Treatment of nontuberculous mycobacterial infections

Abstract

The present invention relates to a method of achieving a positive therapeutic response against nontuberculous mycobacterial (NTM) infections by administering an oral dose of epetravorole to a human subject.

Description

Detailed Description of the Invention

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 286,989, filed December 7, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] BACKGROUND OF THEINVENTION There is a need for improved methods for treating nontuberculous mycobacterial (NTM) infections in human subjects.

[0003] Summary of the Invention In one aspect, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering epetravorole to a human subject in need of treatment for the infection using a dosing regimen comprising administering the epetravorole at an oral dose of between about 250 mg and about 1000 mg on the first day of the dosing regimen, the oral dose being administered daily or every other day, wherein the dosing regimen is continued until a positive therapeutic response is achieved.

[0004] Detailed Description of the Invention (I. Definition) In order to more fully understand this application, several definitions are provided below. Such definitions are intended to encompass all grammatical equivalents.

[0005] The term "about" in connection with a numerical value can include the numerical value itself as well as a range of values ​​from that numerical value plus or minus 10%. For example, the amount "about 10" includes 10 and any amount between 9 and 11. For example, the term "about" in connection with a numerical value can also include a range of values ​​from the numerical value plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0006] Certain embodiments disclosed herein may be further limited in the claims using the terms "consisting of" or "consisting essentially of." When used in a claim, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to the materials or steps specified and those materials or steps that do not materially affect the basic and novel characteristics. The embodiments of the disclosure described in the claims are essentially or explicitly described and operative in the present specification.

[0007] As used in the context of describing this disclosure (particularly in the context of the claims which follow), the terms "a," "an," "the," and similar reference words are intended to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0008] The following abbreviations are used: ADH = alcohol dehydrogenase; AE = adverse event; AESI = adverse event of special interest; AIDS = acquired immune deficiency syndrome; ALIS = Amikacin liposome inhalation suspension; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATS = American Thoracic Society; AUC = area under the concentration-time curve; AUC ∞ = area under the concentration-time curve from time 0 to infinity; AUC 0-24= area under the concentration-time curve from time 0 to 24 hours; CD4 = cluster of differentiation 4; CDAD = Clostridioides difficile-associated diarrhea; C. difficile = Clostridioides difficile; CL = total body clearance from plasma; CLSI = Clinical and Laboratory Standards Institute; C max = peak plasma drug concentration; C min=Minimum Plasma Drug Concentration;CRA=Clinical Research Associate;CrCl=creatinine clearance;CRO=Contract Research Organization;CT=Computed Tomography;CTA=Clinical trial authorization;CTCAE=Common Terminology Criteria for Adverse Events;CYP=cytochrome P450;DSMB=Data and Safety Monitoring Board;ECG=Electrocardiogram;eCRF=Electronic case report form;EDC=Electronic data capture;EIU=Exposure In Utero;EOT=End of Therapy;ERS=European Respiratory Society;ESCMID=European Society of Clinical Microbiology and Infectious Diseases;FAS-PRO=Full Analysis Set-Patient Reported Outcomes Set-Patient-Reported Outcome);FDA=Food and Drug Administration;FOCP=Female patient of childbearing potential;GCP=Good Clinical Practice;GI=Gastrointestinal;HFM=Hollow-fiber macrophage;HIV=Human immunodeficiency virus;ICF=Informed consent form;ICH=International Council for Harmonisation;IDSA=Infectious Diseases Society of America;IEC=Independent Ethics Committee;IR=Immediate-release;IRB=Institutional Review Board;IRT=Interactive Response Technology;ITT=Intent-to-Treat;IV=Intravenous;LAR=Legally authorized representative;LFU=Late Follow-up;Log=Logarithmic;LPA=Line probe assay;MAC=Mycobacterium avium complex;M. avium=Mycobacterium avium;M. chimaera=Mycobacterium chimaera;MCID=Minimal clinically important difference difference);MedDRA=Medical Dictionary for Regulatory Activities;MIC=Minimum inhibitory concentration;M. intracellulare=Mycobacterium intracellulare;NADPH=Nicotinamide adenine dinucleotide phosphate;NIMP=Non-investigational medical product;NTM=Nontuberculous mycobacteria(l);OBR=Optimized background regimen;PD=Pharmacodynamic(s);P-gp=P-glycoprotein;PK=Pharmacokinetic(s);Patient- Reported Outcome;PT=Preferred term;QD=Once daily;QTcF=QT interval corrected using Fridericia's formula;RBC=Red blood cell;rRNA=ribosomal ribonucleic acid;SAE=Serious adverse event;SAP=Statistical Analysis Plan;SOC=System organ class;SUSAR=Suspected Unexpected Serious Adverse Reaction;t; 1 / 2 = elimination half-life; TEAE = treatment-emergent adverse event; T max = Time to reach maximum plasma drug concentration; tRNA = Transferred ribonucleic acid; ULN = Upper limit of normal; Vd = Volume of distribution; V ss = apparent volume of distribution at steady state.

[0009] As used herein, "epetravorol of the present invention" refers to epetravorol, salts (eg, pharma- ceutically acceptable salts), solvates, and hydrates of these compounds.

[0010] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.

[0011] symbol

[0012] [ka]

[0013] indicates where the displayed moiety is attached to the remainder of the molecule, whether utilized as a bond or displayed perpendicular to a bond.

[0014] As used herein, IC 50 refers to the amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0015] As used herein, EC 50 refers to the dose, concentration, or amount of a particular test compound that induces a dose-dependent response of 50% of the maximal expression of a particular response induced, elicited, or potentiated by the particular test compound.

[0016] As used herein, the term "positive therapeutic response" refers to a reduction or amelioration or elimination of the progression, severity, and / or effects associated with an infection as described herein, or an improvement in the infectious state, or an improvement in the disease associated with an infection, or an enhancement of the immune system response in a human subject, or an improvement in one or more symptoms (preferably one or more identifiable symptoms) of an infection as described herein, resulting from the administration of one or more therapies. In certain embodiments, the term "positive therapeutic response" refers to an improvement in at least one measurable physical parameter of an infection as described herein, such as colony count, degree of infection, or severity of infection. In other embodiments, the term "positive therapeutic response" refers to an inhibition of the progression of an infection as described herein, either physically, e.g., by stabilization of an identifiable symptom, physiologically, e.g., by stabilization of a physical parameter, or both. In other embodiments, the term "positive therapeutic response" refers to an enhancement of the immune system response of a human subject. In exemplary embodiments, achieving a positive therapeutic response to an infection as described herein provides an improvement in the disease associated with the infection, or lack of disease progression, and / or an improvement in symptoms associated with the infection, or lack of symptom progression. For example, achieving a positive therapeutic response to an infection described herein refers to one or more of the following: (1) a reduction in bacterial colony count; (2) a reduction in the extent of the infection; (3) a reduction in the severity of the infection; and (4) some relief from one or more other symptoms associated with a disease or condition. In some embodiments, achieving a positive therapeutic response to an infection described herein comprises administering a composition described herein for a predefined period of time, discontinuing administration for another specific period of time, and resuming administration of a composition described herein for yet another specific period of time.In some embodiments, achieving a positive therapeutic response to an infection as described herein includes administering a composition as described herein until one of the responses as described herein is achieved, pausing administration of the composition as described herein while the positive therapeutic response continues to be observed, and resuming administration of the composition as described herein when the positive therapeutic response is no longer observed.In an exemplary embodiment, achieving a positive therapeutic response is treating an infection as described herein.In an exemplary embodiment, achieving a positive therapeutic response is treating a disease as described herein.

[0017] A positive therapeutic response according to the present invention includes a "therapeutically effective amount" of the pharmaceutical agent used. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.

[0018] A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the drug to elicit a desired response in the individual, and is an amount in which any toxic or detrimental effects of the treatment are outweighed by the beneficial effects of the treatment.

[0019] As used herein, the term "fasted state" can refer to when a human subject has not consumed food for at least 1 hour prior to administration of a test agent, or when a human subject has not consumed food for at least 2 hours after administration of a test agent, or when a human subject has not consumed food for at least 1 hour prior to administration of a test agent and at least 2 hours after administration of a test agent.

[0020] As used herein, the term "in need of treatment" may refer to when a human subject is found to have an infection as described herein, such as an NTM infection, by clinical and / or microbiological and / or radiological evaluation. As used herein, the term "in need of treatment" may refer to when a human subject is found to have an infection as described herein, such as an NTM infection, by microbiological and / or radiological evaluation. As used herein, the term "in need of treatment" may refer to when a human subject is found to have an infection as described herein, such as an NTM infection, by microbiological evaluation. As used herein, the need for treatment may be assessed by analyzing a sputum sample, as used herein. As used herein, the need for treatment may be assessed by analyzing a deep bronchial sample, as described herein. As used herein, the need for treatment may be assessed by radiographic analysis of the human subject, as described herein. As used herein, the need for treatment may be assessed by a computed tomography (CT) scan of the chest of the human subject, as described herein. As used herein, the need for treatment may be assessed by a computed tomography (CT) scan of the lungs of the human subject, as described herein.

[0021] The amount of a particular compound described herein provided to a human subject may depend on the body weight of the human subject, which may be obtained by a human, such as a medical professional (such as a doctor or nurse) or a human subject, by conventional and commercially available means.

[0022] As used herein, the terms "patient" and "human subject" may be used interchangeably.

[0023] (II. Overview) The present invention provides methods of achieving a positive therapeutic response against nontuberculous mycobacterial (NTM) infections by orally administering epetravorole according to the dosing regimens described herein.

[0024] (III. Epetravorole) Epetraborole has a structure according to the following formula:

[0025] [ka]

[0026] Epetravorole can be prepared according to the methods disclosed in PCT Patent Publication No. WO2008 / 157726 (PCT Patent Application No. PCT / US2008 / 07550); U.S. Patent No. 7,816,344 (U.S. Patent Application No. 12 / 142,692); PCT Patent Publication No. WO2011 / 127143 (Patent Application No. PCT / US2011 / 031384); and U.S. Patent No. 9,243,003 (U.S. Patent Application No. 13 / 639,594), all of which are expressly incorporated herein by reference.

[0027] Epetraborole may form hydrates with water; may form solvates with alcohols such as methanol, ethanol, propanol, etc.; may form adducts with amino compounds such as ammonia, methylamine, ethylamine, etc.; may form adducts with acids such as formic acid, acetic acid, etc.; may form complexes with ethanolamine, quinoline, amino acids, etc.

[0028] In an exemplary embodiment, the invention provides epetravorol, or a salt, hydrate, or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides epetravorol, or a salt, hydrate, or solvate thereof. In an exemplary embodiment, the invention provides epetravorol, or a salt thereof. In an exemplary embodiment, the salt is a pharma- ceutically acceptable salt. In an exemplary embodiment, the invention provides epetravorol hydrochloride. In an exemplary embodiment, the invention provides epetravorol, or a hydrate thereof. In an exemplary embodiment, the invention provides epetravorol, or a solvate thereof. In an exemplary embodiment, the epetravorol is epetravorol hydrochloride.

[0029] In an exemplary embodiment, epetravorol is administered in an amount between about 200mg and about 1100mg. In an exemplary embodiment, epetravorol is administered in an amount between about 250mg and about 1000mg. In an exemplary embodiment, epetravorol is administered in an amount between about 200mg and about 300mg, or between about 225mg and about 275mg, or between about 240mg and about 260mg, or about 250mg, or 250mg. In an exemplary embodiment, epetravorol is administered in an amount between about 400mg and about 600mg, or between about 450mg and about 550mg, or between about 475mg and about 525mg, or between about 490mg and about 510mg, or about 500mg, or 500mg. In exemplary embodiments, epetravorole is administered in an amount between about 600mg and about 900mg, or between about 650mg and about 850mg, or between about 700mg and about 800mg, or between about 725mg and about 775mg, or between about 740mg and about 760mg, or about 750mg, or 750mg.In exemplary embodiments, epetravorole is administered in an amount between about 900mg and about 1100mg, or between about 925mg and about 1075mg, or between about 950mg and about 1050mg, or between about 975mg and about 1025mg, or between about 990mg and about 1010mg, or about 1000mg, or 1000mg.For any of the embodiments in this paragraph, epetravorole is suitable for oral administration. For any of the embodiments in this paragraph, the epetravorol is in a unit dosage suitable for oral administration, for example, a single pill or capsule or tablet containing between about 475 mg and about 525 mg of epetravorol.

[0030] Once prepared, epetravorol can be administered to a human subject as described herein, such as in the dosing regimens described herein.

[0031] (III.a) Pharmaceutical Compositions and Pharmaceutical Administration Epetravorol can be incorporated into pharmaceutical compositions suitable for administration to human subjects according to the dosing regimens described herein.

[0032] Typically, the pharmaceutical composition comprises epetravorole and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, etc., that are physiologically compatible and suitable for administration to a subject in the methods described herein.

[0033] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and a filler. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and cellulose. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and microcrystalline cellulose.

[0034] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and a glidant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and silicon dioxide. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and colloidal silicon dioxide.

[0035] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and a disintegrant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and sodium. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and croscarmellose sodium.

[0036] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and a stearate salt. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole and magnesium stearate.

[0037] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, a filler, and a flow agent. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, cellulose, and silicon dioxide. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, microcrystalline cellulose, and colloidal silicon dioxide.

[0038] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, a filler, and a disintegrant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, cellulose, and sodium. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, microcrystalline cellulose, and croscarmellose sodium.

[0039] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a filler, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, cellulose, and a stearate salt. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, microcrystalline cellulose, and magnesium stearate.

[0040] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, a glidant, and a disintegrant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, silicon dioxide, and sodium. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, colloidal silicon dioxide, and croscarmellose sodium.

[0041] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a glidant, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, silicon dioxide, and a stearate. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, colloidal silicon dioxide, and magnesium stearate.

[0042] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a disintegrant, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, sodium, and a stearate. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, croscarmellose sodium, and magnesium stearate.

[0043] In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, a filler, a glidant, and a disintegrant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, cellulose, silicon dioxide, and sodium. In an exemplary embodiment, the pharmaceutical composition comprises epetravorole, microcrystalline cellulose, colloidal silicon dioxide, and croscarmellose sodium.

[0044] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a filler, a flow agent, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, cellulose, silicon dioxide, and a stearate. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

[0045] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a glidant, a disintegrant, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, silicon dioxide, sodium, and a stearate salt. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.

[0046] In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, a filler, a flow agent, a disintegrant, and a lubricant. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, cellulose, silicon dioxide, sodium, and stearate. In an exemplary embodiment, the pharmaceutical composition comprises epetravorol, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.

[0047] In an exemplary embodiment, the pharmaceutical composition comprises an amount of epetravorol between about 200mg and about 1100mg. In an exemplary embodiment, the pharmaceutical composition comprises an amount of epetravorol between about 250mg and about 1000mg. In an exemplary embodiment, the pharmaceutical composition comprises an amount of epetravorol between about 200mg and about 300mg, or between about 225mg and about 275mg, or between about 240mg and about 260mg, or about 250mg, or 250mg. In an exemplary embodiment, the pharmaceutical composition comprises an amount of epetravorol between about 400mg and about 600mg, or between about 450mg and about 550mg, or between about 475mg and about 525mg, or between about 490mg and about 510mg, or about 500mg, or 500mg. In exemplary embodiments, the pharmaceutical composition comprises epetravorol in an amount between about 600mg and about 900mg, or between about 650mg and about 850mg, or between about 700mg and about 800mg, or between about 725mg and about 775mg, or between about 740mg and about 760mg, or about 750mg, or 750mg. In exemplary embodiments, the pharmaceutical composition comprises epetravorol in an amount between about 900mg and about 1100mg, or between about 925mg and about 1075mg, or between about 950mg and about 1050mg, or between about 975mg and about 1025mg, or between about 990mg and about 1010mg, or about 1000mg, or 1000mg. For any of the embodiments of this paragraph, the pharmaceutical composition is suitable for oral administration. For any of the embodiments in this paragraph, the pharmaceutical composition is a unit dose suitable for oral administration, for example, a single pill or capsule or tablet containing between about 475 mg and about 525 mg of epetravorol. For any of the embodiments in this paragraph, the pharmaceutical composition comprises epetravorol hydrochloride.

[0048] Epetravorol can be administered by various methods known in the art.In an exemplary embodiment, the route / mode of administration is oral.As will be understood by those skilled in the art, the route and / or mode of administration will vary depending on the desired results.

[0049] (IV. Other Nontuberculous Mycobacterial Treatments) In an exemplary embodiment, epetravorole may be administered with other compounds to achieve a positive therapeutic response against nontuberculous mycobacterial infections. Examples of these other compounds are provided below: (Ethambutol) Ethambutol has a structure according to the following formula:

[0050] [ka]

[0051] Ethambutol is produced commercially by a number of manufacturers, including Barr Laboratories, Akorn, Sanofi, Cadila, Lupin, and Delmar. Ethambutol hydrochloride tablets of 100 mg and 400 mg for oral administration are available.

[0052] Paragraph Z: In an exemplary embodiment, ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg.

[0053] Paragraph Y: In an exemplary embodiment, ethambutol or a hydrate, solvate, or pharma- ceutically acceptable salt thereof is administered daily at an oral dose of between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg. In an exemplary embodiment, between about 600 mg and about 2000 mg, or between about 600 mg and about 800 mg, or between about 800 mg and about 1000 mg, or between about 1000 mg and about 1200 mg, or between about 1200 mg and about 1400 mg, or between about 1400 mg and about 1600 mg, or between about 1600 mg and about 1800 mg, or between about 1800 mg and about 2000 mg of ethambutol or a hydrate, solvate, or pharma- ceutically acceptable salt thereof is administered daily.

[0054] Paragraph X: In an exemplary embodiment, ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, three days per week. In exemplary embodiments, ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered three days per week at an oral dose of between about 900 mg and about 3400 mg, or between about 900 mg and about 1200 mg, or between about 1200 mg and about 1500 mg, or between about 1500 mg and about 1800 mg, or between about 1800 mg and about 2100 mg, or between about 2100 mg and about 2400 mg, between 2400 mg and about 2700 mg, or between about 2700 mg and about 3000 mg, or between about 3000 mg and about 3400 mg.

[0055] (clarithromycin or azithromycin) Azithromycin is produced commercially by a number of manufacturers, including Pfizer, Sandoz, Teva, Alembic, Lupin, Fresenius, Hospira, and Aurobindo. Azithromycin is available in 250 mg, 500 mg, and 600 mg tablets for oral administration. Azithromycin is available in 500 mg / vial for intravenous administration. Azithromycin is available in 100 mg / 5 mL suspension for oral administration.

[0056] Paragraph W: In exemplary embodiments, azithromycin is administered in an oral dose of between about 200 mg and about 550 mg, or between about 200 mg and about 300 mg, or between about 225 mg and about 275 mg, or about 250 mg, or about 250 mg, or between about 450 mg and about 550 mg, or between about 475 mg and about 525 mg, or about 500 mg, or 500 mg. In exemplary embodiments, azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily or three days per week in an oral dose of between about 200 mg and about 550 mg.

[0057] Paragraph V: In an exemplary embodiment, azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 225 mg and about 275 mg, or about 250 mg. In an exemplary embodiment, azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 475 mg and about 525 mg, or about 500 mg.

[0058] Paragraph U: In an exemplary embodiment, azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 475 mg and about 525 mg, or about 500 mg, three days per week.

[0059] Clarithromycin is produced commercially by a number of manufacturers, including Sandoz, Century Pharmaceuticals, Teva, Wockhardt, and Alembic. Clarithromycin is available in 250 mg and 500 mg tablets for oral administration. Clarithromycin is available in 125 mg / 5 mL or 250 mg / 5 mL suspensions for oral administration.

[0060] Paragraph T: In exemplary embodiments, clarithromycin is administered in an oral dose of between about 400 mg and about 600 mg, or between about 450 mg and about 550 mg, or between about 475 mg and about 525 mg, or about 500 mg, or 500 mg, or between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg. In exemplary embodiments, clarithromycin is administered at an oral dose of between about 950 mg and about 1050 mg daily, or at an oral dose of about 1000 mg daily, or at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at about 500 mg twice daily, or at an oral dose of 500 mg twice daily. In exemplary embodiments, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg daily or three days a week. In exemplary embodiments, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 400 mg and about 600 mg twice daily, at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, every day or three days a week.

[0061] Paragraph S: In an exemplary embodiment, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or at a dose of 1000 mg. In an exemplary embodiment, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily.

[0062] Paragraph R: In an exemplary embodiment, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg, three days per week. In an exemplary embodiment, clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily, three days per week.

[0063] (Rifampicin) Rifampicin, also known as rifampin, is commercially produced by a number of manufacturers, including Akorn, Lupin, Epic Pharma, Oxford, Fresenius, Sanofi Aventis, Novartis, Otto Brandes, Arudavis Labs, and Sichuan Long March Pharma. Rifampicin 150 mg and 300 mg capsules for oral administration are available. Rifampicin 600 mg / vial for intravenous administration is available.

[0064] Paragraph Q: In an exemplary embodiment, rifampicin is administered at an oral dose of between about 5 mg / kg and about 15 mg / kg, or between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg, or 10 mg / kg. In an exemplary embodiment, rifampicin is administered at an oral dose of between about 350 mg and about 700 mg, or between about 350 mg and about 500 mg, or between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg, or 450 mg, or between about 500 mg and about 700 mg, or between about 550 mg and about 650 mg, or between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg, or 600 mg. In an exemplary embodiment, rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg, daily or three days per week.

[0065] Paragraph P: In an exemplary embodiment, rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg. In an exemplary embodiment, rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg. In an exemplary embodiment, rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg.

[0066] Paragraph O: In an exemplary embodiment, rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered three days per week at an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg.

[0067] (Rifabutin) Rifabutin is commercially produced by a number of manufacturers, including Pfizer, Chongqing Huapont Pharma, Lupin, Novitium Pharmaand Guangzhou Tosun Pharma. 150 mg capsules of rifabutin for oral administration are available.

[0068] Paragraph N: In exemplary embodiments, rifabutin is administered in an oral dose of between about 100 mg and about 350 mg, or between about 100 mg and about 200 mg, or between about 125 mg and about 175 mg, or between about 140 mg and about 160 mg, or about 150 mg, or 150 mg, or between about 250 mg and about 350 mg, or between about 275 mg and about 325 mg, or between about 290 mg and about 310 mg, or about 300 mg, or 300 mg.

[0069] Paragraph M: In an exemplary embodiment, rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg. In an exemplary embodiment, rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily at an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or between about 600 mg.

[0070] Paragraph L: In an exemplary embodiment, rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered three days per week at an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg.

[0071] (Amikacin for injection) Amikacin is commercially available as an injectable formulation from a number of manufacturers, including Teva, Hospira, Abbott Laboratories, Apothecon, and Fresenius. Amikacin sulfate is available in 50 mg / mL and 250 mg / mL forms for intravenous administration.

[0072] Paragraph K: In exemplary embodiments, amikacin is administered daily at an intravenous dose of between about 8 mg / kg and about 17 mg / kg, or between about 10 mg / kg and about 15 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 10 mg / kg, or 10 mg / kg, or about 15 mg / kg, or 15 mg / kg.

[0073] Paragraph J: In an exemplary embodiment, amikacin is administered at an intravenous dose of between about 13 mg / kg and about 27 mg / kg, or between about 15 mg / kg and about 25 mg / kg, or about 15 mg / kg, or 15 mg / kg, or about 25 mg / kg, or 25 mg / kg, three days per week.

[0074] (Amikacin for Inhalation) Amikacin liposomal suspension for inhalation (ARIKAYCE®) is commercially available from Insmed, Inc. A 590 mg / 8.4 mL inhalation formulation is available.

[0075] Paragraph I: In an exemplary embodiment, the inhaled dose of amikacin is between about 580 mg and about 600 mg, or about 590 mg, or 590 mg, administered daily.

[0076] (Ciprofloxacin) Ciprofloxacin is commercially produced by a number of manufacturers, including Bayer, Dr. Reddy's, Aurobindo, Taro, and Watson. Ciprofloxacin hydrochloride tablets for oral administration are available in 100 mg, 250 mg, and 500 mg strengths.

[0077] (Linezolid) Linezolid is produced commercially by a number of manufacturers, including Alembic, Pfizer, Glenmark, and Zydus. Linezolid is available in 600 mg tablets for oral administration.

[0078] (Moxifloxacin) Moxifloxacin is produced commercially by a number of manufacturers, including Teva, Dr. Reddy's, and Aurobindo. 400 mg tablets of moxifloxacin hydrochloride for oral administration are available.

[0079] (streptomycin) Streptomycin is commercially produced by Xgen Pharmaceuticals. It is available in 1 g / vial form of streptomycin sulfate for intravenous administration.

[0080] (Tigecycline) Tigecycline is produced commercially by a number of manufacturers, including Prism, Sandoz, Fresenius, and Apotex. Tigecycline 50 mg / vial for intravenous administration is available.

[0081] (Synergistic effect of epetravorol and ethambutol) A synergistic effect between epetravorole and ethambutol has been discovered, allowing for more effective treatment of NTM infections.

[0082] V. Epetravorole Administration / Dosage Regimen In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, to a human subject in need of treatment for said infection, thereby achieving a positive therapeutic response. For any of the embodiments of Section V, the epetravorole is epetravorole hydrochloride. In an exemplary embodiment, the epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof is administered in an amount as described herein. In an exemplary embodiment, for any of the methods described herein, the positive therapeutic response is treating the nontuberculous mycobacterial (NTM) infection. In an exemplary embodiment, for any of the dosing regimens described herein, the positive therapeutic response is treating the nontuberculous mycobacterial (NTM) infection. In an exemplary embodiment, for any of the dosing regimens described herein, the epetravorole is epetravorole hydrochloride. For any of the embodiments in section V, the epetravorole is epetravorole hydrochloride.

[0083] In an exemplary embodiment, the compositions described herein may be used to achieve a positive therapeutic response against nontuberculous mycobacterial (NTM) infections. In an exemplary embodiment, a combination of compositions described herein may be used to achieve a positive therapeutic response against nontuberculous mycobacterial (NTM) infections. In an exemplary embodiment, an epetravorol composition is administered according to the methods described herein to achieve a positive therapeutic response against nontuberculous mycobacterial (NTM) infections. In an exemplary embodiment, the nontuberculous mycobacterial (NTM) infection is amenable to treatment with epetravorol.

[0084] (Vi) Epetravorol and Ethambutol) In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and ethambutol is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg.

[0085] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an oral dose of ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or three days per week.

[0086] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 250 mg and about 1000 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 10 mg / kg and about 30 mg / kg of ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, or a daily dose or 3 days per week. In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg of ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof. In an exemplary embodiment, the dosing regimen comprises the daily administration of an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the daily administration of an oral dose of between about 600 mg and about 2000 mg, or between about 600 mg and about 800 mg, or between about 800 mg and about 1000 mg, or between about 1000 mg and about 1200 mg, or between about 1200 mg and about 1400 mg, or between about 1400 mg and about 1600 mg, or between about 1600 mg and about 1800 mg, or between about 1800 mg and about 2000 mg of ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and an oral dose of between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg of ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, three days per week.In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg, of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and an oral dose of between about 900 mg and about 3400 mg, or between about 900 mg and about 1200 mg, or between about 1200 mg and about 1500 mg, or between about 1500 mg and about 1800 mg, or between about 1800 mg and about 2100 mg, or between about 2100 mg and about 2400 mg, or between 2400 mg and about 2700 mg, or between about 2700 mg and about 3000 mg, or between about 3000 mg and about 3400 mg, of ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, three days per week.

[0087] (V.ii.) Epetravorole and Azithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered in an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg; and azithromycin is administered in an oral dose of between about 200 mg and about 550 mg, or between about 200 mg and about 300 mg, or between about 225 mg and about 275 mg, or about 250 mg, or about 250 mg, or between about 450 mg and about 550 mg, or between about 475 mg and about 525 mg, or about 500 mg, or 500 mg.

[0088] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an oral dose of azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or three days per week.

[0089] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 250 mg and about 1000 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 200 mg and about 550 mg of azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, or a daily dose or 3 days per week. In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 225 mg and about 275 mg, or about 250 mg of azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg, of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg, of azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg, of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg, of azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, three days a week.

[0090] (V.iii.) Epetravorole and Clarithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered in an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg; and clarithromycin is administered in an oral dose of between about 400 mg and about 600 mg, or between about 450 mg and about 550 mg, or between about 475 mg and about 525 mg, or about 500 mg, or 500 mg, or between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or at a 500 mg oral dose, and clarithromycin is administered at an oral dose of between about 950 mg and about 1050 mg daily, or at an oral dose of about 1000 mg daily, or at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily.

[0091] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an oral dose of clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or three days per week.

[0092] In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 250 mg and about 1000 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and an oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg of clarithromycin, daily or three days per week.

[0093] In an exemplary embodiment, the dosing regimen comprises administering epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, at an oral dose of between about 250 mg and about 1000 mg daily, and clarithromycin, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily, every day or three days per week. In an exemplary embodiment, the dosing regimen comprises administering epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg, and clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at a daily oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg. In an exemplary embodiment, the dosing regimen comprises administering epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 475 mg and about 525 mg, or about 500 mg daily, and clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 900 mg and about 1100 mg, or between about 975 mg and about 1025 mg, or about 1000 mg, or 1000 mg, three days per week.In an exemplary embodiment, the dosing regimen comprises administering epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 475 mg and about 525 mg, or about 500 mg daily, and clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily. In an exemplary embodiment, the dosing regimen comprises administering epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 475 mg and about 525 mg, or about 500 mg daily, and clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily, three days per week.

[0094] (V.iv.) Epetravorole and Rifampicin) In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and rifampicin is administered at an oral dose of between about 5 mg / kg and about 15 mg / kg, or between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg, or 10 mg / kg. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and rifampicin is administered at an oral dose of between about 350 mg and about 700 mg, or between about 350 mg and about 500 mg. or between about 500 mg, or between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg, or 450 mg, or between about 500 mg and about 700 mg, or between about 550 mg and about 650 mg, between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg, or 600 mg.

[0095] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an oral dose of rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or three days per week.

[0096] In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 250 mg and about 1000 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, or 3 days per week, and an oral dose of between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg of rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and an oral dose of between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg of rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily.

[0097] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg of rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof.

[0098] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg of rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and administering an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg of rifampicin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, three days per week.

[0099] (Vv) Epetravorole and Rifabutin) In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0100] In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered in an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg; and rifabutin is administered in an oral dose of between about 100 mg and about 350 mg, between about 100 mg and about 200 mg, between about 125 mg and about 175 mg, between about 140 mg and about 160 mg, or about 150 mg, or 150 mg, or between about 250 mg and about 350 mg, or between about 275 mg and about 325 mg, between about 290 mg and about 310 mg, or about 300 mg, or 300 mg.

[0101] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an oral dose of rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or three days per week.

[0102] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily oral dose of between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg of rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof.

[0103] In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and administering an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg of rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily. In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, daily, and administering an oral dose of between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg of rifabutin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, three days per week.

[0104] (V.vi.) Epetravorol and Ethambutol and Rifampicin) In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0105] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg. and rifampicin is administered at an oral dose of between about 5 mg / kg and about 15 mg / kg, or between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg, or 10 mg / kg, or between about 350 mg and about 700 mg, or between about 350 mg and about 500 mg, or between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg, or 450 mg, or between about 500 mg and about 700 mg, or between about 550 mg and about 650 mg, between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg, or 600 mg.

[0106] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, in accordance with paragraph Y, and administering rifampicin in accordance with paragraph P.

[0107] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering rifampicin in accordance with paragraph P.

[0108] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof according to paragraph Y, and administering rifampicin according to paragraph O.

[0109] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering rifampicin in accordance with paragraph O.

[0110] (V.vii.) Epetravorol and Ethambutol and Rifabutin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0111] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg; and ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or 15 mg / kg, or and rifabutin is administered at an oral dose of between about 100 mg and about 350 mg, or between about 100 mg and about 200 mg, or between about 125 mg and about 175 mg, or between about 140 mg and about 160 mg, or about 150 mg, or 150 mg, or between about 250 mg and about 350 mg, or between about 275 mg and about 325 mg, or between about 290 mg and about 310 mg, or about 300 mg, or 300 mg.

[0112] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering rifabutin in accordance with paragraph M.

[0113] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, and administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with paragraph X, and administering rifabutin in accordance with paragraph M.

[0114] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering rifabutin in accordance with paragraph L.

[0115] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering rifabutin in accordance with paragraph L.

[0116] (V.viii.) Epetravorol and Ethambutol and Azithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0117] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or at a dose of 500 mg; ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or at a dose of about 15 mg / kg. g / kg, or 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg, and azithromycin is administered in an oral dose of between about 200 mg and about 550 mg, or between about 200 mg and about 300 mg, or between about 225 mg and about 275 mg, or about 250 mg, or about 250 mg, or between about 450 mg and about 550 mg, or between about 475 mg and about 525 mg, or about 500 mg, or 500 mg.

[0118] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering azithromycin in accordance with paragraph V.

[0119] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering azithromycin in accordance with paragraph V.

[0120] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering azithromycin in accordance with paragraph U.

[0121] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering azithromycin in accordance with paragraph U.

[0122] (V.ix.) Epetravorol and Ethambutol and Clarithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0123] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or at a dose of 500 mg; ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or at a dose of ... or at an oral dose of between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg, and clarithromycin is administered at an oral dose of between about 950 mg and about 1050 mg daily, or at an oral dose of about 1000 mg daily, or at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily.

[0124] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering clarithromycin in accordance with paragraph S.

[0125] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering clarithromycin in accordance with paragraph S.

[0126] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering clarithromycin in accordance with paragraph R.

[0127] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering clarithromycin in accordance with paragraph R.

[0128] (Vx) Epetravorol and Ethambutol and Rifampicin and Azithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0129] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, and administering azithromycin according to paragraph V.

[0130] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, and administering azithromycin according to paragraph V.

[0131] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph P, and administering azithromycin according to paragraph V.

[0132] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, and administering azithromycin according to paragraph V.

[0133] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, and administering azithromycin according to paragraph U.

[0134] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, and administering azithromycin according to paragraph U.

[0135] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, and administering azithromycin according to paragraph U.

[0136] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, and administering azithromycin according to paragraph U.

[0137] (V.xi.) Epetravorol and Ethambutol and Rifampicin and Clarithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0138] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg. g, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg; and rifampicin is administered at an oral dose of between about 5 mg / kg and about 15 mg / kg, or between about 9 mg / kg and about 11 mg / kg, or about 10 mg / kg, or 10 mg / kg, or about 350 mg / kg. or between about 700 mg, or between about 350 mg and about 500 mg, or between about 425 mg and about 475 mg, or between about 440 mg and about 460 mg, or about 450 mg, or 450 mg, or between about 500 mg and about 700 mg, or between about 550 mg and about 650 mg, or between about 575 mg and about 625 mg, or between about 590 mg and about 610 mg, or about 600 mg, or 600 mg. and clarithromycin is administered at an oral dose of between about 950 mg and about 1050 mg daily, or at an oral dose of about 1000 mg daily, or at an oral dose of between about 400 mg and about 600 mg twice daily, or at an oral dose of between about 450 mg and about 550 mg twice daily, or at an oral dose of between about 475 mg and about 525 mg twice daily, or at an oral dose of about 500 mg twice daily, or at an oral dose of 500 mg twice daily.

[0139] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, and administering clarithromycin according to paragraph S.

[0140] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, and administering clarithromycin according to paragraph S.

[0141] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, and administering clarithromycin according to paragraph S.

[0142] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, and administering clarithromycin according to paragraph S.

[0143] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, and administering clarithromycin according to paragraph R.

[0144] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, and administering clarithromycin according to paragraph R.

[0145] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, and administering clarithromycin according to paragraph R.

[0146] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph O, and administering clarithromycin according to paragraph R.

[0147] (V.xii.) Epetravorol, Ethambutol, Rifabutin, and Azithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0148] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, and administering azithromycin according to paragraph V.

[0149] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, and administering azithromycin according to paragraph V.

[0150] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph M, and administering azithromycin according to paragraph V.

[0151] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, and administering azithromycin according to paragraph V.

[0152] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, and administering azithromycin according to paragraph U.

[0153] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, and administering azithromycin according to paragraph U.

[0154] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, and administering azithromycin according to paragraph U.

[0155] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, and administering azithromycin according to paragraph U.

[0156] (V.xiii.) Epetravorol, Ethambutol, Rifabutin, and Clarithromycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0157] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, and administering clarithromycin according to paragraph S.

[0158] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, and administering clarithromycin according to paragraph S.

[0159] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with paragraph X, administering rifabutin in accordance with paragraph M, and administering clarithromycin in accordance with paragraph S.

[0160] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph L, and administering clarithromycin according to paragraph S.

[0161] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, and administering clarithromycin according to paragraph R.

[0162] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph Y, administering rifabutin according to paragraph L, and administering clarithromycin according to paragraph R.

[0163] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph M, and administering clarithromycin in accordance with Paragraph R.

[0164] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph L, and administering clarithromycin in accordance with Paragraph R.

[0165] (V.xiv.) Epetravorol and Amikacin In an exemplary embodiment, the present invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, to a human subject in need of treatment for said infection, thereby achieving a positive therapeutic response. In an exemplary embodiment, the present invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, to a human subject in need of treatment for said infection, thereby achieving a positive therapeutic response. In exemplary embodiments, epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or at an intravenous dose of 500 mg, and an intravenous dose of amikacin is administered at an oral dose of between about 8 mg / kg and about 30 mg / kg, or between about 8 mg / kg and about 17 mg / kg. or between about 10 mg / kg and about 15 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 10 mg / kg, or 10 mg / kg, or about 15 mg / kg, or 15 mg / kg, or between about 13 mg / kg and about 27 mg / kg, or between about 15 mg / kg and about 25 mg / kg, or about 15 mg / kg, or 15 mg / kg, or about 25 mg / kg, or 25 mg / kg.

[0166] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an intravenous dose of amikacin, as described herein, every day or three days per week.

[0167] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily intravenous dose of between about 8 mg / kg and about 17 mg / kg, or between about 10 mg / kg and about 15 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 10 mg / kg, or about 10 mg / kg, or about 15 mg / kg, or about 15 mg / kg of amikacin.

[0168] In an exemplary embodiment, the dosing regimen comprises an oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administered daily, and an intravenous dose of between about 13 mg / kg and about 27 mg / kg, or between about 15 mg / kg and about 25 mg / kg, or about 15 mg / kg, or about 15 mg / kg, or about 25 mg / kg, or about 25 mg / kg, administered three days per week.

[0169] (V.xv.) Epetravorol and inhaled amikacin In an exemplary embodiment, the present invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment for said infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin for inhalation, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg, and the inhaled dose of amikacin is between about 580 mg and about 600 mg, or about 590 mg, or 590 mg.

[0170] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection a dosing regimen comprising: administering an oral dose of epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, as described herein, every day or every other day; and administering an inhaled dose of amikacin, as described herein, every day.

[0171] In an exemplary embodiment, the dosing regimen comprises a daily oral dose of between about 475 mg and about 525 mg, or about 500 mg of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, and a daily inhaled dose of between about 580 mg and about 600 mg, or about 590 mg, or 590 mg of amikacin.

[0172] (V.xvi.) Epetravorol and Ethambutol and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0173] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or at a dose of 500 mg; ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or at a dose of about 25 mg / kg. and amikacin is administered at an oral dose of between about 8 mg / kg and about 30 mg / kg, or between about 8 mg / kg and about 17 mg / kg, or between about 10 mg / kg and about 15 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 10 mg / kg, or 10 mg / kg, or about 15 mg / kg, or 15 mg / kg, or about 13 mg / kg and about 27 mg / kg, or between about 15 mg / kg and about 25 mg / kg, or about 15 mg / kg, or 15 mg / kg, or about 25 mg / kg.

[0174] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering amikacin in accordance with paragraph K.

[0175] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering amikacin in accordance with paragraph K.

[0176] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph Y, and administering amikacin in accordance with paragraph J.

[0177] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof in accordance with paragraph X, and administering amikacin in accordance with paragraph J.

[0178] (V.xvii.) Epetravorol and Ethambutol and Amikacin for Inhalation In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0179] In exemplary embodiments, epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 250 mg and about 1000 mg, or between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg; ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg, or between about 13 mg / kg and about 17 mg / kg, or about 15 mg / kg, or 15 mg / kg, or between about 23 mg / kg and about 27 mg / kg, or about 25 mg / kg, or 25 mg / kg; and amikacin is administered at an inhaled dose of between about 580 mg and about 600 mg, or about 590 mg, or 590 mg.

[0180] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof according to paragraph Y, and administering amikacin according to paragraph I.

[0181] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof according to paragraph X, and administering amikacin according to paragraph I.

[0182] (V.xviii.) Epetravorol and Ciprofloxacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and ciprofloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0183] (V.xix.) Epetravorol and Ethambutol and Ciprofloxacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and ciprofloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0184] (V.xx.) Epetravorole and Linezolid In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and linezolid, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0185] (V.xxi.) Epetravorol and Ethambutol and Linezolid In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and linezolid, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0186] (V.xxii.) Epetravorol and moxifloxacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0187] (V.xxiii.) Epetravorol and Ethambutol and Moxifloxacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0188] (V.xxiv.) Epetravorole and streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0189] (V.xxv.) Epetravorol and Ethambutol and Streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0190] (V.xxvi.) Epetravorole and Tigecycline In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and tigecycline, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0191] (V.xxvii.) Epetravorol and Ethambutol and Tigecycline In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and tigecycline, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0192] (V. xxviii.) Epetravorol and Ethambutol and Rifampicin and Azithromycin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0193] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0194] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0195] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0196] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0197] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0198] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0199] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, administering amikacin, and administering according to paragraph K.

[0200] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0201] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0202] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0203] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0204] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0205] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0206] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0207] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0208] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0209] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0210] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0211] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0212] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0213] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0214] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph O, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0215] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0216] In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, daily; administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X; administering rifampicin according to paragraph O; administering azithromycin according to paragraph U; and administering amikacin according to paragraph I.

[0217] (V.xxix.) Epetravorol and Ethambutol and Rifampicin and Clarithromycin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0218] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0219] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0220] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0221] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0222] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0223] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0224] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0225] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0226] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0227] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0228] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0229] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0230] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph K.

[0231] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0232] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0233] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph K.

[0234] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0235] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0236] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with paragraph X, administering rifampicin in accordance with paragraph P, administering clarithromycin in accordance with paragraph R, and administering amikacin in accordance with paragraph K.

[0237] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0238] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph P, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0239] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph K.

[0240] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0241] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifampicin according to paragraph O, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0242] (V.xxx.) Epetravorol and Ethambutol and Rifabutin and Azithromycin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for said infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for said infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0243] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0244] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0245] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0246] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0247] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0248] In an exemplary embodiment, the dosing regimen comprises administering an oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph Y; administering rifabutin, according to paragraph L; administering azithromycin, according to paragraph V; and administering amikacin, according to paragraph I.

[0249] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0250] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph J.

[0251] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0252] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, administering azithromycin according to paragraph V, and administering amikacin according to paragraph K.

[0253] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof; administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X; administering rifabutin according to paragraph L; administering azithromycin according to paragraph V; and administering amikacin according to paragraph J.

[0254] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph L, administering azithromycin according to paragraph V, and administering amikacin according to paragraph I.

[0255] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0256] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0257] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0258] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0259] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0260] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0261] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0262] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0263] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0264] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph K.

[0265] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph J.

[0266] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph L, administering azithromycin according to paragraph U, and administering amikacin according to paragraph I.

[0267] (V.xxxi.) Epetravorol and Ethambutol and Rifabutin and Clarithromycin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for said infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0268] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0269] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0270] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0271] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0272] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0273] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0274] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph K.

[0275] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph J.

[0276] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph S, administering amikacin, and administering according to paragraph I.

[0277] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph L, administering clarithromycin in accordance with Paragraph S, and administering amikacin in accordance with Paragraph K.

[0278] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to Paragraph X, administering rifabutin according to Paragraph L, administering clarithromycin according to Paragraph S, and administering amikacin according to Paragraph J.

[0279] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph S, and administering amikacin according to paragraph I.

[0280] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph K.

[0281] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0282] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0283] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph K.

[0284] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0285] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph Y, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0286] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph M, administering clarithromycin in accordance with Paragraph R, and administering amikacin in accordance with Paragraph K.

[0287] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph M, administering clarithromycin in accordance with Paragraph R, and administering amikacin in accordance with Paragraph J.

[0288] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph M, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0289] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, in accordance with Paragraph X, administering rifabutin in accordance with Paragraph L, administering clarithromycin in accordance with Paragraph R, and administering amikacin in accordance with Paragraph K.

[0290] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof according to paragraph X, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph J.

[0291] In an exemplary embodiment, the dosing regimen comprises administering a daily oral dose of between about 450 mg and about 550 mg, or between about 490 mg and about 510 mg, or about 500 mg, or 500 mg of epetravorol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, administering ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, according to paragraph X, administering rifabutin according to paragraph L, administering clarithromycin according to paragraph R, and administering amikacin according to paragraph I.

[0292] (V.xxxii.) Epetravorol and Ethambutol and Rifampicin and Azithromycin and Streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0293] (V.xxxiii.) Epetravorol and Ethambutol and Rifampicin and Clarithromycin and Streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0294] (V.xxxiv.) Epetravorol and Ethambutol and Rifabutin and Azithromycin and Streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, azithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0295] (V.xxxv.) Epetravorol and Ethambutol and Rifabutin and Clarithromycin and Streptomycin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, clarithromycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and streptomycin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0296] (V.xxxvi.) Epetravorol and Ethambutol and Rifampicin and Moxifloxacin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorole, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifampicin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0297] (V.xxxvii.) Epetravorol and Ethambutol and Rifabutin and Moxifloxacin and Amikacin In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and intravenous amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response for a nontuberculous mycobacterial (NTM) infection, the method comprising administering to a human subject in need of treatment for the infection epetravorol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, ethambutol, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, rifabutin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, moxifloxacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and inhaled amikacin, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, thereby achieving a positive therapeutic response.

[0298] (Va) Nontuberculous mycobacterial (NTM) infection In an exemplary embodiment, the nontuberculous mycobacteria in the infection are rapidly multiplying. In exemplary embodiments, the nontuberculous mycobacteria in the infection are selected from the group consisting of M. abscessus, M. arabiense, M. aromaticivorans, M. bacteremicum, M. barrassiae, M. bourgelatii, M. celeriflavum, M. chelonae, M. crocinum, M. fukienense, M. hippocampi, M. insubricum, M. iranicum, M. litorale, M. litorale, M. llatzerense, M. monacense, M. pallens, M. rufum, M. rutilum, M. salmoniphilum, M. sediminis, or Mycobacterium setense, or a combination thereof.

[0299] In an exemplary embodiment, the nontuberculous mycobacteria in the infection are slow growing. In exemplary embodiments, the nontuberculous mycobacteria in the infection are selected from the group consisting of M. algericum, M. alsiense, M. arosiense, M. bouchedurhonense, M. engbaekii, M. europaeum, M. fragae, M. heraklionense, M. indicus pranii, M. koreense, M. kumamotonense, M. kyorinense, M. lepromatosis, M. rifflandii, M. liflandii, M. longobardum, M. mantenii, M. marseillense, M. minnesotense, M. noviomagense, M. paraaffinicum, M. paragordonae, M. parakoreense, M. paraseoulense, M. paraterrae, M. riyadhense, M. senuense, M. seoulense, M. sherrisii, M. sigaiense shigaense, M. shinjukuense, M. simulans, M. sinense, M. stomatepiae, M. timonense, M. vulneris, or M. yongonense, or a combination thereof.

[0300] In exemplary embodiments, the nontuberculous mycobacteria in the infection is selected from the group consisting of M. abscessus, M. avium complex (MAC), M. chelonae, M. fortuitum, M. gordonae, M. kansasii, M. mucogenicum, M. peregrinum, and M. xenopi. In exemplary embodiments, the nontuberculous mycobacteria in the infection is selected from the group consisting of M. abscessus, M. avium complex (MAC), M. fortuitum complex, M. gordonae, M. kansasii, and M. xenopi.

[0301] In an exemplary embodiment, the nontuberculous mycobacteria in the infection is Mycobacterium avium complex. In an exemplary embodiment, the nontuberculous mycobacteria in the infection is M. avium, M. intracellulare, M. marseillaise, M. timonense, M. bouchedurhonense, M. colombiense, M. vulneris, or M. chimaera. In an exemplary embodiment, the nontuberculous mycobacteria in the infection is M. intracellulare. In an exemplary embodiment, the nontuberculous mycobacteria in the infection is M. intracellulare subsp. intracellulare, or M. intracellulare subsp. In an exemplary embodiment, the nontuberculous mycobacteria in the infection is M. avium.

[0302] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxiv.);V.xxv.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.);V.xxxii.);V.xxxiii.);V.xxxiv.);V.xxxv.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0303] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against Mycobacterium avium infection, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxiv.);V.xxv.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.);V.xxxii.);V.xxxiii.);V.xxxiv.);V.xxxv.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium infection, as described herein, e.g., in Sections III) or III.a.).

[0304] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against Mycobacterium intracellulare infection, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxiv.);V.xxv.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.);V.xxxii.);V.xxxiii.);V.xxxiv.);V.xxxv.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0305] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against Mycobacterium kansasii infection, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0306] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against Mycobacterium kansasii infection, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0307] In an exemplary embodiment, the human further has a disease that is cystic fibrosis, chronic obstructive pulmonary disease, or chronic thromboembolic pulmonary hypertension. In an exemplary embodiment, the human further has a disease that is interstitial lung disease, post-inflammatory pulmonary fibrosis, bronchiectasis, neoplastic disease, diabetes, bronchial asthma, hypothorax, mediastinal cyst, or rheumatoid arthritis. In an exemplary embodiment, the human further has a disease that is interstitial lung disease, the interstitial lung disease being idiopathic pulmonary fibrosis, sarcoidosis, or proteinosis. In an exemplary embodiment, the human further has a neoplastic disease, the neoplastic disease being myelofibrosis or lung cancer. In an exemplary embodiment, the human has previously suffered from tuberculosis.

[0308] In an exemplary embodiment, the infection occurs in the lungs of a human. In an exemplary embodiment, the infection occurs in two or more organs in the body. In an exemplary embodiment, the infection occurs in a lymph node.

[0309] In an exemplary embodiment, the infection is treatment naive. In an exemplary embodiment, the infection is treatment resistant.

[0310] In a further aspect, the nontuberculous mycobacteria infection is part of a nontuberculous mycobacteria-associated disease in a human subject. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is a nontuberculous mycobacteria-associated disease, a disseminated nontuberculous mycobacteria-associated disease, or a nontuberculous mycobacteria-associated lymphadenitis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is Mycobacterium avium complex (MAC) pulmonary disease, a disseminated Mycobacterium avium complex (MAC) disease, and a Mycobacterium avium complex (MAC)-associated lymphadenitis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is nodular bronchiectasis. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is fibrocavitary.

[0311] In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is treatment-naive. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is treatment-resistant. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is treatment-resistant Mycobacterium avium complex (MAC) pulmonary disease. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is cavitary Mycobacterium avium complex (MAC) pulmonary disease. In an exemplary embodiment, the nontuberculous mycobacteria-associated disease is nodular-bronchiectacic Mycobacterium avium complex (MAC) pulmonary disease.

[0312] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against nodular-bronchiectatic Mycobacterium avium complex (MAC) pulmonary disease, as described herein, e.g., in Sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0313] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against cavitary Mycobacterium avium complex (MAC) pulmonary disease, as described herein, e.g., in sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xvi.);V.xxiv.);V.xxv.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.);V.xxxii.); and V.xxxiii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against cavitary Mycobacterium avium complex (MAC) pulmonary disease, e.g., as described herein in Sections V.xv.) or V.xvii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, e.g., as described herein in Sections III) or III.a.).

[0314] In exemplary embodiments, the invention provides methods for achieving a positive therapeutic response against treatment-resistant Mycobacterium avium complex (MAC) pulmonary disease, as described herein, e.g., in sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxiv.);V.xxv.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.);V.xxxii.); and V.xxxiii.), whereby said positive therapeutic response is achieved. In exemplary embodiments, the invention provides compositions or methods for achieving a positive therapeutic response against Mycobacterium avium complex infection, as described herein, e.g., in Sections III) or III.a.).

[0315] In an exemplary embodiment, the disease is treated through oral administration of a compound of the invention. In an exemplary embodiment, the disease is treated through oral administration of epetravorole.

[0316] (Vb) Evaluation of positive treatment response In an exemplary embodiment, the positive therapeutic response may be assessed by an assay or tool described herein.

[0317] In an exemplary embodiment, prior to administration, the human subject is assessed for infection markers, thereby obtaining a baseline assessment; after the first administration, the human subject is assessed for infection markers, thereby obtaining a response assessment. The baseline assessment and the response assessment are compared, and a positive therapeutic response is achieved if the response assessment is improved over the baseline assessment. Multiple response assessments can be performed during the course of administration. A positive therapeutic response is achieved if a later response assessment is improved over a previous response assessment or baseline assessment.

[0318] In an exemplary embodiment, prior to administration of the dosing regimen described herein, the human subject's infection markers are evaluated, thereby obtaining a baseline assessment; after the first administration of the dosing regimen, the human subject's infection markers are evaluated, thereby obtaining a response assessment, and the baseline assessment and the response assessment are compared, and a positive therapeutic response is achieved if the response assessment is improved over the baseline assessment. In an exemplary embodiment, the infection markers are evaluated within 2 days, or within 3 days, or within 4 days, or within 5 days, or within 6 days, or within 7 days of the end of the development of the dosing regimen. In an exemplary embodiment, the infection markers are evaluated within 2 days, or within 3 days, or within 4 days, or within 5 days, or within 6 days, or within 7 days of the end of the development of the dosing regimen described in paragraph A. In certain methods, the dosing regimen occurs multiple times. In certain methods, the dosing regimen occurs as described in paragraph B. If a multiple dosing regimen is administered, the markers of infection in the human subject may be assessed within 2, or 3, or 4, or 5, or 6, or 7 days after completion of the accrual of the pre-dosing regimen described in paragraph A. A positive therapeutic response is achieved if the subsequent response assessment is an improvement over the previous response assessment, or baseline assessment.

[0319] In an exemplary embodiment, the NTM infection described herein may be assessed for a positive therapeutic response by assessing one or more characteristics of the NTM infection in the patient prior to administration of the compositions described herein, thereby obtaining a baseline assessment or identification. After at least one first administration of the dosing regimen described herein, the characteristics of the NTM infection are again assessed or identified, thereby obtaining a response assessment. By comparing the baseline assessment with the response assessment, it can be determined whether a positive therapeutic response has been achieved. If the response assessment is improved over the baseline assessment, a positive therapeutic response to the NTM infection is achieved. In an exemplary embodiment, one or more response assessments are performed at different times during the course of treatment (during one or more administrations of the dosing regimen). In an exemplary embodiment, the assessment of the NTM infection is performed by assessing one or more markers of infection in the human subject.

[0320] In an exemplary embodiment, a positive therapeutic response can be assessed by quantitative colony counts. In an exemplary embodiment, the positive therapeutic response can be assessed by quantitative colony scores. In an exemplary embodiment, the positive therapeutic response can be assessed by radiographic analysis.

[0321] Vb) i.) Quantitative colony count Quantification of bacteria by colony count on solid agar medium can be performed according to standard procedures known in the art. Such an example is described in Griffith, et al.Semiquantitative culture analysis during therapy for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2015;192(6):754-760, where colony count was a predictor of symptomatic and radiographic improvement. As described in Griffith, quantitative colony counts can be obtained from respiratory samples obtained from patients (e.g., sputum samples, such as expectorated or induced sputum samples). The induced sputum samples can be obtained from human subjects, for example, by administering hypertonic saline (e.g., 7% saline) to the human subject via a nebulizer. The sputum samples can be processed according to procedures such as decontamination, fluorochrome microscopy, solid medium culture on biplates of Middlebrook 7H10 agar with or without antibiotics, and broth culture (BACTEC 960 [Becton Dickinson, Sparks, MD] or ESP [TREK Diagnostic Systems, Cleveland, OH]) as described in Wallace et al, Initial clarithromycin monotherapy for Mycobacterium avium- intracellulare complex lung disease. Am J Respir Crit Care Med 1994; 149:1335-1341; Wallace et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med 1996; 153:1766-1772. MAC isolates can be identified, for example, with AccuProbe (Hologic-GenProbe, San Diego, Calif.).

[0322] The microbiological evaluation of the sputum sample can include an evaluation of a quantitative colony count. In an exemplary embodiment, a quantitative colony count lower at a later evaluation than at a previous evaluation is a positive therapeutic response. In an exemplary embodiment, a quantitative colony count lower at a response evaluation than at a baseline evaluation is a positive therapeutic response. In an exemplary embodiment, a quantitative colony count lower at a later response evaluation than at a previous response evaluation is a positive therapeutic response. In an exemplary embodiment, a quantitative colony count lower at a second (or third or fourth, etc.) response evaluation than at a first response evaluation is a positive therapeutic response. In an exemplary embodiment, a quantitative colony count lower at a third (or fourth or fifth, etc.) response evaluation than at a second response evaluation is a positive therapeutic response. In an exemplary embodiment, a quantitative colony count at a later evaluation that is about 1% to about 99% lower than at a previous evaluation is a positive therapeutic response. In exemplary embodiments, the variance is about 1% to about 5% lower than the previous evaluation, or about 4% to about 9% lower, or about 8% to about 13% lower, or about 12% to about 17% lower, or about 16% to about 21% lower, or about 20% to about 25% lower, or about 24% to about 29% lower, or about 28% to about 33% lower, or about 32% to about 37% lower, or about 36% to about 41% lower, or about 40% to about 45% lower, or about 44% to about 49% lower, or about 48% to about 53% lower, or about 52% to about 56% lower, or about 58% to about 60% lower, or about 62% to about 64% lower, or about 66% to about 68% lower, or about 68% to about 70% lower, or about 72% to about 76% lower, or about 78% to about 78% lower, or about 79% to about 80% lower, or about 82% to about 84% lower, or about 85% to about 86% lower, or about 87% to about 88% lower, or about 89% to about 90% lower, or about 90% to about 92% lower, or about 93% to about 94% lower, or about 95% to about 96% lower, or about 97% to about 98% lower, or about 99% to about 100% lower, or about 102% to about 106% lower, or about 108% to about 109% lower, or about 109% to about 110% lower, or about 112% to about 114% lower, or about 116% to about 116% lower, or about A quantitative colony count at subsequent evaluation that is 7% lower, or about 56% to about 61% lower, or about 60% to about 65% lower, or about 64% to about 69% lower, or about 68% to about 73% lower, or about 72% to about 77% lower, or about 76% to about 81% lower, or about 80% to about 85% lower, or about 84% to about 89% lower, or about 88% to about 93% lower, or about 92% to about 97% lower, or about 96% to about 100% lower, or a combination of one or more thereof, is a positive treatment response.

[0323] In exemplary embodiments, the change is from about 5% to about 25% lower than the previous evaluation, or from about 5% to about 30% lower, or from about 5% to about 35% lower, or from about 5% to about 40% lower, or from about 5% to about 45% lower, or from about 5% to about 50% lower, or from about 5% to about 55% lower, or from about 5% to about 60% lower, or from about 5% to about 65% lower, or from about 5% to about 70% lower, or from about 5% to about 75% lower, or A quantitative colony count at subsequent evaluation that is 5% to about 80% lower, or about 5% to about 85% lower, or about 5% to about 90% lower, or about 5% to about 95% lower, or about 5% to about 99% lower, or about 5% to about 99.2% lower, or about 5% to about 99.5% lower, or about 5% to about 99.7% lower, or about 5% to about 99.9% lower, or about 5% to about 100% lower is a positive treatment response.

[0324] In exemplary embodiments, the assessment is from about 10% to about 25% lower than the previous assessment, or from about 10% to about 30% lower, or from about 10% to about 35% lower, or from about 10% to about 40% lower, or from about 10% to about 45% lower, or from about 10% to about 50% lower, or from about 10% to about 55% lower, or from about 10% to about 60% lower, or from about 10% to about 65% lower, or from about 10% to about 70% lower, or from about 10% to about 75% lower, or A quantitative colony count at subsequent evaluation that is about 10% to about 80% lower, or about 10% to about 85% lower, or about 10% to about 90% lower, or about 10% to about 95% lower, or about 10% to about 99% lower, or about 10% to about 99.2% lower, or about 10% to about 99.5% lower, or about 10% to about 99.7% lower, or about 10% to about 99.9% lower, or about 10% to about 100% lower is a positive treatment response.

[0325] In exemplary embodiments, the change is from about 15% to about 25% lower than the previous evaluation, or from about 15% to about 30% lower, or from about 15% to about 35% lower, or from about 15% to about 40% lower, or from about 15% to about 45% lower, or from about 15% to about 50% lower, or from about 15% to about 55% lower, or from about 15% to about 60% lower, or from about 15% to about 65% lower, or from about 15% to about 70% lower, or from about 15% to about 75% lower, or A quantitative colony count at subsequent evaluation that is 15% to about 80% lower, or about 15% to about 85% lower, or about 15% to about 90% lower, or about 15% to about 95% lower, or about 15% to about 99% lower, or about 15% to about 99.2% lower, or about 15% to about 99.5% lower, or about 15% to about 99.7% lower, or about 15% to about 99.9% lower, or about 15% to about 100% lower is a positive treatment response.

[0326] In exemplary embodiments, the variance is about 20% to about 30% lower than the previous evaluation, or about 20% to about 35% lower, or about 20% to about 40% lower, or about 20% to about 45% lower, or about 20% to about 50% lower, or about 20% to about 55% lower, or about 20% to about 60% lower, or about 20% to about 65% lower, or about 20% to about 70% lower, or about 20% to about 75% lower, or about 20% to about 80% lower. % lower, or about 20% to about 85% lower, or about 20% to about 90% lower, or about 20% to about 95% lower, or about 20% to about 99% lower, or about 20% to about 99.2% lower, or about 20% to about 99.5% lower, or about 20% to about 99.7% lower, or about 20% to about 99.9% lower, or about 20% to about 100% lower quantitative colony counts at the subsequent evaluation are a positive treatment response.

[0327] In an exemplary embodiment, prior to administering the dosing regimen, the human subject is assessed for infection markers, where the infection marker is a quantitative colony count, thereby obtaining a baseline assessment; after the first administration of epetravorole, the human subject is assessed for infection markers, thereby obtaining a response assessment, and the baseline assessment and the response assessment are compared, and if the response assessment is improved over the baseline assessment, a positive therapeutic response is achieved.

[0328] In an exemplary embodiment, the NTM infection may be assessed for a positive therapeutic response by assessing one or more characteristics of the NTM infection in the patient prior to administration of a composition described herein, thereby obtaining a baseline assessment or identification. After at least one first administration of a composition described herein, the characteristics of the NTM infection are again assessed or identified, thereby obtaining a response assessment. By comparing the baseline assessment with the response assessment, it can be determined whether a positive therapeutic response has been achieved. If the response assessment is improved over the baseline assessment, a positive therapeutic response to the NTM infection is achieved. In an exemplary embodiment, one or more response assessments are performed at different times during the course of treatment (during one or more administrations of a dosing regimen). In an exemplary embodiment, the assessment of the NTM infection is performed by assessing one or more markers of infection in the human subject. In an exemplary embodiment, the marker of infection is a quantitative colony count.

[0329] (Quantitative colony score) Microbiological evaluation of sputum samples can include evaluation by quantitative colony scoring, which can be assigned as a categorical score as reported in Griffith, et al. Semiquantitative culture analysis during therapy for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2015;192(6):754-760. In an exemplary embodiment, a negative culture shows no mycobacterial growth and can be assigned a quantitative colony score of zero; a positive culture growth only in broth medium can be assigned a quantitative colony score of 1; a positive growth on solid medium with between 0 and 49 countable colonies can be assigned a quantitative colony score of 2; a positive growth on solid medium with between 50 and 99 countable colonies can be assigned a quantitative colony score of 3; a positive growth on solid medium with between 100 and 199 countable colonies can be assigned a quantitative colony score of 4; a positive growth on solid medium with between 200 and 299 countable colonies can be assigned a quantitative colony score of 5; a positive growth on solid medium with 300 or more countable colonies can be assigned a quantitative colony score of 6. Human subjects who showed no mycobacterial growth (score "0") in three or more consecutive cultures over a minimum of three months were classified as "converters."

[0330] In an exemplary embodiment, a quantitative colony score lower at a later assessment than at a previous assessment is a positive therapeutic response. In an exemplary embodiment, a quantitative colony score lower at a response assessment than at a baseline assessment is a positive therapeutic response. In an exemplary embodiment, a quantitative colony score lower at a later response assessment than at a previous response assessment is a positive therapeutic response. In an exemplary embodiment, a quantitative colony score lower at a second (or third or fourth, etc.) response assessment than at a first response assessment is a positive therapeutic response. In an exemplary embodiment, a quantitative colony score lower at a third (or fourth or fifth, etc.) response assessment than at a second response assessment is a positive therapeutic response. In an exemplary embodiment, a positive therapeutic response is when the quantitative colony score at a later assessment is 1 lower than the previous assessment. In an exemplary embodiment, a positive therapeutic response is when the quantitative colony score at a later assessment is 1 or more lower than the previous assessment. In an exemplary embodiment, a positive therapeutic response is when the quantitative colony score at a later assessment is 2 or more lower than the previous assessment. In an exemplary embodiment, a positive therapeutic response is when the quantitative colony score at a later assessment is 2 or more lower than the previous assessment. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 3 lower than the previous evaluation. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 3 or more lower than the previous evaluation. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 4 lower than the previous evaluation. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 4 or more lower than the previous evaluation. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 6 lower than the previous evaluation. In an exemplary embodiment, a positive treatment response is when the quantitative colony score at the later evaluation is 6 or more lower than the previous evaluation.

[0331] In an exemplary embodiment, the quantitative culture score is assessed prior to the first administration of epetravorole. In an exemplary embodiment, the baseline assessment of the quantitative culture score is performed between 56 days and 1 day prior to the first administration of epetravorole. In an exemplary embodiment, the baseline assessment of the quantitative culture score is performed the day prior to the first administration of epetravorole. In an exemplary embodiment, the response assessment of the quantitative culture score is performed after the first administration of epetravorole. In an exemplary embodiment, the response assessment of the quantitative culture score is performed between about 21 days and about 35 days after the first administration of epetravorole. In an exemplary embodiment, a positive therapeutic response is achieved when the quantitative culture score in the response assessment is at least one or more category scores lower than the quantitative culture score in the baseline assessment. In an exemplary embodiment, a positive therapeutic response is achieved when the quantitative culture score in the response assessment is 1 or 2 or 3 or 4 or 5 or 6 lower than the quantitative culture score in the baseline assessment. In an exemplary embodiment, a positive therapeutic response is achieved when the quantitative culture score in the response assessment is 1 or 2 lower than the quantitative culture score in the baseline assessment. In an exemplary embodiment, a positive therapeutic response is achieved when the quantitative culture score in the response assessment is 1 lower than the quantitative culture score in the baseline assessment. In an exemplary embodiment, a positive therapeutic response is achieved when the quantitative culture score in the response assessment is at least 1 lower than the quantitative culture score in the baseline assessment.

[0332] (Radiographic evaluation) In an exemplary embodiment, a positive therapeutic response is an improvement in radiographic assessment, such as a chest radiology exam or a chest computed tomography (CT) scan or a chest high resolution computed tomography (CT) scan. These assessments are known in the art and are described, for example, in Griffith, et al. Semiquantitative culture analysis during therapy for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2015;192(6):754-760.

[0333] In an exemplary embodiment, a chest radiography (CXR) and high resolution computed tomography (HRCT) scan of the chest may be performed prior to initiation of the dosing regimen described herein, with chest radiography at 1-2 month intervals and chest CT scans at 6 month intervals, with chest CT scans being performed more frequently at the discretion of the medical professional / radiologist. In an exemplary embodiment, baseline and response chest radiography and / or CT scans may be reviewed by the medical professional treating the patient and a radiologist experienced in evaluating radiographs from NTM patients (such as MAC human subjects with nodular / bronchiectatic disease). In an exemplary embodiment, a second radiologist may review the human subject's radiographs. In an exemplary embodiment, radiographs may be classified as improved (score, 1), unchanged (score, 0), or worsening (score, -1) compared to the previous radiograph. In an exemplary embodiment, the assignment of a particular score is based on an overall or global impression of the radiograph appearance. In an exemplary embodiment, the radiograph may have a "composite" response with some areas of improvement and some areas of increased density compared to previous radiographic studies. In an exemplary embodiment, discrepancies in interpretation between the radiologist and clinician of the radiograph may be resolved by a second radiologist blinded to the clinical condition of the human subject.

[0334] In an exemplary embodiment, a higher radiographic assessment score at a later assessment than at a previous assessment is a positive treatment response. In an exemplary embodiment, a higher radiographic assessment score at a response assessment than at a baseline assessment is a positive treatment response. In an exemplary embodiment, a higher radiographic assessment score at a later response assessment than at a previous response assessment is a positive treatment response. In an exemplary embodiment, a higher radiographic assessment score at a second (or third or fourth, etc.) response assessment than at a first response assessment is a positive treatment response. In an exemplary embodiment, a higher radiographic assessment score at a third (or fourth or fifth, etc.) response assessment than at a second response assessment is a positive treatment response.

[0335] (Vc) Continue administration In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi)-V.xxxvii.) can be continued until a positive therapeutic response is achieved. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi)-V.xxxvii.) can be continued while there is a positive therapeutic response. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi)-V.xxxvii.) can be continued as long as there is a positive therapeutic response. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi)-V.xxxvii.) can be continued for about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for about 11 months, or about 12 months, or about 13 months, or about 14 months, or about 15 months, or about 16 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 25 months, or about 26 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.), can continue for about 26 months, or about 27 months, or about 28 months, or about 29 months, or about 30 months.In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for at least about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for at least about 11 months, or about 12 months, or about 13 months, or about 14 months, or about 15 months, or about 16 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for at least about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for at least about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 25 months, or about 26 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) can continue for at least about 26 months, or about 27 months, or about 28 months, or about 29 months, or about 30 months.

[0336] In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated after there is no longer a positive therapeutic response. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated at about 6 months, or about 7 months, or about 8 months, or about 9 months, or about 10 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated at about 11 months, or about 12 months, or about 13 months, or about 14 months, or about 15 months, or about 16 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated at about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated at about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 25 months, or about 26 months. In some embodiments, the administration described herein, e.g., in Sections III or IIIa or Vi) through V.xxxvii.) is terminated at about 26 months, or about 27 months, or about 28 months, or about 29 months, or about 30 months.

[0337] (Vd) Occurrence / Repetition of Dosing Regimen In some embodiments, the dosing regimens described herein, such as in Sections Vi) through V.xxxvii.), have the parameters described in this section.

[0338] Paragraph A: In an exemplary embodiment, the dosing regimen is continued for a period between about 21 days and about 35 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 22 days and about 34 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 23 days and about 33 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 24 days and about 32 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 25 days and about 31 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 26 days and about 30 days. In an exemplary embodiment, the dosing regimen is continued for a period between about 27 days and about 29 days. In an exemplary embodiment, the dosing regimen is continued for about 28 days. In an exemplary embodiment, the dosing regimen is continued for 28 days.

[0339] Paragraph B: In an exemplary embodiment, the dosing regimen occurs once. In an exemplary embodiment, the dosing regimen occurs twice. In an exemplary embodiment, the dosing regimen occurs three times. In an exemplary embodiment, the dosing regimen occurs four times. In an exemplary embodiment, the dosing regimen occurs five times. In an exemplary embodiment, the dosing regimen occurs six times. In an exemplary embodiment, the dosing regimen occurs seven times. In an exemplary embodiment, the dosing regimen occurs eight times. In an exemplary embodiment, the dosing regimen occurs nine times. In an exemplary embodiment, the dosing regimen occurs ten times. In an exemplary embodiment, the dosing regimen occurs eleven times. In an exemplary embodiment, the dosing regimen occurs twelve times. In an exemplary embodiment, the dosing regimen occurs thirteen times. In an exemplary embodiment, the dosing regimen occurs fourteen times. In an exemplary embodiment, the dosing regimen occurs fifteen times. In an exemplary embodiment, the dosing regimen occurs sixteen times. In an exemplary embodiment, the dosing regimen occurs seventeen times. In an exemplary embodiment, the dosing regimen occurs eighteen times. In an exemplary embodiment, the dosing regimen occurs nineteen times. In an exemplary embodiment, the dosing regimen occurs 20 times. In an exemplary embodiment, the dosing regimen occurs 21 times. In an exemplary embodiment, the dosing regimen occurs 22 times. In an exemplary embodiment, the dosing regimen occurs 23 times. In an exemplary embodiment, the dosing regimen occurs 24 times. In an exemplary embodiment, the dosing regimen occurs 25 times. In an exemplary embodiment, the dosing regimen occurs 26 times. In an exemplary embodiment, the dosing regimen occurs 27 times. In an exemplary embodiment, the dosing regimen occurs 28 times. In an exemplary embodiment, the dosing regimen occurs 29 times. In an exemplary embodiment, the dosing regimen occurs 30 times. In an exemplary embodiment, the dosing regimen occurs 31 times. In an exemplary embodiment, the dosing regimen is repeated until a positive therapeutic response is achieved. In an exemplary embodiment, the dosing regimen is continued until a positive therapeutic response is achieved. In an exemplary embodiment, the dosing regimen is repeated as long as there is a positive therapeutic response.In an exemplary embodiment, the dosing regimen is continued as long as there is a positive therapeutic response. In an exemplary embodiment, the dosing regimen is administered to a human subject as long as there is a positive therapeutic response.

[0340] Paragraph C: In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 20 hours and about 28 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 21 hours and about 27 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 22 hours and about 26 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 23 hours and about 25 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every about 24 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every 24 hours.

[0341] Paragraph D: In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 44 hours and about 52 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 45 hours and about 51 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 46 hours and about 50 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every hour between about 47 hours and about 49 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every about 48 hours. In an exemplary embodiment, the oral dose of epetravorol is administered once every 48 hours.

[0342] Paragraph E: In an exemplary embodiment, the oral dose of epetravorole is between about 200 mg and about 1100 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 200 mg and about 300 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 225 mg and about 275 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 240 mg and about 260 mg. In an exemplary embodiment, the oral dose of epetravorole is about 250 mg. In an exemplary embodiment, the oral dose of epetravorole is 250 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 400 mg and about 600 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 425 mg and about 575 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 450 mg and about 550 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 475 mg and about 525 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 490 mg and about 510 mg. In an exemplary embodiment, the oral dose of epetravorole is about 500 mg. In an exemplary embodiment, the oral dose of epetravorole is 500 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 650 mg and about 850 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 675 mg and about 825 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 700 mg and about 800 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 725 mg and about 775 mg. In an exemplary embodiment, the oral dose of epetravorole is about 750 mg. In an exemplary embodiment, the oral dose of epetravorole is 750 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 900 mg and about 1100 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 925 mg and about 1075 mg.In an exemplary embodiment, the oral dose of epetravorole is between about 950 mg and about 1050 mg. In an exemplary embodiment, the oral dose of epetravorole is between about 975 mg and about 1025 mg. In an exemplary embodiment, the oral dose of epetravorole is about 1000 mg. In an exemplary embodiment, the oral dose of epetravorole is 1000 mg.

[0343] In an exemplary embodiment, the oral dose of epetravorole is about 250 mg and is administered in one about 250 mg unit dosage form. In an exemplary embodiment, the oral dose of epetravorole is about 500 mg and is administered in two about 250 mg unit dosage forms. In an exemplary embodiment, the oral dose of epetravorole is about 500 mg and is administered in one about 500 mg unit dosage form. In an exemplary embodiment, the oral dose of epetravorole is 250 mg and is administered in one 250 mg unit dosage form. In an exemplary embodiment, the oral dose of epetravorole is 500 mg and is administered in two 250 mg unit dosage forms. In an exemplary embodiment, the oral dose of epetravorole is 500 mg and is administered in one 500 mg unit dosage form.

[0344] In an exemplary embodiment, the oral dose of epetravorole is a tablet. In an exemplary embodiment, the oral dose of epetravorole is a pill. In an exemplary embodiment, the oral dose of epetravorole is a capsule.

[0345] In an exemplary embodiment, the oral dose of epetravorole is 250 mg and is administered in one 250 mg tablet. In an exemplary embodiment, the oral dose of epetravorole is 500 mg and is administered in two 250 mg tablets. In an exemplary embodiment, the oral dose of epetravorole is 500 mg and is administered in one 500 mg unit dosage form.

[0346] A medical professional of ordinary skill in the art can easily determine and prescribe the effective amount of oral composition required.For example, a physician can start a dose of the drug employed in the epetravorol composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0347] The dosage regimen is adjusted to provide the optimum desired response (e.g., a therapeutic response). As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the subjects to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0348] The specifications for the dosage unit forms of the present invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active compound for the treatment of hypersensitivity in an individual.

[0349] (Ve) Specific Dosing Regimen Embodiments In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole according to a dosing regimen comprising: an oral dose of epetravorole described in paragraph E administered on a first day of the dosing regimen, and said oral dose being administered as described in paragraph C, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of epetravorole between about 240 mg and about 260 mg administered on a first day of the dosing regimen, and said oral dose being administered as described in paragraph C, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 475 mg and about 525 mg and is administered on the first day of the dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B.In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 725 mg and about 775 mg and is administered on the first day of the dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 1075 mg and about 1125 mg and is administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen is as described in paragraph A and said dosing regimen occurs as described in paragraph B. For any embodiment in this paragraph, said oral dose is administered with food. For any embodiment in this paragraph, said oral dose is in the fasted state.

[0350] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of epetravorole described in paragraph E administered on a first day of said dosing regimen, and said oral dose being administered as described in paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of epetravorole between about 240 mg and about 260 mg administered on a first day of said dosing regimen, and said oral dose being administered as described in paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 475 mg and about 525 mg and is administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B.In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 725 mg and about 775 mg and is administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: said oral dose of epetravorole is between about 1075 mg and about 1125 mg and is administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B. For any embodiment in this paragraph, said oral dose is administered with food. For any embodiment in this paragraph, said oral dose is in the fasted state.

[0351] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of epetravorole described in paragraph E administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph C or paragraph D, wherein said dosing regimen is as described in paragraph A, and wherein said dosing regimen occurs as described in paragraph B.

[0352] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, and said oral dose being administered as described in paragraph C, wherein said dosing regimen continues for a period of between about 26 days and about 30 days, and wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen continues for a period of between about 26 days and about 30 days, wherein said dosing regimen occurs as described in paragraph B.

[0353] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on a first day of said dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen is continued for about 28 days, wherein said dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on a first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen is continued for about 28 days, wherein said dosing regimen occurs as described in paragraph B.

[0354] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen continues for about 28 days, wherein said dosing regimen occurs between 4 and 20 times, or between 12 and 17 times. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen continues for about 28 days, wherein said dosing regimen occurs between 4 and 20 times, or between 12 and 17 times. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph C, wherein said dosing regimen is continued for about 28 days, wherein said dosing regimen occurs for as long as there is a positive therapeutic response.In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering to a human subject in need of such treatment epetravorole in a dosing regimen comprising: an oral dose of between about 475 mg and about 525 mg of epetravorole administered on the first day of said dosing regimen, said oral dose being administered as described in paragraph D, wherein said dosing regimen is continued for about 28 days, wherein said dosing regimen is administered for as long as there is a positive therapeutic response. For any embodiment in this paragraph, said oral dose is administered with food. For any embodiment in this paragraph, said oral dose is in the fasted state.

[0355] In an exemplary embodiment, the present invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering epetravorol to a human subject in need of treatment with a standard of care NTM infection. In an exemplary embodiment, the human subject is administered at least one of the aforementioned NTM therapeutics, which is not epetravorol. Wherein the human subject is administered at least two of the aforementioned NTM therapeutics, which are not epetravorol. In an exemplary embodiment, the aforementioned NTM therapeutics are selected from the group consisting of at least two antimycobacterial agents according to current international treatment guidelines for at least six of the past twelve months prior to the first administration of the dosing regimen. In an exemplary embodiment, the aforementioned NTM therapeutics are selected from the group consisting of clarithromycin, azithromycin, ethambutol, rifampin, rifabutin, amikacin, bedaquiline, clofazimine, linezolid, and a fluoroquinolone. In an exemplary embodiment, the method further comprises administering to the human subject an optimized background regimen (OBR) therapy. In an exemplary embodiment, the optimized background regimen (OBR) therapy is at least two antimycobacterial agents in accordance with current American Thoracic Society (ATS) / European Respiratory Society (ERS) / European Society for Clinical Microbiology and Infectious Diseases (ESCMID) / Infectious Diseases Society of America (IDSA) treatment guidelines.

[0356] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response to a nontuberculous mycobacterial (NTM) infection, comprising administering a dosing regimen described herein to a human subject in need of such treatment, wherein the dosing regimen has a duration as described in paragraph A, and wherein the dosing regimen occurs as described in paragraph B.

[0357] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against nontuberculous mycobacterial (NTM) infection comprising administering a dosing regimen described in sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.) to a human subject in need of such treatment, wherein the dosing regimen has a duration described in paragraph A and the dosing regimen occurs as described in paragraph B.

[0358] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against nontuberculous mycobacterial (NTM) infection comprising administering a dosing regimen described in sections Vi);V.ii.);V.iii.);V.iv.);Vv);V.vi.);V.vii.);V.viii.);V.ix.);Vx);V.xi.);V.xii.);V.xiii.);V.xiv.);V.xv.);V.xvi.);V.xvii.);V.xxviii.);V.xxix.);V.xxx.);V.xxxi.) to a human subject in need of such treatment, wherein the dosing regimen has a duration of between about 27 days and about 29 days, and wherein the dosing regimen occurs as described in paragraph B.

[0359] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering a dosing regimen described in Sections Vi);V.ii.);V.iii.);V.iv.);Vv); to a human subject in need of such treatment, wherein the dosing regimen has a duration described in paragraph A, and wherein the dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering a dosing regimen described in Sections Vi);V.ii.);V.iii.);V.iv.);Vv); to a human subject in need of such treatment, wherein the dosing regimen has a duration between about 27 days and about 29 days, and wherein the dosing regimen occurs as described in paragraph B.

[0360] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering to a human subject in need of such treatment a dosing regimen as described in Sections Vx);V.xi.);V.xii.);V.xiii.), wherein the dosing regimen has a duration of between about 27 days and about 29 days, and wherein the dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering to a human subject in need of such treatment a dosing regimen as described in Sections Vx);V.xi.);V.xii.);V.xiii.), wherein the dosing regimen has a duration of between about 27 days and about 29 days, and wherein the dosing regimen occurs as described in paragraph B.

[0361] In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering to a human subject in need of such treatment a dosing regimen as described in Sections V.xxviii.), V.xxix.), V.xxx.), and V.xxxi.), wherein the dosing regimen has a duration as described in paragraph A, and wherein the dosing regimen occurs as described in paragraph B. In an exemplary embodiment, the invention provides a method of achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising administering to a human subject in need of such treatment a dosing regimen as described in Sections V.xxviii.), V.xxix.), V.xxx.), and V.xxxi.), wherein the dosing regimen has a duration of between about 27 days and about 29 days, and wherein the dosing regimen occurs as described in paragraph B.

[0362] VI. Selection of Human Subjects In an exemplary embodiment, the methods described herein may be administered to a human subject having one or more of the inclusion and / or exclusion criteria described herein. In an exemplary embodiment, the methods described herein may be administered to a human subject having one or more of the criteria described in Section VI. In an exemplary embodiment, the methods described herein may be administered to a human subject having one or more of the inclusion criteria described herein. In an exemplary embodiment, the methods described herein may be administered to a human subject having one or more of the exclusion criteria described herein.

[0363] The human subject may be selected based on the criteria described herein. In an exemplary embodiment, the human subject is male. In an exemplary embodiment, the human subject is female. In an exemplary embodiment, the human subject is 18 years of age or older. In an exemplary embodiment, the human subject is between 18 and 100 years of age. In an exemplary embodiment, the human subject is between 18 and 80 years of age. In an exemplary embodiment, the human subject is between 45 and 90 years of age. In an exemplary embodiment, the human subject is between 45 and 80 years of age. In an exemplary embodiment, the human subject is between 50 and 90 years of age. In an exemplary embodiment, the human subject is between 55 and 85 years of age. In an exemplary embodiment, the human subject is between 60 and 80 years of age. In an exemplary embodiment, the human subject is between 60 and 70 years of age.

[0364] In an exemplary embodiment, the human subject has a diagnosis of NTM infection. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant NTM infection. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant NTM disease. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant NTM pulmonary disease. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant MAC infection. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant MAC disease. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant MAC pulmonary disease. In an exemplary embodiment, the human subject is experiencing progression of NTM infection. In an exemplary embodiment, the human subject is capable of providing written informed consent. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant MAC pulmonary disease consisting of the following microbiological criteria: one pre-study MAC-positive respiratory specimen. This specimen may have been taken within six months prior to screening based on the patient's medical records. The respiratory specimen can be a voided or induced sputum sample, or a deep bronchial sample (e.g., bronchoalveolar lavage, bronchial brush, or lung biopsy) collected while the patient was continuously or intermittently treated with an OBR consisting of at least two antimycobacterial agents according to current ATS / ERS / ESCMID / IDSA treatment guidelines for at least 6 of the past 12 months prior to randomization. If the pre-study respiratory specimen was collected more than 8 weeks to 6 months prior to randomization, the patient may only be enrolled in the study after a screening sputum sample (below) is reported as MAC positive by the central microbiology laboratory. In an exemplary embodiment, the human subject has a diagnosis of treatment-resistant MAC pulmonary disease consisting of the following microbiological criteria: one screening MAC-positive voided or induced sputum sample. These MAC-positive cultures are based on two to three screening sputum samples (excluding deep bronchial specimens) collected within the 8-week screening period and sent to a central microbiology laboratory for culture and identification (see laboratory manual for details). Screening sputum samples can be collected on consecutive days if necessary.To be included in the screening, at least one sputum sample had to have a positive culture result for MAC.

[0365] Antimycobacterial susceptibility results prior to randomization are not required (Note: if a pre-study respiratory specimen was collected within 8 weeks prior to randomization, at the investigator's discretion, patients may be enrolled in the study after a screening sputum sample is collected with culture results pending (not yet MAC positive) at the time of randomization).

[0366] In an exemplary embodiment, the human subject is able to comply with all study activities and procedures throughout the study period, including willingness to comply with the antimycobacterial combination therapy regimen (including oral, plus inhaled and parenteral, as appropriate) from screening through the LFU visit (study period of up to about 20 months, not including screening), and willingness to comply with scheduled study visits and study procedures (including all scheduled sputum collections). In an exemplary embodiment, the human subject is expected to survive by continuing antimycobacterial therapy and appropriate supportive care from screening through the LFU visit, as determined by the investigator.

[0367] In an exemplary embodiment, the human subject agrees to use an effective method of contraception. In an exemplary embodiment, the human subject is female and is neither pregnant nor breastfeeding. In an exemplary embodiment, female human subjects of childbearing potential (FOCPs) practice sexual abstinence or use at least two medically accepted effective methods of contraception. The methods may be a combination of highly effective methods (e.g., oral contraceptives, intrauterine devices, hormonal implants / patches, injections, or approved cervical rings) and barrier methods (e.g., condoms, spermicidal gels) from screening to the EOT visit and for 90 days after the last dose of epetravorole. Not of childbearing potential is defined as postmenopausal (i.e., amenorrhea for at least one year) or surgically / naturally infertile. In an exemplary embodiment, the human subject is male and the FOCP and sexually active aale patients agree to use an effective barrier method of contraception from screening to the EOT visit and for 90 days after the last dose of epetravorole.

[0368] In an exemplary embodiment, the human subject does not have a predominantly fibrocavitary MAC pulmonary disease. In an exemplary embodiment, the human subject does not have a history of treatment-resistant MAC pulmonary disease for more than 5 years. In an exemplary embodiment, the human subject does not have cystic fibrosis or other genetic disorders of airway ciliary dysfunction (e.g., primary ciliary dyskinesia). In an exemplary embodiment, the human subject does not have active allergic bronchopulmonary mycosis. In an exemplary embodiment, the human subject has not undergone anticipated or planned pulmonary surgery for the treatment of MAC pulmonary disease. In an exemplary embodiment, the human subject does not have disseminated MAC infection or other known or suspected non-pulmonary sources of infection (e.g., infective endocarditis, osteomyelitis, meningitis, or urinary tract infection) that require non-trial antimicrobial therapy. In an exemplary embodiment, the human subject does not have a concurrent pulmonary infection requiring antimicrobial therapy, including infections caused by fungi, viruses, non-MAC mycobacteria (e.g., Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium kansasii), or other bacteria (e.g., Pseudomonas aeruginosa, Staphylococcus aureus). In an exemplary embodiment, the human subject does not have an active pulmonary malignancy (primary or metastatic), or a malignancy that has required or may require chemotherapy or radiation therapy within one year prior to randomization through an LFU visit. In an exemplary embodiment, the human subject does not have a creatinine clearance (CrCl) of 50 mL / min or less at screening or randomization as estimated by the Cockcroft-Gault formula: Estimated CrCl (mL / min) = (140 - age [years]) x actual weight [kg] x [0.85 (for women)]) / (72 x serum creatinine [mg / dL]). In an exemplary embodiment, the human subject does not have a hemoglobin less than 10.0 g / dL or less than 6.2 mmol / L (grade 2 anemia or worse based on Common Terminology of Adverse Events [CTCAE] criteria) at screening.In an exemplary embodiment, the human subject has not donated blood or plasma within 28 days prior to treatment. In an exemplary embodiment, the human subject has not had any symptomatic blood loss or bleeding within 28 days prior to treatment. In an exemplary embodiment, the human subject has not had severe hemoptysis, defined as 100mL (more than about 7 tablespoons of blood) for any 24 hours, or severe or very severe hemoptysis, within 28 days prior to treatment. In an exemplary embodiment, the human subject has not had severe liver damage as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 3x upper limit of normal (ULN), or total bilirubin above 2x ULN, or clinical signs of cirrhosis or end-stage liver disease (e.g., ascites, hepatic encephalopathy). In an exemplary embodiment, the human subject is not pregnant or lactating. In an exemplary embodiment, the human subject has a mean QT interval corrected using the Fridericia formula (QTcF) of not more than 480 milliseconds based on a triple 12-lead electrocardiogram at screening. In an exemplary embodiment, the human subject has no immunodeficiency or immunocompromised conditions, and is not at risk for opportunistic pulmonary infections. In an exemplary embodiment, the human subject has no known history of human immunodeficiency virus (HIV) infection, plus any active disease that defines acquired immune deficiency syndrome (AIDS) within the past 12 months. In an exemplary embodiment, the human subject has a known cluster differentiation 4 (CD4) count of 200 / mm within the past 12 months. 3 In an exemplary embodiment, the human subject is neutropenic (absolute neutrophil count 1,000 neutrophils / mm) during treatment. 3In an exemplary embodiment, the human subject has not started immunosuppressive therapy, including cancer chemotherapy, transplant rejection medication, or chronic use of systemic corticosteroids, defined as 20 mg / day or more of prednisone or systemic equivalent, within 8 weeks of randomization. In an exemplary embodiment, the human subject is not expected to start a new non-investigational antimycobacterial therapy during the dosing regimen provided herein. In an exemplary embodiment, the human subject has not received any other investigational drug for 30 days or 5 half-lives, whichever is longer, prior to treatment. In an exemplary embodiment, the human subject has not been previously exposed to epetravorole. In an exemplary embodiment, the human subject has no condition that would interfere with the patient's ability to safely complete the study or comply with the study requirements, including the patient's inability or unwillingness to comply with all study assessments and visits.

[0369] In an exemplary embodiment, the methods described herein cannot be administered to a human subject who has received a prior therapy described herein. In an exemplary embodiment, the methods described herein cannot be administered to a human subject who has received a prohibitive therapy described herein. In an exemplary embodiment, the methods described herein can be administered to a human subject who has received a combination therapy described herein.

[0370] (VII. Others) In an exemplary embodiment, the methods described herein can be administered according to the objectives described in Example 1. In an exemplary embodiment, the dosing regimens described herein can be administered according to the objectives described in Example 1. In an exemplary embodiment, the methods described herein can be administered according to the endpoints described in Example 1. In an exemplary embodiment, the dosing regimens described herein can be administered according to the endpoints described in Example 1.

[0371] In an exemplary embodiment, the human subject is administered at least one of the aforementioned NTM therapeutics, which is not epetravorol. In an exemplary embodiment, the human subject is administered at least two of the aforementioned NTM therapeutics, neither of which is epetravorol. In an exemplary embodiment, the aforementioned NTM therapeutics are selected from the group consisting of at least two antimycobacterial agents, according to current international treatment guidelines, for at least six of the past twelve months prior to the first administration of the dosing regimen. In an exemplary embodiment, the aforementioned NTM therapy is selected from the group consisting of clarithromycin, azithromycin, ethambutol, rifampin, rifabutin, amikacin, bedaquiline, clofazimine, linezolid, and a fluoroquinolone. In an exemplary embodiment, the method further comprises administering an optimized background regimen (OBR) therapeutic to the human subject. In an exemplary embodiment, the optimized background regimen (OBR) therapeutic agents are at least two antimycobacterial agents in accordance with current American Thoracic Society (ATS) / European Respiratory Society (ERS) / European Society for Clinical Microbiology and Infectious Diseases (ESCMID) / Infectious Diseases Society of America (IDSA) treatment guidelines.

[0372] All cited references are expressly incorporated herein by reference in their entirety.

[0373] Although particular embodiments of the invention have been described above for purposes of illustration, those skilled in the art will appreciate that many changes in detail may be made therein without departing from the invention as set forth in the claims below.

[0374] All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes. In the event of a conflict between the teachings of one or more references incorporated herein and the teachings of this specification, the teachings of this specification shall control.

[0375] [Example] The following examples are provided to illustrate the invention and are not intended to bind the invention to any particular application or theory of operation.

[0376] The general and specific science and technology are outlined in U.S. Pat. No. 7,816,344, as well as PCT Publication WO2008 / 157726A1, each of which is expressly incorporated by reference in its entirety and in particular with respect to the technology outlined therein.

[0377] Example 1 Treatment planning Phase 2 Objectives and Endpoints The primary objective of Phase 2 is to evaluate the microbiological response of oral epetravorole compared to placebo. Another primary objective of Phase 2 is to evaluate the safety of oral epetravorole compared to placebo. A secondary objective of Phase 2 is to evaluate the plasma PK of oral epetravorole; the dose of epetravorole can be confirmed based on PK analysis from approximately 16 epetravorole patients.

[0378] Exploratory objectives of phase 2 are to evaluate clinical and microbiological responses in subgroups (e.g., age, use of amikacin liposomal inhalation suspension [ALIS] at baseline [pre-randomization], MAC resistance phenotype). Another exploratory objective of phase 2 is to evaluate lung radiographic response. Another exploratory objective of phase 2 is to evaluate microbiological response by epetravorol MIC. Another exploratory objective of phase 2 is to evaluate whether post-baseline MAC isolates have decreased susceptibility to epetravorol compared to baseline. Another exploratory objective of phase 2 is to evaluate time to microbiological response. Another exploratory objective of phase 2 is to evaluate microbiological reinfection and relapse.

[0379] The primary endpoint of Phase 2 is subject-specific sputum conversion at monthly intervals through Month 6. Sputum conversion can be assessed using culture conversion based on three consecutive monthly negative sputum cultures for MAC. Another primary endpoint of Phase 2 is the assessment of changes from baseline in TEAEs and changes in clinical laboratory values, electrocardiograms (ECGs), and vital signs.

[0380] A secondary endpoint for Phase 2 is microbiological improvement by subject per month through Month 6. Microbiological improvement can be assessed using reduction in MAC colony counts by one or more categories as described herein. Another secondary endpoint is the improvement of PK parameters (e.g., Vd, C) in epetravorol-treated patients. max , AUC).

[0381] Exploratory endpoints for phase 2 are clinical and microbiological response (by subject-specific sputum culture conversion and subject-specific microbiological improvement) at 3 and 6 months as indicated by age category, baseline ALIS use, and MAC resistance phenotype (i.e., macrolide resistance and amikacin resistance). Another exploratory endpoint for phase 2 is radiographic response at 6 months and end of treatment (EOT), defined as an overall change from baseline based on blinded central reading of chest CT scans. An exploratory endpoint for phase 2 is subject-specific microbiological response (by subject-specific sputum culture conversion and subject-specific microbiological improvement) by epitravorol MIC at 6 months. Another exploratory endpoint for phase 2 is the rate of decrease in susceptibility of MAC isolates after baseline (defined as a 4-fold or greater increase in epitravorol MIC over baseline isolate MIC) in patients who remain MAC culture positive after 4 months. Another exploratory endpoint in phase 2 is the time (months) to first negative sputum culture and reduction in MAC colony count by ≥1 category.Another exploratory endpoint in phase 2 is the rate of reinfection (new pulmonary MAC infections caused by a pathogen different from the baseline MAC isolate as determined by molecular typing) and relapse (pulmonary MAC infections caused by the same pathogen as the baseline MAC isolate as determined by molecular typing) at 6 months.

[0382] Phase 3 Objectives and Endpoints The primary objective of Phase 3 is to determine whether epetravorole + OBR is superior to placebo + OBR in microbiological response. A secondary objective of Phase 3 is to evaluate the safety of oral epetravorole compared to placebo. Another secondary objective of Phase 3 is to evaluate the plasma PK of oral epetravorole. An exploratory objective of Phase 3 is to evaluate clinical and microbiological responses in subgroups (e.g., age, baseline ALIS use, MAC resistance phenotype). Another exploratory objective of Phase 3 is to evaluate lung radiographic response. Another exploratory objective of Phase 3 is to evaluate microbiological response by epetravorole MIC. Another exploratory objective of Phase 3 is to evaluate whether post-baseline MAC isolates have decreased susceptibility to epetravorole compared to baseline. Another exploratory objective of Phase 3 is to evaluate time to microbiological response. Another exploratory objective of Phase 3 is to evaluate microbiological reinfection and relapse.

[0383] The primary endpoint of Phase 3 is subject-specific sputum conversion based on 3 consecutive monthly negative sputum cultures for MAC through 6 months. Secondary endpoints of Phase 3 are subject-specific microbiological improvement at 3 and 6 months using a reduction in MAC colony counts of ≥1 category. Additional secondary endpoints of Phase 3 are assessment of TEAEs and change from baseline in clinical laboratory values, ECGs, and vital signs. Another secondary endpoint of Phase 3 is the evaluation of PK parameters (e.g., Vd, C) in patients receiving epetravorol. maxThe exploratory endpoints for phase 3 are the clinical and microbiological responses (subject-specific sputum culture conversion and subject-specific microbiological improvement) at 3 and 6 months as indicated by age category, baseline ALIS use, and MAC resistance phenotype (macrolide resistance and amikacin resistance). Another exploratory endpoint for phase 3 is radiographic response at 6 months and EOT, defined as an overall change from baseline based on blinded central reading of chest CT scans. Another exploratory endpoint for phase 3 is the subject-specific microbiological response by epetravorol MIC at 6 months (subject-specific sputum culture conversion and subject-specific microbiological improvement). Another exploratory endpoint for phase 3 is the rate of decline in susceptibility in MAC isolates after baseline (defined as a 4-fold or greater increase in epetravorol MIC over baseline isolate MIC) in patients who remain MAC culture positive at or after 4 months. Another exploratory endpoint in phase 3 is time (months) to first negative sputum culture and reduction in MAC colony count by ≥1 category. Another exploratory endpoint in phase 3 is reinfection (new pulmonary MAC infection caused by a strain different from the baseline MAC isolate as determined by molecular typing) and relapse (pulmonary MAC infection caused by the same strain as the baseline MAC isolate as determined by molecular typing) at 6 months, EOT, and late follow-up (LFU).

[0384] (Research design) This is a phase 2 / 3, double-blind, placebo-controlled study of epetravorole + OBR (optimized background regimen) vs placebo + OBR in patients with treatment-resistant MAC lung disease. The study can enroll adult patients with treatment-resistant MAC lung disease who meet all eligibility criteria. In addition to the clinical criteria required to meet the disease definition, microbiological criteria define "treatment-resistant" MAC lung disease as a positive respiratory specimen culture for MAC while the patient has been continuously or intermittently treated with an OBR consisting of at least two antimycobacterial agents according to current international treatment guidelines for at least 6 of the last 12 months prior to randomization. Randomization can be stratified by baseline use of amikacin liposomal inhalation suspension (ALIS) and age at informed consent (<65 vs ≥65 years).

[0385] The study features a sequential Phase 2 / 3 approach with symptom-based clinical response, microbiological response, safety, and PK associated with oral epetravorolone initially evaluated in Phase 2 prior to a superiority analysis of oral epetravorolone versus placebo in Phase 3 of the study.

[0386] In the Phase 2 part of the trial, approximately 80 patients can be randomized in a 1:1 ratio (40 patients will receive active epetravorole tablets and 40 patients will receive matching placebo tablets) using an interactive responsive technology (IRT) system.

[0387] After the last patient in phase 2 completes the 6-month visit, the sponsor may unblind for phase 2 data analysis. Patients, investigators, and other study staff may also remain blinded to treatment allocation until the last study visit (LFU). Phase 2 data analysis includes review of microbiological, safety, and PK data collected at multiple time points through month 6. The phase 3 portion of the study may begin enrollment after the last patient in the phase 3 dose has been identified with review of phase 2 PK data. Patients enrolled in phase 2 of the study may not participate in phase 3. Phase 2 patients may continue to receive blinded study drug for 12 months after the first negative MAC culture, which defines sputum culture conversion. Patients who remain MAC culture positive despite 6 months of treatment with study drug may discontinue study drug (based on sputum culture results at month 4).

[0388] The diagram below illustrates the study design.

[0389] [Table 1]

[0390] The phase 3 part of the study can test the superiority of epetravorol + OBR compared to placebo + OBR. This part of the study will randomize approximately 234 patients in a 2:1 ratio (156 patients will receive active epetravorol tablets and 78 patients will receive matching placebo tablets) using an IRT system. In addition, the sponsor can decide whether to adjust the phase 3 sample size and validate the phase 3 epetravorol dosing regimen based on observed plasma epetravorol exposure. After the last patient in phase 3 completes the 6-month visit, the sponsor can unblind for phase 3 data analysis, and patients, investigators, and other study staff can remain blinded to treatment allocation until the last study visit (LFU). Phase 3 data analysis will include review of patient-reported clinical symptom responses, microbiological data, safety data, and PK data collected at multiple time points through 6 months. Patients in phase 3 may continue study drug in a double-blind fashion for 12 months after the first negative MAC culture, which defines sputum culture conversion, and study drug may be discontinued in patients who remain MAC culture positive despite 6 months of treatment with study drug (based on sputum culture results at month 4).

[0391] During the conduct of the study, an independent Data and Safety Monitoring Board (DSMB) may be responsible for periodic review of the open-label study safety data by performing qualitative and quantitative safety assessments. In addition, the DSMB may determine whether the basic study premise remains valid and evaluate the overall integrity, scientific merit, and conduct of the study if it continues to be acceptable. The DSMB may make recommendations to the sponsor regarding continuation or discontinuation of the study or proposed changes to the study design / procedures.

[0392] (Test evaluation and procedures) Study assessments and procedures may be completed at the following visits for both the Phase 2 and Phase 3 portions of the study: Screening Visit: Screening assessments to determine study eligibility may be performed within 8 weeks prior to randomization. Two to three sputum samples may be collected during screening and may be collected on separate consecutive days. The screening sputum sample may be sent to a central microbiology laboratory (National Jewish Lab) for culture, identification, quantification, susceptibility testing, and molecular biological testing. If the pre-study MAC-positive respiratory specimen was collected within 8 weeks prior to randomization, the patient may be enrolled in the study after the screening sputum sample is collected and the screening culture result is pending (not yet MAC-positive). Pre-randomization antimycobacterial susceptibility results are not required. If the pre-study MAC-positive respiratory specimen was collected more than 8 weeks to 6 months prior to randomization, the patient may be enrolled in the study after the screening sputum sample is reported as MAC-positive by the central microbiology laboratory (only MAC-level identification, not species-level, is required for randomization).

[0393] NOTE: Patients whose screening sputum sample culture is final MAC negative after randomization may discontinue study medication early and continue OBR when their final screening hold culture is reported as negative; however, they may remain on study (i.e., not withdrawn from study) to undergo all scheduled EOT and LFU evaluations, including safety evaluations.

[0394] Treatment Duration: Patients receive blinded study medication (epetravorol or placebo) from day 1 until EOT, which can be up to 12 months from the time of conversion of the first sputum culture to MAC culture negative for patients with culture conversion by month 6, or until study medication is discontinued earlier for any reason. Study medication may be discontinued for patients who remain MAC culture positive (based on sputum culture results at month 4) despite 6 months of treatment with study medication. Reporting of final respiratory culture and identification results can be up to 8 weeks after receipt of specimen at the central laboratory.

[0395] During the first 6 months of the treatment period, study evaluations (including microbiological, clinical, safety, and PK evaluations) may be performed from Day 1 (the calendar day of the first dose of study drug) and every 28 days (± 7 days) thereafter, up to a maximum of Month 6 (Day 169 ± 7).

[0396] Patients who had three consecutive monthly negative sputum cultures for MAC by month 6 (day 169 ± 7 days) and culture converted could continue on blinded study drug (investigator, study site, and patient remained blinded) for 12 months from the first month that defined sputum culture conversion, up to a maximum of 16 months.

[0397] For patients who continue on blinded study drug during the treatment period beyond the 6th month, study evaluations (including microbiological, clinical, safety, and PK evaluations) may be performed every 3 months (84 days ± 7 days) thereafter until the EOT (up to 12 months from the time the first sputum culture converted to a negative MAC culture).

[0398] EOT Visit: An EOT visit may occur within 7 calendar days after the last dose of study drug. Patients who require MAC pulmonary treatment for any reason beyond the maximum of 16 months may discontinue study drug and be treated with an appropriate open-label antimycobacterial regimen. EOT may occur up to 12 months after the first negative respiratory culture for MAC (i.e., the first month that defines sputum MAC culture conversion) or if study drug is discontinued early for any reason, such as persistent positive cultures despite 6 months of study drug treatment. For patients who withdraw from the study before study completion, EOT visit procedures may be performed at the early termination visit. EOT assessments may be performed during routine clinical care if within the EOT period.

[0399] LFU Visit: The LFU visit can occur 3 months (84 days ± 14 days) after the last dose of study medication.

[0400] Patients who discontinue study drug early for any reason will be allowed to remain in the study (i.e., will not be withdrawn from the study) in order to undergo all scheduled EOT and LFU evaluations, including safety evaluations.

[0401] (Participation period) In the Phase 2 and Phase 3 parts of the study, each patient will remain in the study for a maximum of approximately 19 months, excluding screening.

[0402] The duration of each patient's study participation will depend on the timing of microbiological sputum MAC culture conversion. To receive study drug beyond month 6, subjects must achieve microbiological sputum MAC culture conversion based on three consecutive monthly negative sputum cultures by month 6. Patients may continue receiving blinded study drug for 12 months from the first month of defined sputum culture conversion, up to a maximum of 16 months. For patients who remain MAC culture positive despite 6 months of study drug treatment (based on sputum culture results at month 4), study drug administration may be discontinued.

[0403] For example, a subject with three consecutive negative results at months 4, 5, and 6 may continue on blinded study drug for 12 months from month 4 (first month of crossover) through month 16. The EOT visit for this subject is at month 16 (i.e., 12 months after month 4) and the LFU visit is at month 19 (i.e., 3 months [84 days ± 14 days] after the last dose).

[0404] Inclusion criteria Inclusion criteria for study subjects include: 1. Male or female patients aged 18 years or older. 2. Willing and able to provide written informed consent. 3. Patients diagnosed with treatment-resistant MAC pulmonary disease consisting of the following microbiological and / or radiological criteria: Microbiological Criteria: One pre-study MAC-positive respiratory specimen. In an exemplary embodiment, this specimen is collected within 6 months prior to screening based on documentation in the patient's medical record. In an exemplary embodiment, documentation of a MAC-positive specimen collected according to standard of care within 6 months prior to signing the Informed Consent Form (ICF) is provided. In an exemplary embodiment, the respiratory specimen is a voided or induced sputum sample, or a deep bronchial sample (e.g., bronchoalveolar lavage, bronchial brush, or lung biopsy) taken while the patient was receiving treatment with an OBR consisting of at least two antimycobacterial agents, either continuously or intermittently, for at least six of the last twelve months prior to randomization, in accordance with current American Thoracic Society (ATS) / European Respiratory Society (ERS) / European Society for Clinical Microbiology and Infectious Diseases (ESCMID) / Infectious Diseases Society of America (IDSA) treatment guidelines. In an exemplary embodiment, the pre-trial is taken while the patient was receiving treatment with an OBR consisting of at least two antimycobacterial agents, either continuously or intermittently, for at least six of the last twelve months prior to randomization, in accordance with current American Thoracic Society (ATS) / European Respiratory Society (ERS) / European Society for Clinical Microbiology and Infectious Diseases (ESCMID) / Infectious Diseases Society of America (IDSA) treatment guidelines. In an exemplary embodiment, if the pre-study respiratory specimen was collected more than 8 weeks to 6 months prior to randomization, the patient may only be enrolled in the study after the screening sputum sample is reported as MAC positive by the central microbiology laboratory. In an exemplary embodiment, the pre-study respiratory specimen may be a voided or induced sputum sample, or a deep bronchial sample (e.g., bronchoalveolar lavage, bronchial brush, or lung biopsy). One screening MAC positive voided or induced sputum sample.In an exemplary embodiment, MAC positive cultures are based on 2 to 3 screening sputum samples (not deep bronchial specimens) taken within an 8-week screening period, which are sent to a central microbiology laboratory for culture and identification. In an exemplary embodiment, MAC positive cultures are based on 2 to 3 screening sputum samples (not deep bronchial specimens) taken within an 8-week screening period (after signing the ICF), which are sent to a central microbiology laboratory for culture and identification. In an exemplary embodiment, screening sputum samples may be taken on consecutive separate days, if necessary; at least one sputum sample will have a culture that is MAC positive for inclusion in the screen. In an exemplary embodiment, screening sputum samples may be taken on the same day or on consecutive separate days. Antimycobacterial susceptibility results prior to randomization are not required. If the pre-study MAC-positive respiratory specimen was collected >8 weeks but 6 months prior to randomization, the patient may only be enrolled in the study after a screening sputum sample is reported as MAC-positive by the central microbiology laboratory. If the pre-study MAC-positive respiratory specimen was collected within 8 weeks prior to randomization, the patient may be enrolled (at the investigator's discretion) after a screening sputum sample has been collected and the screening culture result is pending (not yet MAC-positive). Radiographic criteria: Chest CT scan performed within 8 weeks prior to randomization showing abnormalities consistent with MAC pulmonary disease. Note: Radiographically cavitated MAC pulmonary disease is recognized if the largest cavity on chest CT is 3.0 cm or less in maximum diameter. Predominantly fibrocavitary MAC pulmonary disease or the presence of cavities >3.0 cm in diameter is excluded. 4. Patients who are willing to adhere to a combination antimycobacterial treatment regimen (including oral plus inhaled and parenteral agents as needed) and willing to comply with all study activities and procedures for the duration of the study, including willingness to comply with all scheduled visits and study procedures (including all scheduled sputum collections) from screening through the LFU visit (study duration excluding screening is approximately 19 months maximum). 5. All patients must agree to use an effective method of contraception.a. Female patients must not be pregnant or breastfeeding. Female patients of childbearing potential (FOCP) must agree to sexual abstinence or the use of at least two effective medically accepted methods of contraception. Methods may be any combination of highly effective methods (e.g., oral contraceptives, intrauterine devices, hormonal implants / patches, injections, or approved cervical rings) and barrier methods (e.g., condoms, spermicidal gels) from screening through the EOT visit and for 90 days after the last dose of study drug. Not of childbearing potential is defined as postmenopausal (i.e., amenorrhea for at least 1 year) or surgical / natural infertility. b. Male patients who are sexually active with FOCP must agree to use effective barrier contraception from screening through the EOT visit and for 90 days after the last dose of study drug. 6. Patients who will continue antimycobacterial therapy from screening through the LFU visit and are expected to survive with appropriate supportive care.

[0405] Exclusion criteria Exclusion criteria for study inclusion included the following: 1. Patients with suspected or confirmed disease or condition present at screening or randomization that the investigator judges may confound symptom-based assessment of clinical response, including, but not limited to: predominantly fibrocavitary MAC lung disease or the presence of cavities >3.0 cm on radiographs; history of treatment-resistant MAC lung disease for >5 years; cystic fibrosis or other inherited disorders of airway ciliary dysfunction (e.g., primary ciliary dyskinesia); active allergic bronchopulmonary mycosis; scheduled or planned pulmonary surgery for treatment of MAC lung disease; disseminated MAC infection or a known or suspected source of infection other than the lung requiring off-study antibiotic treatment (e.g., infective endocarditis, osteomyelitis, meningitis, or urinary tract infection); fungal, viral, or non-MAC mycobacterial (e.g., Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium tuberculosis ... Concomitant pulmonary infection requiring antibiotic treatment, including infections caused by Mycobacterium abscessus, Mycobacterium kansasii, or other bacteria (e.g., Pseudomonas aeruginosa, Staphylococcus aureus); Note: Patients with MAC lung disease and concomitant non-MAC pulmonary infection requiring antibiotic treatment may complete antibiotic treatment prior to randomization. Patients with respiratory specimen cultures containing growth of non-MAC organisms judged by the investigator to be respiratory coliforms and who do not require and are not receiving specific antibiotic treatment may remain eligible. 2. Patients with active pulmonary malignancy (primary or metastatic), or malignancies that have required or may require chemotherapy or radiation therapy by an LFU visit within 1 year prior to randomization. 3. Patients with creatinine clearance (CrCl) ≤ 50 mL / min as estimated by the Cockcroft-Gault formula at screening or randomization: Estimated CrCl (mL / min) = (140 - age [years]) × actual body weight [kg] × [0.85 (for women)]) ÷ (72 × serum creatinine [mg / dL]).4. Patients with hemoglobin <10.0 g / dL or <6.2 mmol / L (grade 2 anemia or worse based on Common Terminology of Adverse Events (CTCAE) criteria) at screening; blood or plasma donation within 28 days prior to randomization; or symptomatic bleeding or blood loss within 28 days prior to randomization. 5. Patients with severe hemoptysis, defined as more than 100 mL (> approximately 7 tablespoons) of blood within 24 hours, within 28 days prior to randomization. 6. Patients with severe hepatic impairment as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) or total bilirubin > 2 × ULN, or clinical signs of cirrhosis or end-stage liver disease (e.g., ascites, hepatic encephalopathy). 7. Patients who are pregnant or breastfeeding. 8. Patients with a mean QT interval corrected using the Fridericia formula (QTcF) of >480 milliseconds based on a triple 12-lead electrocardiogram at screening. 9. Patients with immunodeficiency or immunocompromised states and risk of opportunistic pulmonary infections, including: known history of human immunodeficiency virus (HIV) infection plus active acquired immunodeficiency syndrome (AIDS)-defining disease within the past 12 months or a known cluster differentiation 4 (CD4) count of 200 / mm within the past 12 months. 3 neutropenia (absolute neutrophil count < 1,000 neutrophils / mm3) at screening 310. Patients with anticipated initiation of new non-study antimycobacterial therapy any time from screening through 6 months (day 169 ± 7 days). 11. Patients who have received any investigational drug within 30 days or 5 half-lives prior to randomization, whichever is longer. 12. Patients with a history of exposure to epetravorole. 13. Patients with any condition that, in the investigator's judgment, would interfere with their ability to safely complete the study or comply with the requirements of the study (including the patient's inability or unwillingness to comply with all study evaluations and visits).

[0406] Withdrawal from the study A patient's participation in this clinical trial may be discontinued for any of the following reasons, including, but not limited to: if the patient withdraws consent for any reason or requests to be discontinued from the study; if the patient is lost to follow-up; if the patient fails to comply with the protocol requirements or study-related procedures; if the investigator determines that it is in the patient's best interest to be withdrawn from the protocol for reasons other than an AE (e.g., the occurrence of a medical condition or circumstance that imposes substantial risk to the patient and / or prevents the patient from complying with the protocol requirements); if the study is terminated or temporarily suspended by the Sponsor or regulatory authority for any reason, including, but not limited to, an unexpected life-threatening serious adverse event (SAE) related to the study drug detected during safety monitoring.

[0407] Early discontinuation of study drug Premature discontinuation of study drug by the investigator is an important discussion that should be conducted, if possible, with the medical monitor prior to discontinuing study drug. Reasons for premature discontinuation of study drug for safety reasons include, but are not limited to, the following: occurrence of an AE that, in the investigator's judgment, requires permanent discontinuation of administration of study drug to the patient; at least 3-fold elevation of ALT or AST greater than ULN, elevation of serum total bilirubin to greater than 2×ULN without elevation of serum alkaline phosphatase, and failure to find other diseases or conditions to explain the liver test abnormalities; known pregnancy or lactation during the study drug administration period; decreased renal function after baseline with estimated CrCl ≤50 mL / min; persistent positive sputum culture beyond 6 months of treatment; culture of screening sputum sample confirmed as no growth of MAC (culture negative) after randomization. Note: Reporting of final respiratory culture and identification results may take up to 8 weeks after receipt of specimen at the central laboratory. Unless the patient withdraws consent, patients who discontinue study medication early will remain in the study for safety follow-up (i.e., will not be withdrawn from the study entirely) and will be evaluated at the EOT and LFU visits.

[0408] Unit Dosage Form and Route of Administration The following unit dosage forms and routes of administration were utilized: epetravorol oral tablets: 250 mg; epetravorol dose: 500 mg (two 250 mg oral tablets) once daily (QD); placebo oral tablets: matched to epetravorol tablets; placebo regimen: matched to epetravorol dose (two oral tablets QD).

[0409] Eligible patients will be randomized to one of the following treatment arms: a) epetravorol oral tablets 500 mg (2 x 250 mg oral tablets) QD + OBR; or b) placebo oral tablets QD + OBR to match epetravorol dose. In this study, OBR at the time of randomization must consist of at least two oral antimycobacterial agents administered according to current ATS / ERS / ESCMID / IDSA treatment guidelines.

[0410] A total of approximately 314 patients are being enrolled in this Phase 2 / 3 study: the Phase 2 portion of the study may consist of approximately 80 randomized patients (40 in the epetravorole + OBR group and 40 in the placebo + OBR group). The Phase 3 portion of the study may consist of approximately 234 randomized patients (156 in the epetravorole + OBR group and 78 in the placebo + OBR group). The number of patients in the Phase 3 portion of the study may be adjusted based on the results of the Phase 2 analysis.

[0411] Labeling, Packaging, Storage, and Handling Epetravorol is provided as white to off-white modified oval, film-coated IR tablets containing 250 mg of epetravorol as the free base (288.5 mg as the hydrochloride salt) for oral administration. Color-matched placebo tablets may also be provided.

[0412] Study drug administration Active epetravorol and matching placebo oral tablets may be administered at a dose of 500 mg QD. Study drug tablets may be administered in the fasted state (no food for at least 1 hour before and at least 2 hours after study drug administration). If study drug administration on an empty stomach causes gastrointestinal upset, study drug administration may be combined with a small snack or at bedtime to improve tolerability.

[0413] The first dose of study medication may be administered in the presence of the investigator or his / her designee on post-randomization Day 1. After the first dose of study medication, patients will self-administer study medication orally QD.

[0414] Interactive Responsive Technology and Study Drug Allocation The IRT system is used for study drug management activities, which may include randomization, study drug supply management, inventory control and supply ordering, s...

Claims

1. 1. A composition for achieving a positive therapeutic response against a nontuberculous mycobacterial (NTM) infection comprising: epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; and ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof.

2. The epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, is administered in an oral dose of between about 250 mg and about 1000 mg; or Optionally, the epetravorole, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, is administered in an oral dose of between about 450 mg and 550 mg; or Optionally, the composition of claim 1, wherein the epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered in an oral dose of about 500 mg.

3. 2. The composition of claim 1, wherein the epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is epetravorol hydrochloride.

4. The ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 10 mg / kg and about 30 mg / kg; or Optionally, the ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 13 mg / kg and about 17 mg / kg; or Optionally, the ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered at an oral dose of about 15 mg / kg; or Optionally, the ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof, is administered at an oral dose of between about 23 mg / kg and about 27 mg / kg; or 2. The composition of claim 1, wherein optionally, the ethambutol, or a hydrate, solvate, or a pharma- ceutically acceptable salt thereof is administered at an oral dose of about 25 mg / kg.

5. said administration continues until said positive therapeutic response is achieved; or The method of claim 1 , wherein the administration is continued while a positive therapeutic response exists.

6. wherein the administration is according to a dosing regimen comprising: (a) an oral dose of between about 250 mg and about 1000 mg of the epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily or every other day; and an oral dose of between about 10 mg / kg and about 30 mg / kg of the ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, administered daily or three days a week; or (b) an oral dose of between about 450 mg and about 550 mg of the epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily; and (c) an oral dose of between about 13 mg / kg and about 17 mg / kg of said ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily; or an oral dose of between about 450 mg and about 550 mg of the epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered daily; and an oral dose of between about 23 mg / kg and about 27 mg / kg of the ethambutol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered three days per week; or Optionally, the dosing regimen continues for a period of between about 27 days and about 29 days.

7. The dosing regimen is repeated two or three or four or five times; or Optionally, the dosing regimen is repeated between about 15 and 30 times; or 7. The composition of claim 6, optionally wherein the dosing regimen is repeated 15 or 16 or 17 or 18 or 19 or 20 times.

8. The oral dose of epetravorole, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered with food; or 3. The composition of claim 2, wherein the oral dose of epetravorol, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof, is administered in the fasted state.

9. further comprising a rifamycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; Optionally, the rifamycin is rifampicin (rifampin), rifabutin, rifapentine, or rifaximin; or Optionally, the rifamycin is rifampicin (rifampin), which is administered at an oral dose of between about 5 mg / kg and about 15 mg / kg; or Optionally, the rifampicin (rifampin) is administered at an oral dose of between about 9 mg / kg and about 11 mg / kg; or Optionally, the rifamycin is rifampicin (rifampin), and the rifampicin (rifampin) is administered in an oral dose of between about 425 mg and about 625 mg; or Optionally, the rifamycin is rifabutin, and the rifabutin is administered in an oral dose of between about 125 mg and about 325 mg; or Optionally, the rifamycin is rifabutin, and the rifabutin is administered in an oral dose of between about 125 mg and about 175 mg, or between about 275 mg and about 325 mg; or 2. The composition of claim 1, optionally wherein the rifamycin is rifabutin, and wherein the rifabutin is administered in an oral dose of between about 150 mg and about 300 mg.

10. further comprising azithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; Optionally, the azithromycin is administered in an oral dose of between about 225 mg and about 525 mg; or 10. The composition of claim 1, wherein optionally, the azithromycin is administered in an oral dose of between about 250 mg and about 500 mg.

11. further comprising clarithromycin, or a hydrate, solvate, or pharma- ceutically acceptable salt thereof; Optionally, the clarithromycin is administered in an oral dose of between about 475 mg and about 1025 mg; or Optionally, the clarithromycin is administered at an oral dose of about 1000 mg; or Optionally, the clarithromycin is administered twice daily, with each oral dose being between about 475 mg and about 525 mg; or Optionally, the composition of claim 1, wherein the clarithromycin is administered twice daily, each oral dose being about 500 mg.

12. Further containing amikacin, Optionally, the amikacin is administered at an intravenous dose of between about 5 mg / kg and about 30 mg / kg; or Optionally, the amikacin is administered at an intravenous dose of between about 10 mg / kg and about 15 mg / kg; or Optionally, the amikacin is administered at an intravenous dose of between about 15 mg / kg and about 25 mg / kg; or Optionally, the amikacin is administered in an intravenous dose of between about 475 mg and about 525 mg; or Optionally, the amikacin is administered in an intravenous dose of about 500 mg; or Optionally, the amikacin is administered in an inhaled dose of between about 580 mg and about 600 mg; or Optionally, the amikacin is administered in an inhaled dose of about 590 mg; or Optionally, the amikacin is in a liposomal suspension.

13. The nontuberculous mycobacteria grow rapidly; Optionally, the nontuberculous mycobacteria are rapidly growing and are selected from the group consisting of M. abscessus, M. arabiense, M. aromaticivorans, M. bacteremicum, M. barrassiae, M. bourgelatii, M. celeriflavum, M. chelonae, M. crocinum, M. franklinii, M. franklinii, M. fukienense, M. hippocampi, M. insubricum, M. iranicum, M. litorale, M. llatzerense, M. monacense, M. pallens, M. rufum, M. rutilum, M. salmoniphilum, M. sediminis, and M. setense, or The nontuberculous mycobacteria grow slowly, Optionally, the nontuberculous mycobacteria are slow growing and are selected from the group consisting of M. algericum, M. alsiense, M. arosiense, M. bouchedurhonense, M. engbaekii, M. europaeum, M. fragae, M. heraklionense, M. indicus pranii, M. koreense, M. kumamotonense, M. kyorinense, M. lepromatosis, M. liflandii, M. M. longobardum, M. mantenii, M. marseillense, M. minnesotense, M. noviomagense, M. paraffinicum, M. paragordonae, M. parakoreense, M. paraseoulense, M. paraterrae, M. riyadhense, M. senuense, M. seoulense, M. sherrisii, M. shigaense, M. or selected from the group consisting of M. shinjukuense, M. simulans, M. sinense, M. stomatepiae, M. timonense, M. vulneris, and M. yongonense; or the nontuberculous mycobacteria are selected from the group consisting of M. abscessus, M. avium complex (MAC), M. chelonae, M. fortuitum, M. gordonae, M. kansasii, M. mucogenicum, M. peregrinum, and M. xenopi, or the nontuberculous mycobacteria are selected from the group consisting of M. abscessus, M. avium complex (MAC), M. fortuitum complex, M. gordonae, M. kansasii, and M. xenopi, or the nontuberculous mycobacteria are Mycobacterium avium complex, or the nontuberculous mycobacteria are M. avium, M. intracellulare, M. marseillaise, M. timonense, M. bouchedurhonense, M. colombiense, M. vulneris, and M. chimaera, or the nontuberculous mycobacteria is M. intracellulare, or the nontuberculous mycobacteria is M. intracellulare subsp. intracellulare or M. intracellulare subsp. chimaera, or the nontuberculous mycobacteria is M. avium, or 2. The composition of claim 1, wherein the nontuberculous mycobacteria is M. avium subsp. avium, M. avium subsp. hominissium, M. avium subsp. silvaticum, or M. avium subsp. paratuberculosis.

14. A method for treating a pulmonary syndrome comprising administering to a patient a therapeutically effective amount of at least one NTM therapeutic agent as described above, the NTM therapeutic agent being not epetravorole, or 10. The composition of claim 1, comprising at least two of the aforementioned NTM therapeutic agents, none of which is epetravorol.

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