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US-12616708-B2 - Methods for treating pulmonary non-tuberculous mycobacterial infections

US12616708B2US 12616708 B2US12616708 B2US 12616708B2US-12616708-B2

Abstract

Provided herein are methods for treating a pulmonary infection in a patient in need thereof, for example, a nontuberculous mycobacterial pulmonary infection for at least one treatment cycle. The method comprises administering to the lungs of the patient a pharmaceutical composition comprising a liposomal complexed aminoglycoside comprising a lipid component comprising electrically neutral lipids and an aminoglycoside. Administration comprises aerosolizing the pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free aminoglycoside and liposomal complexed aminoglycoside, and administering the aerosolized pharmaceutical composition via a nebulizer to the lungs of the patient. The methods provided herein result in a change from baseline on the semi-quantitative scale for mycobacterial culture for a treated patient, and/or NTM culture conversion to negative during or after the administration period.

Inventors

  • Gina Eagle
  • Renu Gupta

Assignees

  • INSMED INCORPORATED

Dates

Publication Date
20260505
Application Date
20241107

Claims (20)

  1. 1 . A method for treating a Mycobacterium avium complex (MAC) lung infection in a patient in need thereof, comprising: administering to the lungs of the patient a pharmaceutical composition comprising about 500 mg to about 650 mg amikacin, or a pharmaceutically acceptable salt thereof, encapsulated in a plurality of liposomes, wherein the lipid component of the plurality of liposomes consists of dipalmitoylphosphatidylcholine (DPPC) and cholesterol, wherein administering to the lungs of the patient comprises aerosolizing the pharmaceutical composition to provide an aerosolized pharmaceutical composition comprising a mixture of free amikacin, or a pharmaceutically acceptable salt thereof, and liposomal complexed amikacin, or a pharmaceutically acceptable salt thereof, and administering the aerosolized pharmaceutical composition via a nebulizer to the lungs of the patient once daily in a single dosing session, for an administration period of at least 6 months, wherein the treating comprises achieving a negative MAC sputum culture in the patient.
  2. 2 . The method of claim 1 , wherein the patient is previously unresponsive to an American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) MAC guideline-based therapy (GBT).
  3. 3 . The method of claim 2 , wherein the patient is previously unresponsive to the GBT for at least 6 months.
  4. 4 . The method of claim 1 , wherein the patient has a non-cystic fibrosis underlying lung disease.
  5. 5 . The method of claim 1 , wherein the method further comprises administering a macrolide antibiotic to the patient.
  6. 6 . The method of claim 5 , wherein the macrolide antibiotic is azithromycin, clarithromycin, erythromycin, carbomycin A, josamycin, kitamycin, midecamycin, oleandomycin, solithromycin, spiramycin, troleandomycin, tylosin, roxithromycin, or a combination thereof.
  7. 7 . The method of claim 5 , wherein the macrolide antibiotic is azithromycin or clarithromycin.
  8. 8 . The method of claim 1 , wherein the method further comprises administering a rifamycin compound to the patient.
  9. 9 . The method of claim 8 , wherein the rifamycin compound is rifampin or rifabutin.
  10. 10 . The method of claim 1 , wherein the pharmaceutical composition comprises from about 550 mg to about 625 mg amikacin, or pharmaceutically acceptable salt thereof.
  11. 11 . The method of claim 1 , wherein the amikacin or pharmaceutically acceptable salt thereof is amikacin sulfate.
  12. 12 . The method of claim 1 , wherein the plurality of liposomes comprises unilamellar vesicles, multilamellar vesicles, or a mixture thereof.
  13. 13 . The method of claim 1 , wherein the pharmaceutical composition comprises about 70 mg/mL amikacin; about 30 to about 35 mg/mL DPPC; and about 15 to about 17 mg/mL cholesterol.
  14. 14 . The method of claim 13 , wherein the pharmaceutical composition further comprises about 1.5% NaCl.
  15. 15 . The method of claim 14 , wherein the pharmaceutical composition has a pH of about 6.5.
  16. 16 . The method of claim 1 , wherein during the single dosing session, the aerosolized pharmaceutical composition is administered in less than about 15 minutes.
  17. 17 . The method of claim 1 , wherein during the single dosing session, the aerosolized pharmaceutical composition is administered in about 10 minutes to about 14 minutes.
  18. 18 . The method of claim 1 , wherein the treating comprises achieving MAC sputum culture conversion in the patient, wherein the MAC sputum culture conversion is defined as three consecutive negative MAC sputum cultures.
  19. 19 . The method of claim 5 , wherein the treating comprises achieving MAC sputum culture conversion in the patient, wherein the MAC sputum culture conversion is defined as three consecutive negative MAC sputum cultures.
  20. 20 . The method of claim 8 , wherein the treating comprises achieving MAC sputum culture conversion in the patient, wherein the MAC sputum culture conversion is defined as three consecutive negative MAC sputum cultures.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/845,688, filed Jun. 21, 2022, now U.S. Pat. No. 12,168,021, which is a continuation of U.S. application Ser. No. 17/031,744, filed Sep. 24, 2020, now U.S. Pat. No. 11,395,830, which is a continuation of U.S. application Ser. No. 16/778,506, filed Jan. 31, 2020, now U.S. Pat. No. 10,828,314, which is a continuation of U.S. application Ser. No. 16/515,303, filed Jul. 18, 2019, now U.S. Pat. No. 10,588,918, which is a continuation of U.S. application Ser. No. 16/250,476, filed Jan. 17, 2019, now U.S. Pat. No. 10,398,719, which is a continuation of U.S. application Ser. No. 15/311,488, filed Feb. 7, 2017, now U.S. Pat. No. 10,238,675, which is a 371 National Stage Entry of International Application No. PCT/US2015/031079, filed May 15, 2015, which claims priority to U.S. Provisional Application Ser. No. 61/993,439, filed May 15, 2014; 62/042,126, filed Aug. 26, 2014; 62/048,068, filed Sep. 9, 2014; and 62/056,296, filed Sep. 26, 2014, the disclosure of each of which is incorporated by reference herein in their entireties for all purposes. BACKGROUND OF THE INVENTION Certain technologies suitable for administration by inhalation employ liposomes and lipid complexes supply a prolonged therapeutic effect of drug in the lung. These technologies also provide the drug with sustained activities, and the ability to target and enhance the uptake of the drug into sites of disease. Inhalation delivery of liposomes is complicated by their sensitivity to shear-induced stress during nebulization, which can lead to change in physical characteristics (e.g., entrapment, size). However, as long as the changes in characteristics are reproducible and meet acceptability criteria, they need not be prohibitive to pharmaceutical development. Pulmonary infection with non-tuberculous Mycobacterium (NTM) in the susceptible host can lead to potentially severe morbidity and even mortality among those affected. As infection rates are rising, pulmonary nontuberculous mycobacterial disease (PNTM) represents an emerging public health concern in the United States. NTM are ubiquitous in the environment. Over 80% of pulmonary NTM (PNTM) infections in the US are due to Mycobacterium avium complex (MAC). In addition, M. Kansasii, M. abscessus, and M. fortuitum are regularly isolated. The prevalence of pulmonary NTM infections in the United States has more than doubled in the last 15 years. The ATS/IDSA PNTM reported 2-year period prevalence of pulmonary NTM infections is 8.6/100,000 persons. The prevalence of pulmonary NTM infections increases with age with 20.4/100,000 in those at least 50 years of age and is especially prevalent in females (median age: 66 years; female: 59%). In the susceptible individual, pulmonary NTM infections can be serious or life threatening. Available therapies may be poorly tolerated, and may have significant adverse events. The present invention addresses this and other needs by providing methods for treating pulmonary NTM infections in patients in need thereof. SUMMARY OF THE INVENTION The present invention, in one aspect, provides methods for treating or providing prophylaxis against a nontuberculous mycobacterial (NTM) infection (pulmonary infection caused or due to one or more nontuberculous mycobacteria), via inhalation administration of an effective amount of a composition comprising a liposomal complexed aminoglycoside, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. The patient in need of treatment, in one embodiment, is a cystic fibrosis patient, a bronchiectasis patient, suffers from asthma or suffers from chronic obstructive pulmonary disorder (COPD). In one embodiment, the NTM infection is a pulmonary NTM infection selected from an M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium, M. avium complex (MAC) (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. gordonae, M. ulcerans, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae) infection or a combination thereof. In a further embodiment, the NTM infection is an M. avium complex (MAC) (M. avium and M. intracellulare) infection. In one embodiment, the NTM infection is a pulmonary recalcitrant NTM infection. In one embodiment, the composition comprising the liposomal complexed aminoglycoside is a dispersion (e.g., a liposomal solution or suspension). The liposomal portion of the composition comprises a lipid component that includes electrically neutral lipids. In a further embodiment, the electrically neutral lipids comprise a phosphatidylcholine and a sterol (e.g., dipalmitoylphosphatidylcholine and chole