Combination in treatment of nontuberculous mycobacterial diseases

Abstract

To provide a combination in treatment of nontuberculous mycobacterial diseases.SOLUTION: The present invention relates to a combination of bedaquiline, a macrolide (e.g. clarithromycin) and, optionally, ethambutol for use in the treatment of a disease associated with nontuberculous mycobacteria (NTM).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a combination used for the treatment of non-tuberculous mycobacteria, the combination comprising bedaquiline (such as bedaquiline fumarate marketed as Sirturo®), macrolide (such as clarithromycin or azithromycin), and optionally, another component (such as ethambutol) used for the treatment of non-tuberculous mycobacteria. Other components that may be part of such a combination include injectable aminoglycosides. n (such as bedaquiline fumarate marketed as Sirturo®), mac rolide (such as clarithromycin or azithromycin), and, optionally, another component (such as ethambutol) used for the treatment of non-tuberculous mycobacteria. Other components that may be part of such a combin ation include injectable aminoglycosides.

Background Art

[0002] Lung diseases caused by non-tuberculous mycobacteria (NTM) are a major cause of morbidity and death among individuals with pre-existing lung conditions such as bronchiectasis and COPD (chronic obstructive pulmonary disease).

[0003] Mycobacterium avium complex (MAC), Mycobacterium abscessus (Mab), and Mycobacterium kansasii are Mycobacterium species that cause NTM pulmonary disease (NTM-PD). NTM-PD is different from pulmonary infections caused by Mycobacterium tuberculosis. Mycobacterium · avium is part of MAC, which accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences), and is one of the three NTM-PD species associated with human disease. MAC is a naturally occurring species that is common in water and soil. Mycobacterium species that cause NTM pulmonary disease (NTM-PD). NTM-PD is different from pulmonary infections caused by Mycobacterium tuberculosis. Mycobacterium · tuberculosis. Mycobacterium · avium is part of MAC, which accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences), and is one of the three NTM-PD species associated with human disease. MAC is a naturally occurring species that is common in water and soil, and is part of MAC, which accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences), and is one of the three NTM-PD species associated with human disease. species that is common in water and soil, and is part of MAC, which accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences), and is one of the three NTM-PD species associated with human disease. MAC is a naturally occurring is an organism that often colonizes natural water sources such as indoor water systems, hot tubs, and pools. MAC pulmonary disease (MAC-PD) most commonly occurs in postmenopausal women and patients with underlying lung diseases such as cystic fibrosis, bronchiectasis, or immunodeficiency. Clinical manifestations vary in range and severity but generally include chronic cough, often with purulent sputum, and may also include hemoptysis. Systemic symptoms in advanced disease may include malaise, fatigue, and weight loss.

[0004] Current treatment of MAC-PD involves long-term antibiotic therapy (often exceeding 18 months) with combinations of at least three antibiotics (rifamycin (rifampin or rifabutin), macrolide (azithromycin or clarithromycin), ethambutol, and / or (especially) injectable aminoglycosides), but these are associated with side effects and a high failure rate. This treatment regimen is currently based on Griffith et al, American Journal of Respiratory and Critical Care Medicine Vol 175, 2007, page 367 (replacing the American Thoracic Society (ATS Mycobacterial Diseases Subcommittee “An official ATS / IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases”), and provides substantial in vitro and clinical activity against MAC. ​ is recommended by the International Guideline. In recent years, Amikacin liposome inhalation suspension (ALIS, Arikayce®) has been approved by the US FDA for the treatment of MAC-PD in adults. Apart from this, for this disease / symptom, treatment options are limited or there is no choice. No other antibiotics have been approved for the treatment of MAC-PD, and the recommended use of the above-mentioned agent is based solely on experience.

[0005] Bedaquiline was developed as part of a combination therapy for the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients and is an inhibitor of mycobacterial adenosine 5'-triphosphate (ATP) synthase. It is approved under the trademark Sirturo® in regions including the United States, Russia, the EU, Japan, South Africa, and the Republic of Korea under specific conditions for its indication.

[0006] The commercially available bedaquiline fumarate product Sirturo® is a tablet containing 100 mg of the bedaquiline active ingredient. In the adult population, the first approval in Europe was for the use of Sirturo® as part of a combination regimen suitable for pulmonary MDR-TB under specific conditions (when an effective treatment regimen cannot be otherwise constituted for reasons of resistance or tolerance). Among them, it has been shown (inter alia) that Sirturo® should be used in combination with at least three pharmaceutical products whose patient isolates are shown to be susceptible in vitro. In vitro test results If the results are not available, treatment may be initiated with Sirturo® in combination with at least four pharmaceutical products to which the patient's isolate is likely to be susceptible. The product may also be administered by directly observed therapy (DOT). The recommended dosage is: (i) 1 - 2 weeks: 400 mg once daily (4 tablets of 100 mg tablets); (ii) 3 - 24 weeks: 200 mg three times a week (with at least 48 hours between doses) (2 tablets of 100 mg tablets). The total duration of treatment with Sirturo® is 24 weeks. Other pharmaceutical products used in combination may be continued after completion of treatment with Sirturo®, or should be continued.

[0007] In the product Sirturo®, the active ingredient bedaquiline is in the form of the fumarate : (alphaS,betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl -2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol, in particular, (alphaS,betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl -2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3- quinolineethanol (2E)-2-butenedioate (1:1), and may be represented by the following formula: :

Chemical formula

[0008] The fumarate can be prepared by reacting the corresponding free base with fumaric acid in the presence of a suitable solvent, such as isopropanol.

[0009] Bedaquiline is active against Mycobacteria, including drug-resistant strains, in particular Mycobacterium tuberculosis, M. bovis, M. bovis, M. avium, M. leprae, M. leprae, M. marinum, M. leprae, M. ulcerans, M. kansasii, and M . abscessus. The active ingredient, including its salts, is active against active, susceptible, and vulnerable Mycobacteria strains, and latent, dormant, persistent Mycobacteria strains. WO 2004 / 011436 first disclosed the activity of the free base of bedaquiline against Mycobacteria. More recent literature, e.g., WO 2005 / 117875 and WO 2006 / 067048, disclose, inter alia, further uses in the treatment of drug-resistant tuberculosis and latent tuberculosis. WO 2008 / 068231 first described the suitability of the fumarate as a pharmaceutical product showing its acceptable bioavailability. The fumarate of bedaquiline is described as non-hygroscopic and stable. This document also discloses the preparation of specific formulations and tablets containing bedaquiline fumarate.

[0010] In non-tuberculous mycobacteria (especially Mycobacterium abscessus) terium abscessus) and Mycobacterium avium Considering its in vitro activity against Mycobacterium avium, there have been reports that bedaquiline fumarate is being used off-label, as described in the journal article “Preliminary Results of Bedaquiline as Salvage Therapy for Patients with Nontuberculous Mycobacterial Lung Disease” by Philliy et al, Chest 2015;148(2):499-506. This article shows that bedaquiline has not been clinically tested for NTM disease, and describes a small study of patients treated for 1-8 years who were already on treatment at the time bedaquiline treatment was initiated and 80% had macrolide-resistant isolates. Bedaquiline was administered according to the dosage used in TB trials, and in these studies, patients were also receiving

[0011] concomitant medications (mean of 5). Further studies are clearly needed to determine whether bedaquiline has a role in the management of NTM lung disease and, if so, to guide its appropriate use. "Disease Treated with Bedaquiline". And a patient (suffering from macrolide-resistant MAC lung disease) was administered bedaquiline in combination with concomitant medications given at the discretion of two NTM pulmonary physicians, following the package guidelines. It was described that. The limited treatment options for macrolide-resistant MAC lung disease and the fact that bedaquiline used in combination therapy can be an option for drug-resistant diseases were shown. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0012] Now, a novel combination for clinically treating diseases associated with NTM is provided. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure provides a combination comprising bedaquiline, a macrolide (e.g., clarithromycin or azithromycin), and optionally ethambutol (e.g., consisting of). Such a combination is used for treating diseases associated with non-tuberculous mycobacteria (NTM). In one embodiment, the combination comprises bedaquiline, a macrolide (e.g., clarithromycin or azithromycin), and ethambutol (e.g., consisting of). In one embodiment, such a combination is used clinically (i.e., in vivo), for example, in a human subject.

[0014] In one embodiment, a method for treating a disease associated with NTM in a patient, the method comprising administering to the patient: (i) bedaquiline; ​​​(ii) a macrolide (e.g., clarithromycin or azithromycin); and (iii) ethambutol There is provided a method comprising administering an effective amount of a combination comprising (e.g., consisting of).

[0015] In one embodiment, a method of treating a disease associated with NTM in a patient, the patient to: (i) bedaquiline; and (ii) a macrolide (e.g., clarithromycin or azithromycin) There is provided a method comprising administering an effective amount of a combination comprising (e.g., consisting of).

[0016] These combinations described herein are referred to herein as "the combinations of the invention". As shown above, the combinations of the invention comprise two or three active ingredients (bedaquiline, macrolide, and, optionally, ethambutol; in one embodiment, ethambutol is essential), which are active against Mycobacterium and, in particular, in this case, non-tuberculous mycobacteria (especially Mycobacterium avium and Mycobacterium abscessus). Therefore, these three components can be regarded as antibacterial agents or antibiotics and, essentially, act on Mycobacterium bacteriostatically (stopping bacteria from replicating but not necessarily killing them) or bactericidally (killing bacteria). In one embodiment, the combination of the invention contains only these two or three active ingredients. However, in one embodiment, such combinations may also be used, for example, in severe cases of Mycobacterium infection or as a first choice in, for example, severe cases of Mycobacterium infection or as a first choice in severe cases of Mycobacterium infection or as a first choice (first-line) For patients for whom oral therapy is ineffective, injectable aminoglycosides may be included. In one embodiment, and in particular, for certain patient populations (e.g., where not required or where it can be avoided), injectable aminoglycosides are not used. In embodiments where they are used, the aminoglycoside may be any suitable one already approved by the regulatory authorities, for example, any suitable one approved by the US Food and Drug Administration (FDA), for example, gentamicin, tobramycin, amikacin, plazomycin, streptomycin, neomycin, and / or paromomycin. In one embodiment, the combination of the present invention is shown to consist of two or three specific active ingredients (bedaquiline, macrolide, and, optionally, ethambutol; and in a further embodiment, may further include an aminoglycoside), by which the inventors mean that the combination (or a method of treatment including administering such a combination to a patient) does not include any other active ingredients, for example, compounds active against Mycobacterium, antibacterial agents or compounds regarded as antibiotics.

[0017] The essential components of the combination of the present invention or the antibacterial drugs (i.e., bedaquiline, macrolide, and, in one embodiment, ethambutol) may be formulated separately (e.g., as defined herein) or together. In one embodiment, such components (including bedaquiline, macrolide, and ethambutol) ) is, for example, in a commercially available / commercially viable form (for existing approved indications). and is formulated separately.

[0018] In various embodiments (including methods of treating diseases associated with NTM in a patient), the antimicrobial drugs of the combination of the present invention can be administered simultaneously. In other embodiments, the antimicrobial drugs (of the combination) may be administered sequentially. In yet other embodiments, they may be administered substantially simultaneously. In some of the latter embodiments, the administrations are within 30 minutes of each other, and in some embodiments within 15 minutes of each other, and such antimicrobial drugs need to be ingested. In some embodiments, the antimicrobial drugs are administered once a day, almost at the same time each day. For example, the antimicrobial drugs are within a time range of 4 hours from the first hour of administration on the first day, i.e., ±2 hours or ±1 hour, or in yet other embodiments within ±30 minutes from the time of the first administration day. However, in one embodiment, the combination of antimicrobial drugs of the present invention (including bedaquiline, macrolide, and ethambutol) is administered according to existing guidelines (e.g., according to the regulatory label for approved indications for the relevant activities).

[0019] In some embodiments, the combination of antimicrobial drugs of the present invention, or a pharmaceutically acceptable salt thereof, is administered as separate oral capsules or oral tablets. Other formulations may include solid dispersions.

[0020] Bedaquiline can be used in its non-salt form or in a suitable pharmaceutically acceptable salt form, such as an acid addition salt form or a base addition salt form.

[0021] Pharmaceutically acceptable acid addition salts are defined to include therapeutically active non-toxic acid addition salt forms that vedagliptin can form. The acid addition salts are formed by treating the free form of vedagliptin with suitable acids, such as inorganic acids, such as hydrohalic acids, especially hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids, such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid. In particular, fumarate is considered in view of the form already adopted in the commercially available product Sirturo®. The considered therapeutically active non-toxic base addition salt forms can be prepared by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts, and alkaline earth metal salts, especially lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts, salts with organic bases, such as benzathine salts, N-methyl-D-glucamine salts, hybramine salts, and salts with amino acids, such as arginine and lysine.

[0022] Conversely, the acid addition salt forms or base addition salt forms can be converted to the free form by treatment with a suitable base or acid.

[0023] Solvates are also included. Such solvates are, for example, hydrates and alcoholates.

[0024] Any reference to bedaquiline used herein is to the single stereoisomeric form used in the commercial product Sirturo® and disclosed as an anti - mycobacterial agent in WO 2004 / 011436 pamphlet. It refers to the single stereoisomeric form used in the commercial product Sirturo® and disclosed as an anti - mycobacterial agent in WO 2004 / 011436 pamphlet. It refers to the single stereoisomeric form used in the commercial product Sirturo® and disclosed as an anti - mycobacterial agent in WO 2004 / 011436 pamphlet.

[0025] The fumarate of the present invention can be prepared by reacting the corresponding free base with fumaric acid in the presence of a suitable solvent, such as isopropanol. The fumarate of the present invention can be prepared by reacting the corresponding free base with fumaric acid in the presence of a suitable solvent, such as isopropanol.

[0026] Similarly, macrolides (e.g., clarithromycin or azithromycin) and ethambutol may be used in their non - salt form (or free form) or in a pharmaceutically acceptable salt form. In one embodiment, the macrolide and ethambutol are in already available / commercial form. Similarly, macrolides (e.g., clarithromycin or azithromycin) and ethambutol may be used in their non - salt form (or free form) or in a pharmaceutically acceptable salt form. In one embodiment, the macrolide and ethambutol are in already available / commercial form. Similarly, macrolides (e.g., clarithromycin or azithromycin) and ethambutol may be used in their non - salt form (or free form) or in a pharmaceutically acceptable salt form. In one embodiment, the macrolide and ethambutol are in already available / commercial form. Similarly, macrolides (e.g., clarithromycin or azithromycin) and ethambutol may be used in their non - salt form (or free form) or in a pharmaceutically acceptable salt form. In one embodiment, the macrolide and ethambutol are in already available / commercial form.

[0027] For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose). For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose). For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose). For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose). For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose). For example, bedaquiline may be formulated as, for example, a fumarate and administered as a tablet containing 100 mg of the active ingredient bedaquiline. If the macrolide used is clarithromycin, it may be administered as a 500 mg tablet (or, depending on the required dose and the patient, as a suspension, e.g., an available suspension containing 250 mg / 5 ml). Ethambutol may be administered as a 100 mg or 400 mg tablet (depending on the required dose).

[0028] In one embodiment, the combination of the present invention is used in a particular treatment or administration regimen. For example, a method of treating a disease (associated with NTM) in a patient disclosed herein may have a specific treatment or dosing regimen. Such a treatment or dosing regimen may include the following : (i) Bedaquiline: 1 - 2 weeks: 400 mg once daily (or “qd”); 3 - 24 weeks (and optionally up to 52 weeks, i.e., 3 - 52 weeks): 3 times per week (or “tiw”) (with at least 48 hours between doses) 200 mg; (ii) Macrolide: For example, when clarithromycin, 1000 mg per day, e.g., 500 mg twice daily (i.e., 500 mg “bid”), and when azithromycin, 250 mg per day (among others, clarithromycin may also be administered, e.g., once daily, 500 mg per day; it may also be administered according to local guidelines); (iii) Ethambutol: This will depend on the patient's weight and, according to current guidelines, the dosing will be 15 mg / kg per day (ethambutol may also be administered according to local guidelines).

[0029] For example, the dosing regimens described herein are applicable to diseases associated with NTM, particularly NTM - PD, as defined / explained hereinafter. Also, the severity or type of the disease, or the severity of the mycobacterial infection, may determine the dosage or dosing regimen. In one embodiment , for guidelines regarding the administration of macrolides (e.g., clarithromycin) and ethambutol for specific diseases associated with NTM, the guidelines of the American T horacic Society (ATS) may be followed.

[0030] ​​ The total treatment regimen may last for at least 24 weeks, such as at least 32 weeks, for example for about 48 weeks or The treatment period may be up to about 52 weeks (however, in one embodiment, the treatment period may be up to 18 months). In this respect, the dosing regime of bedaquiline is similar to that already presented above. The proposed period is 52 weeks, and (if the period extends to 18 or 24 months) The dosing scheme will continue for a period of 3–52 weeks; similarly, macrolides (e.g. Administration of drugs such as clarithromycin and ethambutol should be continued for the relevant period, e.g. at least At least 24 weeks, at least 32 weeks, for example about 48 weeks or about 52 weeks (or, in separate embodiments, In one embodiment, the treatment will continue for up to 18 months, or up to 24 months. Placental regimes also include injectable aminoglycosides (e.g., as described in the ATS guidelines). In situations where this is recommended, for example, when the disease is severe; in this case, for example, once a week (Three injections may be given.) In one embodiment, the treatment regime does not include other drugs. however, it is possible to administer a concomitant drug, e.g., for treating another disease (e.g., a drug already administered to the patient), (especially when such a drug is for a disease other than a bacterial infection, and For example, drug-drug interactions with the essential antibacterial agents of the combination of the present invention have already been investigated. In one embodiment, no other drugs are permitted, although in some cases, the The drug will not be administered during any treatment regimen in which the

[0031] In one embodiment, the macrolide used in the combination of the present invention is clarithromycin. It is.

[0032] In one embodiment, bedaquiline is administered after a meal because the bioavailability of the drug is This is because the availability can be increased.

[0033] In one embodiment, the administration of a macrolide (such as clarithromycin) and ethambutol shall follow local guidelines.

[0034] In one embodiment, the antibacterial drug combination of the present invention is orally ingested, and the administrations occur at approximately the same time each day.

[0035] All amounts described in this disclosure refer to the free form (i.e., the non-salt form). The values shown below represent the equivalent amounts in the free form, i.e., the amounts when the free form is administered. If a salt is administered, the amount needs to be calculated according to the molecular weight ratio between the salt and the free form.

[0036] The daily dosages described herein are calculated for an average body weight of approximately 70 kg, and need to be recalculated when administered to children or patients with substantially deviated body weights.

[0037] It is shown herein that the combinations used herein are useful for the treatment of diseases associated with non-tuberculous mycobacteria (NTM). Also, a method of treatment is described herein which relates to the treatment of diseases associated with NTM in a patient, and to the patient being administered an effective amount of the combination of the present invention.

[0038] As used herein, the term "diseases associated with NTM in a patient" refers to non-tuberculous mycobacteria (especially Mycobacterium abscessus and Mycobacterium avium) ​​​refers to a patient (or subject, e.g., a human patient) infected with such a disease may be a pulmonary disease caused by NTM, so in one embodiment , the disease is NTM-PD. NTM-PD, unlike pulmonary infections caused by Mycobacterium tuberculosis , currently requires bedaquiline. Mycobacterium avium is part of the Mycobacterium avium complex (MAC), which accounts for up to 70% of NTM-positive sputum cultures (although there are regional differences ), and is one of the three NTM-PD species most commonly associated with human disease in North America. MAC is a naturally occurring organism common in water and soil and often colonizes natural water sources , e.g., indoor water systems, hot tubs, and pools. MAC pulmonary disease (MAC-P D) is most often seen in postmenopausal women and patients with underlying lung disease, e.g., cystic fibrosis, bronchiectasis , or immunodeficiency. Clinical symptoms vary in extent and intensity but generally include a chronic cough, often with purulent sputum, while hemoptysis may also be present. Systemic symptoms in advanced disease include malaise, fatigue, and weight loss. Included within NTM-PD are treatment-refractory NTM-PD patients, and as shown previously , the most common NTM-PD is MAC-PD. Therefore, in one embodiment

[0039] , the term "disease associated with NTM," when referred to in this specification, generally refers to N TM-PD, and in a further embodiment, NTM-P in treatment-refractory patients D refers to D; in a further embodiment, refers to MAC-PD, and in still other embodiments refers to MAC-PD in treatment-refractory patients. Treatment-refractory MAC-PD patients are sputum positive for MAC after at least 6 months of guideline-based therapy for MAC-PD infections and are defined as patients. Treatment-refractory patients treated with current standard therapies have a rather poor clinical outcome, and ultimately approximately 10% of cultures convert after 12 months of treatment, even with intensified treatment and the use of aminoglycosides. Thus, this patient population also represents an area of unmet medical need. In one embodiment, diseases associated with NTM (e.g., NTM-PD, e.g., MAC-PD) are associated with underlying lung diseases (e.g., cystic fibrosis, or another one mentioned herein).

[0040] Due to its novel mechanism of action (inhibition of ATP synthase), bedaquiline defines a new class of anti-TB compounds and, currently, since no other drugs belonging to the same pharmacological class are available, minimizes the potential for cross-resistance. Thus, the combinations of the invention described herein have the advantage that bedaquiline is a component thereof.

[0041] As used herein, "effective amount" refers to an amount of each component of the combination of the invention, or any pharmaceutically acceptable salt thereof, which induces a biological or drug response in a tissue system (e.g., blood, plasma, biopsy) or in a warm-blooded animal (e.g., human). This is what is required by healthcare providers and includes the alleviation of the symptoms of the disease to be treated.

[0042] ​ A patient to be treated according to the methods of the present disclosure can be a "first-choice" patient. As used herein this refers to a patient who has not previously received treatment with any (investigational or approved) drug for the disease (associated with NTM) to be treated. In a further embodiment, the patient to be treated is not a first-choice patient but a patient who has already received treatment, e.g., a patient diagnosed with the disease (who tested positive on examination even after 6 months of other guideline-based treatment (i.e., who tested positive on sputum culture for MAC at least 6 months after guideline-based treatment)). Thus, in one embodiment the patient is a treatment-refractory patient or a salvage patient. In a further embodiment, the NTM isolate is not macrolide-resistant. However in a further embodiment, if the NTM isolate is macrolide-resistant, it can be a combination of bedaquiline and ethambutol (without macrolide), in which case the combination of active substances can consist of only those two drugs (however, optionally, in this embodiment, a different antibacterial agent that is not a macrolide may also be added). To date, surrogate markers for predicting clinical treatment response have not been defined. The current primary endpoint for "treatment" is sputum culture conversion, defined as three consecutive monthly negative sputum cultures up to the time point 6 months after the start of treatment. The primary efficacy outcome time point is selected at 6 months. Because, for example, in "Randomized Trial of Liposomal Amikacin for by Griffith et al ...

[0043] To date, surrogate markers for predicting clinical treatment response have not been defined. The current primary endpoint for "treatment" is sputum culture conversion, defined as three consecutive monthly negative sputum cultures up to the time point 6 months after the start of treatment. The primary efficacy outcome time point is selected at 6 months. Because, for example, in "Randomized Trial of Liposomal Amikacin for ... by Griffith et al Inhalation in Nontuberculous Mycobacter ial Lung Disease”American Journal of Res. piratory and critical care medicine volume me 195 Number 6, March 15, 2017, and Gri The AJRCCM paper “Ami kacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Cause d by Mycobacterium avium Complex (CONVER T):A Prospective,Open-Label,Randomized S As described in the “ALIS study,” the recently completed ALIS trial showed that This is because most microbiological responses occurred during this time.

[0044] As described herein, the antibacterial drug combinations described herein are The combinations may be administered simultaneously (as described herein) or sequentially, or may be administered substantially simultaneously. Therefore, the individual dosage forms of each antibacterial drug may be administered in accordance with the alternative dosage forms described herein. It can be administered in individual forms (e.g., as separate tablets or capsules). .

[0045] In one embodiment, a process for preparing a combination product as defined herein. hand: The components of a combination product (e.g., as separate pharmaceutical formulations) are associated causing it (e.g., as a kit of parts) to be co-packaged, or indicating that the intended use is to be combined with (other components); and / or in the preparation of a pharmaceutical formulation comprising such components, providing a process that includes correlating each component is is provided.

[0046] In the current MAC-PD regimen in which rifamycin is combined with clarithromycin, exposure to clarithromycin is suboptimal due to induction of metabolism by the rifamycin component, as reported, for example, in Shimomura et al., “Serum concentrations of clarithromycin and rifampicin in pulmonary Mycobacterium avium complex disease: long term changes due to drug interactions and their association with clinical outcomes” Journal of Pharmaceutical Health care and Sciences (2015) 1:32. The combination of the present invention can overcome this. Also, the combination of the present invention can have the advantage of being more effective than existing or previously recommended (e.g., by ATS) treatment regimens, having a better safety profile, and / or having fewer side effects.

[0047] The following examples are merely illustrative and are not intended to limit the present disclosure to the materials, conditions, or process parameters described herein.

Example

[0048] Reference Example 1. In vitro activity of bedaquiline Bedaquiline is specific for mycobacteria in humans, such as important atypical species, e.g., M. avium, M. kansasii, and rapidly growing species, e.g., M. fortuitum and M. abscessus. M. avium, M. kansasii, and M. abscessus can cause NTM disease. um), M. kansasi, and rapidly growing species (fast gro wer) M. fortuitum and M. abscessus. M. avium, M. kansasi bscessus), and M. abscessus are specific for mycobacteria, and the spectrum is unique. M. avium, M. kansasi i), and M. abscessus can cause NTM disease. i), and M. abscessus can cause NTM disease. become the cause.

[0049] The minimum inhibitory concentration (MIC) range of bedaquiline against Mycobacterium tuberculosis was ≤0.008 μg / ml to 0.12 μg / ml regardless of the resistant subtype. The bedaquiline MIC was naturally resistant to many other anti-TB agents and was involved in opportunistic infections, e.g., M. avium, M. abscessus M. abscessus), M. fortuitum, and M For other mycobacterial species, e.g., M. marinum, which are involved in opportunistic infections, the MIC was generally <0.1 μg / ml. In comparison with Mycobacterium tuberculosis M. abscessus), M. fortuitum, and M . marinum species, higher MICs were found for each isolate of M. abscessus (0.25 μ g / ml) and M. ulcerans (0.50 μg / ml) (see the following table). The activity of bedaquiline was against mycobacteria (M g / ml) and M. ulcerans (0.50 μg / ml) for each isolate (see the following table). The activity of bedaquiline was against mycobacteria (M isolate per isolate (see the following table). The activity of bedaquiline was against mycobacteria (M It seemed to be specific to the species of the genus Mycobacterium).

[0050]

Table 1

[0051] Example 1: Further in vitro tests against slow grower non-tuberculous mycobacteria (NTM) Further in vitro tests Objective According to the following paper by Martin A et al, "Resazurin micro titer assay plate testing of Mycobacteri um tuberculosis susceptibilities to seco nd-line drugs: rapid, simple, and inexpens ive method. AAC, 2003 Nov; 47(11):3616-9, use the resazurin microtiter assay (REMA) to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of bedaquiline against clinical isolates of NTM, the most common NTM respiratory pathogens.

[0052] Methodology In the REMA plates, the concentration range of bedaquiline was 2 - 0.0035 μg / ml. Each experiment was performed in triplicate in 7H9 medium supplemented with OADC and glycerol. The plates were sealed in plastic bags and incubated at 37°C for 7 days. Seven days after incubation, 30 μl of 0.01% resazurin was added to all wells, and the plates were also sealed here and incubated overnight for color development.

[0053] ​​​​The MIC was interpreted as the lowest concentration of bedaquiline that prevented the color change of resazurin. MI The MIC values were scored for each NTM species. The positive control (growth control positive = medium + bacteria) should show positive growth, and the negative control (or sterile control containing only medium) should not show growth during the incubation period (also, there is a bedaquiline control consisting of bedaquiline + only medium).

[0054] Determination of MBC by resazurin microtiter assay (REMA) The MBC test enables determination of the lowest concentration of an agent essential to achieve a bactericidal effect. The MIC was determined first, and then the MBC was determined. To perform the MBC, dilutions representing the MIC, and at least two more concentrated test product dilutions were plated and enumerated to determine the viable CFU / ml. The MBC is the lowest concentration at which bedaquiline demonstrated bactericidal activity against a specific NTM species.

[0055] Strains for quality control For bedaquiline, Mycobacterium xenopi was used as a quality control for MIC. This species is known to be naturally resistant to bedaquiline (as described in the journal article by Andries K et al: “A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis” Science, 2005 Jan 14;307(5707):223 -7). This strain was tested each time a new lot, medium, or drug was prepared.

[0056] ​​​​​ Mycobacterium slow-growing species proposed to be tested The NTM clinical isolates used in this study were isolated from patients. In total, (in addition to the control strains ) 18 isolates were present: Mycobacterium avium (×4 isolates), Mycobacterium intracellulare (×4), Mycobacterium chimaera (×3), Mycobacterium kansasii (×2), Mycobacterium ulcerans (×2) (×2), Mycobacterium simiae (×2), and Mycobacterium marinum (×1). 、Mycobacterium simiae (×2) 、and Mycobacterium marinum (×1).

[0057] Summary of MIC and MBC results The MIC and MBC ranges were determined for 19 NTM slow-growing species tested.

[0058]

Table 2

[0059] Bedaquiline showed bactericidal activity against most of the clinical isolates tested. MBC was considered the lowest concentration at which bedaquiline killed 100% of the bacteria.

[0060] Example 2: In vivo test Purpose The first purpose The first purpose is to study NTM- Regarding the treatment of PD, in addition to rifamycin, macrolide (clarithromycin) and ethambutol (rifamycin / clarithromycin / ethambutol), and compared with bedaquiline, in addition to macrolide (clarithromycin) and ethambutol ( bedaquiline / clarithromycin / ethambutol), it is to evaluate the effectiveness.

[0061] The second objective The second objective is, in adult patients with treatment-refractory NTM-PD caused by MAC, to do the following: · Over a treatment period of 3 and 6 months: To evaluate the change in the number of quantitative sputum colony-forming units (CFU) by bedaquiline / clarithromycin / ethambutol compared with rifamycin / clarithromycin / ethambutol. · At the 1st, 2nd, 3rd, 4th, and 5th months during treatment, and 3 months after 12 months of treatment, after the end of the 12-month follow-up survey, to evaluate sputum culture negativity. · To evaluate sputum culture conversion 12 months after treatment. · To evaluate the proportion of subjects who developed resistance to clarithromycin after baseline. · To evaluate the proportion of subjects who developed resistance to bedaquiline (at least a 4-fold increase in bedaquiline MIC) compared with baseline. · To evaluate the safety and tolerability of treatment with bedaquiline / clarithromycin / ethambutol compared with rifamycin / clarithromycin / ethambutol. · To evaluate the percentage of patients who deviated from the protocol, including those whose treatment was changed. · To evaluate the safety and tolerability of treatment with bedaquiline / clarithromycin / ethambutol To evaluate the change in health status of patients according to reports at 6 and 12 months after treatment with linezolid / ethambutol. To evaluate the changes in pulmonary function parameters at 6 and 12 months after treatment with linezolid / ethambutol: forced expiratory volume in 1 second (FEV1 [L]), forced vital capacity (FVC [L]), inspiratory capacity (IC L), functional residual capacity (FRC [L]), total lung capacity (TLC [L]). To evaluate the change in 6-minute walk distance (6MWD) at 6 and 12 months after treatment with linezolid / ethambutol. To evaluate the pharmacokinetics of bedaquiline and clarithromycin as part of the proposed NTM regimen. To evaluate the pharmacokinetic-pharmacodynamic relationship regarding the safety and efficacy of bedaquiline as part of the proposed NTM regimen. To evaluate the long-term safety and tolerability of bedaquiline over 120 weeks after baseline. Endpoint Primary endpoint Sputum culture conversion (defined as three consecutive monthly negative sputum cultures) by 6 months after the start of the treatment under investigation. Secondary endpoints The secondary endpoints are as follows: To evaluate the quantitative sputum C over 3- and 6-month treatment periods with linezolid / ethambutol compared with rifamycin / clarithromycin / ethambutol. To evaluate the change in 6-minute walk distance (6MWD) at 6 and 12 months after treatment with linezolid / ethambutol compared with rifamycin / clarithromycin / ethambutol. To evaluate the pharmacokinetics of bedaquiline and clarithromycin as part of the proposed NTM regimen. To evaluate the pharmacokinetic-pharmacodynamic relationship regarding the safety and efficacy of bedaquiline as part of the proposed NTM regimen.

[0062] Endpoint Primary endpoint Sputum culture conversion (defined as three consecutive monthly negative sputum cultures) by 6 months after the start of the treatment under investigation.

[0063] Secondary endpoints The secondary endpoints are as follows: To evaluate the quantitative sputum C over 3- and 6-month treatment periods with linezolid / ethambutol compared with rifamycin / clarithromycin / ethambutol. To evaluate the change in 6-minute walk distance (6MWD) at 6 and 12 months after treatment with linezolid / ethambutol compared with rifamycin / clarithromycin / ethambutol.​ Changes in FU number (solid culture). · Sputum culture negative (liquid culture) at 1, 2, 3, 4, and 5 months during treatment. · Sputum culture conversion (liquid culture) 12 months after treatment. · Sputum culture negative (liquid culture) after the end of the 3-month follow-up 12 months after treatment. · Proportion of subjects who acquired resistance to clarithromycin after baseline. · Resistance to bedaquiline (at least a 4-fold increase in bedaquiline MIC) compared to baseline, proportion of subjects who acquired it. · Safety and tolerability (including survival follow-up up to 120 weeks after baseline). · Percentage of patients who deviated from the protocol, including those whose treatment was changed. · Differences in health status (SGRQ) reported by patients 6 and 12 months after treatment. · Pulmonary function parameters 6 and 12 months after treatment: differences in FEV1 (L), FVC (L), IC ( L), FRC (L), TLC (L). · Differences in 6-minute walk distance (6MWD) 6 and 12 months after treatment. · Pharmacokinetic parameters of bedaquiline and clarithromycin (by population pharmacokinetic analysis) · PK / PD relationship regarding the safety and efficacy of bedaquiline.

[0064] Study design This is a multi-center, randomized, open-label, active-controlled, phase 2a study to evaluate the efficacy of bedaquiline plus macrolide (clarithromycin) and ethambutol, and rifampicin plus macrolide (clarithromycin) and ethambutol in the treatment of adult patients with treatment-refractory NTM-PD caused by MAC.

[0065] ​​​​​Adult participants with treatment - refractory NTM - PD due to MAC (defined as patients with positive sputum cultures for MAC after at least 6 months of guideline - based treatment) will be enrolled. In one embodiment, subjects with fibro - cavitary NTM - PD and cystic fibrosis will be excluded. All eligible participants will be randomized at a 1:1 ratio to receive one of the following two treatment regimens: · Treatment group A: Rifamycin* + clarithromycin (e.g., 500 mg / day or 1000 mg / day) + ethambutol 15 mg / kg / day (maximum daily dose of 1600 mg)

[0066] · Treatment group B: Bedaquiline** + clarithromycin (e.g., 500 mg / day or 1000 mg / day) + ethambutol 15 mg / kg / day (maximum daily dose of 1600 mg) * Participants may receive rifabutin or rifampin as determined by the treating physician's preference. Rifabutin will be dosed at 150 mg for subjects weighing <50 kg or 300 mg for subjects weighing ≥50 kg. Rifampin will be dosed at 10 mg / kg / day up to a maximum of 600 mg. ** Participants will receive bedaquiline as follows: Weeks 1 - 2: 400 mg (4 tablets of 100 mg) qd. Weeks 3 - 52: 200 mg (2 tablets of 100 mg) tiw (with at least 48 hours between doses). Subjects will be randomly assigned to one of the two treatment groups based on a computer - generated randomization schedule prepared by or under the control of the sponsor prior to the study. * Participants may receive rifabutin or rifampin as determined by the treating physician's preference. Rifabutin will be dosed at 150 mg for subjects weighing <50 kg or 300 mg for subjects weighing ≥50 kg. Rifampin will be dosed at 10 mg / kg / day up to a maximum of 600 mg. ** Participants will receive bedaquiline as follows: Weeks 1 - 2: 400 mg (4 tablets of 100 mg) qd. Weeks 3 - 52: 200 mg (2 tablets of 100 mg) tiw (with at least 48 hours between doses). ** Participants will receive bedaquiline as follows: Weeks 1 - 2: 400 mg (4 tablets of 100 mg) qd. Weeks 3 - 52: 200 mg (2 tablets of 100 mg) tiw (with at least 48 hours between doses). Subjects will be randomly assigned to one of the two treatment groups based on a computer - generated randomization schedule prepared by or under the control of the sponsor prior to the study.

[0067] Subjects will be randomly assigned to one of the two treatment groups based on a computer - generated randomization schedule prepared by or under the control of the sponsor prior to the study. Subjects will be randomly assigned to one of the two treatment groups based on a computer - generated randomization schedule prepared by or under the control of the sponsor prior to the study. This will be the case. Randomization will ensure balance by using randomly replaced blocks. This will be ensured.

[0068] All investigational drugs will be administered orally, and drug administration must occur at approximately the same time each day. This must occur.

[0069] The administration of rifampicin, clarithromycin, and ethambutol will follow the local guidelines. This will be the case.

[0070] The study will consist of a screening period (1 month), a baseline visit (1 day), an open-label treatment period of 12 months (1 day to 48 weeks), and a 3-month follow-up period (48 weeks to 60 weeks). This will be the case. The overall study period for each subject will be 15 months. Participants will return for study visits twice a week for the first 3 months and then at weeks 16, 20, 24, 32, 40, 48, and 60. This will be the case. This will be the case. This will be the case.

[0071] All subjects will be followed up until 120 weeks after baseline to collect long-term safety and tolerability, pharmacokinetics, MAC treatment outcomes, and anti-mycobacterium information. This will be the case. Subjects who discontinue early from the investigational drug and study procedures will be followed up for survival until 120 weeks after baseline as long as they do not withdraw from the study (i.e., do not withdraw consent / assent). This will be the case. This will be the case. This will be the case. The total study period (including the treatment and follow-up phases but excluding the screening phase) will be 120 weeks for each participant. The study will be considered complete at the last visit of the last participant who participated in the study. This will be the case. This will be the case.

[0072] To improve the bioavailability of bedaquiline, it should be administered with food. This is because it is improved approximately two-fold.

[0073] Sample size determination (will be determined) The primary endpoint is sputum culture conversion 6 months after treatment. The sample size will be determined based on, for example, the response rate of historical controls and the results of clinical trials of ALIS in a similar population. Based on this, the total number of subjects (and the number of subjects per arm) to be enrolled will be determined.

[0074] Statistical analysis The primary analysis in this study will be performed when the subject reaches 6 months after the start of the treatment under investigation or has been discontinued earlier. The primary endpoint is sputum culture conversion (defined as three consecutive monthly negative sputum cultures) up to 6 months after the start of the treatment under investigation. In addition to sputum culture conversion, drug susceptibility testing, the effect of bedaquiline on clinical course endpoints (next to endpoints related to safety), and PK will be analyzed to support early phase 3 preparation (including regulatory interactions).

[0075] MAC-PD treatment outcome analysis The Mantel-Haenszel test will be used to compare the 6-month culture conversion rate (primary endpoint). The same test will be used to compare the proportion of patients who are culture negative at other time points (including 1, 2, 4, 6, and 12 months). The Kaplan-Meier method will be used to estimate the proportion of subjects who achieved culture conversion over a 12-month treatment period, and the difference between treatment groups will be compared using the log-rank test. 。The important microbiological endpoint is the reduction of bacterial load quantified by CFU. This is exploratory and, to the inventors' knowledge, there is relatively little data on the early microbiological activity in patients by NTM. Janssen will use the Wilcoxon rank sum test to compare the change from baseline in the median log CFU count out to 3 months and at the time of intervention. Safety analysis will include a descriptive summary of the frequency of adverse events, a summary of large changes in laboratory values, ECG parameters 10 , and vital signs up to the time point. The present invention may be described by the following claims (or "claims").

[0076] ​

Claims

1. bedaquiline, macrolides (e.g., clarithromycin or azithromycin), and and ethambutol.

2. The combination according to claim 1, for use in the treatment of diseases associated with nontuberculous mycobacteria (NTM). height.

3. 1. A method of treating a disease associated with NTM in a patient, comprising administering to the patient: (i) bedaquiline; (ii) a macrolide (e.g., clarithromycin or azithromycin); and (iii) Ethambutol The method comprises administering an effective amount of a combination comprising (e.g., consisting of).

4. Administering to said patient comprises (in each case) a particular regimen, The regimen comprises: Bedaquiline: Weeks 1-2: 400 mg once daily (or "qd"); Weeks 3-24 (and optional) Alternatively, up to 52 weeks, i.e., weeks 3-52): three times per week (or "tiw") (administration (at least 48 hours between doses) 200 mg The combination according to claim 1 or 2, which is administered in a specific regimen comprising the administration of Or the method according to claim 3.

5. The regimen comprises: For example, in the case of clarithromycin, 1000 mg per day, for example 500 mg twice a day (i.e., 500 mg "bid"), and azithromycin, 250 mg daily 5. The combination or method of claim 4, comprising administration of a macrolide of

6. The regimen comprises:

6. The method according to claim 4 or 5, comprising administering ethambutol at a dose of 15 mg / kg per day. The above combinations or methods.

7. The combination or method according to any one of claims 4 to 6, wherein the total treatment regimen is about 52 weeks. method.

8. The method according to any one of claims 4 to 7, wherein the treatment regimen does not include any other drugs. The above combinations or methods.

9. The disease associated with nontuberculous mycobacteria (NTM) is NTM-PD.

2. The combination or method according to any one of claims 1 to 11.

10. The disease is NTM-PD, in which the isolated strain of NTM is not macrolide resistant. Item 10. The combination or method according to item 9.

11. The combinations of antibacterial drugs described herein may be administered simultaneously or sequentially. The method according to any one of claims 1, 2, and 4 to 10, wherein the two or more of the compounds are administered simultaneously or substantially simultaneously. The combination described.

12. A process for preparing the combination of claim 11, comprising: Each component of the combination product (e.g., as a separate pharmaceutical formulation) may be associated with (e.g., , kit of parts) or the intended use is and / or In preparing a pharmaceutical formulation containing such components, the components are associated with each other. A process including.

Images