes for the treatment of breakthrough infections in patients receiving prophylaxis with triazoles active against molds. Compound 1 has the potential to provide antifungal activity against A. fumigatus and rare mold species without the potential toxicity caused by polyenes. Due to its wide tissue penetration, Compound 1 may be useful in the treatment of patients with invasive fungal infections of the eyes and central nervous system.

[00106] Compound 1 may benefit patients with invasive fungal infections who are unable to receive treatment with an azole active against molds due to intolerance, toxicity, or clinically significant drug interactions. Compound 1 has the potential to provide broad-spectrum antifungal activity without the risk of hepatic or other azole-associated toxicity and is expected to be less likely to cause clinically significant drug interactions.

[00107] Compound 1 has a novel mechanism of action with broad spectrum activity against Candida spp. (yeasts) and Aspergillus spp. (molds), including activity against polyene- and azole-resistant strains of Aspergillus spp. Compound 1 has demonstrated efficacy in a number of animal models of IMI, including Aspergillus spp., Fusarium spp., Scedosporium spp. and species of the order Mucorales. Compound 1 is available in both intravenous and oral forms with broad tissue distribution, including ocular tissue and the central nervous system, and is safe and well tolerated, with a favorable safety profile and DDI that is distinct from SOC antifungal therapy. Compound 1 can be used as a first-line treatment for IMIs due to its unique mechanism of action. Thus, Compound 1 has the potential to address the unmet needs of patients with limited antifungal treatment options due to confirmed/suspected resistance, contraindications, intolerance, or lack of clinical response to standard antifungal therapy (SOC) or without it.

Relevant terminology

[00108] Unless otherwise specified, the following terms as used in this application have the definitions given below. The use of the term “including,” as well as other forms such as “include,” “includes,” and “included,” is not intended to be limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[00109] The term "acceptable" with respect to a formulation, composition, or ingredient as used herein means no persistent adverse effect on the general health of the subject being treated.

[00110] The term "pharmaceutically acceptable salt" in relation to a compound refers to a salt of the compound that does not cause significant irritation to the mammal to which it is administered and does not substantially abolish the biological activity and properties of the compound. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, : Wiley-VCH/VHCA, 2002. In some embodiments, pharmaceutical salts are generally more soluble and dissolve more quickly in gastric and intestinal juices than nonionic compounds, making them useful in solid dosage forms. In addition, since their solubility is often a function of pH, it is possible for them to dissolve selectively in one part or another of the digestive tract, and in some cases this ability can be manipulated to provide delayed and sustained release. Also, since the salt-forming molecule is in some cases in equilibrium with the neutral form, in some cases its passage through biological membranes can be controlled.

[00111] In some embodiments, pharmaceutically acceptable salts are typically prepared by reacting the free base with a suitable organic or inorganic acid or by reacting an acid with a suitable organic or inorganic base. The term can be used in relation to any compound of the present invention. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate , glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, N - methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, trimethylammonium and valerate. In some embodiments, when an acid substituent such as -CO ₂ H is present, ammonium, morpholinium, sodium, potassium, barium or calcium salts and the like are formed. In some embodiments, when a basic group, such as an amino, or a basic heteroaryl ring, such as pyridyl, is present, an acid addition salt is formed, e.g., a hydrochloride salt, a hydrobromide salt, a phosphate salt, a sulfate salt, a trifluoroacetate salt, a trichloroacetate salt, an acetate salt. salt, oxalate salt, maleate salt, pyruvate salt, malonate salt, succinate salt, citrate salt, tartrate salt, fumarate salt, mandelate salt, benzoate salt, cinnamate salt, methanesulfonate salt, ethanesulfonate salt, picrate salt, etc. . Additional pharmaceutically acceptable salt forms of therapeutic agents are listed in Berge, et al., Journal of Pharmaceutical Sciences, Vol. 66(1), pp. 1-19 (1977).

[00112] The term “modulate” as used herein means interacting with a target directly or indirectly to modify the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[00113] The term "modulator" as used herein refers to a molecule that interacts with a target directly or indirectly. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, disruptor, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is a destructor.

[00114] The terms “administration,” “administer,” “administered,” and the like as used herein refer to methods that, in some cases, deliver compounds or compositions to the desired site of biological action. These routes include, but are not limited to, oral, intraduodenal, and parenteral routes of administration (including intravenous, intraperitoneal, intravascular, or infusion). Those skilled in the art will be familiar with methods of administration that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. In some embodiments, the compounds and compositions described herein are administered intravenously. In some embodiments, the compounds and compositions described herein are administered by intravenous infusion.

[00115] The terms “co-administration” and the like as used herein are intended to cover the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or in the same and the same or different times.

[00116] The terms “effective amount” or “therapeutically effective amount” as used herein refer to a sufficient amount of an agent or compound administered that relieves to some extent one or more symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of signs, symptoms or causes of disease or any other desired change in a biological system. For example, an “effective amount” for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in each individual case is not necessarily determined using methods such as, for example, dose escalation.

[00117] The terms "enhance" or "enhance" as used herein mean to increase or prolong either the effectiveness or duration of a desired effect. Thus, with respect to enhancing the action of therapeutic agents, the term "enhancement" refers to the ability to enhance or prolong either the effectiveness or duration of action of other therapeutic agents on the system. "Effect enhancing amount" as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

[00118] As used herein, the term "pharmaceutical combination" means a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, for example, a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and the co-agent are administered to a patient simultaneously in a single dose, dosage unit. The term "unfixed combination" means that the active ingredients, for example, a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a coagent are administered to a patient as separate components either simultaneously, in parallel (at the same time) or sequentially without specific interim time restrictions, and such administration provides effective levels of both compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

[00119] The terms “kit” and “manufactured item” are used synonymously.

[00120] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees, other apes, and ape species. In one aspect, the mammal is a human.

[00121] The terms “treat,” “treatment,” or “treatment” as used herein include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, such as stopping the progression of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition prophylactically and/or therapeutically.

[00122] As used herein, the term “about/about” means within “±10% of the value.”

Pharmaceutical compositions

[00123] In some embodiments, the compounds described herein are included in pharmaceutical compositions. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable inactive ingredients to facilitate processing of the active compounds into pharmaceutically usable preparations. The appropriate composition depends on the chosen route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for this disclosure.

[00124] In some embodiments, the compounds described herein are administered in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein is accomplished by any method that provides delivery of the compounds to the site of action. These methods include, but are not limited to, delivery by the enteral route (including oral, gastric or duodenal tube) or parenteral route (injection or infusion), although the choice of the most appropriate route of administration in some cases depends, for example, on the condition and disease of the recipient.

[00125] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is included in a pharmaceutical composition. As used herein, the term "pharmaceutical composition" refers to a liquid or solid composition containing a pharmaceutically active ingredient (eg, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof) and at least a carrier, wherein none of the ingredients is typically is not biologically undesirable in administered amounts.

[00126] Pharmaceutical compositions comprising Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, can take any physical form that is pharmaceutically acceptable. In some embodiments, the pharmaceutical compositions described herein are in a suitable form for oral administration. In one embodiment, such pharmaceutical compositions include a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00127] In some embodiments, conventional inert ingredients and conventional method of preparing pharmaceutical compositions are used. In some embodiments, known methods for preparing pharmaceutical compositions are used. All conventional types of compositions are contemplated, including, but not limited to, tablets, capsules and solutions. However, the amount of Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate is best defined in terms of an effective amount, that is, the amount of Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate that provides the desired dose to a subject in need of a given treatment.

[00128] In some cases, capsules are prepared by mixing Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof with a suitable diluent and filling the capsules with the appropriate amount of the mixture. Common diluents include inert powders such as various types of starch, powdered cellulose, particularly crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and similar food powders.

[00129] In some cases, tablets are prepared by direct compression, wet granulation, or dry granulation. Their formulations typically include diluents, binders, lubricants and disintegrants, as well as Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders are starch, gelatin and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums are also convenient, including gum acacia, alginates, methylcellulose, polyvinylpyrrolidine, etc. In some cases, polyethylene glycol, ethylcellulose and waxes are used as binders.

[00130] In some cases, the lubricant in the tablet helps prevent the tablet and punches from sticking to the die. In some cases, the lubricant is selected from solids such as talc, magnesium and calcium stearates, stearic acid and hydrogenated vegetable oils.

[00131] Tablet disintegrators are substances that swell when wet, breaking the tablet and releasing the compound. These include starches, clays, celluloses, alginates and gums. Specifically, tablet disintegrants include corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, and sodium lauryl sulfate.

[00132] Enteric formulations are often used to protect the active ingredient from the acidic contents of the stomach. Such compositions are created by coating a solid dosage form with a film of a polymer that is insoluble in acidic media and soluble in alkaline media. Examples of films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

[00133] Tablets are often coated with sugar as a flavoring and sealant. The tablets can also be coated in the desired color.

[00134] In some embodiments, pharmaceutical compositions for use in any of the methods presented herein are described in the Examples.

Subjects of the study

[00135] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is an immunocompromised human. In some embodiments, the human subject is approximately 1 year of age. In some embodiments, the human subject is over 1 year of age. In some embodiments, the human subject is an infant under about 1 month of age.

[00136] In some embodiments, the subject is infected with HIV/AIDS. In some embodiments, the subject is undergoing or has already undergone chemotherapy treatment for cancer. In some embodiments, the subject suffers from acute myeloid leukemia or acute lymphoid leukemia. In some embodiments, the subject has neutropenia, lymphopenia, or graft-versus-host disease. In some embodiments, the subject is or has been treated with corticosteroids. In some embodiments, the subject is or has been treated with a TNF inhibitor. In some embodiments, the subject is a transplant recipient. In some embodiments, the subject is the recipient of a hematopoietic stem cell transplant, bone marrow transplant, lung transplant, liver transplant, heart transplant, kidney transplant, pancreas transplant, or a combination thereof. In some embodiments, the subject is a recipient of a hematopoietic stem cell transplant. In some embodiments, the subject is a bone marrow transplant recipient. In some embodiments, the subject is a lung transplant recipient. In some embodiments, the subject is a liver transplant recipient. In some embodiments, the subject is a heart transplant recipient. In some embodiments, the subject is a kidney transplant recipient. In some embodiments, the subject is a pancreas transplant recipient.

[00137] In some embodiments, the subject is immunocompromised.

[00138] In some embodiments, the subject is undergoing therapy with at least one immunosuppressive drug. In some embodiments, the immunosuppressive drug increases the risk of opportunistic infections in a subject.

[00139] Immunosuppressants/medicines that can weaken the immune system include, but are not limited to, corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, everolimus, pomalidomide, omalizumab, azathioprine, lenalidomide, thalidomide, anti-TNF inhibitors, interleukin inhibitors, Janus inhibitors -kinases, sphingosine-1-phosphate receptor (S1P) agonists, S1P antagonists, calcineurin inhibitors, mTOR inhibitors, nucleotide synthesis inhibitors, biologics and monoclonal antibodies.

[00140] Corticosteroids include, but are not limited to, prednisolone, budesonide, prednisolone, methylprednisolone.

[00141] Janus kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib and upadacitinib.

[00142] Sphingosine-1-phosphate receptor antagonists include, but are not limited to, FTY720.

[00143] S1P agonists include, but are not limited to, ozanimod, etrasimod.

[00144] Calcineurin inhibitors include, but are not limited to, cyclosporine and tacrolimus.

[00145] mTOR inhibitors include, but are not limited to, sirolimus and everolimus.

[00146] Interleukin inhibitors include, but are not limited to, rilonacept, canakinumab, anakinra, reslizumab, brodalumab, ustekinumab, benralizumab, mepolizumab, tocilizumab, ixekizumab, dupilumab, secukinumab, tildrakizumab, guselkumab, sarilumab, basiliximab , risanklizumab, dadaclizumab, siltuxumab.

[00147] Nucleotide synthesis inhibitors include, but are not limited to, azathioprine, leflunomide, mycophenolate.

[00148] Biologics include, but are not limited to, TNF-alpha inhibitors, integrin inhibitors, IL-12/23 inhibitors. Biologics include, but are not limited to, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, etrolizumab, vedolizumab.

[00149] Monoclonal antibodies include, but are not limited to, basiliximab, daclizumab, alemtuzumab, rituximab, belatacept.

Dosage methods and treatment regimens

[00150] In one embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is used in the preparation of medicaments for the treatment of diseases or conditions caused by fungal infections in mammals. Methods of treating any of the diseases or conditions described herein in a mammal in need of such treatment include administering pharmaceutical compositions containing Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, or an active metabolite of Compound 1 (i.e., Compound 1A) in therapeutically effective amounts for the specified mammal.

[00151] In some embodiments, compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially relieve at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, prior therapy, the patient's medical condition, weight and response to medications, and the judgment of the treating physician. Therapeutically effective amounts are not necessarily determined by methods including, but not limited to, dose escalation and/or dose range clinical testing.

[00152] For prophylactic purposes, compositions containing Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof are administered to a patient predisposed or otherwise at risk of a particular disease or condition. Such amount is defined as a “prophylactically effective amount or dose.” In this application, the exact amounts also depend on the patient's health, weight, etc. When used, effective amounts for such use will depend on the underlying risk for fungal infection, prior therapy, the patient's medical condition and response to medications, and the judgment of the prescribing physician. In one aspect, the prophylactic treatment includes administering to a mammal that has previously suffered from at least one symptom of the disease causing the treatment and is currently in remission, a pharmaceutical composition containing Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, to prevent return of symptoms of a disease or condition.

[00153] In some embodiments, if the patient's condition does not improve, at the discretion of the physician, administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered continuously, that is, over an extended period of time, including throughout the life of the patient, to improve or control or stabilize symptoms of a disease or condition of a patient.

[00154] After the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced depending on the symptoms to a level at which the improved disease or condition is maintained. However, in some embodiments, the patient requires intermittent treatment on a long-term basis for any recurrence of symptoms.

[00155] In one aspect, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered daily to subjects in need of therapy with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered once daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily.

[00156] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily, for example, morning and evening.

[00157] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks , at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 1 month, at least 2 months, according to at least 3 months, at least 4 months, or more.

[00158] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered to a human subject on a continuous dosing schedule. In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a human subject on a continuous daily dosing schedule.

[00159] The term "continuous dosing regimen" refers to the administration of a specific therapeutic agent at regular intervals. In some embodiments, a continuous dosing regimen refers to the administration of a particular therapeutic agent at regular intervals without any interruption in taking the particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent in cycles. In some other embodiments, a continuous dosing regimen refers to the administration of a particular therapeutic agent in a cyclic manner, followed by a break in taking the particular drug (eg, a washout period or other similar period of time when no drug is administered). For example, in some embodiments, the therapeutic agent is administered once a day, twice a day, daily for a week and alternated with a subsequent week without administration of the therapeutic agent; or daily for two weeks followed by one or two weeks without administration of the therapeutic agent; or daily for three weeks, followed by one, two, or three weeks without administration of a therapeutic agent; daily for four weeks followed by one, two, three, or four weeks without administration of a therapeutic agent; administration of the therapeutic agent once a week followed by a week of no administration of the therapeutic agent; administration of the therapeutic agent every two weeks followed by two weeks of no administration of the therapeutic agent. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice daily.

[00160] The term "continuous daily dosing schedule" refers to the administration of a specific therapeutic agent each day at approximately the same time. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice daily. In some embodiments, the daily administration is three times daily. In some embodiments, the daily administration is more than three times per day.

[00161] In some embodiments, a specified amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered once daily. In some other embodiments, a specified amount of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered twice daily.

[00162] In some embodiments, in which no improvement in the human condition or disease is observed, the daily dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is increased. In some embodiments, the once-daily dosing schedule is changed to a twice-daily dosing schedule. In some embodiments, the frequency of administration is increased to provide continuous or more regular exposure to Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the frequency of administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is increased to provide repeated high levels of C _max on a regular basis and to maintain or more regular exposure, for example, at a higher AUC level.

[00163] In any of the foregoing aspects, further embodiments are provided comprising a single administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, including such further embodiments wherein Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered (i) once a day; or (ii) several times in one day.

[00164] In any of the above aspects, further embodiments are provided including repeated administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, including such further embodiments in which (i) Compound 1 is administered continuously or intermittently, e.g. in a single dose; (ii) the period between multiple administrations is 6 hours; (iii) Compound 1 is administered to a mammal every 8 hours; (iv) Compound 1 is administered to a mammal every 12 hours; (v) Compound 1 is administered to a mammal every 24 hours. In additional or alternative embodiments, the method includes a drug-free period during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of this period, dosing of the compound is resumed. In one embodiment, the duration of the drug-free period ranges from 2 days to 1 year.

[00165] Generally, a suitable dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for administration to a human will range from about 500 mg/day to about 2000 mg/day; from about 600 mg/day to about 2000 mg/day; from about 800 mg/day to about 2000 mg/day; or from about 1000 mg/day to about 2000 mg/day.

[00166] In some embodiments, administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises a treatment regimen that consists of administration of a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof followed by a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in a manner different from the maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in the same manner as a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00167] In some embodiments, the loading dose is administered as a solution by intravenous (IV) infusion.

[00168] In some embodiments, maintenance doses are administered orally in solid dosage forms. In some embodiments, the solid dosage forms are tablets. In some embodiments, maintenance doses are administered as a solution by intravenous (IV) infusion.

[00169] In some embodiments, the loading dose contains from about 1500 mg to about 2500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the loading dose contains about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (IV) infusion. In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion over about 30 minutes to about 3 hours. In some embodiments, each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to a subject by intravenous (IV) infusion over more than about 30 minutes, more than about 45 minutes, more than about 1 hour, more than about 1.5 hours, more than about 2 hours, more than about 2.5 hours, more than about 3 hours, or more than 3 hours. In some embodiments, each of the two loading doses contains about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[00170] In some embodiments, the loading dose comprises administering about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject via intravenous (IV) infusion followed by a second administration of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate thereof or hydrate to the subject by intravenous (IV) infusion over approximately 24 hours after the first infusion. In some embodiments, the second loading dose is administered within about 12 hours after the first loading dose, within about 13 hours after the first loading dose, within about 14 hours after the first loading dose, within about 15 hours after the first loading dose, within approximately 16 hours after the first loading dose, within approximately 17 hours after the first loading dose, within approximately 18 hours after the first loading dose, within approximately 19 hours after the first loading dose, within approximately 20 hours after the first loading dose, within approximately 21 hours after the first loading dose, within approximately 22 hours after the first loading dose, within approximately 23 hours after the first loading dose, or within approximately 24 hours after the first loading dose.

[00171] In some embodiments, maintenance dosing begins on the second day of treatment. In some embodiments, the maintenance dose is administered once daily, beginning on the second day of treatment.

[00172] In some embodiments, each maintenance dose comprises a single daily administration of from about 1000 mg to about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of from about 600 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 600 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of about 650 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 700 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 750 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 800 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of about 850 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 950 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of about 1050 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 1100 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of about 1150 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises a single daily administration of more than about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[00173] In some embodiments, each maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 3 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, each maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, or over 3 hours by intravenous infusion, starting on the second, third or fourth day of treatment.

[00174] In some embodiments, maintenance doses of about 600 mg to about 1500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof are administered by intravenous infusion over a period of about 30 minutes to about 5 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, maintenance doses are about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg , about 1150 mg or about 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 5 hours, starting on the second, third or fourth day of treatment.

[00175] In some embodiments, maintenance doses of about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof are administered over a period of about 30 minutes to about 3 hours by intravenous infusion, starting on the second, third, or fourth day of treatment. In some embodiments, maintenance doses are about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; such doses are administered over a period of about 30 minutes to about 3 hours by intravenous infusion, beginning on the second, third, or fourth day of treatment.

[00176] In some embodiments, each maintenance dose comprises a single daily administration of more than about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, each maintenance dose comprises once daily administration of from about 900 mg to about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, maintenance doses of about 900 mg to about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof are administered by intravenous infusion over a period of about 30 minutes to about 3 hours, beginning on the second, third, or fourth day of treatment. In some embodiments, maintenance doses of about 900 mg to about 2000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof are administered by intravenous infusion over more than 3 hours, beginning on the second, third, or fourth day of treatment.

[00177] In some embodiments, a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally to the subject beginning on the second, third, or fourth day of treatment.

[00178] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily to the subject beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 800 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject orally once daily beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject orally once daily, beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the subject orally once daily beginning on the second, third, or fourth day of treatment.

[00179] In some embodiments, a maintenance dose of about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily, or a daily dose is administered twice daily, in equal doses, to a subject starting from the second, third or fourth day of treatment. In some embodiments, a maintenance dose of about 800 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily, or a daily dose is administered twice daily in equal portions to the subject beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily, or a daily dose is administered twice daily in equal parts to the subject beginning on the second, third, or fourth day of treatment. In some embodiments, a maintenance dose of about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered orally once daily, or a daily dose is administered twice daily in equal parts to the subject beginning on the second, third, or fourth day. treatment.

[00180] In some embodiments, beginning on the second, third, or fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by intravenous infusion; or b) from about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[00181] In some embodiments, beginning on the second day of treatment, about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered over a period of about 30 minutes to about 3 hours by intravenous infusion; and beginning on the fourth day of treatment: a) about 600 mg to about 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered by intravenous infusion over a period of about 30 minutes to about 3 hours; or b) from about 800 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily.

[00182] In some embodiments, the daily dose or amount of active substance in a dosage form is lower or higher than the ranges specified herein due to a number of variables encountered during an individual's treatment regimen. In various embodiments, the daily and unit dosage varies depending on a number of variables, taking into account, but not limited to, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, subject parameters (eg, weight ) and the specific additional therapeutic agents to be administered (if applicable), as well as the judgment of the practitioner.

[00183] The toxicity and therapeutic efficacy of such therapeutic regimens is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD ₅₀ and ED ₅₀ . The dose relationship between toxic and therapeutic effects is the therapeutic index and is expressed as the ratio between LD ₅₀ and ED ₅₀ . In some embodiments, data obtained from cell culture assays and animal studies are used to determine a therapeutically effective daily dosage range and/or a therapeutically effective unit dose amount for use in mammals, including humans. In some embodiments, the daily dose of Compound 1 is within a circulating concentration range that includes the ED50 with minimal toxicity. In some embodiments, the daily dosage range and/or unit dosage amount varies within this range depending on the dosage form used and the route of administration used.

[00184] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvement in clinical symptoms associated with the infection, improvement in radiographic abnormalities, and resolution of fungemia, if present. In some embodiments, clinical symptoms associated with infection include, for example, general appearance, including the appearance of the skin, head, eyes, ears, nose, throat, neck, torso, or lymph nodes, or respiratory, cardiovascular, gastrointestinal, intestinal, musculoskeletal, genitourinary, nervous, lymphatic/hematological and endocrine/metabolic systems of the mammalian subject, as well as the mental state of the subject.

[00185] In some embodiments, the improvement in one or more outcome measures is at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more than 95%. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof to a mammal with a fungal or mold infection results in an improvement in one or more endpoints by at least or about 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2-fold. ,5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10 or more than 10 times. Such improvements are, in some embodiments, compared to a control. In some embodiments, the control is an individual who did not receive Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the control is an individual who did not receive a full dose of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the control is a baseline for the individual prior to receiving Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[00186] In some embodiments, methods of treating a fungal or mold infection in a subject with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in an improvement in one or more outcome measures. In some embodiments, a baseline score is determined, typically prior to administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Improvements in outcome measures are assessed using repeat assessments conducted during treatment with Compound 1 and compared to the baseline assessment and/or any previous assessment(s).

[00187] Screening patients for the presence of fungal infections and assessing the effectiveness of treatment with Compound 1 or its pharmaceutically acceptable salt, solvate or hydrate is carried out by several diagnostic testing methods, including: radiological analysis, including CT scans of the chest, sinuses and abdomen; culture and microscopy of samples from the respiratory tract; blood, serum or bronchoalveolar fluid test for fungal antigen; analysis of blood, serum or bronchoalveolar fluid for pathogenic DNA; lung biopsy (open, percutaneous or transbronchial); urine test for aspergillosis; and other molecular studies of samples obtained from the respiratory tract.

[00188] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by radiological techniques such as computed tomography (CT) scanning. In some embodiments, imaging modalities that detect inflammation are used, such as positron emission tomography or indium-labeled leukocyte scintigraphy. In some embodiments, radiological techniques are used to determine the presence of a fungal infection, such as allergic bronchopulmonary aspergillosis (ABPA), or aspergilloma, or a fungal ball. In some embodiments, CT signs of aspergillosis include: a halo sign, indicating pulmonary hemorrhage; air crescent sign indicating cavitation; and the hypoattenuation sign, as a precursor to the air crescent sign, which appears as relative hypoattenuation within the nodular lesion(s) (see A. Prasad, et al. J Clin Diagn Res. 2016 Apr; 10(4): TE01-TE05 ). In some embodiments, radiological techniques are used to determine the size or extent of the infection. In some embodiments, CT scans are performed every 7 days or 14 days while the mammal is being treated with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the overall infectious load is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% in a treatment regimen with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00189] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by fungal culture assay in a body fluid, such as bronchoalveolar fluid, sputum, bronchial scraping, or sinus aspirate. In some embodiments, the fungal load determined in the fungal culture is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after a treatment regimen with Compound 1 or a pharmaceutically acceptable salt thereof, solvate or hydrate.

[00190] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by a fungal antigen detection test such as 1,3-β-D-glucan or galactomannan in bodily fluid such as blood, serum or bronchoalveolar fluid. Measurement of galactomannan, 1,3-β-D-glucan as a biomarker is widely used for early diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients along with polymerase chain reaction (PCR) analysis.

[00191] 1,3-β-D-glucan is a common cell wall polysaccharide and is found in most fungi, such as, for example, Aspergillus spp. (ES Theel, et al., J Clin Microbiol. 2013 Nov; 51(11): 3478-3483). In some embodiments, methods of treating fungal infections in mammals with Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, result in improvements measured using a suitable 1,3-β-D-glucan test. In some embodiments, 1,3-β-D-glucan levels are measured in serum samples of the mammal. In some embodiments, 1,3-β-D-glucan levels are determined using a known 1,3-β-D-glucan detection assay, such as Fungitell (Associates of Cape Code, Inc., East Falmouth, MA, USA) , Wako (Wako Pure Chemical Industries, Ltd., Tokyo, Japan), Fungitec-G (Seikagaku, Kogyo, Tokyo, Japan), and Maruha (Maruha-Nichiro, Foods Inc., Tokyo, Japan). In some embodiments, the level of 1,3-β-D-glucan is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, not less than 35%, not less than 40%, not less than 45%, not less than 50%, not less than 55%, not less than 60%, not less than 65%, not less than 70%, no less than 75%, no less than 80%, no less than 85%, no less than 90%, or at least 95% after treatment with Compound 1 or a pharmaceutically acceptable salt thereof, solvate or hydrate. In some embodiments, continuous reduction of 1,3-β-D-glucan levels during treatment results in a favorable therapeutic response in patients with confirmed or probable invasive fungal infections.

[00192] Galactomannan is a polysaccharide antigen present primarily in the cell walls of Aspergillus spp. (M. Hites, et al., Ann Transl Med. 2016 Sep; 4(18): 353). Galactomannan can be released into the blood and other body fluids even in the early stages of Aspergillus infection, and the presence of this antigen can be detected for 1 to 8 weeks. In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by a suitable galactomannan test. In some embodiments, galactomannan levels are measured in serum samples of the mammal. In some embodiments, galactomannan levels are measured in bronchoalveolar lavage fluid samples of the mammal. In some embodiments, galactomannan levels are determined by a known galactomannan detection assay. In some embodiments, galactomannan levels are determined using a galactomannan enzyme-linked immunosorbent assay (ELISA). In some embodiments, galactomannan levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after administration of a treatment regimen with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, consistent reductions in galactomannan levels during treatment results in a favorable therapeutic response in patients with known or probable invasive fungal infections. In some embodiments, the sensitivity of the galactomannan assay is higher in neutropenic patients than in non-neutropenic patients because galactomannan molecules are in some cases cleared from neutrophils.

[00193] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by a suitable pathogen DNA test. In some embodiments, pathogen DNA levels are measured in blood samples of the mammal. In some embodiments, pathogen DNA levels are measured in serum samples of the mammal. In some embodiments, pathogen DNA levels are measured in bronchoalveolar lavage fluid samples of the mammal. In some embodiments, pathogen DNA levels are determined using a known pathogen DNA detection assay. In some embodiments, pathogen DNA levels are determined using next generation sequencing and/or polymerase chain reaction (PCR) analysis. In some embodiments, pathogen DNA levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% when using a treatment regimen with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00194] In some embodiments, methods of treating fungal infections in a subject with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in histological improvements in biopsy tissue samples collected from a subject with a fungal or mold infection. In some embodiments, the biopsy tissue is lung tissue.

[00195] In some embodiments, methods of treating aspergillosis in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof result in improvements measured by a urine aspergillosis test (K A Marr, et al., Clinical Infectious Diseases, Volume 67 , Issue 11, 1 December 2018, Pages 1705-1711). Briefly, a urine test for aspergillosis detects the presence of fungal antigens in the urine. Antigens contain galactofuranose and are detected using antibodies specific for such antigens. In some embodiments, the levels of these antigens are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, by at least 40%, by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% after administration of a treatment regimen with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00196] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof increase overall survival of the subject by at least 10%, at least 20%, at least 30% , not less than 40%, not less than 50%, not less than 60%, not less than 70%, not less than 80%, not less than 90%, not less than 95% or 100%. In some embodiments, overall survival is measured at 42 days. In some embodiments, overall survival is measured at 84 days.

[00197] In some embodiments, methods of treating fungal infections in mammals with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof reduce the all-cause mortality rate of a subject by at least 10%, by at least 20%, by at least 20%. by 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%, by at least 90%, by at least 95% or 100%. In some embodiments, the all-cause mortality rate is measured at 42 days. In some embodiments, the all-cause mortality rate is measured at 84 days.

Combined procedures

[00198] In some cases, it is advisable to administer Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof in combination with one or more other therapeutic agents.

[00199] In one embodiment, the therapeutic efficacy of Compound 1 or a pharmaceutically acceptable salt thereof is enhanced by administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic effect for the patient is increased). Or, in some embodiments, the beneficial effects to a patient are enhanced by administering Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof with another agent (which also includes a therapeutic regimen) that also has a therapeutic effect.

[00200] In one specific embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is co-administered with a second therapeutic agent, wherein Compound 1 or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate various aspects of the disease or condition being treated, thereby thereby providing a greater overall beneficial effect than administration of either therapeutic agent individually.

[00201] In any case, regardless of the disease or condition being treated, the overall beneficial effect experienced by the patient is either the sum of the effects of the two therapeutic agents or is the result of a synergistic interaction of the agents.

[00202] In some embodiments, various therapeutically effective doses of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof are used in the formulation of a pharmaceutical composition and/or in treatment regimens in which Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in combination with one or more additional agents, such as an additional therapeutically effective drug, adjuvant or the like. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens are not necessarily determined in a manner similar to that set out above for the active substances themselves. In addition, the methods of prevention/treatment described herein include the use of metronomic dosing, i.e. administering lower doses more frequently to minimize toxic side effects. In some embodiments, the combination treatment regimen includes treatment regimens in which administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof begins before, during, or after treatment with a second agent described herein and continues until any point during treatment with the second agent or after stopping treatment with a second agent. Combination treatment also includes treatment in which Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a second agent used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes intermittent treatment that is started and stopped at different times to facilitate clinical management of the patient.

[00203] It is understood that a dosage regimen for treating, preventing, or ameliorating the condition being treated will be modified according to a variety of factors (eg, the specific disease or condition from which the subject is suffering; age, weight, sex, diet, and health status subject). Thus, in some cases, the dosage regimen actually used may vary and, in some embodiments, differ from the dosage regimens set forth herein.

[00204] For the combination therapy described herein, the dosages of the co-administered compounds vary depending on the type of co-drug used, the specificity of the particular drug used, the disease or condition being treated, and so on. In additional embodiments, when coadministered with one or more other therapeutic agents, Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered either simultaneously with one or more other therapeutic agents or sequentially.

[00205] In combination therapy, multiple therapeutic agents (one of which is Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof) are administered in any order or even simultaneously. If administration is simultaneous, multiple therapeutic agents may be provided, by way of example only, in one unitary form or in multiple forms (e.g., as a single tablet or as two separate tablets; or as an intravenous infusion solution or as two separate infusion solutions for intravenous infusions).

[00206] Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, and combination therapy agents are administered before, during or after the onset of a disease or condition, and the time of administration of a composition containing Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof , may vary. Thus, in one embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is used as a prophylactic agent and is continuously administered to subjects prone to developing conditions or diseases for the purpose of preventing the occurrence of the disease or condition. In another embodiment, Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to a subject at or as soon as possible after the onset of symptoms. In specific embodiments, Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered as soon as possible after detection or suspicion of onset of the disease or condition and for a period of time necessary to treat the disease. In some embodiments, the duration of administration required for treatment varies and the duration of treatment is adjusted according to the specific needs of each subject. For example, in specific embodiments, Compound 1 or a pharmaceutically acceptable salt or solvate thereof, or a composition containing Compound 1 or a pharmaceutically acceptable salt or solvate thereof, is administered for at least 4 weeks, at least 6 weeks, at least 8 weeks , at least 10 weeks at least 12 weeks or more than 12 weeks.

Examples of agents for use in combination therapy

[00207] In some embodiments, Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in combination with one or more additional therapeutic agents used to treat fungal and/or mold infections in mammals.

[00208] In some embodiments, at least one additional therapeutic agent is administered concomitantly with Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the at least one additional therapeutic agent is administered less frequently than Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, at least one additional therapeutic agent is administered more frequently than Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, at least one additional therapeutic agent is administered prior to administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, at least one additional therapeutic agent is administered after administration of Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[00209] In some embodiments, the at least one additional therapeutic agent is an antifungal agent. In some embodiments, the second additional therapeutic agent is an antifungal agent selected from the group consisting of a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, and an echinocandin antifungal agent.

[00210] In some embodiments, the polyene antifungal agent is amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, or rimocidin.

[00211] In some embodiments, the azole antifungal agent is an imidazole, triazole, or thiazole. In some embodiments, the imidazole is bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, sertaconazole, sulconazole, or tioconazole. In some embodiments, the triazole is albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, or voriconazole. In some embodiments, the thiazole is abafungin.

[00212] In some embodiments, the allylamine antifungal agent is amorolfine, butenafine, naftifine, or terbinafine.

[00213] In some embodiments, the echinocandin antifungal agent is selected from the group consisting of anidulafungin, caspofungin, micafungin, and rezafungin.

Additional treatments

[00214] In addition to antifungal treatment, optimal treatment for patients with fungal infections includes surgical debulking of infected tissue and removal of venous catheters in some patients with confirmed catheter-based fungal infections. In some embodiments, treatment with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises G-CSF or GM-CSF, G-CSF stimulated granulocyte transfusions. In some embodiments, treatment with Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof involves the use of interferon gamma.

Kits and production products

[00215] Disclosed herein are kits for the treatment of a fungal infection in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00216] For use in the therapeutic applications described herein, kits and manufactured articles are also described herein. In some embodiments, such kits include a carrier, package, or container divided into compartments to accommodate one or more containers, such as vials, tubes, and the like, each of the containers including one of the individual elements used as described herein way. Suitable containers include, for example, bottles, vials, syringes and tubes. In some embodiments, the containers are made from a variety of materials, such as glass or plastic.

[00217] The industrial products provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, vials, tubes, inhalers, pumps, pouches, bottles, containers, syringes, tubes, and any other packaging material suitable for the selected formulation and intended route of administration and treatment. There are a wide range of compound formulations and compositions provided herein, as well as various treatment regimens that would benefit from administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[00218] The container(s) optionally have a sterile access opening (eg, the container is an IV bag or a vial with a stopper pierced by a hypodermic needle). Such kits optionally contain the compound with accompanying description or labeling or instructions regarding its use in the methods described herein.

[00219] The kit typically includes one or more additional containers, each containing one or more different materials (such as reagents, optionally in concentrated form, and/or enclosed in devices) desired from a commercial and user perspective for use of the compound described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels on the media, packaging, container, vial and/or tube indicating the contents and/or instructions for use, and package inserts with instructions for use. A list of instructions is usually also included.

[00220] In some embodiments, the label is on or associated with the container. In some cases, the label is on the container, especially when the letters, numbers or other symbols that form the label are affixed, cast or engraved on the container itself; a label is in some cases associated with a container if it is present in a container or carrier that also contains the container, for example, the label is provided as an insert. The label is in some cases used to describe how the contents are to be used for a particular therapeutic application. The label in some cases provides instructions for use of the contents, such as in the methods described here.

[00221] In some embodiments, a pharmaceutical composition containing Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is presented in a package or dispenser, which in some cases contains one or more unit dosage forms. The packaging in some cases, for example, contains metal or plastic foil, for example, is a blister pack. In some cases, instructions for use are included with the packaging or dispensing device. The package or dispenser is also in some cases accompanied by a notice associated with the container, in a form prescribed by the government agency that regulates the manufacture, use, or sale of pharmaceuticals, and describes the agency's approved forms of the drug for human or veterinary use. Such notice, for example, in some cases is FDA-approved labeling for prescription drugs or an agency-approved package insert. Compositions containing a compound provided herein in a compatible pharmaceutical carrier are, in some cases, also formulated, packaged and labeled for the treatment of the specified condition.

EXAMPLES

[00222] The following examples are presented for illustrative purposes only, without limiting the scope of the claims presented herein.

Example 1: Injection of Compound 1

[00223] Compound 1 for injection is prepared as a sterile solution, which is further diluted with 0.9% sodium chloride injection before administration. Compound 1 injection is a solution with a concentration of 20 mg/ml. The drug consists of Compound 1 drug, sodium chloride, potassium phosphate (dibasic and monobasic), hydrochloric acid, sodium hydroxide and water for injection (WFI).

[00224] A sterile 50 ml glass vial is filled with 35 ml of Compound 1 for injection, resulting in 700 mg/vial. Compound 1 Injection is further diluted and administered by intravenous infusion as specified in the clinical protocol. During the preparation of a solution containing Compound 1, Compound 1 for injection is filtered using a 0.2 μm filter before infusion to remove any inherent particles.

[00225] Table 1 describes the composition of Compound 1 injection, 20 mg/ml, to fill a 35 ml 50 ml vial.

Table 1 Component Approximate
concentration Contents per package Connection 1 20 mg/ml 700 mg Sodium chloride 6.1 mg/ml 213.5 mg Potassium phosphate, monobasic 0.16 mg/ml 5.6 mg Potassium phosphate, dibasic 3.27 mg/ml 114.5 mg Sodium hydroxide If necessary If necessary Hydrochloric acid If necessary If necessary Water for injections not applicable Q.S. 35 ml

QS=quantity sufficient

[00226] To prepare the injection composition of Compound 1, you must: 1. add sodium chloride, potassium phosphate (monobasic and dibasic) to a vessel containing water for injection; 2. adjust the pH to 8.0 using 1M hydrochloric acid solutions and/or 1M sodium hydroxide solutions; 3. slowly add the medicinal agent Compound 1 to the solution and mix at a temperature of 15°C to 30°C; 4. adjust the pH to 8.0 using hydrochloric acid solutions and/or sodium hydroxide solutions for dissolution; 5. Q.S. water for injection (dilute as prescribed by your doctor) and continue stirring at a temperature of 15°C to 30°C; 6. Aseptically filter through 2 x 0.2 µm membrane filters into sterile 50 ml vials with a filling volume of 35 ml, closed with a chlorobutyl stopper. (Note: At the completion of each batch manufactured, the integrity of the filter is verified using a bubble point test and the result is documented in the batch report); and 7. inspect vials before packaging and labeling.

Example 2: Compound 1 Tablets

[00227] Compound 1 tablets are formulated as 100 mg and 200 mg coated white tablets. Table 2 and Table 3 indicate the contents of Compound 1 tablets at doses of 100 and 200 mg, respectively.

table 2 Component Amount per tablet (% of weight) Function Connection 1 100 mg (25.0%) Active Ingredient Avicel DG ³ 231 mg (57.75% ¹ ) Diluent Pregelatinized starch 40 mg (5.0% ¹ , 5% ² ) Baking powder Colloidal Silicon Dioxide (Cab-o-sil M5P) 3 mg (0.75% ² ) Glidant Povidone 12 mg (3.0% ¹ ) Baking powder Talc 8 mg (2.0% ¹ ) Glidant Magnesium stearate
(HyQual) Plant Source 6 mg (0.5% ¹ , 1.00% ² ) Lubricant Kernel mass (mg) 400 mg Opadry II AMB, white coating ⁴ 20 mg (5.0%) Film coating Purified water not applicable Solvent Coated tablet weight (mg) 420 mg

¹ intragranular ² extragranular. ³ Avicel DG consists of 75% microcrystalline cellulose and 25% anhydrous dibasic calcium phosphate. ⁴ Opadry II AMB film coating is manufactured by ColorCon and consists of polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate and sodium lauryl sulfate.

Table 3 Component Amount per tablet (% of weight) Function Connection 1 200 mg (25.0%) Active Ingredient Avicel DG ³ 462 mg (57.75% ¹ ) Diluent Pregelatinized starch 80 mg (5.0% ¹ , 5% ² ) Baking powder Colloidal Silicon Dioxide (Cab-o-sil M5P) 6 mg (0.75% ² ) Glidant Povidone 24 mg (3.0% ¹ ) Baking powder Talc 16 mg (2.0% ¹ ) Glidant Magnesium stearate
(HyQual) Plant Source 12 mg (0.5% ¹ , 1.00% ² ) Lubricant Kernel mass (mg) 800 mg Opadry II AMB, white coating ⁴ 40 mg (5.0%) Film coating Purified water Not applicable Solvent Coated tablet weight (mg) 840 mg

¹ intragranular ² extragranular. ³ Avicel DG consists of 75% microcrystalline cellulose and 25% anhydrous dibasic calcium phosphate. ⁴ Opadry II AMB film coating is manufactured by ColorCon and consists of polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate and sodium lauryl sulfate.

Example 3: Open-label Phase 2 Study to Evaluate the Safety and Efficacy of Compound 1 in the Treatment of Patients with Invasive Mold Infections Caused by Aspergillus Species or Rare Molds

[00228] Indications: Treatment of patients with invasive mold infections (IMI) caused by Aspergillus spp. or rare molds.

[00229] Objectives: The primary objective of this study is to evaluate the safety and effectiveness of Compound 1 for the treatment of adult patients 18 years of age and older with infectious mold infections caused by Aspergillus spp. or infections caused by rare molds (eg, Scedosporium spp., Fusarium spp., and Mucorales) with limited antifungal treatment options.

[00230] The secondary objectives of this study are to: evaluate the overall response at the end of treatment (EOST); assessment of the safety parameters of Compound 1; assessment of pharmacokinetic (PK) parameters of Compound 1.

[00231] Population: This study will include male and female patients aged 18 years or older with a confirmed diagnosis of invasive aspergillosis or invasive rare mold infection. Patients have limited or no treatment options due to documented/suspected resistance, contraindications, intolerance, or lack of clinical response to standard of care (SOC) antifungal therapy recommended by appropriate regional/state authorities.

[00233] Patients must meet all of the following criteria to be eligible to participate in the study:

1. Male or female, 18 years of age or older.

2. Patients with proven or probable infectious mold infection (IMI) caused by Aspergillus spp. Patients with IMI caused by other filamentous fungi (eg, Scedosporium spp., Fusarium spp., and Mucorales fungi such as Mucor spp. or Rhizopus spp.) may also be included. Proven or suspected IMI is identified according to criteria from the modified version of the 2008 Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) Consensus Group.

3. Patients have limited or no treatment options due to documented or expected resistance, contraindications, intolerance, or lack of clinical response to SOC antifungal therapy prescribed according to regional/state treatment guidelines.

4. Patients for whom, in the opinion of the investigator, there is a potential benefit of using Compound 1 over the current SOC (eg, broad spectrum activity, activity against resistant mold pathogens, intravenous and oral formulations, favorable DDI profile, favorable liver safety profile, and kidney, widespread tissue distribution, including brain) and/or in which SOC antifungal therapy poses a significant risk of toxicity or treatment failure (eg, occurrence of IMI during antifungal prophylaxis, DDI risk, safety/toxicity risk, site of infection not accessible for use SOC).

5. Female patients of non-childbearing age must meet one of the following conditions:

A. Surgical sterility (hysterectomy, bilateral tubal ligation, bilateral salpingectomy and/or bilateral oophorectomy).

b. Postmenopause (amenorrhea for more than 12 months without an alternative medical cause).

6. Women of childbearing potential (i.e., not postmenopausal or surgically sterilized) must have a negative urine or serum pregnancy test within 96 hours prior to treatment (i.e., prior to the Day 1 dose). Participating women of childbearing age with male partners and men with female partners of childbearing age must agree to use 2 forms of contraception, one highly effective and the other an acceptable barrier method (male or female condom), throughout the study and in within 90 days after the last administration of the study drug. Highly effective methods of contraception include:

A. Combined (estrogen and progestogen containing) hormonal contraception associated with ovulation inhibition (PO, intravaginal or transdermal), progestogen hormonal contraception associated with ovulation inhibition (PO, injectable or implantable), intrauterine device or hormone-releasing intrauterine system contraception.

b. Bilateral tubal occlusion or partner vasectomy.

c. Sexual abstinence.

7. Male patients must agree to abstain from sperm donation and to use condoms with spermicide during sexual intercourse between screening and for at least 90 days after the last dose of study drug. Male patients should ensure that non-pregnant female partners of childbearing age agree to the contraceptive requirements specified in inclusion criterion 6.

8. Patients must be willing to participate in the study, provide written informed consent, and abide by the limitations of the study; Where permitted by local law, written informed consent may be obtained from a legally authorized representative for patients who are unable to provide informed consent.

[00234] Exclusion Criteria

[00235] Patients meeting any of the following criteria may not be eligible to participate in the study:

1. Refractory hematological malignancy.

2. Chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis.

3. Receipt of systemic (oral, intravenous, or inhaled) active antifungal therapy against molds for ≥120 hours immediately prior to initial dosing.

Note: An exception is authorized antifungal prophylaxis, which must be discontinued after initiation of Compound 1 treatment.

Additionally, patients with an invasive fungal mold infection with documented resistance or who have not been exposed to SOC may have received treatment more than 120 hours prior and still be eligible for the study. Enrollment of these patients should be discussed with the supervising healthcare professional prior to enrollment and prior treatment should not exceed >168 hours.

4. Signs of significant liver dysfunction, in the presence of any of the following:

A. Total bilirubin ≥3 x upper limit of normal (ULN), except in cases of isolated hyperbilirubinemia or documented Gilbert's disease.

b. Alanine transaminase or aspartate aminotransferase ≥5×ULN.

V. Severe or moderate hepatic impairment (Child-Pugh score >6) at any time within 2 weeks before dosing.

5. History of neurological disorders, including abnormal movements or seizures.

6. Patient receiving palliative care only.

7. Known hypersensitivity or other serious reaction to Compound 1 or any ingredient of Compound 1.

8. The patient is breastfeeding and/or pregnant or intends to become pregnant during the study period.

9. The study drug has already been administered for 30 days or 5 terminal half-lives (whichever is longer) prior to dosing of the study drug.

Note. Approved agents for the treatment of the underlying disease were permitted to be used during the study.

10. Previous participation in this study or any previous study of Compound 1.

11. Concomitant use of drugs that are strong inducers of CYP enzymes (for example, rifampin, carbamazepine, phenytoin, rifabutin, efavirenz, nevirapine, phenobarbital, modafinil, enzalutamide, drugs based on St. John's wort).

12. The presence of any other conditions or laboratory abnormalities that, in the opinion of the Investigator or Sponsor, place the patient at an unacceptable risk for participation in the study or may interfere with the evaluations included in the study.

[00236] Study design and duration:

[00237] The study is a multicenter, open-label, single-arm, phase 2 study to evaluate the safety and efficacy of Compound 1 for the treatment of IMIs caused by Aspergillus spp. or rare molds (eg Scedosporium spp., Fusarium spp. and Mucorales fungi). Patients aged 18 years and older will undergo screening procedures for up to 5 days, after which eligible patients will participate in study drug treatment for up to 6 weeks, followed by a follow-up visit 4 weeks after EOST and a follow-up telephone interview 12 weeks after day 1 (at day 84). The total duration of patient participation in the study will be approximately 12 weeks, including a follow-up telephone survey required on day 84. at the discretion of the investigator and after consultation with a medical supervisor, if the situation allows. Patients requiring treatment for more than 6 weeks may be switched to another licensed antifungal therapy (OLAT) at the discretion of the investigator and in consultation with a medical supervisor if the situation allows.

[00238] This study will consist of a single treatment arm involving the administration of a loading dose of 1000 mg of Compound 1 administered over 3 hours by twice daily intravenous infusion (BID) during the first 24 hours after the start of the first infusion. On days 2 and 3, 600 mg of Compound 1 will be administered over 3 hours by intravenous infusion once daily (QD). From day 4 to EOST, the intravenous dose of Compound 1 remains 600 mg administered over 3 hours by intravenous QD infusion, or patients can be switched to oral 800 mg Compound 1 QD. The decision to switch from intravenous administration to Compound 1 orally is at the discretion of the investigator and can be made any day beginning on day 4. Patients may be switched back to intravenous treatment as needed if they cannot tolerate oral medications. Oral Compound 1 can be administered on an outpatient basis.

[00239] Administration of Compound 1 should be continued for at least 4 weeks, but not more than 6 weeks (including the loading dose [Day 1]). After 4 weeks, if the investigator documents improvement or resolution of clinical signs and symptoms, for example, if follow-up imaging shows improvement (if applicable); or a mycological response is observed (if repeat sampling is possible), the investigator may decide to discontinue the dose.

[00240] Dosage forms and route of administration:

[00241] On Study Day 1 (or during the first 24 hours if dosing begins in the evening), a loading dose of Compound 1 of 1000 mg will be administered over 3 hours by intravenous infusion twice daily.

[00242] On study days 2 and 3, a maintenance dose of 600 mg of Compound 1 will be administered over 3 hours by QD intravenous infusion.

[00243] On study day 4 prior to EOST, a maintenance dose of Compound 1 will be administered as follows:

600 mg Compound 1 by QD IV infusion over 3 hours, or

800 mg PO QD

[00244] Criteria for switching from intravenous to oral dosage:

[00245] Patients who have completed at least 3 days of intravenous administration of Compound 1 may be eligible for oral (PO) replacement on study day 4 and beyond. Patients must meet all of the following criteria to switch from intravenous (IV) to oral (PO) administration of Compound 1:

The patient is clinically stable according to the investigator.

The patient is able to swallow tablets

[00246] The decision to switch from intravenous to oral administration of Compound 1 will be based on the judgment of the investigator and can be made on any day from day 4 onwards. Patients may be switched back to intravenous treatment as needed if they cannot tolerate oral medications. Oral administration of Compound 1 can be performed on an outpatient basis.

[00247] Rationale for the choice of dose and treatment regimen:

[00248] In a pharmacokinetic/pharmacodynamic (PK-PD) study, immunocompromised mice were infected with 6 strains of A. fumigatus, including wild-type, azole-resistant, and echinocandin-resistant strains. Groups of animals were administered Compound 1 at various fractionated doses. The ratio AUC 0 to 24 hours (AUC _(0-24) )/MEC was found to be the PK-PD index that best correlates with antifungal efficacy assessed by fungal load (conidial equivalents [CEs] measured by qPCR in real time) in lung homogenates. Stasis and log1 fall endpoints were defined as the number of A. fumigatus in CEs immediately before Compound 1 administration compared to CEs at the 96-hour assessment endpoint. The median total drug AUC/MEC at which stasis and 1-log kill endpoints were achieved for each A. fumigatus strain were 2801.6 and 5258.2.

[00249] In 2017 and 2018, the antifungal activity of Compound 1A against Aspergillus spp. surveillance data from clinical isolates indicate that the majority (98.5%) of Aspergillus isolates have MEC values between 0.008 and 0.03 μg/ml. The 90% patient MEC (MEC90) for Aspergillus isolates likely to be found in the clinical patient population studied is 0.03 μg/mL.

[00250] This study will evaluate a single-dose regimen of Compound 1. In Phase 1 studies in healthy volunteers, this dosing regimen was found to be safe and well tolerated in this study. Although the study allows for switching to PO as early as day 4, the following table describes the estimated overall AUC _(0-24) and PTA values for stasis in CE at MEC ₉₀ with a concomitant switch to PO (oral) on day 7 .

Loading IV BID
(Day 1 [Baseline]) IV
Supporting QD
(Days 2-7) P.O.
Supporting QD
(Days 8-42) AUC _(0-24)
(Days 7/14/42) PTAs at MEC ₉₀
(stasis [Day 14]) 1000 mg 600 mg 800 mg 195/224/224 ≥90%

AUC _(0-24) = area under the plasma concentration-time curve from point 0 to point 24 hours; BID=twice daily; IV=intravenous; MEC90=minimum effective concentration in 90% of patients; PO=oral ;PTA=probability of goal achievement; QD=once daily.

[00251] The dosing regimen used in this study provided a stable AUC of ≥200 μg×h/ml, and was effective (as measured by colony counts and improved survival) in immunocompromised mice with IPA. In addition, formal studies of PK-PD demonstrated that the dosing regimen had a favorable PTA for the majority of isolates expected to be found in this study.

[00252] Formal PK-PD diagnostics for invasive infections of rare molds (eg, Fusarium spp., Scedosporium spp., Mucorales fungi) have not yet been performed. However, immunocompromised animal models of rare mold infections show improvements in colony counts and survival at AUC provided by the dosing regimen used in this study.

[00253] Effectiveness endpoints

[00254] Primary: All-cause mortality through day 42. Note: All-cause mortality will represent the percentage of patients who die between the first dose of study drug and day 42 from any cause.

[00255] Secondary: overall clinical response in EOST

[00256] Research: All-cause mortality up to day 84; change from baseline in galactomannan levels; change from baseline β-d-glucan levels.

[00257] Drug safety parameters:

[00258] Safety assessments will include physical examination, vital signs, clinical laboratory evaluations, 12-lead ECG, any other tests, and adverse events. Assessment of adverse adverse events is performed at screening, baseline, during study drug treatment, at EOST, and 2 and 4 weeks after EOST or early discontinuation.

[00259] Results:

[00260] Population: A total of 12 patients received primary treatment. All of these patients have limited treatment options based on confirmed/suspected resistance, contraindications, intolerance, or lack of clinical response to standard antifungal therapy (SoC), such as amphotericin B treatment; or patients have serious underlying diseases and a poor prognosis due to the underlying disease and fungal infection. Most of these patients have probable invasive aspergillosis.

[00261] Response: Four patients completed treatment within 42 days. Four additional patients who did not complete 42 days of treatment showed early signs of response. Overall, treatment demonstrated a good response (on or before day 42) in 8 patients, with seven of 12 treated patients surviving at day 42. Five of the deaths observed were due to: an underlying disease/condition such as malignancy or COPD (3 patients); progression of fungal disease (1 patient); and unknown cause (1 patient). Patients also demonstrated a good overall response on clinical and radiological follow-up.

[00262] Advanced Access Program:

[00263] Population: A total of 15 patients with life-threatening/serious fungal infections were treated with minor modifications. These patients were either treatment naïve, denied, or refused standard antifungal therapy (SoC) such as amphotericin B and had no other treatment options. Of these patients, 12 had invasive Fusarium infection, and the remaining patients had Aspergillus/Lichtheimia infection, C. albicans infection, or L. prolificans infection. All patients had poor/no response to SoC antifungals such as amphotericin B and/or developed treatment toxicity/intolerance. These patients had a wide range of fungal infection sites in the sinuses, spine, ankles, skin, eyes, brain, or disseminated infections. Many of these patients were also diagnosed with an underlying disease/condition such as AML/ALL/MDS, SC/solid organ transplant, or trauma.

[00264] Dosing Regimen Additions: Seven patients received an intravenous dose of Compound 1, and six of these seven switched to oral doses. Eight patients received oral doses only. Two patients received a higher starting dose of Compound 1 (1000 mg PO QD). In addition, eight patients received 400 mg of Compound 1 orally twice daily rather than 800 mg once daily.

[00265] Due to the nature of the patient population that has either no or poor response to SoC antifungals such as amphotericin B, there was no SoC washout period before starting treatment: nine patients continued to receive amphotericin B treatment for a specified period time in combination with Compound 1; of these, seven of nine patients discontinued amphotericin B within 15 days of starting Compound 1; three patients were unable to continue treatment with amphotericin B due to renal toxicity problems.

[00266] Clinical Response: Of the fourteen patients treated long enough to assess response, twelve had either a favorable response or a response with improvement in signs and symptoms of infection, such as reduction in skin lesions, and/or improvement confirmed by radiographic examination . Seven of 11 patients who discontinued treatment with amphotericin B experienced improvement in renal function; while renal function remained stable in four patients who showed no obvious improvement in renal function.

[00267] Compound 1 was generally well tolerated by patients with significant underlying medical conditions over the long treatment period.

[00268] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the scope of this application and the scope of the appended claims.

Claims (51)

1. A method of treating a fungal infection in a subject, comprising administering to the subject with the fungal infection a therapeutically effective amount of Compound 1 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein the fungal infection in the subject is a mold infection caused by Aspergillus spp., Scedosporium spp., Fusarium spp. or Mucorales or a combination thereof; a therapeutically effective amount of Compound 1 provides a stable area over a 24-hour period under the concentration-time curve (AUC _0-24 ) of Compound 1A in a subject greater than 200 μg⋅h/ml of Compound 1A 1A; and administering Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject comprises a treatment regimen comprising daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for a period of at least 4 weeks, wherein the treatment regimen includes a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is 2000 mg and wherein the maintenance dose includes a single daily administration of 600 to 1500 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. 2. The method according to claim 1, where the mold infection is caused by Aspergillus spp. 3. The method according to claim 2, where the mold infection is caused by A. fumigatus . 4. The method according to claim 3, wherein the A. fumigatus strain is a Cyp51 or Fks1 mutant strain. 5. The method of claim 4, wherein the A. fumigatus strain is AF293, AF41, EMFR S678P, F11628, AF72 or F14532. 6. Method according to any one of claims 1 to 5, where the subject has a weakened immune system. 7. Method according to any one of claims 1 to 6, wherein the subject is infected with HIV/AIDS or has cancer. 8. Method according to any one of paragraphs. 1-7, where: the subject has acute myeloid leukemia, acute lymphoid leukemia, neutropenia, lymphopenia, or a combination thereof; or the subject is undergoing or has undergone chemotherapy treatment for cancer, treatment with corticosteroids, treatment with a tumor necrosis factor (TNF) inhibitor, or treatment with a combination thereof; or the subject is an organ transplant recipient, a hematopoietic stem cell transplant recipient, or has graft-versus-host disease; or Any combination of the above is observed. 9. Method according to any one of claims 1 to 8, wherein the fungal infection is superficial, locally invasive or disseminated throughout the subject. 10. The method according to any one of claims 1 to 9, wherein the fungal infection is a skin infection, a pulmonary infection, a sinus infection, a central nervous system infection, a brain infection, an eye infection, a heart infection, a kidney infection, a gastrointestinal tract infection , stomach infection, pelvic infection, blood infection, or a combination of these. 11. The method of claim 1, wherein a loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to a subject by intravenous (I.V.) infusion. 12. The method of claim 1, wherein the loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof comprises administering two doses of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (I.V.) infusion. 13. The method of claim 12, wherein each loading dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to a subject by intravenous (I.V.) infusion over a period of 30 minutes to 4 hours. 14. The method of claim 12 or 13, wherein each loading dose contains 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof. 15. Method according to any one of paragraphs. 1-14, wherein the loading dose comprises administering 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (I.V.) infusion followed by a second administration of 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof to a subject by intravenous (IV) infusion. I.V.) infusion within 24 hours after the first infusion. 16. The method according to any one of claims 1-15, where the maintenance dose is administered once a day starting from the second day of treatment. 17. The method according to any one of claims 1 to 16, wherein a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of 30 minutes to 4 hours beginning on the second, third or fourth day of treatment. 18. The method according to any one of claims 1 to 16, wherein the maintenance dose is from 600 to 1200 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and said maintenance dose is administered over a period of 30 minutes to 4 hours by intravenous infusion starting from the second, third or fourth day of treatment. 19. Method according to any one of paragraphs. 1-16, wherein a maintenance dose of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally to the subject beginning on the second, third or fourth day of treatment. 20. Method according to any one of paragraphs. 1-16, wherein the maintenance dose is 800 to 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and said maintenance dose is administered orally once daily to the subject beginning on the second, third or fourth day of treatment. 21. Method according to any one of paragraphs. 1-16, where starting from the second, third or fourth day of treatment: a) 600 to 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of 30 minutes to 3 hours; or b) 800 to 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily. 22. Method according to any one of paragraphs. 1-16, where starting on the second day of treatment, 600 to 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of 30 minutes to 3 hours; and starting from the fourth day of treatment: a) 600 to 900 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered by intravenous infusion over a period of 30 minutes to 3 hours; or b) 800 to 1000 mg of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered orally once daily. 23. Method according to any one of paragraphs. 1-22, wherein Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in combination with an additional therapeutic agent. 24. The method of claim 23, wherein the additional therapeutic agent is an antifungal agent. 25. The method of claim 24, wherein the antifungal agent is a polyene antifungal agent, an azole antifungal agent, an allylamine antifungal agent, or an echinocandin antifungal agent. 26. The method according to claim 24, where the antifungal agent is amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, sertaconazole, sulconazole, thioconazole, albeconazole, efinaconazole, epoxiconazole, fluconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine or terbinafine, anidulafungin, caspofungin, micafungin, rezafun gin or a pharmaceutically acceptable salt of any of the above antifungal agents. 27. The method of claim 1, wherein the subject has resistance, contraindication, intolerance, or lack of clinical response to standard antifungal therapy. 28. The method of claim 27, wherein the standard antifungal therapy comprises an azole-based antifungal agent, an allylamine-based antifungal agent, an echinocandin-based antifungal agent, or a polyene-based antifungal agent. 29. The method according to claim 27, where the standard antifungal therapy includes amphotericin B, candicidin, filipin, gamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isavuconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxyconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine or terbinafine, anidulafungin, caspofungin, mi kafungin, rezafungin or a pharmaceutically acceptable salt of any of the above antifungal agents. 30. Method according to any one of paragraphs. 1-29, wherein the treatment regimen comprises daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for a period of 4 to 12 weeks. 31. Method according to any one of paragraphs. 1-30, wherein the treatment regimen comprises daily administration of Compound 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for a period of 4 to 6 weeks. 32. Method according to any one of paragraphs. 1-31, wherein the treatment regimen increases the subject's chances of survival, reduces the subject's galactomannan levels, reduces the subject's β-d-glucan levels, or provides a combination thereof.