9-Aminomethyl Minocycline Compounds And Use Thereof In Treating Community-Acquired Bacterial Pneumonia (CABP)

Abstract

The invention disclosed herein provides a method for treating Community-Acquired Bacterial Pneumonia (CABP) using 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof, in either oral or IV doses or a combination of both.

What is claimed is: 
     
         1 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three intravenous doses of about 100 mg each, administered 12 hours apart, followed by,   (2) one or more intravenous doses of about 100 mg each, each administered 24 hours following the immediate preceding intravenous dose, followed by,   (3) optionally, one oral dose of about 300 mg, administered in the morning and 12-24 hrs after the immediate preceding intravenous dose, followed by,   (4) optionally, one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding oral dose,   such that said subject is treated.   
     
     
         2 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three intravenous doses of about 100 mg each, administered 12 hours apart, followed by,   (2) optionally, one or more intravenous doses of about 100 mg each, each administered 24 hours following the immediate preceding intravenous dose, followed by,   (3) optionally, one oral dose of about 300 mg, administered in the morning and 12-24 hrs after the immediate preceding intravenous dose, followed by,   (4) optionally, one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding oral dose,   such that said subject is treated.   
     
     
         3 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three intravenous doses of about 100 mg each, administered 12 hours apart, followed by,   (2) one or more intravenous doses of about 100 mg each, each administered 24 hours following the immediate preceding intravenous dose, followed by,   (3) one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding dose,   such that said subject is treated.   
     
     
         4 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three intravenous doses of about 100 mg each, administered 12 hours apart, followed by,   (2) optionally, one or more intravenous doses of about 100 mg each, each administered 24 hours following the immediate preceding intravenous dose, followed by,   (3) one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding dose,   such that said subject is treated.   
     
     
         5 . The method of  claim 3  or  4 , wherein step (2) consists of one intravenous dose of about 100 mg of said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or salt thereof. 
     
     
         6 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three intravenous doses of about 100 mg each, administered 12 hours apart, followed by,   (2) one or more intravenous doses of about 100 mg each, each administered 24 hours following the immediate preceding intravenous dose,   such that said subject is treated.   
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the steps are completed within 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days. 
     
     
         8 . The method of any one of  claims 1 - 6 , wherein the steps are completed within 7-14 days. 
     
     
         9 . The method of  claim 8 , wherein the steps are completed within 7-10 days. 
     
     
         10 . The method of  claim 8 , wherein the steps are completed within 11-14 days. 
     
     
         11 . The method of  claim 8 , wherein the steps are completed within 10 days. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the number of days of IV dosing is 3-10 days. 
     
     
         13 . The method of  claim 12 , wherein the number of days of IV dosing is 3-6 days. 
     
     
         14 . The method of  claim 12 , wherein the number of days of IV dosing is 7-10 days. 
     
     
         15 . The method of  claim 12 , wherein the number of days of IV dosing is 5 days. 
     
     
         16 . The method of any one of  claims 1 - 15 , comprising one or more oral doses, and wherein the number of days of IV dosing is 4-7 days. 
     
     
         17 . The method of  claim 16 , wherein the number of days of IV dosing is 4-5 days. 
     
     
         18 . The method of  claim 16 , wherein the number of days of IV dosing is 6-7 days. 
     
     
         19 . The method of  claim 16 , wherein the number of days of IV dosing is 5 days. 
     
     
         20 . The method of any one of  claims 16 - 19 , wherein the number of days of oral dosing is 1-7 days. 
     
     
         21 . The method of  claim 20 , wherein the number of days of oral dosing is 1-4 days. 
     
     
         22 . The method of  claim 20 , wherein the number of days of oral dosing is 5-7 days. 
     
     
         23 . The method of  claim 20 , wherein the number of days of oral dosing is 5 days. 
     
     
         24 . The method of  claim 16 , wherein the number of days of IV dosing is 5 days, and the number of days of oral dosing is 5 days. 
     
     
         25 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) three oral doses of about 300-450 mg each, administered 12 hours apart, followed by,   (2) optionally, one or more oral doses of about 300-600 mg each, each administered 24 hours following the immediate preceding oral dose,   such that said subject is treated.   
     
     
         26 . The method of  claim 25 , wherein each oral dose is about 300 mg. 
     
     
         27 . The method of  claim 25 , wherein each oral dose is about 450 mg. 
     
     
         28 . The method of  claim 25 , wherein each oral dose in step (1) is about 300 mg. 
     
     
         29 . The method of  claim 25 , wherein each oral dose in step (1) is about 450 mg. 
     
     
         30 . The method of  claim 25 ,  28 , or  29 , wherein each oral dose in step (2) is about 300 mg. 
     
     
         31 . The method of  claim 25 ,  28 , or  29 , wherein each oral dose in step (2) is about 450 mg. 
     
     
         32 . The method of  claim 25 ,  28 , or  29 , wherein each oral dose in step (2) is about 600 mg. 
     
     
         33 . The method of  claim 25 , wherein the first two oral doses of step (1) are each 300 mg, and the last oral dose of step (1) is about 300, 450, or 600 mg. 
     
     
         34 . The method of  claim 25 , wherein the first two oral doses of step (1) are each 450 mg, and the last oral dose of step (1) is about 300, 450, or 600 mg. 
     
     
         35 . A method of treating Community-Acquired Bacterial Pneumonia (CABP) in a subject in need of treatment thereof, comprising administering to said subject 9-[(2,2-dimethyl-propyl amino)-methyl]-minocycline or a salt thereof according to the following dosing regimen:
 (1) one or two once-daily oral dose(s) of about 450-600 mg (administered 24 hrs apart for two once-daily oral doses), followed by,   (2) one or more oral doses of about 300-600 mg each, each administered 24 hours following the immediate preceding oral dose,   such that said subject is treated.   
     
     
         36 . The method of  claim 35 , wherein said dosing regimen is:
 (1) one or two once-daily oral dose(s) of about 450 or 600 mg (administered 24 hrs apart for two once-daily oral doses), followed by,   (2) one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding oral dose.   
     
     
         37 . The method of  claim 35 , wherein said dosing regimen is:
 (1) two once-daily oral doses of about 450 mg, administered 24 hrs apart, followed by,   (2) one or more oral doses of about 300 mg each, each administered 24 hours following the immediate preceding oral dose.   
     
     
         38 . The method of any one of  claims 25 - 37 , wherein the steps are completed within 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. 
     
     
         39 . The method of any one of  claims 25 - 37 , wherein the steps are completed within 7-14 days, within 7-10 days, within 11-14 days, or within 10 days. 
     
     
         40 . The method of any one of  claims 1 - 39 , wherein said CABP is caused by  Staphylococcus aureus  including methicillin-resistant  Staphylococcus aureus  (MRSA),  Streptococcus pneumoniae  including penicillin-resistant  Streptococcus pneumoniae  (PRSP),  Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Escherichia coli , or a combination thereof. 
     
     
         41 . The method of  claim 40 , wherein said  Streptococcus pneumoniae  is penicillin-resistant  Streptococcus pneumoniae  (PRSP), macrolide-resistant  Streptococcus pneumoniae , cephalosporin-resistant  Streptococcus pneumoniae , or multidrug-resistant  Streptococcus pneumoniae  (MDRSP). 
     
     
         42 . The method of any one of  claims 1 - 39 , wherein said CABP is caused by intracellular pathogens, such as  Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii , or a combination thereof. 
     
     
         43 . The method of any one of  claims 1 - 39 , wherein said CABP is caused by  Haemophilus parainfluenzae.    
     
     
         44 . The method of any one of  claims 1 - 43 , wherein said subject is a human. 
     
     
         45 . The method of any one of  claims 1 - 44 , wherein each of said oral dose is administered independently as two 150-mg tablets. 
     
     
         46 . The method of any one of  claims 1 - 45 , wherein each of said intravenous dose is administered continuously over about 30 minutes (e.g., at least 30 minutes and not more than 45 minutes). 
     
     
         47 . The method of any one of  claims 1 - 46 , wherein said dosing regimen has a clinical success rate that is within 10% (or 12.5%) margin of non-inferiority compared to moxifloxacin administered as 400 mg intravenous dose once every 24 hours for three or more days, followed by one or more doses of 400 mg oral doses of moxifloxacin once every 24 hours. 
     
     
         48 . The method of any one of  claims 1 - 47 , wherein said subject experience improvement, at day 3 to day 5 after step (1), in at least two symptoms selected from: chest pain, frequency or severity of cough, amount of productive sputum, and difficulty breathing, wherein said symptoms are evaluated on a four-point scale of absent, mild, moderate, and severe, and wherein improvement is at least a one-point improvement from baseline to the assessment at said day 3 to day 5 (e.g., from severe to moderate, from moderate to absent, or from mild to absent). 
     
     
         49 . The method of any one of  claims 1 - 47 , wherein said subject, at day 3 to day 5 after step (1), experience improvement in at least two symptoms and no worsening in any of the symptoms selected from: chest pain, frequency or severity of cough, amount of productive sputum, and difficulty breathing, and improvement in at least one vital sign selected from: body temperature, blood pressure, heart rate, and respiratory rate. 
     
     
         50 . The method of any one of  claims 1 - 49 , wherein the subject undergoes fasting overnight, with no food or drink except water for at least 6 hours, just before step (3) dosing (if present), and wherein the subject continues fasting after step (3) dosing, with no food for 2 hours, and no dairy products for 4 hours. 
     
     
         51 . The method of any one of  claims 1 - 50 , wherein said salt is a tosylate salt. 
     
     
         52 . The method of any one of  claims 1 - 51 , which method has a clinical success rate of about 70%-100%. 
     
     
         53 . The method of  claim 52 , wherein said clinical success rate is about 75-95%, about 80-95%, about 75-90%, about 80-90%, about 75-85%, about 80-85%, about 85-90%, about 90-95%, about 80-82%, or about 81%. 
     
     
         54 . The method of  claim 53 , wherein said clinical success rate is about 75-85%, observed at about 72-120 hours after the administration of the first intravenous dose. 
     
     
         55 . The method of  claim 54 , wherein said clinical success rate is about 80-82%, or 80% or 81%. 
     
     
         56 . The method of  claim 53 , wherein said clinical success rate is observed at about 5-10 days after the last dose of treatment (e.g., equivalent to a time for post treatment evaluation in clinically evaluable population, or CE-PTE; or in ITT population). 
     
     
         57 . The method of  claim 56 , wherein said clinical success rate is about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, or 97%. 
     
     
         58 . The method of any one of  claims 1 - 57 , wherein said subject has CABP categorized as PORT Risk Class II. 
     
     
         59 . The method of  claim 58 , wherein said method has a clinical success rate of about 70-100%, about 75-96%, about 75-90%, about 80-83%, about 82%, about 80-96%, about 90-96%, or about 95%. 
     
     
         60 . The method of  claim 59 , wherein said clinical success rate is about 75-85%, or about 90-100%, observed at about 5-10 days after the last dose of treatment. 
     
     
         61 . The method of  claim 60 , wherein said clinical success rate is about 82%, or about 95%. 
     
     
         62 . The method of any one of  claims 1 - 57 , wherein said subject has CABP categorized as PORT Risk Class III. 
     
     
         63 . The method of  claim 62 , wherein said method has a clinical success rate of about 80-100%, about 85-95%, about 90-95%, about 90-91%, or about 93-94%. 
     
     
         64 . The method of  claim 63 , wherein said clinical success rate is about 85-100%, observed at about 5-10 days after the last dose of treatment. 
     
     
         65 . The method of  claim 64 , wherein said clinical success rate is about 90-91%, or about 93-94%. 
     
     
         66 . The method of any one of  claims 1 - 57 , wherein said subject has CABP categorized as PORT Risk Class IV. 
     
     
         67 . The method of  claim 66 , wherein said method has a clinical success rate of about 70-100%, about 75-95%, about 80-95%, about 83-85%, or about 90-91%. 
     
     
         68 . The method of  claim 67 , wherein said clinical success rate is about 80-95%, observed at about 5-10 days after the last dose of treatment. 
     
     
         69 . The method of  claim 68 , wherein said clinical success rate is about 83-85%, or about 90-91%. 
     
     
         70 . The method of any one of  claims 1 - 57 , wherein said subject has CABP categorized as PORT Risk Class III or IV. 
     
     
         71 . The method of  claim 70 , wherein said method has a clinical success rate of about 75-100%, about 85-95%, about 85-90%, about 88-89%, about 90-95%, or about 92-93%. 
     
     
         72 . The method of  claim 71 , wherein said clinical success rate is about 85-95%, observed at about 5-10 days after the last dose of treatment. 
     
     
         73 . The method of  claim 72 , wherein said clinical success rate is about 88-89%, or about 92-93%. 
     
     
         74 . The method of any one of  claims 1 - 73 , wherein gastrointestinal (GI) adverse events (AEs) associated with treatment of said subject are mild. 
     
     
         75 . The method of any one of  claims 1 - 73 , wherein GI adverse events (AEs) associated with treatment of said subject do not result in discontinuation of therapy with said method. 
     
     
         76 . The method of any one of  claims 1 - 75 , wherein treatment of said subject (1) does not result in increased risk of  C. difficile  (e.g.,  C. difficile  colitis and Pseudomembranous colitis) infection in said subject, or (2) does not substantially disrupting gut microbiome in said subject. 
     
     
         77 . The method of  claim 76 , wherein said subject is at risk of, or is predisposed to, developing a  C. difficile  infection. 
     
     
         78 . The method of  claim 77 , wherein said subject has recently been treated with one or more antibiotics (such as broad spectrum antibiotics), has had surgery of the gastrointestinal tract, has a disease of the colon (such as an inflammatory bowel disease or colorectal cancer), has a kidney disease, has a weakened immune system; is on chemotherapy, has previously had  C. difficile  infection, is 65 years or older, takes proton-pump inhibitors, or is living in an environment that predisposes said subject to developing  C. difficile  infection (such as in a hospital, a nursing home, or an assisted living facility).