9-aminomethyl minocycline compounds and use thereof in treating community-acquired bacterial pneumonia (CABP)

Abstract

To provide a method for treating Community-Acquired Bacterial Pneumonia (CABP).SOLUTION: A method comprises administering, to a subject, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to a following dosing regimen: (1) three intravenous doses of about 100 mg each, which are administered every 12 hours; (2) subsequent optional one or more intravenous doses of about 100 mg each, each of which is administered 24 hours after the immediate preceding intravenous dose; (3) subsequent optional one oral dose of about 300 mg, which is administered in the morning and 12-24 hours after the immediate preceding intravenous dose; and (4) subsequent optional one or more oral doses of about 300 mg each, each of which is administered 24 hours after the immediate preceding oral dose.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] The development of tetracycline antibiotics was a direct result of the systematic screening of soil samples from around the world for evidence of microorganisms capable of producing bactericidal and / or bacteriostatic compositions. The first of these new compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. Elucidation of the chemical structures of these compounds confirmed their similarity and also provided the analytical basis for the preparation of the third member of this group, tetracycline, in 1952. A new family of minocycline compounds, lacking the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967, with minocycline being in use until 1972.

[0002] Recently, research efforts have been focused on developing new tetracycline antibiotic compositions that are effective under varying therapeutic conditions and routes of administration. New tetracycline analogs that may prove to be as effective or more effective than the originally introduced minocycline compound have also been investigated. Examples include U.S. Patent Nos. 2,980,584, 2,990,331, 3,062,717, 3,165,531, 3,454,697, 3,557,280, 3,674,859, 3,957,980, 4,018,889, 4,024,272 and 4,126,680. These patents are representative of the range of pharma- ceutical active tetracyclines and tetracycline analog compositions.

[0003] Historically, shortly after its initial development and introduction, tetracyclines were found to be highly pharmacologically effective against rickettsiae, several gram-positive and gram-negative bacteria, and the causative pathogens of conjunctivitis and lymphogranulomatosis venereum, including psittacosis. Thus, tetracyclines became known as "broad-spectrum" antibiotics. With the subsequent establishment of in vitro antibacterial activity, efficacy in experimental infections, and pharmacological properties, tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both severe and mild illnesses and diseases directly led to the emergence of resistance to these antibiotics, even among highly susceptible bacterial species, both commensal and pathogenic (e.g., Pneumococci and Salmonella). The rise in tetracycline-resistant organisms has led to an overall decline in the use of tetracyclines and tetracycline analog compositions as antibiotics of choice. In addition, other antibacterial agents have also been overused, creating multidrug-resistant bacterial strains. Thus, there is a need for effective antibacterial agents for the treatment of bacterial infections in general, and in particular, antibacterial agents that are not or are less severely resisted by disease-causing pathogens.

[0004] Community-acquired bacterial pneumonia (CABP), also known as community-acquired pneumonia (CAP) (these terms may be used interchangeably), is defined as an acute bacterial infection of the pulmonary parenchyma accompanied by chest pain, cough, sputum production, dyspnea, chills, shivers, fever, or hypotension, with the presence of new lobar or multilobar infiltrates on chest radiograph. Common common bacterial pathogens causing CABP include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis. Atypical bacterial pathogens such as Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila also cause CABP.

[0005] CABP is a leading cause of morbidity and mortality in the United States (US) and worldwide (Mandell et al., Clin. Infect. Dis. 44:S27-S72, 2007). In the US, 4-6 million cases of CABP occur annually, resulting in 10 million physician visits, 600,000 hospitalizations, and tens of thousands of deaths. The total cost of CABP to the annual US health care budget exceeds $10 billion (in 2007 adjusted dollars) (Niederman et al., Clin. Ther. 20(4):820-37, 1998). Furthermore, resistance to antibiotics is increasing among common pathogens, resulting in a critical need for new antibiotics (Spellberg et al., Clin. Infect. Dis. 46(2):155-164, 2008). Bacterial resistance to the most frequently prescribed currently available antibiotics has limited their potential to treat infections, which has hindered their use as first-line empirical monotherapy. Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDR-SP) in the community in CABP have posed treatment challenges due to resistance to penicillins (100% resistance rate to both), cephalosporins (100% and 11% to ceftriaxone, respectively), macrolides (83% and 86% to azithromycin / erythromycin, respectively), and quinolones (73% and 2% to levofloxacin, respectively). Furthermore, growing concerns about "collateral damage" associated with the use of quinolone and beta-lactam class antibiotics further highlight the need for novel antibiotic treatment options for CABP (Paterson, Clin Infect Dis. Vol. 38 Suppl. 4:S341-345, 2004). Therapy failure due to resistance continues to contribute to morbidity and mortality in CABP, and treatment failure of mild disease leads to increased hospitalizations and contributes to increased healthcare costs. Summary of the Invention [Means for solving the problem]

[0006] The invention described herein provides 9-aminomethyl minocyclines, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (Omadacycline or "Compound 1") for use in the treatment of CABP.

[0007] The present invention is also based in part on the discovery that 9-aminomethyl minocycline, such as Compound 1, can be provided as an IV dosage form, alone or in combination with an oral dosage form (such as an oral step-down after an initial IV dose), for the treatment of CABP. In certain embodiments, the present invention provides for the use of 9-aminomethyl minocycline, such as Compound 1, as an IV dosage form for the treatment of CABP.

[0008] The present invention is further based on the discovery that 9-aminomethylminocycline, such as compound 1, has a relatively broad spectrum against a variety of pathogens associated with CABP, including intracellular CABP pathogens. The findings that compound 1 has in vitro activity against common typical and atypical pathogens and sustained 24-hour enrichment in airway epithelial lining fluid (ELF) and alveolar cells (AC), including alveolar macrophages (AM), suggest that compound 1 has utility as an antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens, such as intracellular CABP pathogens, including Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydophila psittaci, and / or Coxiella burnetii.

[0009] The present invention is further based on the discovery that 9-aminomethyl minocyclines, such as compound 1, have relatively broad spectrum activity against a variety of pathogens associated with CABP as further described below.

[0010] 9-aminomethyl minocycline such as Compound 1 is also advantageous for the treatment of CABP associated with antibiotic-resistant pathogens such as MRSA and penicillin-resistant Streptococcus pneumoniae (PRSP). Due to its effectiveness against resistant pathogens, 9-aminomethyl minocycline such as Compound 1 can also be used as a front-line therapeutic agent when known or suspected drug-resistant bacteria may be the causative pathogen. On the other hand, 9-aminomethyl minocycline such as Compound 1 can also be used as a therapeutic agent in patients who have been previously treated with other antibiotics but have had an inadequate response or have developed / presented with unacceptable or undesirable adverse events (AEs), such as gastrointestinal AEs (GI tract AEs) and / or C. difficile infections.

[0011] Accordingly, one aspect of the present invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need of such treatment, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) one oral dose of about 300 mg in the morning administered 12-24 hours after the immediately preceding intravenous dose, followed by (4) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0012] A related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) optionally one oral dose of about 300 mg in the morning, administered 12-24 hours after the immediately preceding intravenous dose, followed by (4) optionally one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0013] A related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding dose, such that the subject is treated.

[0014] Another related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding dose, such that the subject is treated.

[0015] In certain embodiments, step (2) consists of a single intravenous dose of about 100 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof.

[0016] Yet another related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding intravenous dose, such that the subject is treated.

[0017] In certain embodiments, the steps of the method are completed within 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days.

[0018] In certain embodiments, the steps are completed within 7-14 days, for example, 7-10 days, 11-14 days, or 10 days.

[0019] In certain embodiments, the number of days of IV dosing is 3-10 days, for example, 3-6 days, 7-10 days, or 5 days.

[0020] In certain embodiments, the method includes one or more oral doses and the number of days of IV dosing is 4-7 days, for example, 4-5 days, 6-7 days, or 5 days.

[0021] In certain embodiments, the number of days of oral dosing is 1 to 7 days, for example, 1 to 4 days, 5 to 7 days, or 5 days.

[0022] In a particular embodiment, the number of days of IV dosing is 5 days and the number of days of oral dosing is 5 days.

[0023] Another related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0024] In certain embodiments, each oral dose is about 300 mg.

[0025] In certain embodiments, each oral dose is about 450 mg.

[0026] In certain embodiments, each oral dose in step (1) is about 300 mg.

[0027] In certain embodiments, each oral dose in step (1) is about 450 mg.

[0028] In certain embodiments, each oral dose in step (2) is about 300 mg.

[0029] In certain embodiments, each oral dose in step (2) is about 450 mg.

[0030] In certain embodiments, each oral dose in step (2) is about 600 mg.

[0031] In certain embodiments, the first two oral doses of step (1) are 300 mg each, and the final oral dose of step (1) is about 300, 450, or 600 mg.

[0032] In certain embodiments, the first two oral doses of step (1) are 450 mg each, and the final oral dose of step (1) is about 300, 450 or 600 mg.

[0033] Another related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered as a once daily oral dose of 300 mg for 5, 6, 7 or 8 consecutive days.

[0034] Another related aspect of the invention provides a method of treating community-acquired bacterial pneumonia (CABP) in a subject in need of such treatment, comprising administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing regimen: (1) one or two oral doses per day of about 450-600 mg administered 24 hours apart for the two daily oral doses, followed by (2) one or more oral doses of about 300-600 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0035] In a particular embodiment, the dosing regimen is (1) one or two oral doses per day of about 450 or 600 mg (administered 24 hours apart for the twice daily oral doses), followed by (2) one or more oral doses of about 300 mg each, each administered 24 hours after the immediately preceding oral dose.

[0036] In a particular embodiment, the dosing regimen is (1) two daily oral doses of about 450 mg administered 24 hours apart, followed by (2) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose.

[0037] In certain embodiments, the steps are completed within 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days.

[0038] In certain embodiments, the steps are completed within 7-14 days, within 7-10 days, within 11-14 days, or within 10 days.

[0039] In certain embodiments, the 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, Chlamydia pneumoniae, Mycoplasma pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Escherichia coli, or a combination thereof.

[0040] In certain embodiments, the Streptococcus pneumoniae is penicillin-resistant Streptococcus pneumoniae (PRSP), macrolide-resistant Streptococcus pneumoniae, cephalosporin-resistant Streptococcus pneumoniae or multidrug-resistant Streptococcus pneumoniae (MDRSP).

[0041] In certain embodiments, the CABP is caused by an intracellular pathogen such as Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila psittaci, Coxiella burnetii, or a combination thereof.

[0042] In certain embodiments, the CABP is caused by Haemophilus parainfluenzae.

[0043] In certain embodiments, the subject is a human.

[0044] In a particular embodiment, each of said oral doses is administered independently as two 150 mg tablets.

[0045] In certain embodiments, each of the intravenous doses is administered sequentially over about 30 minutes (eg, at least 30 minutes and no more than 45 minutes).

[0046] In certain embodiments, the dosing regimen has a clinical success rate that is (1) higher than that of moxifloxacin, or (2) within a 10% (or 12.5%) margin of non-inferiority compared to moxifloxacin, where moxifloxacin is administered as one or more doses of an intravenous dose of 400 mg once every 24 hours for three or more days, followed by one or more doses of an oral dose of 400 mg moxifloxacin once every 24 hours.

[0047] In certain embodiments, the subject experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea on days 3 to 5 following step (1), where the symptoms are rated on a 4-point scale of none, mild, moderate, and severe, and the improvement is an improvement of at least one level from baseline to the rating on days 3 to 5 (e.g., from severe to moderate, moderate to none, or mild to none).

[0048] In certain embodiments, between days 3 and 5 following step (1), the subject experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea, without worsening in any of the symptoms selected therefrom, and improvement in at least one vital sign selected from body temperature, blood pressure, heart rate, and respiratory rate.

[0049] In certain embodiments, the subject fasts overnight and has not consumed food or beverages other than water for at least 6 hours immediately prior to dosing in step (3), and the subject continues to fast after dosing in step (3), having not consumed food for 2 hours and not consumed dairy products for 4 hours.

[0050] In certain embodiments, the salt is a tosylate salt.

[0051] In certain embodiments, the method has a clinical success rate of about 70% to 100%.

[0052] In certain embodiments, the 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%.

[0053] In certain embodiments, the clinical success rate is about 75-85% observed at about 72-120 hours after administration of the first intravenous dose.

[0054] In certain embodiments, the clinical success rate is about 80-82%, or 80%, or 81%.

[0055] In certain embodiments, clinical success rates are observed about 5-10 days after the last dose of treatment (e.g., corresponding to the time of post-treatment assessment in a clinically evaluable population or CE-PTE, or in an ITT population).

[0056] In certain embodiments, the clinical success rate is about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% or 97%.

[0057] In certain embodiments, the subject has CABP classified as PORT risk class II.

[0058] In certain embodiments, the 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%.

[0059] In certain embodiments, the clinical success rate is about 75-85% or about 90-100%, observed about 5-10 days after the last dose of treatment.

[0060] In certain embodiments, the clinical success rate is about 82% or about 95%.

[0061] In certain embodiments, the subject has CABP classified as PORT risk class III.

[0062] In certain embodiments, the method has a clinical success rate of about 80-100%, about 85-95%, about 90-95%, about 90-91%, or about 93-94%.

[0063] In certain embodiments, the clinical success rate is about 85-100%, observed about 5-10 days after the last dose of treatment.

[0064] In certain embodiments, the clinical success rate is about 90-91% or about 93-94%.

[0065] In certain embodiments, the subject has CABP classified as PORT risk class IV.

[0066] In certain embodiments, the method has a clinical success rate of about 70-100%, about 75-95%, about 80-95%, about 83-85%, or about 90-91%.

[0067] In certain embodiments, the clinical success rate is about 80-95%, observed about 5-10 days after the last dose of treatment.

[0068] In certain embodiments, the clinical success rate is about 83-85% or about 90-91%.

[0069] In certain embodiments, the subject has CABP classified as a PORT risk class III or IV.

[0070] In certain embodiments, the 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%.

[0071] In certain embodiments, the clinical success rate is about 85-95%, observed about 5-10 days after the last dose of treatment.

[0072] In certain embodiments, the clinical success rate is about 88-89% or about 92-93%.

[0073] In certain embodiments, the subject experiences mild gastrointestinal (GI) adverse events (AEs) associated with treatment.

[0074] In certain embodiments, GI adverse events (AEs) associated with treatment of said subject do not result in discontinuation of therapy with the method.

[0075] In certain embodiments, treating a subject (1) does not result in an increased risk of C. difficile (also known as C. difficile colitis and pseudomembranous colitis) infection in the subject, or (2) does not substantially disrupt the gut microbiome in the subject.

[0076] In certain embodiments, the subject is at risk or predisposed to developing a C. difficile infection.

[0077] In certain embodiments, the subject has recently been treated with one or more antibiotics (such as broad-spectrum antibiotics), has undergone surgery of the digestive tract, has a disease of the colon (e.g., inflammatory bowel disease or colorectal cancer), has kidney disease, has a weakened immune system, is undergoing chemotherapy, has a previous C. difficile infection, is 65 years of age or older, is taking a proton pump inhibitor, or lives in an environment that predisposes the subject to developing a C. difficile infection (e.g., a hospital, nursing home, or assisted living facility).

[0078] It should be understood that any one embodiment may be combined with any other embodiment unless expressly prohibited or inappropriate. [Brief description of the drawings]

[0079] [Figure 1] FIG. 1 shows the mean Compound 1 (omadacycline) concentration versus time profiles in AC (alveolar cells), plasma and ELF. [Diagram 2]FIG. 2 illustrates that Compound 1 ("omadacycline") demonstrated statistical non-inferiority (10% margin) to moxifloxacin for early clinical response (ECR) in the ITT (intent to treat) population (see left pair of bars) (FDA primary endpoint), and for clinical success at PTE (post-treatment / therapy evaluation) in both the ITT population (see center pair of bars) and the CE-PTE (clinically evaluable population at PTE) population (see right pair of bars) (FDA secondary endpoint). [Diagram 3] FIG. 3 shows that Compound 1 ("omadacycline") demonstrated statistical non-inferiority (10% margin) to moxifloxacin based on clinical success in PTE (EMA co-primary endpoint) in both the ITT population restricted to patients with CABP classified as PORT risk class III / IV (see left pair of bars) and the CE-PTE population restricted to patients with CABP classified as PORT risk class III / IV (see right pair of bars). [Figure 4] Figure 4 shows clinical success rates for PTE of both Compound 1 (omadacycline) and moxifloxacin by baseline pathogen in Compound 1 treatment groups with 10 or more isolates. N1 = number of subjects with the baseline pathogen specified. n = number of subjects in the category specified. Percentages are based on number of subjects with the baseline pathogen specified. [Diagram 5] FIG. 5 shows plasma concentration versus time curves of omadacycline after oral administration. Mean (±SD) plasma concentration of omadacycline versus time is shown by omadacycline dose (300, 450 or 600 mg) for the pharmacokinetic population. Oral omadacycline doses were administered at time 0 on each of 5 consecutive days of dosing in each of the 3 periods. Blood samples were collected for PK analysis on Day 1 (left panel) and Day 5 (right panel). Data were pooled by omadacycline dose for all subjects, regardless of the period during which they received a particular dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] The present invention relates, at least in part, to the discovery that 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (Compound 1 / omadacycline), based on specified dosage amounts and dosing schedules, is effective for treating certain bacterial infections, such as CABP.

[0081] The present invention is further based on the discovery that 9-aminomethyl minocyclines, such as compound 1, have relatively broad spectrum activity against a variety of pathogens associated with CABP as further described below.

[0082] In addition, 9-aminomethyl minocyclines such as compound 1 also have a relatively broad spectrum against intracellular CABP pathogens. The findings that compound 1 has in vitro activity against common typical and atypical pathogens and sustained enrichment in airway epithelial lining fluid (ELF) and alveolar cells (AC) including alveolar macrophages (AM) for 24 hours suggest that compound 1 has utility as an antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens such as intracellular CABP pathogens including Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila sitassii, and / or Coxiella burnetii.

[0083] Thus, in one aspect, the present invention provides a method of treating CABP in a subject in need of such treatment.

[0084] In a first embodiment, the method includes administering to a subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (e.g., as the tosylate salt) according to the following dosing schedule: (1) three intravenous (IV) doses of about 100 mg each administered 12 hours apart, followed by (2) one or more IV doses of about 100 mg each administered 24 hours after the immediately preceding IV dose, followed by (3) one oral dose of about 300 mg in the morning administered 12-24 hours after the immediately preceding intravenous dose, followed by (4) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0085] In a related second embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) optionally one oral dose of about 300 mg in the morning administered 12-24 hours after the immediately preceding intravenous dose, followed by (4) optionally one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0086] In a related third embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (1) three intravenous doses of about 100-125 mg each administered 12 hours apart, followed by (2) optionally one or more intravenous doses of about 100-125 mg each administered 24 hours after the immediately preceding intravenous dose, followed by (3) optionally one oral dose of about 300-475 mg (i.e., three times the IV dose administered in the oral dose) administered 12-24 hours after the immediately preceding intravenous dose in the morning, followed by (4) optionally one or more oral doses of about 300-475 mg each (i.e., three times the IV dose administered in the oral dose), each administered 24 hours after the immediately preceding oral dose. In certain embodiments, the 100-125 mg IV doses are about 100-120 mg, about 100-115 mg, about 100-110 mg, and about 100-105 mg, and the 300-475 mg oral doses are three times the corresponding IV doses (i.e., the 300-475 mg oral doses are about 300-360 mg, about 300-345 mg, about 300-330 mg, and about 300-315 mg, respectively).

[0087] In a fourth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (e.g., as the tosylate salt) according to the following dosing schedule: (1) a single intravenous (IV) dose of about 200 mg, followed by (2) optionally one or more IV doses of about 100 mg each administered 24 hours after the immediately preceding IV dose, followed by (3) optionally a single oral dose of about 300 mg in the morning administered 12-24 hours after the immediately preceding intravenous dose, followed by (4) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0088] In a fifth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding dose, such that the subject is treated.

[0089] In a related sixth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (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 administered 24 hours after the immediately preceding intravenous dose, followed by (3) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding dose, such that the subject is treated.

[0090] In a related seventh embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing regimen: (1) three intravenous doses of about 100-125 mg each administered 12 hours apart, followed by (2) optionally one or more intravenous doses of about 100-125 mg each administered 24 hours after the immediately preceding intravenous dose, followed by (3) one or more oral doses of about 300-475 mg each administered 24 hours after the immediately preceding dose (i.e., three times the IV dose administered orally), such that the subject is treated. In certain embodiments, the 100-125 mg IV doses are about 100-120 mg, about 100-115 mg, about 100-110 mg, and about 100-105 mg, and the 300-475 mg oral doses are three times the corresponding IV doses (i.e., the 300-475 mg oral doses are about 300-360 mg, about 300-345 mg, about 300-330 mg, and about 300-315 mg, respectively).

[0091] In an eighth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing regimen: (1) a single intravenous dose of about 200 mg, followed by (2) optionally one or more intravenous doses of about 100 mg each, each administered 24 hours after the immediately preceding intravenous dose, followed by (3) optionally one or more oral doses of about 300 mg each, each administered 24 hours after the immediately preceding dose, such that the subject is treated.

[0092] In a ninth embodiment, step (2) in the method of any one of the fifth to eighth embodiments comprises a single intravenous dose of about 100 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof.

[0093] In a tenth embodiment, the method includes administering to a subject 9-[(2,2-dimethyl-propylamino)-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 administered 24 hours after the immediately preceding intravenous dose, such that the subject is treated.

[0094] In a related eleventh embodiment, the method comprises administering to a subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing schedule: (1) three intravenous doses of about 100-125 mg each administered 12 hours apart, followed by (2) one or more intravenous doses of about 100-125 mg each administered 24 hours after the immediately preceding intravenous dose, such that the subject is treated. In certain embodiments, the 100-125 mg IV doses are about 100-120 mg, about 100-115 mg, about 100-110 mg, and about 100-105 mg.

[0095] In a related twelfth embodiment, the method includes administering to a subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof according to the following dosing regimen: (1) one intravenous dose of about 200 mg, followed by (2) one or more intravenous doses of about 100 mg each, each administered 24 hours after the immediately preceding intravenous dose, such that the subject is treated.

[0096] In a thirteenth embodiment, the method steps of any one of the first to twelfth embodiments are completed within 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In certain related embodiments, the method steps are completed within 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. In yet another embodiment, the method steps are completed within 5, 6, or 21 days. In certain related embodiments, the method steps are completed within 5 or 6 days. In certain related embodiments, the method steps are completed within 7 to 14 days.

[0097] In a fourteenth embodiment, the method steps of any one of the first to twelfth embodiments are completed within 7 to 14 days, such as within 7 to 10 days, 11 to 14 days, or 10 days.

[0098] In a fifteenth embodiment, the number of days of IV administration in the fourteenth embodiment is 3 to 10 days, for example, 3 to 6 days, 7 to 10 days, or 5 days.

[0099] In a sixteenth embodiment, the method of any one of the first to fifteenth embodiments includes one or more oral doses, and the number of days of IV dosing is 4 to 7 days, for example, 4 to 5 days, 6 to 7 days, or 5 days.

[0100] In a seventeenth embodiment, the number of days of oral administration in the sixteenth embodiment is 1 to 7 days, for example, 1 to 4 days, 5 to 7 days, or 5 days.

[0101] In an eighteenth embodiment, the number of days of IV dosing in any one of the first to seventeenth embodiments is five days, and the number of days of oral dosing is five days.

[0102] In a nineteenth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (e.g., as the tosylate salt) according to the following dosing regimen: (1) three oral doses of about 300-450 mg (e.g., 300 mg or 450 mg) administered 12 hours apart, followed by (2) optionally one or more oral doses of about 300-600 mg (e.g., 300 mg, 450 mg, or 600 mg) each, each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0103] In a twentieth embodiment, each oral dose of the nineteenth embodiment is about 300 mg.

[0104] In a twenty-first embodiment, each oral dose of the nineteenth embodiment is about 450 mg.

[0105] In a twenty-second embodiment, each oral dose in step (1) of the nineteenth embodiment is about 300 mg.

[0106] In a twenty-third embodiment, each oral dose in step (1) of the nineteenth embodiment is about 450 mg.

[0107] In a twenty-fourth embodiment, each oral dose in step (2) of the nineteenth, twenty-second, or twenty-third embodiment is about 300 mg.

[0108] In a twenty-fifth embodiment, each oral dose in step (2) of the nineteenth, twenty-second, or twenty-third embodiment is about 450 mg.

[0109] In a twenty-sixth embodiment, each oral dose in step (2) of the nineteenth, twenty-second, or twenty-third embodiment is about 600 mg.

[0110] In a twenty-seventh embodiment, the first two oral doses in step (1) of the nineteenth embodiment are 300 mg each, and the final oral dose in step (1) is about 300, 450, or 600 mg.

[0111] In a twenty-eighth embodiment, the first two oral doses in step (1) of the nineteenth embodiment are 450 mg each, and the final oral dose in step (1) is about 300, 450, or 600 mg.

[0112] In a twenty-ninth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (e.g., as the tosylate salt) according to the following dosing regimen: (1) one or two daily oral doses of about 450-600 mg (e.g., 450 mg or 600 mg) administered 24 hours apart for the two daily oral doses, followed by (2) one or more oral doses of about 300-600 mg (e.g., 300 mg, 450 mg, or 600 mg), each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0113] In a thirtieth embodiment, the method includes administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (e.g., as the tosylate salt) according to the following dosing regimen: (1) one or two oral doses per day of about 300-600 mg (e.g., 300 mg, 450 mg, or 600 mg) administered 24 hours apart for the two daily oral doses, followed by (2) one or more oral doses of about 300-600 mg (e.g., 300 mg, 450 mg, or 600 mg), each administered 24 hours after the immediately preceding oral dose, such that the subject is treated.

[0114] In a thirty-first embodiment, the method comprises administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered as a once daily oral dose of 300 mg for 5, 6, 7, or 8 consecutive days.

[0115] In a thirty-second embodiment, the dosing regimen of the twenty-ninth embodiment is (1) one or two oral doses per day of about 450-600 mg, e.g., 450 mg or 600 mg, administered 24 hours apart for the twice daily oral doses, followed by (2) one or more oral doses of about 300 mg each, each administered 24 hours after the immediately preceding oral dose.

[0116] In a thirty-third embodiment, the dosing regimen of the twenty-ninth embodiment is (1) two daily oral doses of about 450 mg administered 24 hours apart, followed by (2) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose.

[0117] In a thirty-fourth embodiment, the dosing regimen of the twenty-ninth embodiment is (1) two daily oral doses of about 600 mg administered 24 hours apart, followed by (2) one or more oral doses of about 300 mg each administered 24 hours after the immediately preceding oral dose.

[0118] In a 35th embodiment, the steps of any one of the 25th to 34th embodiments are completed within 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days.

[0119] In a thirty-sixth embodiment, the steps of any one of the twenty-fifth to thirty-fourth embodiments are completed within 7 to 14 days, within 7 to 10 days, within 11 to 14 days, or within 10 days.

[0120] In a thirty-seventh embodiment, the CABP of any one of the first to thirty-sixth embodiments 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, Chlamydia pneumoniae, Mycoplasma pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Escherichia coli, or a combination thereof.

[0121] In a thirty-eighth embodiment, the Streptococcus pneumoniae of the thirty-seventh embodiment is penicillin-resistant Streptococcus pneumoniae (PRSP), macrolide-resistant Streptococcus pneumoniae, cephalosporin-resistant Streptococcus pneumoniae or multidrug-resistant Streptococcus pneumoniae (MDRSP).

[0122] In a thirty-ninth embodiment, the CABP of any one of the first to thirty-sixth embodiments is caused by an intracellular pathogen such as Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila psittaci, Coxiella burnetii, or a combination thereof.

[0123] In a fortieth embodiment, the CABP of any one of the first to thirty-sixth embodiments is caused by Haemophilus parainfluenzae.

[0124] In the forty-first embodiment, the subject of any of the first to fortieth embodiments is a human.

[0125] In a forty-second embodiment, each of the oral doses of any of the first to forty-first embodiments is administered independently as two 150 mg tablets.

[0126] In a forty-third embodiment, each of the intravenous doses of any of the first to forty-second embodiments is administered continuously over about 30 minutes (eg, at least 30 minutes and no more than 45 minutes).

[0127] In a 44th embodiment, the dosing regimen of any of the 1-43rd embodiments has a clinical success rate that is within a 10% (or 12.5%) margin of non-inferiority compared to moxifloxacin administered as one or more doses of a 400 mg intravenous dose every 24 hours for three or more days, followed by one or more doses of a 400 mg oral dose of moxifloxacin every 24 hours.

[0128] In a forty-fifth embodiment, the subject of any of the first to forty-fourth embodiments (1) has at least three of the symptoms selected from cough, purulent sputum production, dyspnea (shortness of breath), and pleuritic chest pain; (2) has at least two abnormal vital signs selected from fever or hypothermia (temperature >38.0° C. [100.4° F.] or <36.0° C. [95.5° F.]), hypotension with a systolic blood pressure (SBP) <90 mm Hg, tachycardia (heart rate >90 beats per minute (bpm)), and tachypnea (respiratory rate (RR) >20 breaths / min); and (3) has at least one clinical sign or laboratory finding associated with CABP: hypoxemia (partial pressure of arterial oxygen [PaO2] by arterial blood gas [ABG] <60 mm Hg). Hg or oxygen saturation <90% by pulse oximetry, clinical evidence of pulmonary consolidation (e.g., by physical exam findings) (e.g., dullness to percussion, bronchial breath sounds, or goatee voice), and elevated total white blood cell (WBC) count (>12,000 cells / mm 3 ) or leukopenia (WBC < 4,000 cells / mm 3 ) or increased immature neutrophils (>15% band morphology regardless of total peripheral WBC count); (4) have radiographically confirmed pneumonia (i.e., new or progressing pulmonary infiltrates in a lobar or multilobar distribution on chest x-ray (CXR) or chest computed tomography (CT) scan consistent with acute bacterial pneumonia within 24 or 48 hours prior to step (1)); (5) have disease classified as being in PORT risk class II, III, or IV, or have an adequate sputum specimen characterized by fewer than 10 squamous cells and more than 25 polymorphonuclear cells per low-power field.

[0129] In a 46th embodiment, a subject of any of the 1-44th embodiments experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea on days 3 to 5 after step (1), where the symptoms are rated on a 4-point scale of none, mild, moderate, and severe, and the improvement is an improvement of at least one level from baseline to the rating on days 3 to 5 (e.g., from severe to moderate, moderate to none, or mild to none).

[0130] In a 47th embodiment, a subject of any of the 1-46th embodiments experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea, without worsening in any of the symptoms selected therefrom, and experiences improvement in at least one vital sign selected from body temperature, blood pressure, heart rate, and respiratory rate, 3 to 5 days after step (1).

[0131] Compound 1 was found to have a significant food effect in that food consumption significantly impacted the oral bioavailability of a 300 mg dose of orally administered Compound 1. See Example 3. PK studies in healthy volunteers showed that, compared to the fasted dose, bioavailability was reduced by 15%-17% for a non-dairy meal 4 hours prior to dosing, 40%-42% for a non-dairy meal 2 hours prior to dosing, and 59%-63% for a dairy meal 2 hours prior to dosing. Thus, the food effect was more evident when a high-fat meal was consumed close to dosing and when the meal included dairy. Based on this result, oral Compound 1 must be administered at least 6 hours after a meal to achieve maximum bioavailability of the oral dose designed to achieve therapeutic efficacy.

[0132] Thus, in a 48th embodiment, the subject of any one of the 1-47th embodiments fasts overnight and abstains from food or beverages other than water for at least 6 hours immediately prior to dosing in step (3), and the subject continues to fast after dosing in step (3), abstaining from food for 2 hours and abstaining from dairy products for 4 hours.

[0133] In a forty-ninth embodiment, the salt of any one of the first to forty-eight embodiments is a tosylate salt.

[0134] In a fiftieth embodiment, the method of any one of the first to forty-ninth embodiments has a clinical success rate of about 70% to 100%.

[0135] In a 51st embodiment, the clinical success rate of the 50th embodiment 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%.

[0136] In a fifty-second embodiment, the clinical success rate of the fifty-first embodiment is about 75-85% observed at about 72-120 hours after administration of the first intravenous dose.

[0137] In a fifty-third embodiment, the clinical success rate of the fifty-second embodiment is about 80-82%, or 80%, or 81%.

[0138] In a 54th embodiment, the clinical success rate of the 51st embodiment is observed about 5 to 10 days after the last dose of treatment (e.g., corresponding to the time of post-treatment evaluation in a clinically evaluable population or CE-PTE, or in an ITT population).

[0139] In a 55th embodiment, the clinical success rate of the 54th embodiment is about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% or 97%.

[0140] In a 56th embodiment, the subject of any one of the 1st to 55th embodiments has CABP classified as PORT risk class II.

[0141] In a 57th embodiment, the method of the 56th embodiment 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%.

[0142] In a fifty-eighth embodiment, the clinical success rate of the fifty-seventh embodiment is about 75-85% or about 90-100%, observed about 5-10 days after the last dose of treatment.

[0143] In a fifty-ninth embodiment, the clinical success rate of the fifty-eighth embodiment is about 82% or about 95%.

[0144] In a sixtieth embodiment, the subject of any one of the first to fifty-fifth embodiments has CABP classified as PORT risk class III.

[0145] In a 61st embodiment, the method of any one of the 1st to 60th embodiments has a clinical success rate of about 80 to 100%, about 85 to 95%, about 90 to 95%, about 90 to 91%, or about 93 to 94%.

[0146] In a sixty-second embodiment, the clinical success rate of the sixty-first embodiment is about 85-100%, observed about 5-10 days after the last dose of treatment.

[0147] In a sixty-third embodiment, the clinical success rate of the sixty-second embodiment is about 90-91% or about 93-94%.

[0148] In a 64th embodiment, the subject of any one of the 1st to 55th embodiments has CABP classified as PORT risk class IV.

[0149] In a 65th embodiment, the method of the 64th embodiment has a clinical success rate of about 70-100%, about 75-95%, about 80-95%, about 83-85%, or about 90-91%.

[0150] In a sixty-sixth embodiment, the clinical success rate of the sixty-fifth embodiment is about 80-95%, observed about 5-10 days after the last dose of treatment. In a sixty-seventh embodiment, the clinical success rate of the sixty-sixth embodiment is about 83-85% or about 90-91%.

[0151] In a 68th embodiment, the subject of any one of the 1st to 55th embodiments has CABP classified as PORT risk class III or IV.

[0152] In a 69th embodiment, the method of the 68th embodiment 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%.

[0153] In a seventieth embodiment, the clinical success rate of the sixty-ninth embodiment is about 85-95%, observed about 5-10 days after the last dose of treatment.

[0154] In a seventy-first embodiment, the clinical success rate of the seventieth embodiment is about 88-89% or about 92-93%.

[0155] In a seventy-second embodiment, gastrointestinal (GI) adverse events (AEs) associated with treatment of a subject in a method of any one of the first to seventy-first embodiments are mild.

[0156] In a seventy-third embodiment, a GI adverse event (AE) associated with treatment of a subject with the method of any one of the first to seventy-first embodiments does not result in discontinuation of therapy with the method.

[0157] In a 74th embodiment, treatment of a subject with a method of any one of the first to seventy-third embodiments (1) does not result in an increased risk of C. difficile (also known as C. difficile colitis and pseudomembranous colitis) infection in the subject, or (2) does not substantially disrupt the gut microbiome in the subject.

[0158] In a seventy-fifth embodiment, the subject of the seventy-fourth embodiment is at risk or predisposed to developing a C. difficile infection.

[0159] In a 76th embodiment, the subject of the 75th embodiment has recently been treated with one or more antibiotics (such as a broad-spectrum antibiotic), has undergone surgery of the digestive tract, has a disease of the colon (e.g., inflammatory bowel disease or colorectal cancer), has kidney disease, has a weakened immune system, is undergoing chemotherapy, has had a previous C. difficile infection, is 65 years of age or older, is taking a proton pump inhibitor, or lives in an environment that predisposes the subject to developing a C. difficile infection (e.g., in a hospital, nursing home, or assisted living facility).

[0160] In a seventy-seventh embodiment, in any of the foregoing methods, a GI adverse event (AE) associated with treatment of a subject does not result in discontinuation of therapy with the method, and treatment of the subject (1) does not result in an increased risk of C. difficile (e.g., C. difficile colitis and pseudomembranous colitis) infection in the subject, or (2) does not substantially disrupt the gut microbiome in the subject.

[0161] As used herein, the term "subject" may include animals (e.g., non-human mammals) that can suffer from bacterial infections. Examples of subjects include animals such as livestock (e.g., cows, pigs, horses, goats, rabbits, sheep, etc.), laboratory animals (e.g., mice, rats, etc.), pets (e.g., dogs, cats, ferrets, etc.), and primates (e.g., humans and non-human primates such as monkeys, gorillas, chimpanzees, etc.).

[0162] In any of the above embodiments, the subject may be a human, a non-human primate, or a non-human mammal.

[0163] The term "treating" or "treatment" refers to the amelioration, eradication, or reduction of one or more symptoms of the disorder being treated, e.g., a bacterial infection. In certain embodiments, the term disorder includes the eradication of the bacteria associated with the infection being treated.

[0164] The term "prophylaxis" means preventing or reducing the risk of bacterial infection.

[0165] The terms "resistant" or "resistant" refer to antibiotic / biological standards as defined by the Clinical and Laboratory Standards Institute (CLSI) and / or the Food and Drug Administration (FDA).

[0166] In certain embodiments, the infection may be resistant to other antibiotics, such as penicillin or tetracycline.

[0167] The term "effective amount" includes the amount of tetracycline compound (e.g., Compound 1) required to treat a bacterial infection (e.g., CABP). For example, an effective amount describes an effective level sufficient to achieve a desired therapeutic effect by killing bacteria and / or inhibiting bacterial growth. Preferably, a bacterial infection is treated when a pathogen (e.g., bacteria) is eradicated. A bacterial infection is also treated when at least one symptom of the infection is reduced, alleviated, or eliminated.

[0168] The term "evaluable clinical success" refers to clinical trial participants who (1) did not meet any criteria for evaluable clinical failure, or (2) did not receive a potentially effective non-study antibiotic for any other reason, and (3) the blinded assessor demonstrated that the infection resolved sufficiently in the cure assessment study such that antibiotics were not required.

[0169] The term "evaluable clinical failure" refers to a clinical trial participant who met any one of the following criteria: the blinded assessor indicated that the study drug was discontinued and that the infection responded inadequately such that an alternative antibiotic(s) was required; the blinded assessor discontinued the study drug due to an adverse event that was assessed as possibly or possibly drug related; the primary site of infection was surgically removed; or the subject was not evaluated after the last of intravenous or oral treatment.

[0170] The term "clinical success rate" refers to the number of evaluable clinical successes divided by the total population under trial.

[0171] The term "microbiologically evaluable clinical success rate" refers to those who met the definition of evaluable clinical success and had no infectious pathogens at baseline.

[0172] In one embodiment, the effective amount of a tetracycline compound, for example, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, when administered orally, is about 150 to about 600 mg, about 150 to about 450 mg, about 150 to about 300 mg, or about 300 mg.

[0173] In certain embodiments, each oral dose is administered as multiple 150 mg doses (e.g., 150 mg, 2 x 150 mg, 3 x 150 mg, or 4 x 150 mg). For example, a 300 mg oral dose may consist of two 150 mg tablets / pills / capsules / gels, etc.

[0174] In another embodiment, an effective amount of a tetracycline compound, for example, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, when administered intravenously (IV), is about 50 to about 200 mg, about 50 to about 150 mg, about 50 to about 100 mg, or about 100 mg or about 200 mg.

[0175] The compound can be administered as a salt (e.g., tosylate salt or hydrochloride salt) or as a free base, either in an IV formulation or in an oral formulation. Any salt or salt polymorph, such as the tosylate salt of Compound 1, as described in U.S. Pat. No. 8,383,610 (hereby incorporated by reference), can be used in the present invention. In addition, any formulation, such as the oral formulation in tablet form, as described in U.S. Pat. No. 9,314,475 (hereby incorporated by reference), can be used in the present invention.

[0176] Whenever values ​​and ranges are provided herein, for example, for subject ages, populations, dosages, and blood levels, it should be understood that all values ​​and ranges encompassed by these values ​​and ranges, including the recited upper and / or lower limits of the ranges, are intended to be encompassed within the scope of the invention. Moreover, all values ​​within these values ​​and ranges may also be the upper or lower limits of a range.

[0177] In another embodiment, the tetracycline compound (e.g., Compound 1) may be administered intravenously or orally once or twice per day. In certain embodiments, two doses per day have two equivalent doses.

[0178] In certain embodiments, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline has a microbiologically evaluable clinical success rate of greater than about 60%. In certain embodiments, compounds of the invention have a clinical success rate of greater than about 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 93.7%, 94%, 95%, 96%, 97%, 97.5%, 98%, 99% or more in an intent-to-treat (ITT) patient population or in a clinically evaluable (CE) patient population.

[0179] As used herein, the "intent to treat (or ITT)" population refers to all enrolled clinical trial subjects. In certain embodiments, the ITT population is further restricted to all enrolled clinical trial subjects who received at least one dose of study drug (e.g., Compound 1). The "clinically evaluable (or CE)" population refers to all ITT subjects who had a qualifiable infection as defined by the relevant clinical protocol, e.g., those with CABP. "Clinical success" refers to the continued improvement or complete resolution of baseline symptoms in the ITT or CE population as assessed by the clinical investigator at a period of time (e.g., 10-17 days) after the last dose of study drug.

[0180] In one example, the subject is treated intravenously, followed by an oral step-down. In certain embodiments, the subject is treated directly with an oral dose without a preceding IV dose.

[0181] In certain embodiments, the present invention provides a method of treating a subject for an infectious disease (e.g., CABP), comprising administering to the subject an effective amount of Compound 1 or a salt thereof, wherein the subject is first treated intravenously for about 1, 2, 3, 4, or 5 days, followed by about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days of oral treatment, thereby treating the subject. In certain embodiments, the first day of IV treatment consists of a higher loading dose (e.g., 2x dose or 2x100mg dose). In certain embodiments, each IV dose on the second day and thereafter is administered about 24 hours after the previous IV dose. In certain embodiments, the total treatment period is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In certain embodiments, one or both of the IV loading doses (e.g., the second IV loading dose) are replaced by a 300mg or 450mg oral dose.

[0182] In another embodiment, the invention provides a method of treating a subject for an infection (e.g., CABP), comprising administering to the subject an effective amount of Compound 1 or a salt thereof, wherein the subject is initially treated intravenously to have elevated Compound 1 blood levels, followed by oral treatment to reduce Compound 1 blood levels, thereby treating the subject. In certain embodiments, the initially elevated Compound 1 blood levels are achieved by a higher (e.g., 2x) loading dose, e.g., two IV loading doses of about 100 mg each.

[0183] Pharmaceutical Compositions of the Present Invention The present invention also utilizes or relates to pharmaceutical compositions comprising a therapeutically effective amount of a tetracycline compound (e.g., a 9-aminomethyltetracycline compound, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline) or a salt thereof and, optionally, a pharma- ceutically acceptable carrier.

[0184] In a further embodiment, the invention relates to a pharmaceutical composition comprising about 100 to about 700 mg (e.g., about 300, 450, or 600 mg) of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof and a pharma- ceutically acceptable carrier. In a further embodiment, the pharma- ceutically acceptable carrier is acceptable for oral administration. In another further embodiment, the tetracycline compound is a free base or a tosylate salt.

[0185] In yet another further embodiment, the composition is administered in an amount of about 110 to about 490 mg, about 120 to about 480 mg, about 130 to about 470 mg, about 140 to about 460 mg, about 150 to about 450 mg, about 160 to about 440 mg, about 170 mg to about 430 mg, about 180 mg to about 420 mg, about 190 mg to about 410 mg, about 200 mg to about 400 mg, about 210 mg to about 390 mg, or about 390 mg to about 470 mg. g, about 220 mg to about 380 mg, about 230 mg to about 370 mg, about 240 mg to about 360 mg, about 250 mg to about 350 mg, about 260 mg to about 340 mg, about 270 mg to about 330 mg, about 280 mg to about 320 mg, about 290 mg to about 310 mg, or about 300 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline. Optionally, the pharma- ceutically acceptable carrier is suitable for oral administration.

[0186] In another embodiment, the present invention also relates to a pharmaceutical composition comprising about 50 to about 250 mg (e.g., about 100 mg) of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof (e.g., the hydrochloride salt) and a pharma- ceutically acceptable carrier suitable for intravenous administration.

[0187] In yet another further embodiment, the composition comprises about 100 to about 300 mg, about 125 to about 275 mg, about 150 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg, or about 200 mg of IV or oral 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline.

[0188] The term "pharmaceutical acceptable carrier" includes substances that can be co-administered with the tetracycline compounds of the present invention, e.g., 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, that allow the tetracycline compound to perform its intended function, e.g., treat or prevent bacterial infection. Suitable pharmaceutical acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, flavor oils, fatty acid mono- and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations may be sterilized and, if necessary, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts influencing osmotic pressure, buffers, colorants, flavorings, and / or aromatic substances, that do not adversely react with the active compounds of the present invention.

[0189] The tetracycline compounds of the invention (eg, Compound 1) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharma- ceutically acceptable acid addition salts of the minocycline compounds of the invention that are basic in nature include those which form non-toxic acid addition salts, i.e., salts containing pharma- ceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and palmoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]. Although such salts must be pharma- ceutically acceptable for administration to a subject, e.g., a mammal, in practice it is often desirable to first isolate the minocycline compounds of the present invention from the reaction mixture as pharma- ceutically unacceptable salts, then simply convert the latter to free base compounds by treatment with alkaline reagents, and then convert the latter free bases to pharma- ceutically acceptable acid addition salts. Acid addition salts of the base compounds of the present invention are easily prepared by treating the base compounds with a substantially equivalent amount of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is easily obtained. The tetracycline compounds of the present invention are preferably administered orally as tosylate (e.g., p-toluenesulfonate) salts or as free bases, or intravenously as hydrochloride salts.

[0190] The tetracycline compounds of the present invention (e.g., Compound 1) and its pharma- ceutically acceptable salts can be administered by either oral, parenteral or topical routes. In general, these compounds are most desirably administered in effective doses, depending on the weight and condition of the subject being treated and the particular route of administration selected. Variations may occur depending on the species of subject being treated and its individual response to the drug, as well as the type of pharmaceutical formulation selected and the duration and interval over which such administration is performed.

[0191] The pharmaceutical compositions of the present invention can be administered alone or in combination with other known compositions for treating tetracycline-responsive states in subjects, e.g., mammals. Mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), laboratory animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas). The term "in combination with" a known composition is intended to include simultaneous administration of a composition of the present invention and a known composition, administration of a first composition of the present invention followed by a known composition, and administration of a first known composition followed by a composition of the present invention. Any therapeutic composition known to those skilled in the art for treating tetracycline-responsive states can be used in the methods of the present invention.

[0192] The compounds of the present invention can be administered by any of the previously mentioned routes, either alone or in combination with a pharma- ceutical acceptable carrier or diluent, and administration may be performed in single or multiple doses. For example, the novel therapeutic agents of the present invention can be advantageously administered in a variety of different dosage forms, i.e., they may be combined with various pharma- ceutical acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Furthermore, oral pharmaceutical compositions may be suitably sweetened and / or flavored. In general, the therapeutically effective tetracycline compounds of the present invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

[0193] For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine may be used together with various disintegrating agents such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicic acids, together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be used as fillers in gelatin capsules, and preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0194] For oral administration, when aqueous suspensions and / or elixirs are desired, the active ingredient may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof, as well as various sweetening or flavoring agents, coloring substances or dyes, and, if so desired, emulsifying and / or suspending agents.

[0195] For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of a therapeutic compound of the invention in sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.

[0196] These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For parenteral application, examples of suitable preparations include solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories. The therapeutic compound can be formulated in sterile form in multiple or single dose formats, such as dispersed in a fluid carrier, such as sterile saline or 5% saline dextrose solution, commonly used with injections.

[0197] For enteral application, tablets, dragees or capsules with talc and / or carbohydrate carrier binders or the like are particularly suitable, the carrier being preferably lactose and / or corn starch and / or potato starch. Syrups, elixirs, etc., in which sweetened vehicles are used, can also be used. Sustained-release compositions can be formulated, including those in which the active ingredient is protected with differently degradable coatings, such as by microencapsulation, multiple coatings, etc.

[0198] In addition to treating human subjects, the therapeutic methods of the invention also have important veterinary applications, for example, for the treatment of livestock such as cattle, sheep, goats, cows, pigs, poultry such as chickens, ducks, geese, turkeys, etc., horses, and pets such as dogs and cats. The compounds of the invention can also be used to treat non-animal subjects, such as plants. EXAMPLES

[0199] Exemplification of the Invention [Example 1] An open-label, parallel-group, multiple IV-dose study to assess lung steady-state concentrations of compound 1 and tigecycline in healthy adult subjects To be effective in lower respiratory tract infections (RTIs), antibiotics must reach adequate concentrations in respiratory tissues to affect respiratory pathogens. Both extracellular and intracellular pathogens can cause infections, so the extracellular and intracellular concentrations of antibiotics must be adequate to cover all pathogens. The concentration of antibiotics in the bronchial mucosa provides a reliable indicator of the bronchial penetration of drugs and may be a better predictor of clinical efficacy than serum levels for the treatment of bronchitis and bronchopneumonia.

[0200] Airway epithelial lining fluid (ELF) and alveolar cells (AC), which mainly contain alveolar macrophages (AM), have been proposed as important infection sites for common extracellular and intracellular pathogens, respectively. Direct measurement of antimicrobial concentrations in ELF allows a more informed approach to appropriate dosing of drugs for RTIs, as well as to evaluate drug pharmacokinetics (PK) and exposure-response targets for respiratory tract infections. Bronchoalveolar lavage (BAL) to collect airway fluid and tissue has become the standard method to ascertain both extracellular and intracellular antibiotic concentrations after systemic antibiotic administration. Extracellular concentrations are calculated from fluid reflecting ELF, and intracellular concentrations are measured in AC, including macrophages.

[0201] This study was designed to determine the pulmonary PK of Compound 1 in healthy subjects, and currently there is no information regarding the concentration of Compound 1 in the pulmonary compartment in humans.

[0202] Compound 1 has been found to have in vitro activity against the most common typical and atypical causes of community-acquired bacterial pneumonia (CABP) and is being developed for the treatment of CABP. It is highly active in vitro against most Gram-positive pathogens. It also shows activity against atypical pathogens (e.g., Legionella spp., Chlamydophila spp.) as well as some anaerobic and Gram-negative pathogens. The drug is active against strains expressing both mechanisms of tetracycline resistance as well as strains that are resistant to currently available antibiotics including methicillin, vancomycin, erythromycin and ciprofloxacin. The in vitro activity of Compound 1 was not affected by serum or pulmonary surfactant, an important feature consistent with its potential utility in infections involving the lower respiratory tract. Additionally, it has been found to be effective in mouse models of lower respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae. In mice, compound 1 concentrations in lung tissue exceed plasma concentrations by 3.7-4.4-fold. In vitro results on intracellular bacteria and tissue culture experiments indicate that compound 1 concentrates within mammalian cells.

[0203] Tigecycline has a similar PK profile to Compound 1, and with its documented concentration levels in human ELF, the inclusion of tigecycline is intended to provide assay sensitivity in the study.

[0204] Compound 1 has been developed for both iv and oral administration and has been well characterized in 16 Phase 1 clinical trials involving 536 subjects exposed to Compound 1. Additionally, Compound 1 was evaluated in a Phase 2 trial of 219 subjects with complicated skin and skin structure infections (cSSSI) and a sponsor-completed Phase 3 trial that enrolled 143 subjects with cSSSI. Compound 1 was well tolerated and demonstrated efficacy similar to an established comparator (linezolid).

[0205] The objective of the study was to determine the concentration of Compound 1 in the lung compartment (in the ELF and AC of the lung, including the AM) and to define the time course of lung distribution in comparison with the plasma pharmacokinetic (PK) profile. Compound 1 was administered intravenously to healthy subjects for 4 days (5 doses) to steady-state systemic concentrations. Subjects were grouped to have BAL at set times after the last dose of drug. Concurrent blood samples were taken to compare tissues with serum antibiotic concentrations.

[0206] The data obtained in this trial, i.e., in vitro activity against common common and atypical pathogens and 24-h sustained ELF and AC (mainly AM) concentrations, suggest that compound 1 has the potential to be a useful antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

[0207] Tigecycline has a similar PK profile to Compound 1, and with its ability to achieve concentrations at the ELF, the inclusion of tigecycline provided assay sensitivity in the study.

[0208] Therefore, the primary objective of this study was to determine the concentrations of Compound 1 in the ELF and AC (mainly AM) and to define the time course of pulmonary distribution with concomitant plasma PK sampling of Compound 1 in healthy adult subjects.

[0209] A secondary objective was to evaluate the PK of Compound 1 in the lung and plasma compartments in healthy adult subjects.

[0210] The exploratory objective was to determine the PK of Compound 1 in the lung and plasma compartments compared to tigecycline PK in the lung and plasma compartments in healthy adult subjects.

[0211] This study was designed as a single-center, multiple-dose, open-label study to determine the concentrations of Compound 1 and tigecycline in the lung compartments (ELF and AC) in healthy adult subjects following administration of Compound 1 and tigecycline to steady-state levels of dosing. Enrollment of approximately 62 subjects was planned to ensure that approximately 42 subjects would receive Compound 1 and have bronchoalveolar lavage (BAL) performed, and approximately 20 subjects would receive tigecycline and have BAL performed. Additional subjects were to be enrolled to replace subjects who discontinued or were screen-ineligible.

[0212] Approximately 42 subjects received five doses of Compound 1 100 mg intravenously (30 min infusion at t=0, 12, 24, 48 and 72 hours) and Compound 1 subjects were equally assigned to one of seven BAL sampling time points (approximately 6 subjects per BAL time point group) for collection of ELF and AC samples.

[0213] At study completion, 42 enrolled subjects received Compound 1 (69% male, median age 36 years, median BMI 27 kg / m 2 Six subjects had BAL at each of the seven time points. One subject had a BAL sampling error and was not included in the BAL analysis.

[0214] Compound 1 concentrations in the ELF and AC were measured in only one observation for each subject, and data from all subjects were pooled for PK analysis of mean lung concentrations. Compound 1 concentrations in BAL fluid were normalized by dilution factors to urea levels detected in plasma and BAL.

[0215] One standard bronchoscopy was performed for each subject. Within one BAL time point group, all subjects were evaluated at the same time point, either 0.5, 1, 2, 4, 8, 12, and 24 hours after the last dose administration on day 4. Blood samples were taken at the time of bronchoscopy for plasma urea measurement. In addition, blood samples were taken for plasma PK evaluation for all subjects on day 4 at 0, 0.5 (end of infusion), 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after the dose.

[0216] Blood samples were collected and BAL was performed in Compound 1-treated subjects according to the following schedule:

[0217] [Table 1]

[0218] For patients receiving Compound 1, mean (±SD) plasma pharmacokinetic parameters after the fifth Compound 1 dose included a maximum concentration of 2.26±0.76 μg / mL, a volume of distribution of 165±58 L, a clearance of 8.03±1.43 L / hr, and an elimination half-life of 14.7±4.2 hr. Mean (±SD) Compound 1 concentrations (μg / mL) at the time of bronchoscopy and BAL were:

[0219] [Table 2]

[0220] AUC of mean and median ELF 0-24 The penetration ratios based on the values ​​and plasma concentrations were 1.47 and 1.42, whereas the AC (alveolar cells, mainly AM) to plasma concentration ratios were 25.8 and 24.8.

[0221] Approximately 20 subjects received one dose of 100 mg tigecycline intravenously (30 min infusion at t=0) followed by six doses of 50 mg tigecycline intravenously (30 min infusion at t=12, 24, 36, 48, 60 and 72 hours). Tigecycline subjects were equally assigned to one of four BAL sampling time points (approximately 5 subjects per BAL time point group) for collection of ELF and AC samples. Tigecycline concentrations in ELF and AC were measured at only one observation for each subject, and data from all subjects were pooled for PK analysis of mean lung concentrations. Tigecycline concentrations in BAL fluid were normalized by dilution factors to urea levels detected in plasma and BAL.

[0222] Blood samples were collected and BAL was performed in tigecycline-treated subjects according to the following schedule:

[0223] [Table 3]

[0224] Safety assessments included physical examination, electrocardiogram (ECG), vital signs, standard clinical laboratory evaluations (blood chemistry, hematology), pregnancy testing, and adverse event (AE) and serious adverse event (SAE) monitoring.

[0225] Treatment-emergent adverse events (TEAEs) were reported in 29% of subjects. The most common TEAE was headache (12%). There were no severe or serious TEAEs and no discontinuations due to TEAEs in Compound 1-treated subjects. There were no clinically significant changes in vital signs, laboratory, or ECG parameters.

[0226] The treatment period was designed to ensure that both treatment groups were at steady state by the time of BAL.

[0227] During bronchoscopy, four aliquots of sterile saline solution, each 50 mL, were instilled into the right lobe of the lung, immediately aspirated, and placed on ice. The first bronchoalveolar lavage aliquot instillation (BALX) fraction was prepared and analyzed separately from subsequent instillations. Aspirates from the second through fourth instillations were pooled once to represent the BAL fraction. An aliquot of BAL was removed and used to determine cell counts and differential cellular composition, including lung macrophages. The remaining supernatant was centrifuged, and the supernatant and cell pellet were immediately frozen until analysis. An aliquot of BAL supernatant was frozen separately for urea assay. The amount of test material detected in the cell pellet was normalized by the corresponding fraction of macrophages. The fraction BALX was analyzed in a similar manner, except that the cell pellet was not evaluated or assayed. A blood sample for urea concentration was obtained at the time of the second instillation (± 3 min). Concentrations of test substances detected in BALX and BAL fluids were normalized by dilution factors relative to urea levels detected in the BALX and BAL fractions, respectively.

[0228] Subjects participated in the study for approximately 34 days. After screening, eligible subjects were randomly assigned to Compound 1 or tigecycline treatment and assigned to a BAL lavage sample time point. Subjects had a baseline assessment on day -1 and then underwent 4 days of test article treatment followed by a BAL at their assigned time point. The study completion visit was conducted the day after the last test article dose. The final follow-up assessment was conducted 7-14 days after the subject's last dose of test article, which could be completed by telephone contact or other interactive techniques unless testing was required to evaluate an AE or abnormality noted at the study completion visit.

[0229] Safety assessments included physical examination, electrocardiogram (ECG), vital signs, standard clinical laboratory evaluations (blood chemistry, hematology), pregnancy testing, and AE and SAE monitoring.

[0230] Dosage regimen: The currently intended therapeutic dose of Compound 1 for the treatment of CABP is 100 mg iv every 12 hours (q12h) followed by every 24 hours (q24h) for two doses, with the option to switch to 300 mg orally q24h.

[0231] The approved therapeutic dose of tigecycline (TYGACIL®) for the treatment of CABP is 100 mg iv for one dose, followed by 50 mg iv q12h.

[0232] Patient Inclusion / Exclusion Criteria Enrolled patients were male or female subjects aged between 18 and 55 years, in good health (no clinically significant abnormalities in the investigator's opinion) as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests. Vital signs (oral temperature, systolic and diastolic blood pressure (BP), and pulse rate) were assessed in the sitting position after the subject had rested for at least 3 minutes. Sitting vital signs should be within the following ranges: oral temperature, 35.0°C to 37.5°C (95.0°F to 99.5°F), systolic BP, 90 to 140 mm Hg, diastolic BP, 50 to 90 mm Hg, pulse rate, 40 to 90 bpm; blood pressure and pulse were assessed again after 3 minutes in the upright position at the screening visit. There was a ≤20 mm Hg fall in systolic or 10 mm Hg fall in diastolic BP, and an increased heart rate (>20 bpm) associated with clinical signs of postural hypotension. Vital signs that are out of range may be repeated once, if necessary, at the investigator's discretion.

[0233] Subjects must weigh at least 50 kg and be > 18.0 to < 30.0 kg / m 2 Women had a body mass index (BMI) within the range of 0.01 to 0.05. Women had negative serum pregnancy tests at screening and baseline visits and agreed to use an acceptable form of birth control from screening through the last follow-up assessment. Men agreed to use an acceptable method of birth control with their female partner(s) and did not donate sperm from screening through the last follow-up assessment.

[0234] Patients were excluded from the trial if one or more of the following were present: Use of other investigational drugs within 5 half-lives or 30 days prior to screening, whichever is longer. ·Have a history of hypersensitivity or allergic reaction (e.g., anaphylaxis, hives, or other serious reaction) to any tetracycline (e.g., minocycline, doxycycline, or tigecycline). -Have a clinically significant ECG abnormality or a history of any of the following ECG abnormalities at the Screening or Baseline visit: PR>220 msec, QRS complex>120 msec, Long QT Syndrome, QTcF>450 msec (male) and QTcF>470 msec (female). Pregnant or breastfeeding women. History of treated or untreated malignancy of any organ system (other than localized basal cell carcinoma of the skin) within the past 5 years, with or without evidence of local recurrence or metastasis. Use of tobacco products in the 3 months prior to screening. · Positive urine cotinine test at screening or baseline. Use of any prescription drugs or herbal supplements within 4 weeks prior to the baseline visit and / or over-the-counter (OTC) medications, including nutritional and fitness / bodybuilding supplements (including vitamins), within 2 weeks prior to the baseline visit. Transfusion or loss of 400 mL or more of blood or plasma within 8 weeks prior to the baseline visit, or longer if required by local regulations. Hemoglobin level <12.5g / dL for men and <11.5g / dL for women at the screening / baseline visit. -Major illness within 2 weeks prior to the baseline visit. History of autonomic dysfunction (e.g., recurrent episodes of syncope, palpitations, etc.) within 3 years prior to screening. History of acute or chronic bronchospastic disease (including treated or untreated asthma and chronic obstructive pulmonary disease (COPD)) within 3 years prior to screening. Any surgical or medical condition which, in the opinion of the Investigator, may significantly alter the absorption, distribution, metabolism or excretion of the drug or which may jeopardize the subject if participating in the study. History of active inflammatory bowel disease, ulcers, GI or rectal bleeding or pancreatitis. Liver disease or injury as indicated by abnormal LFTs such as aspartate aminotransferase (AST), ALT, gamma-glutamyl transpeptidase (GGT), CK, alkaline phosphatase (ALP) or serum bilirubin. The investigator must be guided by the following criteria: serum bilirubin does not exceed 1.2 times the upper limit of normal (ULN); any other single parameter listed above does not exceed 1.5 times the ULN; any elevation of 2 or more parameters will exclude the subject from participation in the study. The test may be repeated once more as soon as possible to exclude a test error. To qualify a subject, the recheck results must not meet the above criteria. ·History or presence of impaired renal function as indicated by clinically significant abnormal creatinine or blood urea nitrogen (BUN) and / or urea values ​​or abnormal urinary constituents (e.g., proteinuria). ·Evidence of urinary obstruction or difficulty voiding at the time of screening. · Known to be positive for the Human Immunodeficiency Virus (HIV). -Known chronic hepatitis B or C infection. · A positive alcohol test or positive drug screen at the screening or baseline visit. Previously treated with Compound 1 or previously enrolled in this study. Any concomitant condition that, in the opinion of the investigator, is likely to interfere with the determination of an AE or the completion of study procedures.

[0235] procedure There were three protocol-defined phases: Screening, Treatment, and Follow-up. The study had the following protocol-defined evaluations: Screening visit Baseline visit Visits on days 1, 2 and 3 (test substance administration); Visit on day 4 (test substance administration and BAL) Day 5 Completion Visit Last follow-up assessment: 11–18 days after the last dose of test substance

[0236] Subjects who discontinued study treatment underwent early study completion procedures and final follow-up assessments prior to clinic discharge.

[0237] A screen was used to establish subject eligibility and baseline characteristics for each subject. The following information was collected: outline of inclusion / exclusion criteria, relevant medical / surgical history and current medical conditions (predisposing factors that may affect pulmonary function (e.g., previous pulmonary infection, mild-moderate COPD, asthma, smoking history, chronic cough, etc.)), demographics, physical exam, urine alcohol screen, drug screen, cotinine test, vital signs, 12-lead ECG, laboratory tests (hematology, chemistry, coagulation, pregnancy test (females only)) and AEs since initiation of ICF concomitant medications (past 4 weeks).

[0238] The treatment period was 5 days. Subjects who met the inclusion criteria and did not meet the exclusion criteria received the first dose of test article. The following assessments were performed: vital signs, AEs, concomitant medications, and test article administration and accountability.

[0239] During the intravenous treatment phase (test article), infusions of Compound 1 were administered continuously over approximately 30 minutes (at least 30 minutes and no more than 45 minutes) according to the schedule in Tables 1-3 below. Infusions of tigecycline were administered continuously over approximately 30 minutes (at least 30 minutes and no more than 45 minutes) according to the schedule in Tables 1-4. All infusion start and stop times and compliance (delivery of ≧90% of dose) were recorded on source documents and eCRFs.

[0240] [Table 4]

[0241] During the follow-up phase, subjects were evaluated at two visits after completion of treatment: at the study completion visit on day 5 and at the final follow-up evaluation on study days 11 to 18 (7 to 14 days after the subject's last dose of test article). The final follow-up evaluation was conducted by telephone contact, unless testing was required to evaluate an AE or abnormality noted at study completion.

[0242] For IV injection, Compound 1 was supplied as 100 mg (and 4% overfill) sterile lyophilized powder for reconstitution packaged in clear glass vials with rubber stoppers and aluminum overseals. Excipients included tosylate acid counterion, sucrose, hydrochloric acid, and sodium hydroxide to adjust pH. Each vial was reconstituted to a clear solution by adding 5 mL of sterile water for injection. The vial was gently swirled to ensure complete dissolution before use. Excessive shaking was avoided to prevent foaming. The reconstituted vial was used immediately to prepare the infusion. The infusion was prepared by removing 5 mL of reconstituted solution from the vial and injecting at a slow rate into 100 mL of normal saline (NS) for injection (0.9% sodium chloride) infusion bag. The prepared infusion was used within 8 hours and stored at 2°C to 8°C (35.6°F to 46.4°F) for a maximum of 24 hours. The 100 mL infusion was administered continuously over a period of 30 minutes (at least 30 minutes and not more than 45 minutes) at room temperature.

[0243] Reconstituted Compound 1 was infused as 100 mg iv q12h for the first 2 doses, followed by 100 mg iv q24h for doses 2-3 (starting 24 hours after the first dose). Total treatment consisted of 5 doses and a 5 day duration.

[0244] The comparator test substance tigecycline was infused as a first dose of 100 mg iv, followed by 50 mg iv q12h for 6 doses. Total treatment consisted of 7 doses and a 5 day duration.

[0245] safety Any subject who received at least one dose of test article was included in the evaluation of safety, which was assessed by the following measures: physical examination, AEs and SAEs, vital signs, laboratory evaluations (blood samples for hematology, chemistry, and coagulation (prothrombin time only)), ECG, and pregnancy evaluation.

[0246] 4. Data Analysis All analyses of the data in this study were in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-E9) and sponsor guidance documents and standards. Statistical analyses were performed using statistical analysis software (SAS).

[0247] a) Analysis population Study populations were defined for the various PK and safety analyses and were as follows: The PK population consisted of all subjects who received the test substance and had at least one evaluable PK parameter. The safety population consisted of all subjects who received at least one dose of test substance.

[0248] b) Subject demographics and baseline characteristics Descriptive statistics were provided by treatment group for the following: subject disposition (study substance completed, study substance discontinued due to discontinuation, trial completed, study discontinued due to discontinuation), protocol deviations, medical history, and ongoing medical conditions.

[0249] Baseline demographic and medical variables were analyzed using the two-tailed Fisher exact test (for categorical variables) or the two-tailed Wilcoxon rank-sum test (for ordinal and continuous variables).

[0250] c) Safety outcome measures Safety variables included the incidence of AEs, changes in vital signs, ECG parameters and clinical laboratory results obtained during the course of the study. Subjects were analyzed according to the treatment actually received.

[0251] d) Penalty kick The PK data analysis included all completed subjects with evaluable plasma PK parameter data. The following Compound 1 and tigecycline plasma PK parameters were determined: Area under the curve (AUC) from 0 to 24 hours after administration of compound 1 (AUC 0-24 ) and the AUC of tigecycline from 0 to 12 hours after administration (AUC 0-12 ), ·Maximum plasma concentration (C max ), ·Maximum plasma concentration (T max ) and The terminal elimination half-life (T 1 / 2 ).

[0252] All biofluid concentrations were expressed in ng / mL. All concentrations below the limit of quantification (BLQ) or missing data were so indicated in the concentration data listing. Concentration BLQs were treated as zero in summary statistics for concentration data only. They were not considered for the calculation of PK parameters (with the exception of pre-dose samples). PK parameters were determined using non-compartmental method(s) using WinNonlin Pro.

[0253] The primary objective of this study was to evaluate the concentrations of Compound 1 in the lung ELF and AC (mainly AM). The concentrations of Compound 1 and tigecycline in the lung ELF and AC were correlated with the area under the curve (concentration / time) in epithelial lung fluid (AUC ELF ) / area under the curve in plasma (concentration / time) (AUC plasma ) and area under the curve (concentration / time) in alveolar cells (AUC AC ) / AUC plasma These were calculated based on the above plasma PK parameter calculations (AUC 0-24 and AUC 0-12 ). Tigecycline concentration information served as internal validation for assay sensitivity purposes.

[0254] AUC of Compound 1 and Tigecycline ELF The concentration data were used to investigate the parameters by deriving the corresponding BAL concentrations. Lung ELF (C ELF ) is the concentration of compound 1 or tigecycline in ELF =C BAL *(V BAL / V ELF )(wherein, C BAL is the concentration in the BAL fluid, and V BAL is the volume of BAL fluid aspirated, and V ELF is the lung ELF volume).

[0255] The volume of lung ELF in the BAL fluid was determined as (urea BAL / urea plasma )(in the formula, urea BAL and ureaplasma represented the concentrations of urea in BAL fluid and plasma, respectively).

[0256] Compound 1 and tigecycline concentration data from ELF, AC, and AM are listed. AUC ELF and AUC AC was determined from pooled lung concentration data and summarized by treatment group. For the Compound 1 cohort, there were at least six ELF and AC concentrations for each of the seven time points over the 24-hour dosing interval. For the tigecycline cohort, there were five ELF and AC concentrations for each of the four time points over the 12-hour dosing interval.

[0257] AUC ELF / AUC plasma and AUC AC / AUC plasma Calculated concentrations of Compound 1 and tigecycline in lung ELF and AC as a percentage of total lung volume were summarized by treatment group. BALX was evaluated separately in the same manner. The impact of "BALX" on PK understanding of Compound 1 and tigecycline was evaluated.

[0258] PK samples of compound 1 or tigecycline concentration The permitted windows for PK sample collection were as follows:

[0259] [Table 5]

[0260] For PK blood collection and processing, all blood samples were collected by either direct venipuncture or an indwelling cannula inserted into a forearm vein (in the arm contralateral to the infusion site) at the time specified in the study flow chart. PK blood samples collected at the scheduled time of bronchoscopy were obtained at the time of the second BAL instillation (± 3 min) from the arm contralateral to the infusion site.

[0261] Blood samples were collected into labeled 4 mL tubes containing sodium heparin. Immediately after sample collection, the tubes were gently inverted 5-8 times to thoroughly mix the anticoagulant and then placed upright in a cryoblock or ice-surrounded test tube rack until centrifugation. Samples were centrifuged at 1500 × g (gravity) at approximately 4°C for 10 minutes within 30 minutes of collection. The resulting plasma was divided into two equal aliquots, placed into individual cryovials, and immediately frozen at or below -70°C within 1 hour of collection. Tubes were kept frozen at or below -70°C until transport to the biochemistry analysis laboratory.

[0262] One standard bronchoscopy was performed in each subject after the last administration of test article at the time specified in the study flow chart for BAL and AC sample collection and handling. Subjects were continuously monitored during bronchoscopy. Blood pressure, heart rate, and respiratory rate were recorded immediately (within 30 minutes), 30 minutes, and 60 minutes after the scheduled bronchoscopy procedure. Topical lidocaine, 4% solution for the oropharynx and 2% solution for the nasopharynx, was applied to the upper airways to prepare the subject for bronchoscopy. When necessary, 1% lidocaine solution was used in the lower airways. A fiberoptic bronchoscope was inserted into the middle lobe of the right lung. Four 50 mL aliquots of sterile 0.9% saline solution were instilled into the right lobe, immediately aspirated, and placed on ice. The first 50 mL instilled (fraction BALX) was collected (2 aliquots of 4 mL), immediately placed on ice, and the volume recorded, stored, prepared, and analyzed separately from subsequent instillations. Aspirates from the second through fourth instillations were immediately collected, placed on ice, and the volume recorded. The combined aspirates (second through fourth) once pooled represented the BAL fraction.

[0263] An aliquot of BAL was removed and used to determine cell number and differential cell composition. Pulmonary macrophage fractions were determined during cell count and differentiation. Aliquots of BALX and BAL supernatant were reserved for urea assay. The remaining supernatant was immediately centrifuged at 400×g for 5 minutes in a refrigerated centrifuge. The supernatant and cell pellets, fractionated into 5 mL aliquots, were immediately frozen at -70° C. or below until analysis. Fractionated BALX was analyzed in a similar manner, except that the cell pellet was not evaluated or assayed.

[0264] Blood samples for urea concentration for urea assay in BAL fluid and plasma were obtained at the time of the second BAL instillation (± 3 min). Urea blood samples were collected either by direct venipuncture or by an indwelling cannula inserted into a forearm vein (in the arm contralateral to the infusion site). Plasma was prepared from the urea blood samples in the same manner as the plasma samples for PK analysis.

[0265] Plasma, BAL and BALX supernatant samples were analyzed for urea concentration by a bioanalytical laboratory.

[0266] After all PK samples from a single subject were collected and frozen at or below -70°C, the primary samples from each time point were batched with corresponding primary samples from other subjects, carefully packaged, and shipped frozen at or below -70°C to a biochemistry analytical laboratory designated by the sponsor. Samples were shipped with sufficient dry ice to remain frozen during the overnight transport. The remaining stored aliquots for each subject and time point were kept at or below -70°C in a facility required by the sponsor.

[0267] The bioanalytical laboratory assayed samples for Compound 1 or tigecycline using a specific, sensitive, and validated liquid chromatography / tandem mass spectrometry (LC / MS / MS) method approved by the sponsor.

[0268] To determine ELF volume and the concentration of Compound 1 or tigecycline in the ELF, urea measured in BALX and BAL supernatants and in plasma was used to calculate the volume of the ELF using a conventional urea dilution method. The volume of the ELF was calculated using the following equation: V ELF =V BAL *(urea BAL / urea plasma )(wherein, V ELF = volume of ELF in the BAL sample, V BAL = volume of BAL fluid aspirated, urea BAL = concentration of urea in BAL supernatant and urea plasma = concentration of urea in plasma) was investigated.

[0269] The concentration of compound 1 or tigecycline in the ELF (C ELF )teeth, C ELF =C BAL *(V BAL / V ELF )(wherein, C ELF = concentration of compound 1 or tigecycline in ELF, C BAL = measured concentration of Compound 1 or tigecycline in the BAL supernatant, V ELF = volume of ELF in the BAL sample and V BAL = volume of BAL fluid aspirated) It was calculated as:

[0270] To determine the AC volume and concentration of Compound 1 or tigecycline in the AC and AM, the volume of AC collected in the BAL cell pellet suspension was determined from the BAL fluid cell count. The volume of cells was calculated by multiplying the number of cells in the ELF by the known volume of AC. The volume of cells was calculated by multiplying the number of cells by 2.42 μL / 10 6 The total number of cells was determined by multiplying the average macrophage cell volume by the average macrophage cell volume of individual cells.

[0271] The measured concentrations of Compound 1 or tigecycline in AC (C AC ) is expressed by the following equation: C AC =(C pellet suspension / V AC )(wherein, C pellet suspension is the concentration of compound 1 or tigecycline in 1 mL of cell suspension, and V AC is the volume of AC in 1 mL of cell suspension) was investigated.

[0272] The measured concentrations of Compound 1 or tigecycline in the AM (C AM ) was calculated by adjusting for the percentage of macrophages and monocytes in the AC as determined by differential cell counts of BAL fluid. AC derived from.

[0273] Figure 1 shows the results of the mean Compound 1 concentration vs. time profile in AC, plasma and ELF. It is clear that the mean Compound 1 concentration in AC (mainly AM) is at least an order of magnitude higher (about 25-fold) than in plasma, while the mean Compound 1 concentration in ELF is at least about 40% higher than in plasma. See Table.

[0274] [Table 6]

[0275] [Table 7]

[0276] This data provides important information regarding the time course and magnitude of extracellular and intracellular concentrations of Compound 1 in the lung. Intravenous administration of 100 mg of Compound 1 as a 30-minute infusion resulted in higher concentrations in the airway epithelial lining fluid (ELF) and alveolar cells (AC including AM) than the concurrent plasma concentrations through 24 hours after five doses. The in vitro activity against common conventional and atypical pathogens and the sustained ELF and AC / AM concentrations over 24 hours suggest that Compound 1 may be a useful antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

[0277] Safety Monitoring An AE is any adverse, unwanted or unscheduled event in the form of a sign, symptom, disease, or laboratory or physiological finding that occurs in a person given a test substance or in a clinical trial. The event does not have to be causally related to the test substance or the clinical trial. AEs include, but are not limited to, the following: any clinically significant worsening of a pre-existing condition, AEs resulting from an overdose of the test substance, whether accidental or intentional (an overdose is a dose higher than that specified in the protocol), AEs resulting from abuse of the test substance (e.g., use for non-clinical reasons), and AEs associated with the discontinuation of the use of the test substance.

[0278] An SAE is an AE that results in death, is life-threatening, requires hospitalization or an extension of an existing hospitalization, results in persistent or substantial disability or incapacity, results in a congenital abnormality or birth defect, or, in addition, a significant medical event that may not result in death, is not life-threatening, or does not require hospitalization may also be considered an SAE if, based on appropriate medical judgment, it may put the subject at risk and require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood dyscrasia, or convulsions that do not result in hospitalization, or the occurrence of drug dependence or abuse.

[0279] If there was any doubt as to whether the information constituted an SAE, the information was treated as an SAE.

[0280] A protocol-related AE is an AE that occurs during a clinical trial that is not related to the test substance but is considered by the investigator or medical monitor (or designee) to be related to the study conditions, i.e., to the fact that the subject is participating in the trial. For example, a protocol-related AE may be an untoward event associated with a medical procedure required by the protocol.

[0281] [Example 2] Effect of food on the bioavailability of omadacycline in healthy volunteers. Compound 1 (9-[(2,2-dimethyl-propylamino)-methyl]-minocycline) is a first-in-class aminomethylcycline antibiotic characterized by improved in vitro antibacterial activity (Honeyman et al., Antimicrob Agents Chemother. 59:7044-7053, 2015).

[0282] A Phase 3 clinical trial has been completed with Compound 1 as oral and intravenous (IV) monotherapy in patients with acute bacterial skin and skin structure infections (ABSSSI). During the development process, the oral Compound 1 formulation evolved from the free base in a capsule to a series of tablet and salt formulations to optimize oral bioavailability while improving tolerability. The current Phase 3 tablet formulation is the tosylate salt of Compound 1, which was found to have an absolute bioavailability of 34.5% when administered under fasting conditions. The primary objective of this trial was to evaluate the relative bioavailability of a single oral 300 mg dose of Compound 1 (administered as a Phase 3 tablet formulation) at various times after consumption of food in healthy adult subjects.

[0283] The results of this trial demonstrated that food consumption had an effect on the oral bioavailability of a single 300 mg compound dose.

[0284] Briefly, this was a Phase 1 randomized, open-label, four-period crossover trial. Prior to dosing on Day 1 of Phase 1, subjects were randomized to one of four treatment sequences (see Table 2-1). On Day 1 of each period, subjects received a single oral dose of 300 mg of Compound 1 (2 x 150 mg tablets) at various times after consumption of food. There was a washout period of at least 5 days between each dosing period. The final study completion visit occurred 6-10 days after the last dose of Compound 1.

[0285] [Table 8]

[0286] The high-fat (approximately 50% of the total caloric content of the diet) and high-calorie (approximately 800-1000 calories) meals provided approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively, following Food and Drug Administration guidance recommendations (FDA Guidance, 2002). These meals were to be consumed within 20 minutes. Dose administration for Treatments B, C, and D was based on the completion time of the meal. During all four treatment periods, subjects did not consume food or beverages other than water for at least 3 hours after dosing, and did not consume dairy products, antacids, or multivitamins for 4 hours after dosing.

[0287] A total of 32 subjects were enrolled and dosed in at least one treatment period. Overall mean age was 32.3 years, ranging from 21 to 50 years, and 47% were male (Table 2-2). One subject discontinued the study due to a positive alcohol screen at baseline in Period 3 and did not receive Treatments A and D. One subject required a drug holiday and did not receive Treatments B and C. PK data were available for 31 subjects for each treatment condition.

[0288] [Table 9]

[0289] Blood samples for pharmacokinetic (PK) evaluation of Compound 1 were collected before dosing (before administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing in each period. PK parameters were the area under the plasma concentration-time curve (AUC) from time 0 to 24 hours after dosing (AUC 0-24 ), the AUC from time 0 to the last quantifiable concentration (AUC0-t), and the AUC at time 0 extrapolated to infinity (AUC 0-inf ), maximum (peak) observed plasma concentration (C max ), C max Time to reach (T max), terminal elimination half-life (T 1 / 2 ), and the terminal phase rate constant (λz).

[0290] Safety and tolerability were assessed by adverse events (AEs), vital sign measurements at multiple time points within 24 hours post-dose in each treatment period, and clinical laboratory tests 24 hours post-dose in each treatment period.

[0291] For statistical analysis, the individual PK parameters of Compound 1 were summarized using descriptive statistics. AUC and C max The geometric mean of the mean mean PK parameters was determined. PK parameters were evaluated using noncompartmental analysis using Phoenix® WinNonlin® (Pharsight Corp, St. Louis, Missouri), version 6.2.1. Confidence intervals (CIs) for test treatments (fed state: Treatments B, C, and D) compared with the reference treatment (fasted state: Treatment A) are given by AUC 0-24 , AUC 0-t , AUC 0-inf and C max The 90% CI of the geometric mean test-to-reference ratio (B / A, C / A, or D / A) was constructed for AUC 0-24 , AUC 0-t , AUC 0-inf and C max It was concluded that there was no effect of food when it was contained within the reference interval of 80% to 125%. max A Wilcoxon signed rank test was performed. p ≤ 0.05 was considered statistically significant.

[0292] To estimate the effect of fed compared with fasted state and 90% confidence intervals (CI), linear mixed-effects models with treatment condition, sequence, and period as fixed effects and subject nested within sequence as a random effect were fitted to natural log-transformed PK parameters.

[0293] [Table 10]

[0294] The PK analysis was performed on the fasted AUC 0-inf , AUC 0-t and AUC 0-24 were 10.2, 7.2 and 7.2 mcg*h / mL, respectively, and C max showed that the mean T 1 / 2 ranged from 13.5 to 13.8 hours, with a median T max The mean mean time to presentation ranged from 2.5 to 2.9 hours. No treatment-related adverse events or clinically relevant changes in laboratory values ​​or vital signs occurred. See Table 2-3.

[0295] A significant reduction in systemic exposure to omadacycline was observed for all three treatments (Treatments B, C, and D) versus Treatment A (Figure 1 and Tables 2-4).

[0296] [Table 11]

[0297] The food effect was more pronounced when a high-fat meal was consumed closer to dosing and when the meal contained dairy components. max The AUC and AUC were reduced by 15% to 17% with a non-dairy meal 4 hours prior to dosing, by 40% to 42% with a non-dairy meal 2 hours prior to dosing, and by 59% to 63% with a dairy meal 2 hours prior to dosing. Inter-subject variability in systemic exposure to omadacycline was measured using the C max For CV and AUC, they were similar for Treatments A, B, and C (CV 22.4-29.2%). In contrast, for Treatment D, the CVs for these parameters were 42.6-44.4%.

[0298] Regarding safety and tolerability, two subjects experienced treatment-emergent AEs (one reported nausea and one reported somnolence), both events were of mild intensity and considered unrelated to the study drug. No subjects discontinued the study due to AEs and no subjects experienced serious AEs (SAEs). For Treatment A (i.e., the group with the greatest omadacycline exposure), a small increase from baseline in heart rate (median 8-10 bpm at 4-6 hours post-dose) was observed. In all other treatment groups, the median change from baseline in heart rate was ≦3 bpm at all measured time points. No significant changes in blood pressure were observed. There were no clinically significant changes in laboratory tests.

[0299] Results showed that a single oral dose of Compound 1 was well tolerated. Administration of the 300 mg dose within 2-4 hours of food reduced bioavailability compared to the fasted state. Therefore, preferably, once-daily oral Compound 1 should be administered at least 6 hours after a meal.

[0300] [Example 3] A Phase 3, Randomized, Double-Blind, Multicenter Study to Compare the Safety and Efficacy of Compound 1 IV / PO Versus Moxifloxacin IV / PO for Treating Adult Subjects with Community-Acquired Bacterial Pneumonia (CABP) This trial will evaluate the safety and efficacy of intravenous (iv) and oral (po) Compound 1 compared with iv and po moxifloxacin in the treatment of adults with CABP.

[0301] More specifically, the primary objective of this study is to demonstrate that Compound 1 100 mg iv every 12 hours (q12h) for two doses, followed by 100 mg iv / 300 mg po once every 24 hours (q24h), is non-inferior to moxifloxacin 400 mg iv / po q24h in the treatment of adults with CABP. Secondary objectives are to evaluate the safety of Compound 1 in the treatment of adult subjects with CABP in the safety population, to evaluate the clinical response according to the causative pathogen identified, and to evaluate the pharmacokinetics (PK) of Compound 1 in adult subjects with CABP.

[0302] According to the study design, a randomized (1:1), active-controlled, double-blind, phase 3 study was conducted to compare Compound 1 and moxifloxacin in the treatment of adults with CABP (Pneumonia Outcomes Research Team [PORT] risk class II, III, or IV). The PORT risk class calculation was adapted from Fine et al., N. Engl. J. Med. 336:243-250, 1997 (incorporated by reference). Approximately 750 patients were enrolled. Both the iv and po phases of the study were double-blind. Enrollment of subjects with disease characterized by PORT risk class II was limited to no more than 15% of randomized subjects. Enrollment of subjects who received a single dose of tolerated short-acting antibiotics within 72 hours prior to the first dose of test substance was limited to no more than 25% of randomized subjects. Enrolled subjects participated in the study for approximately 30 days.

[0303] The trial consisted of three phases: screening, double-blind treatment, and follow-up. Screening evaluations were completed within 24 hours prior to randomization, except for blood culture sample collection and radiographic confirmation of pneumonia, which were completed within 24 hours prior to the first dose of test article. After screening, eligible subjects who met the inclusion criteria and did not meet the exclusion criteria were randomly assigned to treatment groups to receive 7-14 days of treatment with either Compound 1 or moxifloxacin. Randomized subjects received their first dose of test article within 4 hours of randomization.

[0304] The comparator drug for this trial is selected to be moxifloxacin (400 mg iv q24h with an option to transition to 400 mg po q24h) given the wide acceptability of fluoroquinolone monotherapy as a safe first-line option for treating subjects with CABP. Moxifloxacin offers broad activity against respiratory pathogens that are causative agents of CABP, including typical (e.g., Streptococcus pneumoniae) and atypical (e.g., Legionella, Chlamydophila, and Mycoplasma species) pathogens, with a similar spectrum of activity to that of Compound 1. Similar to Compound 1, moxifloxacin has both iv and po formulation options, administered once daily.

[0305] A post-therapy assessment visit occurred approximately 5-10 days after the last dose of test article, and a follow-up telephone contact occurred approximately 30-37 days after the first dose of test article. Details of the trial are further described below.

[0306] As used herein, the terms "post-therapy evaluation", "post-treatment assessment" and "PTE" are used interchangeably herein throughout this application without distinction of meaning.

[0307] Dosage regimen: Compound 1 will be administered as 100 mg iv q12h for 2 doses followed by 100 mg iv q24h (starting 24 hours after the first dose) with the option to switch to 300 mg po q24h after a minimum of 3 days (4 doses) of iv treatment.

[0308] Comparator moxifloxacin was administered as 400 mg iv q24h (with a single placebo injection 12 hours after the first dose on Day 1 to match the Compound 1 dosing schedule) with the option to switch to 400 mg po q24h after a minimum of 3 days (4 doses) of iv treatment.

[0309] Patient Inclusion / Exclusion Criteria Patients were male or female, aged 18 years or older. Patients met all of the following criteria: had at least three of the following symptoms: cough, purulent sputum production, dyspnea (shortness of breath), and pleuritic chest pain; abnormal vital signs: fever or hypothermia documented by the investigator (temperature >38.0°C [100.4°F] or <36.0°C [95.5°F]), hypotension with a systolic blood pressure (SBP) <90 mm Hg, heart rate >90 beats per minute (bpm), and respiratory rate (RR) >20 breaths / min; at least one clinical sign or laboratory finding associated with CABP: hypoxemia (partial pressure of arterial oxygen [PaO2] <60 mm Hg by arterial blood gas [ABG]) Hg or oxygen saturation <90% by pulse oximetry, physical exam evidence of pulmonary consolidation (e.g., dullness to percussion, bronchial breath sounds, or goatee voice), and elevated total white blood cell (WBC) count (>12,000 cells / mm 3 ) or leukopenia (WBC < 4,000 cells / mm 3 had radiographically confirmed pneumonia, i.e., new or progressing pulmonary infiltrates on chest x-ray (CXR) or chest computed tomography (CT) scan consistent with acute bacterial pneumonia within 24 or 48 hours prior to the first dose of test article; and had disease classified as being in PORT risk class II, III, or IV at screening and predicted to require a minimum of at least 3 days of iv therapy for the initial treatment of CABP.

[0310] Female patients had a negative urine pregnancy test at screening and agreed to use an acceptable method of birth control as per local requirements from screening to post-therapy evaluation (PTE). Men agreed to use an acceptable method of birth control with their female partner(s) and did not donate sperm from screening to PTE.

[0311] Patients with any of the following conditions were not allowed in the study: had received one or more doses of potentially effective systemic antibiotic therapy within 72 hours prior to the first dose of the test substance (subjects were considered to have received potentially effective systemic antibiotic therapy if the pathogen identified causing the infection was found to be susceptible to the given antibiotic; in situations where no pathogen was identified, the antibiotic was approved for the treatment of pneumonia or found to have activity against any of the primary causes of CABP (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Legionella pneumophila). One exception is that subjects may be eligible regardless of previous antibiotic therapy if they were treated with a single dose of a short-acting antibiotic (i.e., an antibiotic whose standard dosing schedule is more frequent than once daily); Subjects were known or suspected to have CABP caused by Acinetobacter jiroveci, obligate anaerobes, mycobacteria, or fungal pathogens; had suspected or confirmed empyema (parapneumonic pleural effusion was not an exclusion criterion) or lung abscess; subjects were known or suspected to have hospital-acquired pneumonia (HAP) or healthcare-associated pneumonia (HCAP).HAP was defined as pneumonia with onset of clinical signs and symptoms ≥48 hours after admission to an acute in-hospital care facility, and HCAP was defined as pneumonia acquired in a long-term care or subacute / intermediate care facility (e.g., nursing home) or in a subject hospitalized with pneumonia after a recent hospitalization (discharged within 90 days of current hospitalization and previously hospitalized ≥48 hours); known or clinically suspected to have ≥1 of the following prior to randomization: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2× upper limit of normal (ULN), total bilirubin >1.5×ULN, or evidence of end-stage liver disease (e.g., ascites, hepatic encephalopathy); unstable cardiac disease (e.g., pulmonary edema ... had a known medical history of chronic obstructive pulmonary disease (COPD, unstable angina, myocardial infarction, acute congestive heart failure, unstable cardiac arrhythmias, etc.); had a QT interval corrected for heart rate using the Friedreich formula (QTcF) >450 msec (males) or >470 msec (females), were known to have long QT syndrome, used medications with potential arrhythmogenic or QT prolonging effects, and / or exhibited tachyarrhythmias; required any form of dialysis (e.g., hemodialysis, peritoneal dialysis); had a history or evidence of severe renal disease or a calculated creatinine clearance (CrCl) <30 mL / min using the Cockcroft-Gault formula; evidence of significant immunologic disease as determined by any of the following: <500 neutrophils / mm. 3 Current or predicted neutropenia, defined as known human immunodeficiency virus (HIV) infection and unknown or <200 cells / mm within the past year. 3OR had evidence of septic shock as defined by all of the following: investigator-documented fever or hypothermia (temperature >38.0°C [100.4°F] or <36.0°C [95.5°F]), heart rate >90 beats / min, RR >20 respirations / min, WBC >12,000 cells / mm 3 or <4,000 cells / mm 3 or >10% immature (band) morphology regardless of total peripheral WBC count, hypotension with SBP <90 mm Hg despite iv fluid loading of 20-30 cc / kg over 30 minutes and perfusion abnormalities which may include, but are not limited to, lactic acidosis (blood lactate concentration ≥ 4 mmol / L), oliguria, or acute changes in mental status; known or suspected primary or metastatic neoplastic pulmonary disease, aspiration pneumonia, active tuberculosis, cystic fibrosis, bronchiectasis, bronchial obstruction (e.g., post-obstructive pneumonia), chronic neurological disorders impeding clearance of pulmonary secretions, or severe chronic obstructive pulmonary disease (COPD); pregnant or lactating (breast-feeding) women; had a history of hypersensitivity or allergic reactions (e.g., anaphylaxis, urticaria, other serious reactions) to any tetracycline (e.g., minocycline, doxycycline, or tigecycline) or to any fluoroquinolone antibiotic; had a history of pseudotumor cerebri or prior (within 2 weeks prior to screening) or planned concomitant use of isotretinoin; had a history of systemic lupus erythematosus or a lupus-like syndrome; had current evidence of pancreatitis; had a history of a central nervous system disorder that may predispose to epileptic seizures or lower the seizure threshold; use of other investigational drugs within 5 half-lives or 30 days prior to screening, whichever is longer; previously treated with Compound 1 or previously enrolled in this study; any planned medical intervention that may interfere with the ability to comply with the study requirements; and had a life expectancy of 3 months or less or any concomitant condition that, in the opinion of the investigator, may interfere with the evaluation of response to the investigational infection, the determination of adverse events (AEs), or the completion of the expected course of treatment.

[0312] Furthermore, no systemic prior or concurrent antimicrobial therapy was permitted, other than a single dose of a short-acting antimicrobial within 72 hours prior to the first administration of test substance. All other medications not prohibited by the protocol and deemed necessary for the subject's welfare may be administered and / or continued under the supervision of the investigator.

[0313] Dosage regimen The double-blind treatment period was of a maximum duration of 14 days. Subjects who met the inclusion criteria and did not meet the exclusion criteria were randomly assigned to treatment groups and received the first dose of test article within 4 hours after randomization.

[0314] The following assessments were performed: vital signs, physical examination (worsening observations since the screening test was recorded as an AE), AEs and SAEs, concomitant medications, CABP symptom severity scale, microbiological assessment, 12-lead ECG (performed immediately [within 30 minutes] and 30-90 minutes after the start of the first infusion of the 1st and 3rd doses of test article at the Day 7 visit, at the EOT visit, and as otherwise clinically indicated), blood for central laboratory evaluation: hematology, chemistry, pregnancy (for females only), test article dosing and accountability, assessment for need to switch po or continue therapy, and investigator assessment of clinical response.

[0315] Subjects were randomized (1:1) to one of two treatment arms: a. Investigational Therapy: Compound 1 (supplied with tosylate counterion, sucrose, hydrochloric acid, and sodium hydroxide to adjust pH), 100 mg iv q12h (first 2 doses), followed by 100 mg iv q24h (starting 24 hours after the first dose), with the option to switch to 300 mg (two 150 mg Compound 1 tablets and one overencapsulated placebo tablet matching moxifloxacin) po q24h after at least 3 days (4 doses) of iv treatment. b. Reference therapy: Moxifloxacin, 400 mg iv q24h (with a single placebo infusion matching the Compound 1 dosing regimen 12 hours after the first dose on day 1), with the option to switch to 400 mg (one 400 mg moxifloxacin oversealed tablet and two placebo tablets matching the Compound 1 tablet) po q24h after at least 3 days (4 doses) of IV treatment.

[0316] The iv treatment phase (minimum 3 days, 4 doses) followed a double-dummy design with placebo infusions matched to active Compound 1 and moxifloxacin infusions as shown in Table 3-1 below. Compound 1 and matched placebo infusions were administered continuously over approximately 30 minutes. As shown in the table, during the first 24 hours of iv treatment, subjects in the moxifloxacin treatment group received a placebo infusion to correspond to the t=12 hour infusion in the Compound 1 group.

[0317] Moxifloxacin and matched placebo infusions were administered continuously over approximately 60 minutes. All infusion start and stop times were recorded.

[0318] [Table 12]

[0319] Representative (non-limiting) examples of the above treatment regimens for Compound 1 are provided below:

[0320] [Table 13]

[0321] The total duration of treatment (IV + oral (if present)) is usually 7-14 days. While subjects were receiving iv therapy, the investigator assessed the subjects daily and selected one of the following based on the subject's overall clinical assessment: (1) iv continue with the test substance; (2) Switch to po test article (after a minimum of 3 days [4 doses] of iv therapy). Note that the first po dose is administered in the morning, 12-24 hours after the last iv dose; thus, the first po dose can be administered as early as t = 60 hours. (3) Discontinuing the test substance - this decision prompted an EOT assessment. Each day's decisions were recorded.

[0322] At all times during the study, decisions to continue iv, switch to po, or discontinue test substance were made based on the investigator's clinical judgment. Investigators may have used culture and susceptibility results from the local microbiology laboratory to help guide treatment, but the decision to continue or discontinue test substance was based on clinical response rather than susceptibility results (as Compound 1 susceptibility testing was not available at the local site). If CABP was caused by an organism not susceptible to moxifloxacin in vitro, the decision to continue or discontinue study treatment was based on the subject's clinical course and the investigator's clinical judgment. The rationale for this decision was recorded.

[0323] The decision to switch to po treatment was made by the investigator. To be considered clinically stable and meet the criteria for transition to a po regimen, subjects must have the following findings noted and recorded: a.Temperature≦37.8℃(100°F) b. Heart rate ≤ 100 beats / min c.RR≦24 respirations / min d. SBP ≥ 95mm Hg e. Oxygen saturation ≥ 90% as measured by pulse oximetry or PaO2 ≥ 60mm Hg by ABG f. No worsening of CABP symptoms (cough, sputum production, pleuritic chest pain, dyspnea) compared to screening g. Normal mental status ('absence of confusion' or pre-illness baseline for subjects who did not have normal mental status before the onset of pneumonia) Ability to maintain h.po intake.

[0324] Switching to po was not permitted until subjects had completed at least the first 3 days of iv treatment (after 4 iv doses).

[0325] The date and time when the investigator confirmed that the subject's eligibility criteria for po treatment was met and the decision to switch to po treatment was recorded. For subjects who were switched to po test substance and discharged from the hospital before Study Day 6, visits were conducted on Study Days 4 and 5, with the Study Day 6 visit being optional.

[0326] The treatment schedule for po dosing is shown in Table 3-2. When switching from iv to po test substance, the recommended interval between doses was maintained. The first po dose for both Compound 1 and moxifloxacin treatment groups was given in the morning, 12-24 hours after the last iv dose. The po treatment phase also used a double-blind, double-dummy design, using placebo and active moxifloxacin tablets of a size and shape corresponding to, and overfilled with, the active Compound 1 tablets, and corresponding Compound 1 placebo control tablets.

[0327] The tablets had excipients including lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, crospovidone, colloidal silicon dioxide, sodium bisulfite, polyvinyl alcohol, titanium dioxide, talc, soy lecithin, xanthan gum, FD&C Yellow No. 6, and FD&C No. 2. Compound 1 tablets were taken with water in a fasted state (no food, antacids, or multivitamins containing polyvalent cations (e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc) or beverages other than water for at least 6 hours). After dosing, no food was consumed for 2 hours, and no dairy products, antacids, or multivitamins containing polyvalent cations (e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc) were consumed for 4 hours.

[0328] [Table 14]

[0329] While subjects were receiving po therapy, the investigator evaluated the subjects on study days 7, 10, and 14 and selected one of the following actions: a. PO Continue with test substance; b. Test substance was discontinued - this decision prompted an EOT assessment.

[0330] Investigators may have used culture and susceptibility results from the local microbiology laboratory to help guide treatment, but the decision to continue or discontinue study material was based on clinical response rather than susceptibility results (because Compound 1 susceptibility testing was not available at the local site). If CABP was caused by an organism that was not susceptible to moxifloxacin in vitro, the decision to continue or discontinue study treatment was based on the subject's clinical course and the investigator's clinical judgment.

[0331] Dose adjustments and discontinuations of test substance were not permitted.

[0332] Subjects were evaluated at two visits after completion of treatment, PTE 5-10 days after the last treatment day, and the final follow-up evaluation 30-37 days after the first dose of treatment.

[0333] The table below summarizes the study drug exposure in the safety population.

[0334] [Table 15] TIFF2025041746000017.tif239166TIFF2025041746000018.tif148166

[0335] Criteria for switching from IV to oral treatment included: temperature ≦37.8° C. (100° F.); heart rate ≦100 beats / min; respiratory rate <=24 breaths / min; systolic blood pressure ≧95 mmHg; oxygen saturation ≧90% by pulse oximetry or PaO2 ≧60 mmHg by ABG; no worsening of CABP symptoms on screening; normal mental status; and ability to maintain PO intake. For patients receiving Compound 1, 100% of the 295 patients who were switched from an IV dose to an oral dose met each of the above criteria.

[0336] Safety assessment Any subject who received the test substance was included in the safety evaluation. Safety evaluations of enrolled subjects included physical examination, vital signs (blood pressure, pulse rate, temperature), AEs and SAEs, laboratory evaluations (hematology, serum chemistry, urinalysis), 12-lead electrocardiogram (ECG) evaluations, and pregnancy evaluations.

[0337] Physical examinations were performed after screening, on study days, and at the EOT and PTE visits. Any new clinically significant findings occurring after the screening examination (i.e., not noticed at screening) were captured as an AE.

[0338] Prior to each dose while subjects were undergoing iv treatment, vital signs were recorded including temperature, BP, pulse / heart rate and RR.

[0339] Blood samples for hematology, chemistry and coagulation (prothrombin time only) were taken at screening, days 4, 7, 10, EOT and PTE.

[0340] The safety trial included standard 12-lead ECGs at the following times: screening, immediately prior to (within 30 minutes) the start of the first infusion of the first dose of test article (t=0 hours), 30-90 minutes after the start of the first infusion of the first dose of test article, immediately prior to (within 30 minutes) the start of the first infusion of the third dose of test article (t=24 hours), 30-90 minutes after the start of the first infusion of the third dose of test article, at the Day 7 visit, at the EOT visit, any time the subject experienced an AE of non-pleuritic cardiac chest pain, palpitations, tachyarrhythmia, or as otherwise clinically indicated.

[0341] The safety study also included pregnancy and fertility assessments. All women had a urine pregnancy test performed at the screening visit. None were enrolled if a positive urine pregnancy test result was obtained. Serum samples for β-hCG testing were also collected at the screening visit and sent to a central laboratory for confirmation of the urine pregnancy result. Serum samples for central laboratory β-hCG testing were also collected at EOT and PTE. If a positive β-hCG result was reported by the central laboratory after the woman was enrolled, test article administration was discontinued.

[0342] The safety trial also included two sets of blood cultures drawn within 24 hours before the first dose of test article. Each set of blood cultures was drawn by direct venipuncture from separate body sites 15-30 minutes apart. If bacteria were isolated from the baseline blood culture, a repeat blood culture was drawn on the same day that the positive blood culture was detected. If subsequent blood cultures were also positive, blood cultures were repeated, as necessary, until negative blood cultures were obtained.

[0343] Efficacy evaluation To meet the requirements of different health authorities, the primary variables were tested with two response endpoints: Early clinical response or successful ECR (72-120 hours after the first dose) was determined programmatically and defined as improvement in at least two of the four target symptoms (cough, sputum production, pleuritic chest pain, dyspnea) as assessed by the investigator and survival without worsening in any of these four symptoms (FDA primary efficacy point). One such assessment was performed in the ITT population.

[0344] · Successful investigator-assessed clinical response at the PTE visit, defined as survival after completion of the test substance regimen with resolution of signs and symptoms of infection to the extent that no further antimicrobial therapy is required (EMA primary efficacy point). One such assessment was performed in both the ITT and CE populations restricted to PORT risk class III / IV subjects. Furthermore, the 97.5% CI was used for the 10% non-inferiority assessment in addition to the 95% CI level.

[0345] Early clinical response endpoints were examined in the intention to treat (ITT) analysis population. Investigator assessment of clinical response at PTE endpoints was examined in the ITT and clinically evaluable (CE) populations (co-primary endpoints).

[0346] Secondary efficacy variables included: Early Clinical Response Response Category Investigator assessment of clinical response at EOT and PTE, clinical response category Clinical response categories according to identified causative pathogen Below is a list of the key evaluations that were carried out: Investigator assessment of signs and symptoms of CABP Microbiological evaluation of infectious diseases Clinical response assessment Each of the key assessments is described in further detail below.

[0347] a) Assessment of CABP symptom severity Investigator-observed assessments of CABP symptoms were performed at every scheduled assessment, except the final follow-up assessment. Investigators specifically assessed subject symptom severity levels of cough, sputum production, pleuritic chest pain, and dyspnea on a 4-point scale (none, mild, moderate, or severe) based on the Investigator-Assessed Community-Acquired Bacterial Pneumonia Subject Symptom Severity Guidance Framework (see below) and entered symptom severity scores into the eCRF. For subjects who were switched to po test article and discharged from the hospital before Study Day 6, visits were conducted on Study Days 4 and 5, and the Study Day 6 visit was optional.

[0348] [Table 16]

[0349] b) Microbiological evaluation Microbiological evaluation included respiratory culture and Gram stain, urinalysis for Legionella pneumophila and Streptococcus pneumoniae antigen screening, and serology for Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae titers.

[0350] For respiratory culture and Gram stain, an attempt was made to obtain from all subjects at the screening visit expectorated or induced sputum or other respiratory specimens reflecting fluid from the lower respiratory tract of adequate quality (e.g., respiratory fluid obtained by bronchoalveolar lavage or bronchoscopy; pleural fluid obtained by thoracentesis; or expectorated or induced sputum meeting appropriateness criteria) and submit them to the on-site microbiology laboratory for Gram stain and culture. The date, time, and type of specimen submitted were recorded. A sputum specimen of adequate quality was defined as having the following two findings as reported by the on-site laboratory: 1. <10 squamous cells / low power field (lpf) (i.e., 100×) 2. >25 polymorphonuclear cells / lpf (i.e., 100×)

[0351] Sputum specimens of adequate quality and other screening respiratory specimens for culture were obtained prior to the first dose of test article. At the EOT and / or PTE visits, respiratory specimen cultures and Gram stains were obtained only for subjects with clinical failure and requiring alternative antimicrobial treatment for CABP.

[0352] Laboratory reports for Gram stains included semiquantitative descriptions of the number of polymorphonuclear leukocytes per low-power field (i.e., 100×) and descriptions of bacteria seen. For Gram stains of respiratory specimens, semiquantitative descriptions of the number of squamous epithelial cells per low-power field (i.e., 100×) were included.

[0353] Culture results included identification of all pathogens to the genus and species level. Moxifloxacin (or other fluoroquinolones) susceptibility testing was performed using standard methods.

[0354] All isolates identified from expectorated or induced sputum specimens that met the two criteria defining the specimens as being of adequate quality and / or isolated from respiratory specimens or blood and being possible pathogens were submitted to a central laboratory for genus and species verification and for standardized minimum inhibitory concentration (MIC) testing performed for compound 1, moxifloxacin, and a panel of currently approved antibiotics.

[0355] For urine testing for Legionella pneumophila and Streptococcus pneumoniae antigen screening, urine was collected at the screening visit to test for the presence of Legionella pneumophila and Streptococcus pneumoniae antigens.

[0356] Regarding serology testing for Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae titers, blood samples were collected to perform serology for Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae by a central laboratory at the screening visit and at the PTE visit.

[0357] c) Clinical outcome assessment Assessment of clinical outcomes occurring at Early Clinical Response Assessment (by program), EOT, and PTE, as described below.

[0358] 1. Evaluation of Investigational Infectious Diseases in Early Clinical Response Assessment Formal determination of response to therapy at the Early Clinical Response Assessment (72-120 hours after administration of the first dose of test article) was made programmatically using the investigator's assessment of subject symptoms associated with CABP, entered into the eCRF. The investigator was not involved in classifying subjects as clinical success, failure, or indeterminate at the Early Clinical Response Assessment. Subject CABP symptom severity of cough, sputum production, pleuritic chest pain, and dyspnea was rated on a 4-point scale (none, mild, moderate, or severe) based on the Investigator-Rated Community-Acquired Bacterial Pneumonia Subject Symptom Severity Guidance Framework. CABP subject symptom severity assessments were completed at every scheduled assessment, except the final follow-up assessment. For subjects who were switched to po test article and discharged from the hospital before Study Day 6, visits were conducted on Study Days 4 and 5, and the Study Day 6 visit was optional.

[0359] Clinical success: was defined as survival with at least one level of improvement (i.e., from severe to moderate, from moderate to mild, from mild to none) compared to screening in two CABP symptoms (cough, sputum production, pleuritic chest pain, and dyspnea) at the early clinical response assessment, without at least one level of worsening in any other included CABP symptom. To be considered a clinical success, a subject does not have to meet any criteria for clinical failure or indeterminate early clinical response.

[0360] Clinical failure: defined as meeting any of the following criteria: There was no improvement of at least one level compared to screening in the two CABP symptoms (i.e., from severe to moderate, from moderate to mild, or from mild to none). Any of the four CABP symptoms worsened (by at least 1 level) compared to screening. The subject required alternative (rescue) antibiotic treatment for CABP prior to the Early Clinical Response Assessment, which was associated with either (a) the progression or occurrence of new symptoms attributable to CABP or (b) the occurrence of an infectious complication of CABP (e.g., empyema, lung abscess). The subject was receiving antibiotic therapy for an infection different from the one under study that may have been effective for the infection under study.

[0361] - Study therapy was interrupted due to an AE and an alternative antibiotic treatment for CABP was received before the Early Clinical Response Assessment. Death before early clinical response assessment.

[0362] Undetermined: The clinical response to the test substance cannot be adequately inferred due to: Subject was not seen for evaluation because they withdrew consent, were lost to follow-up, or for other reasons (specify). - Any other specific reason.

[0363] 2. Clinical evaluation of investigational infections at EOT EOT assessments were conducted on the calendar day of the last dose of any test article or within 2 days thereafter. If a subject prematurely discontinued or terminated participation in the study prior to completion of planned antibiotic therapy, an EOT visit was conducted.

[0364] Investigators examined whether subjects met criteria for one of the following clinical outcomes: Clinical success: the subject is alive and the infection has resolved sufficiently such that no further antimicrobial therapy was required. These subjects may have some residual symptoms associated with the infection (i.e., cough) that require adjunctive (i.e., non-antibiotic) treatment (e.g., expectorants). To be considered a clinical success at EOT, the subject does not have to meet any criteria for clinical failure or indeterminate at EOT.

[0365] Clinical failure: The subject required alternative antibiotic treatment for CABP prior to EOT, either associated with (a) progression or occurrence of new symptoms of CABP or (b) occurrence of an infectious complication of CABP (e.g., empyema, lung abscess), or (c) the subject experienced an AE that required discontinuation of study therapy. Other reasons for clinical failure include: The subject was receiving antibiotic therapy for an infection different from the one under study that may have been effective for the infection under study. Death before EOT visit. Undetermined: The clinical response to the test substance could not be adequately inferred due to: Subject was not seen for EOT assessment due to withdrawing consent, being lost to follow-up, or other reasons (specify). - Any other specific reason.

[0366] 3. Clinical evaluation of investigational infections in PTE PTE assessments were performed 5-10 days after the subject's last day of therapy. Investigators determined whether subjects met criteria for one of the following clinical outcomes: Clinical success: Freedom from any systemic antimicrobial therapy other than the test substance, survival after completion of the test substance regimen, resolution of signs and symptoms of infection present at screening without new symptoms or complications attributable to CABP and no need for further antimicrobial therapy. Clinical Failure: The subject required alternative antibiotic treatment for CABP prior to PTE in association with either (a) the progression or occurrence of new symptoms of CABP or (b) the occurrence of an infectious complication of CABP (e.g., empyema, lung abscess).

[0367] The subject has received an antibiotic for an infection different from the one under study that may be effective against the infection under study. Death before PTE.

[0368] Undetermined: The clinical response to the test substance could not be adequately inferred due to: Subject was not seen for PTE assessment due to withdrawing consent, being lost to follow-up, or other (specify). - Any other specific reason.

[0369] d) Pharmacokinetic plasma samples for Compound 1 concentration PK data were analyzed using a population PK model. PK samples were collected using a sparse sampling method for the population PK model. The number of samples and collection schedules were different for individual subjects. A maximum of four samples were collected per subject during study days 1-7. Blood was collected by fresh venipuncture or by cannulation using SOLEY for that purpose (PK samples were not drawn by the same iv access used for administration of the test article). All doses of test article and the date and time of PK sample collection were recorded. For doses of test article administered intravenously, the start and stop times of each infusion were recorded. Sample tubes were centrifuged at 1500 x g for 10 minutes, the separated plasma was transferred to two equal aliquots in pre-labeled tubes, and the tubes were frozen at -70°C within 60 minutes of collection. The time the samples were frozen was recorded to the nearest minute. All PK samples were collected from a single subject, frozen at -70°C, and shipped frozen at -70°C to a central laboratory. Samples were assayed in the analytical laboratory for compound 1 using a specific, sensitive, and validated liquid chromatography / tandem mass spectrometry (LC / MS / MS) method.

[0370] e) Safety Monitoring - Adverse Events An AE was defined as any untoward, undesirable or unscheduled event in the form of a sign, symptom, illness, or laboratory or physiological finding that occurred in a person given the test substance or in a clinical trial. The event did not have to be causally related to the test substance or the clinical trial. AEs included, but were not limited to, the following: Any clinically significant worsening of a pre-existing condition. -AEs resulting from an overdose of the test substance, whether accidental or intentional. An overdose is a dose greater than that specified in the protocol. AEs resulting from abuse of the test substance (e.g., use for non-clinical reasons). -AEs associated with discontinuation of test substance use.

[0371] SAE is Caused death It was life-threatening (see below) -had to be hospitalized or have had an existing hospitalization prolonged (see below) · resulting in persistent or substantial impairment or incapacity (see below) -Brought cancer -Causing congenital anomalies or birth defects It's AE. Additionally, a significant medical event that may not result in death, be life-threatening, or require hospitalization may also be considered an SAE if, based on sound medical judgment, it may place the subject at risk and require medical or surgical intervention to prevent one of the outcomes enumerated in this definition. Examples of such events included allergic bronchospasm requiring intensive care in the emergency room or at home, blood dyscrasia, or convulsions that do not result in hospitalization, or the occurrence of drug dependence or abuse.

[0372] A protocol-related AE was defined as an AE that occurred during a clinical trial that was not related to the test substance but was considered by the investigator or medical monitor (or designee) to be related to the study conditions, i.e., related to the fact that the subject was participating in the trial. For example, a protocol-related AE could be an untoward event associated with a medical procedure required by the protocol.

[0373] Certain information would not be considered an SAE, but must be recorded, reported, and followed up as indicated for an SAE. This included pregnancy exposure to the test substance, lactation exposure to the test substance with or without an AE, overdose of the test substance as specified in this protocol with or without an AE, and inadvertent or accidental exposure to the test substance with or without an AE.

[0374] 4. Data Analysis All analyses of the data in this study were in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-E9) and sponsor guidance documents and standards. Statistical analyses were performed using statistical analysis software (SAS).

[0375] a) Analysis population Several study populations were defined for the various efficacy and safety analyses, as follows: The ITT population consisted of all randomized subjects. The microbiological intention-to-treat (microITT) population consisted of subjects in the ITT population who had at least one causative pathogen identified at screening from cultures of respiratory specimens (e.g., respiratory fluids obtained by bronchoalveolar lavage or bronchoscopy, pleural fluids obtained by thoracentesis, or expectorated or induced sputum meeting eligibility criteria), cultures of blood, or from culture-independent methods (e.g., positive urinary antigen tests for Streptococcus pneumoniae or Legionella pneumophila or positive serology for Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae). The expanded microITT population was defined using the same criteria as the microITT population, except that adequate Gram staining was defined as >10 PMN / LPF and <10 SEC / LPF to determine whether isolates from sputum cultures were pathogenic, where PMN = polymorphonuclear, SEC = squamous cells, and LPF = low power field. The CE population consisted of all ITT subjects who received study material, had eligible CABP, outcome assessments, and met all other evaluability criteria detailed in the SAP. The CE-EOT / PTE population consisted of all randomized safety subjects who received any amount of active test substance, completed the investigator's assessment of clinical response at the EOT / PTE visit, had no pending clinical response, and met specific criteria associated with the required assessments, where CE=clinically evaluable, EOT=end of treatment, and PTE=post therapy evaluation. The microbiologically evaluable (ME) population included subjects in the CE population with at least one causative pathogen at screening. · The ME-EOT / PTE consisted of all subjects in both the microITT and CE-EOT / PTE populations. · The safety population consisted of all randomized subjects receiving the study material.

[0376] The various study populations enrolled in the study as defined above are listed below.

[0377] [Table 17]

[0378] b) Subject demographics and baseline characteristics The following information was collected: subject disposition (study material completed, study material discontinued due to discontinuation, completed trial, study discontinued due to discontinuation), protocol deviations, CABP background information (subject demographics: age (years), sex, race, height (cm), weight (kg), body mass index (BMI) (kg / m 2 )), PORT risk class, and historical and ongoing medical conditions by treatment group.

[0379] Baseline demographic and medical variables were analyzed using the two-tailed Fisher exact test (for categorical variables) or the two-tailed Wilcoxon rank-sum test (for ordinal and continuous variables).

[0380] Selected results of these analyses are summarized in the table below.

[0381] [Table 18] TIFF2025041746000022.tif78166

[0382] Percentages are based on the ITT population. P values ​​for differences between treatment groups are derived from Fisher's exact test. The number of subjects prematurely discontinuing study treatment due to adverse events may not correspond to the numbers in the adverse events table because some reasons for discontinuation are coded as death rather than adverse events. Randomized but untreated subjects (total n=4) are counted in the other category. Total number of deaths is 12 (8 omadacycline and 4 moxifloxacin). EOT=end of treatment, PTE=post-treatment evaluation.

[0383] [Table 19] TIFF2025041746000024.tif137166

[0384] Percentages in the above tables are based on the CE-PTE population. p-values ​​for differences between treatment groups were derived from Fisher's exact test. The number of subjects prematurely discontinuing study treatment due to adverse events may not correspond to the numbers in the adverse events tables because some reasons for discontinuation are coded as death rather than adverse events.

[0385] [Table 20] TIFF2025041746000026.tif237166TIFF2025041746000027.tif242166TIFF2025041746000028.tif65166

[0386] In the above table, age is calculated from date of birth for informed consent. p-values ​​for differences between treatment groups are derived from Fisher's exact test (for categorical variables) or Wilcoxon rank sum test (for continuous variables). For each categorical parameter, the denominator of the percentage is the number of subjects who had that parameter assessed. PORT Score (Actual) and PORT Risk Class (Actual) are based on PORT Score (Derived / Corrected) from the CRF.

[0387] [Table 21] TIFF2025041746000030.tif242166TIFF2025041746000031.tif201166

[0388] In the above table, age is calculated from date of birth for informed consent. p-values ​​for differences between treatment groups are derived from Fisher's exact test (for categorical variables) or Wilcoxon rank sum test (for continuous variables). For each categorical parameter, the denominator of the percentage is the number of subjects who had that parameter assessed. PORT Score (Actual) and PORT Risk Class (Actual) are based on PORT Score (Derived / Corrected) from the CRF.

[0389] c) Efficacy Analysis For all efficacy analyses, subject data were analyzed in the group to which the subject was randomized.

[0390] The following table summarizes the primary analyses of early clinical response determined 72-120 hours after the first infusion of test article in the ITT population.

[0391] [Table 22]

[0392] Early clinical success rates (at 72-120 hours) in the ITT population for both Compound 1 and moxifloxacin are presented in Figure 2. See the left-most pair of bars. The data indicate that the observed -1.6% difference in clinical success rates with 95% CI (confidence interval) is well within the 10% margin of statistical non-inferiority between -7.1% and 3.8%, thus the primary efficacy point (for FDA approval) was met.

[0393] For early clinical response efficacy variables (clinical success, clinical failure, or undetermined), undetermined responses were included in the denominator for the calculation of the percentage of subjects in the ITT population with clinical success and were therefore essentially considered clinical failures for the purposes of the primary analysis.

[0394] The following table summarizes the overall clinical response at the PTE visit based on investigator assessment for the ITT and CE-PTE populations.

[0395] [Table 23] TIFF2025041746000034.tif97164

[0396] The overall clinical response rates at the PTE visit based on investigator assessment for the ITT and CE-PTE populations for both Compound 1 and moxifloxacin are also presented in Figure 2. See the middle (ITT) and right-most (CE-PTE) pairs of bars. The data show that the observed 2.5% difference in the overall clinical response rate in the ITT population with 95% CI (confidence interval) is within the 10% margin of statistical non-inferiority between -2.4% and 7.4%, and the observed 2.5% difference in the overall clinical response rate in the CE-PTE population with 95% CI (confidence interval) is within the 10% margin of statistical non-inferiority between -1.7% and 6.8%. Therefore, the secondary efficacy points (for FDA approval) are also met.

[0397] For investigator assessment of clinical response in the PTE efficacy variables (clinical success, clinical failure, or undetermined in the ITT population and clinical success and clinical failure in the CE population), undetermined responses were included in the denominator for the calculation of the percentage of subjects with clinical success in the ITT population and were therefore essentially considered clinical failures for the purposes of the primary analysis of the EMA.

[0398] To demonstrate that the efficacy of Compound 1 was non-inferior to moxifloxacin in treating adults with CABP, the following hypotheses were evaluated by analysis of clinical success rates:

[0399] The null and alternative hypotheses of the early clinical response endpoint were evaluated in the ITT population as follows: H o :θ T -θ C≦ -Δ H ai :θ T -θ C> -Δ

[0400] The clinical success rate of compound 1 regimen is θ T For moxifloxacin, C Δ is the non-inferiority (NI) margin, which was 0.10 (or 10%).

[0401] For the PTE endpoint, similar null and alternative hypotheses can be made with a delta of 0.10. For the early clinical response (FDA) endpoint, a two-sided 95% confidence interval (CI) approach for the difference in clinical success rates (using the point estimate of the difference: Compound 1 response rate - Moxifloxacin response rate) was used to test the NI of the Compound 1 group compared to the Moxifloxacin group in the ITT population. The 95% CI was calculated using the non-stratification method proposed by Miettinen and Nurminen (Statistics in Medicine 4:213-226, 1985). Compound 1 is considered non-inferior to Moxifloxacin if the lower limit of the CI is greater than -0.10 (or -10%). This concept is expressed herein as "within the 10% margin of non-inferiority".

[0402] For investigator assessment of clinical response in the PTE (EMA) primary efficacy analysis in both the ITT and CE populations, a two-sided 97.5% CI approach for the difference in clinical success rates (using the point estimate of the difference: Compound 1 response rate - moxifloxacin response rate) was used to test the NI of the Compound 1 group compared to the moxifloxacin group in subjects with a PORT risk class of III or higher. The 97.5% CI was calculated using the stratified (for randomization stratification factors) method proposed by Miettinen and Nurminen. Compound 1 was considered non-inferior to moxifloxacin if the lower limit of the CI was greater than -0.10 (or -10%).

[0403] Early clinical response and investigator assessment of clinical response in PTE were tested separately and were not co-primary endpoints. The probability of approving an ineffective drug based on PTE efficacy was 1.25%, regardless of the outcome of the early clinical response endpoint, and vice versa. Adjustment would only be required if victory in at least one endpoint led to global approval, which was not the case here. Furthermore, no alpha adjustment was required for the co-primary efficacy endpoint in EMA (ITT and CE populations), since NI must be demonstrated in both populations to conclude NI. Therefore, there was no adjustment for multiple endpoints.

[0404] Addition and sensitivity analyses of the primary efficacy outcomes (early clinical response at PTE and investigator assessment of clinical response) were performed. If the null hypothesis of inferiority is rejected for early clinical response in the ITT population and the observed rate of successful responses for compound 1 is greater than that for moxifloxacin, a formal statistical analysis of superiority will be performed. Compound 1 will be considered superior to moxifloxacin if the lower limit of the two-sided CI for the treatment difference is greater than 0%.

[0405] The primary efficacy outcome was also assessed separately across the stratification factors of PORT risk class, receipt of permitted antibiotic therapy in the 72 hours prior to study treatment, and geographic region strata by treatment group. Two-sided 95% CIs of observed differences in early clinical response rates for each of the PORT risk class strata, each of the prior antibiotic therapy strata, and each of the geographic region strata were calculated for the intention-to-treat population. Further subgroup analyses of the primary efficacy outcome could be performed as descriptive analyses.

[0406] The following two tables summarize the overall clinical response at the PTE visit based on investigator assessment by PORT risk class in the ITT and CE-PTE populations, respectively.

[0407] [Table 24] TIFF2025041746000036.tif238129

[0408] Overall clinical response rates at the PTE visit based on investigator assessment for the ITT population restricted to actual PORT risk class III / IV subjects for both Compound 1 and moxifloxacin are presented in Figure 3. See the pair of bars on the left. The data show that the observed 3.3% difference in overall clinical response rate is within the 10% margin of statistical non-inferiority with a 97.5% CI (confidence interval) between -2.7% and 9.3%. Thus, one of the co-primary efficacy points (for EMA approval) is met.

[0409] [Table 25] TIFF2025041746000038.tif251115

[0410] The overall clinical response rates at the PTE visit based on investigator assessment for the CE-PTE population restricted to patients with PORT III / IV CABP for both Compound 1 and moxifloxacin are also presented in Figure 3. See the right pair of bars. The data show that the observed 2.0% difference in overall clinical response rate is within the 10% margin of non-inferiority between -3.2% and 7.4% with 97.5% CI (confidence interval). Therefore, the other co-primary efficacy point (for EMA approval) is also met.

[0411] Sensitivity analyses include performing adjusted analyses of the primary efficacy outcome based on the randomized stratum and separately based on the stratum to which the subject actually belongs, as well as performing an analysis in which all subjects with pending response are considered clinical successes.

[0412] d) Analysis of secondary variables The number and percentage of subjects classified as clinical success, clinical failure, and indeterminate by investigator assessment at PTE in the ITT and CE populations (by definition, subjects with indeterminate response were excluded from the CE population) were calculated for each treatment group. Two-sided unadjusted 95% CIs were constructed for the observed differences in clinical success rates using the Miettinen and Nurminen method. For the investigator assessment of clinical response at PTE in the ITT and CE populations, the 95% CIs were merely descriptive and no NI conclusions were made. For the microITT population, the number and percentage of subjects in each treatment group in each response category of early clinical response are shown. The number and percentage of subjects classified as clinical success and clinical failure by the investigator at the PTE visit in the ME population were calculated. Two-sided unadjusted 95% CIs were constructed for the observed differences in clinical success rates using the Miettinen and Nurminen method.

[0413] The number and percentage of subjects with early clinical response of success in the microITT and ME populations, as well as the investigator's assessment of clinical response at PTE of clinical success by pathogen, were provided. All-cause mortality (ACM) at 15 and 30 days after the first dose of test article in the ITT population was summarized. For this analysis, subjects lost to follow-up were considered to have died. For ACM, two-sided unadjusted 95% CIs of observed differences in mortality were calculated.

[0414] e) Analysis of Further Efficacy Variables Further efficacy analyses were performed to support the efficacy findings of the primary and secondary outcomes. Descriptively, CIs were determined, but NIs were not concluded. The number and percentage of subjects classified as clinical success, clinical failure, and indeterminate by investigator assessment at EOT in the ITT and CE populations (by definition, subjects with indeterminate response were excluded from the CE population) were calculated. Two-sided unadjusted 95% CIs were constructed for observed differences in clinical success rates using the method of Miettinen and Nurminen. The number and percentage of subjects with stable clinical signs / laboratory findings related to vital signs and CABP at 72-120 hours after the first dose of test substance were presented by treatment group in the ITT population. These were temperature (no fever or hypothermia), SBP (>90 mm Hg), heart rate (<90 bpm), RR (<20 breaths / min), PaO2 (≥60 mm Hg by ABG or ≥90% oxygen saturation by pulse oximetry), physical examination findings (no evidence of pulmonary consolidation), and WBC count (<12,000 cells / mm 3 or ≥ 4,000 cells / mm 3 ) or immature neutrophils (<15%). A summary assessment of clinical signs and symptoms of CABP (number and percentage of subjects) at each time point throughout the study was provided by treatment group in the ITT population. The number and percentage of subjects with resolution of signs and symptoms present at screening (return to pre-CABP state) were also provided by study visit. The number and percentage of subjects without worsening of clinical symptoms of CABP, as well as subjects without new symptoms of CABP, were provided by treatment group in the ITT population.

[0415] Per-subject and per-pathogen microbiological outcomes were provided for the microITT and ME populations at the EOT and PTE visits. For example, the following table summarizes the overall clinical success at the PTE visit in the microITT population based on investigator assessment of baseline pathogens from blood specimens, respiratory specimens, urinary antigen testing and / or serology.

[0416] [Table 26] TIFF2025041746000040.tif223149

[0417] For selected pathogens with 10 or more isolates in the compound 1 treatment group, data were extracted and are shown in Figure 4 .

[0418] Two-sided unadjusted 95% CIs were provided for differences in per-subject rates of microbiologically favorable outcomes. Concordance analyses of early clinical response and investigator assessment of clinical response with PTE in the ITT analysis set were also presented.

[0419] f) Safety outcome measures Safety variables included the incidence of AEs, changes in vital signs, ECG parameters and clinical laboratory results obtained during the course of the study.

[0420] Summary tables were provided for all treatment-emergent adverse events (TEAEs), defined as AEs, with the start date and time on the day of the first dose of test article or the start date and time after the first dose of test article. AEs were summarized by presenting the number and percentage of subjects with each TEAE for each treatment group by system organ class (SOC) and preferred term (PT). Further tabulation provided a summary by SOC and PT of subjects experiencing SAEs, severe TEAEs, TEAEs deemed related to the test article, TEAEs leading to discontinuation of the test article, TEAEs leading to dose discontinuation of the test article, and TEAEs of special interest.

[0421] The following table provides an overview of adverse events (AEs) within the safety population.

[0422] [Table 27]

[0423] The following table provides a summary of selected TEAEs by preferred term within the safety population. With some exceptions, selected TEAEs have an incidence of at least about 2% in the Compound 1 treatment group.

[0424] [Table 28]

[0425] Thus, gastrointestinal (GI) adverse events (AEs including vomiting, nausea, diarrhea and dyspepsia) associated with treatment with Compound 1 appear to be mild.

[0426] Selected TEAEs that led to treatment discontinuation are summarized in the table below.

[0427] [Table 29]

[0428] The following variables were analyzed descriptively as vital signs: Vital signs (systolic and diastolic BP, pulse rate, temperature, RR) including change from screening visit Clinically significant vital signs from the visit (meeting predefined criteria as specified in the SAP)

[0429] Electrocardiogram data (RR interval, PR interval, QRS interval, corrected QT interval [QTc], Bazett's correction of QTc [QTcB], and Friedreich's correction of QTc [QTcF]) were summarized descriptively at each scheduled assessment and with the worst postscreening value overall. Changes from screening at each visit were also provided. Outlier analysis was performed based on the worst postscreening value.

[0430] The following variables were analyzed descriptively for clinical examination: Laboratory variables by visit Change from screening laboratory variables by visit Clinically significant laboratory values ​​by visit (meeting predefined criteria as specified in the SAP)

[0431] g) Penalty kick A population PK analysis was performed to characterize PK parameters. A population PK data set was constructed including subjects with one or more quantified Compound 1 concentration measurements from the date and time of dose and blood sample, along with all biochemical analytical determinations and subject background information. If the actual date or time of blood sample or dose was missing, the associated biochemical analytical determination of PK concentration was excluded from all analyses. Compound 1 concentrations below the limit of quantification were treated as missing data in summary statistics and for the calculation of PK parameters.

[0432] Variables including age (years), weight (kg), sex, and race / ethnicity were incorporated into a population PK database along with other covariates previously determined to be important. Descriptive summaries of these variables at screening were reported based on subjects in the population analysis dataset. Outliers may be excluded from the analysis. These were determined and reported by scatter plots of observed concentrations versus time post-dose. The distribution of the number of samples per subject that contributed to the model-based analysis was tabulated. Simple summary descriptive statistics of sample concentrations by study day or study week were also computed.

[0433] Regarding population PK modeling, results from the Phase 1 trial showed that Compound 1 PK was linear and that after iv infusion, the plasma concentration-time profile exhibited a three-compartment nature. Therefore, the structural PK model was likely to be a three-compartment model with zero-dimensional input for iv infusion and first-dimensional input for po administration. This PK model included parameters clearance, distribution volume, bioavailability and absorption rate constant. The relevant population model was a nonlinear mixed-effects model. The population model added random effects and covariates for PK parameters to recognize differences between individuals and similarities across observations corresponding to the same subject. During population modeling, previously reported structural PK models were considered first. Residual error models combining additive and proportional errors were also considered. If model diagnostics suggest false convergence, simplifications (e.g., fewer random errors or alternative residual error models) may be appropriate. Additional covariates were graphically explored as part of model diagnostics (e.g., sex, race / ethnicity), with some retained in the final model and additional ones in competing models that arguably delivered negligible effect estimates. Scatter plots of observed concentrations versus population-estimated and individually estimated concentrations were used as part of an overall assessment of the overall quality of the fit. During modeling, broad principles outlined by the FDA were followed. Individual model-based exposure measures at steady state (area under the concentration / time curve [AUC 0-24,ss ], time to maximum plasma concentration [T max,ss ], maximum plasma concentration [C max,ss ]) was calculated and compiled by computer.

[0434] The data were examined for relationships between Compound 1 exposure and response (efficacy and safety) as appropriate. A population PK model was used to calculate individual subject AUC and subsequent potential AUC / MIC breakpoints.

[0435] [Example 4] A Phase I, Randomized, Double-Blind, Three-Period Crossover Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of Omadacycline or Placebo in Healthy Adult Subjects The primary objective of this study was to evaluate and compare the pharmacokinetics (PK) of oral omadacycline at 300-, 450-, and 600-mg doses administered daily for 5 days. A secondary objective of this study was to evaluate the safety and tolerability of multiple doses of omadacycline in healthy adult subjects.

[0436] For the treatment of CABP, then, the expected therapeutic daily oral dose (excluding any loading dose) was 300 mg. For potential future trials or for administration of additional doses using oral formulations, it is possible that daily doses greater than 300 mg can be used to achieve sufficient omadacycline concentrations to treat the target bacteria in the organs / tissues of interest. One early clinical trial has evaluated single oral doses of omadacycline up to 600 mg, but no trials have evaluated multiple daily doses greater than 300 mg. This trial was designed to obtain data on the safety, tolerability, and pharmacokinetics (dose linearity and proportionality) of multiple oral doses of omadacycline at daily doses greater than 300 mg. A placebo group was included as a reference to minimize potential bias in the evaluation of tolerability.

[0437] Multiple daily oral doses of 300, 450 and 600 mg of omadacycline or placebo were selected to be administered in this trial. The lowest dose, 300 mg, was evaluated in multiple dose trials and was well tolerated, and this daily dose was also studied in a Phase 3 trial in ABSSSI. In one early clinical trial, single oral doses of up to 600 mg were administered in capsules to healthy adult subjects and determined to have an acceptable safety profile. Although there was some increased frequency of GI AEs with oral doses of 400 mg and above, the events were usually mild (not severe), and it is possible that some of these events may be related to the oral formulation. Multiple daily doses of up to 600 mg using the final optimized tablet formulation of omadacycline were predicted to have an acceptable safety profile, which is important to evaluate in small, carefully controlled Phase 1 trials before evaluating these doses in larger clinical trials.

[0438] Therefore, the trial was designed as a phase 1 randomized, double-blind, three-period crossover trial in healthy adult subjects. The trial consisted of a screening period (days -21 to -2), three baseline periods (day -1 of each period), three treatment periods (days 1 to 6 of each period), and a study completion visit (within 6-10 days after the last dose of study drug during period 3). There was a washout period of at least 5 days between the last dose in one period and the first dose in the next period. Subjects were confined to the study site from day -1 of period 1 until discharge on day 6 of period 3, after 24-hour blood sampling, urine sampling, and safety assessments were completed. Subjects returned to the study center 6-10 days after the last dose of study drug during period 3 for the study completion visit.

[0439] Target Selection Healthy, non-smoking, male and female subjects were eligible for participation in the study if they were between 18 and 55 years of age (inclusive), weighed ≥ 50 kg, had a body mass index between 18 and 30 kg / m2 (inclusive), met all eligibility criteria during screening (performed within 21 days prior to dosing during Period 1) and at baseline (Day -1) of Period 1, and provided written informed consent. Health status was determined by past medical history, clinical examination, vital signs (oral temperature, systolic blood pressure, diastolic blood pressure, and heart rate), 12-lead electrocardiogram (ECG), and physical examination at screening. Eligibility criteria included the ability to swallow up to four tablets consecutively.

[0440] Subjects were excluded from participation in the trial because of prior treatment with omadacycline, recent use of other investigational drugs, abnormal ECG, inability to tolerate oral medications, pregnancy or breast-feeding, use of tobacco products, intake of prescription drugs, herbal supplements or over-the-counter medications or xanthine (e.g., caffeine)-containing foods or beverages within the specified time frame prior to starting the trial, blood loss / transfusion, low hemoglobin levels, high creatinine or blood urea nitrogen levels, urinary obstruction / difficulty urinating, positive alcohol or drug tests, hypersensitivity or allergy to any tetracycline, signs of liver disease or liver damage, significant illness within 2 weeks of starting the trial, any planned medical intervention that may interfere with the trial, or a history of a disease or medical condition as specified in the trial protocol.

[0441] Study design On days 1 through 5 of each period, subjects received one of the following treatments (omadacycline or placebo) once daily after a 6-hour fast according to a randomization schedule: A. 300 mg of omadacycline (2 x 150 mg tablets) AP. Placebo of 300 mg of omadacycline (2 x placebo tablets) B. 450 mg of omadacycline (3 x 150 mg tablets) BP. 450 mg omadacycline placebo (3 × placebo tablets) C. 600 mg of omadacycline (4 x 150 mg tablets) CP. 600 mg omadacycline placebo (4 × placebo tablets)

[0442] All doses of study drug were administered in the morning and subjects had no food or beverages other than water for at least 6 hours prior to dosing. Subjects then had no food or beverages other than water for at least 2 hours after dosing and no dairy products, antacids, or multivitamins for 4 hours after dosing.

[0443] Prior to dosing, subjects underwent a screening assessment to determine eligibility within 21 days prior to dosing during Period 1. Subjects were then admitted to the clinical site the day prior to dosing (Day -1 of Period 1) for a baseline assessment. Prior to dosing on Day 1 of Period 1, up to 30 subjects (24 omadacycline, 6 placebo) were randomly assigned to one of three treatment sequences using a Latin square design as presented in the table below:

[0444] [Table 30]

[0445] Approximately 10 subjects were randomly assigned to each sequence. A placebo was administered to two subjects in each sequence as a reference to assess tolerability. Subjects assigned to omadacycline received omadacycline at all dose levels tested for all three periods. Subjects assigned to placebo received placebo for all three periods. Investigators and subjects were blinded to whether subjects were receiving omadacycline or placebo.

[0446] Clinical Trial Evaluation 1. Plasma Pharmacokinetics Serial blood samples for pharmacokinetic (PK) analysis of omadacycline were collected at designated time points during the 24 hours post-dose on Days 1 and 5 of each period. Specifically, blood samples for PK evaluation of omadacycline were collected from all subjects at the following time points: pre-dose (pre-administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Days 1 and 5 during each period. For each period, the 24-hour blood sample on Day 1 was collected prior to dosing on Day 2.

[0447] Area under the plasma concentration versus time curve (AUC) from 0 to 24 hours after dosing (AUC 0-24 ), the AUC from time 0 to the last quantifiable concentration (AUC last ), maximum observed plasma concentration (C max ), and the time to reach maximum observed plasma concentration (T max ), terminal elimination half-life (T 1 / 2 ), terminal phase rate constant (λ z ) and AUC 0-24 and C max Non-compartmental PK parameters, including the accumulation coefficient (Rac), were determined from plasma omadacycline concentrations and actual time data on days 1 and 5 of each period using Phoenix® WinNonlin® (Certara, Princeton, New Jersey) version 6.2.1.

[0448] Subjects who received omadacycline and had at least one evaluable PK parameter were included in the PK analysis population, but subjects were missing a dose, had diarrhea, or exceeded the median T max Patients may have been excluded from the PK population if vomiting occurred at or before a time equal to twice the time of vomiting.

[0449] 2. Urinary Pharmacokinetics Urine samples were collected from a subset of subjects on Day 5 of Period 2 and at specified intervals: pre-dose, 0-4, 4-8, 8-12, and 12-24 hours post-dose on Day 5 of Period 2. Urine samples at the 12-24 hour interval on Day 1 were collected prior to dosing on Day 2. Urine samples were only collected from a subset of subjects because an amendment to the study protocol added analysis of urinary PK after the trial was already underway.

[0450] From the urinary omadacycline concentration and collection interval data, the following urinary PK parameters were determined using SAS version 9.2: renal clearance (CLr), the proportion of the dose excreted unchanged in the urine 0–24 h after dosing (Fe 0-24 ) and the amount of drug excreted unchanged in urine over 24 hours after dosing (Ae t1-t2 ). Further parameters Ae 0-4 , Ae 4-8 , Ae 8-12 , Ae 12-24 and Ae 0-24 was also calculated.

[0451] 3. Safety and Tolerability Safety assessments included monitoring for adverse events (AEs), clinical laboratory results, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings. All randomly assigned subjects who received at least one dose of any study drug (omadacycline or placebo) were included in the safety analysis population. Adverse events were coded by preferred term and organ system class using MedDRA version 17.1.

[0452] Safety and tolerability were assessed by monitoring and recording AEs, clinical laboratory results (hematology, serum chemistry and urinalysis), vital sign measurements (oral temperature, systolic blood pressure, diastolic blood pressure and HR), 12-lead ECG results and physical examination findings.

[0453] Statistical analysis of pharmacokinetic studies: Individual plasma and urine concentration and time deviation data were presented in the data listing. Plasma and urine concentration data were summarized by each treatment day and time point or interval using descriptive statistics (number of subjects, mean, SD, coefficient of variation [CV], median, minimum and maximum). Concentrations below the limit of quantification (BLQ) were treated as zero in the plasma and urine concentration descriptive statistics summaries. Mean and individual plasma concentration versus time profiles were presented in figures on both linear and semi-log scales.

[0454] Non-compartmental PK parameters were determined from plasma concentration and actual time data using Phoenix® WinNonlin® (Certara, Princeton, New Jersey) version 6.2.1 or higher. Urinary PK parameters were determined from urine concentration and collection interval data using SAS version 9.2 or higher. All further statistical analyses were performed using SAS® software (SAS Institute, Cary, North Carolina), version 9.2.

[0455] For PK analysis, BLQ values ​​were treated as zero, with the exception that BLQ values ​​between two quantifiable concentrations were set as missing. Missing concentrations were treated as missing from PK parameter calculations. If consecutive BLQ concentrations were followed by quantifiable concentrations in the terminal phase, those concentrations after the BLQ concentrations were treated as missing.

[0456] Individual PK parameters are presented in the data listing. PK parameter estimates (e.g., AUC from plasma concentrations) after dosing on days 1 and 5 of each period. 0-24 , AUC last , C max , T max , T 1 / 2 and Rac [only on the 5th day], CLr from urine concentration, Fe 0-24 and Ae 0-24 Descriptive statistics (number of subjects, mean, SD, CV, median, minimum and maximum) of AUC were calculated. 0-24 , AUC last and C maxThe geometric mean of

[0457] For use in estimating effects and constructing confidence intervals (CIs), a linear mixed-effects model (SAS PROC MIXED) with treatment (A, B, and C), sequence (1A, 2A, and 3A), and treatment period as fixed effects and subjects nested within sequence as random effects was fitted to the PK parameter AUC normalized by natural log-transformed dose after dosing on days 1 and 5 of each period. 0-24 / dose, AUC last / Dose and C max Fitting was performed to mean mean ratios / dose. Point estimates and 90% CIs of differences on the log scale were exponentiated to obtain estimates of geometric mean ratios and their respective 90% CIs on the original scale. No adjustment was made for multiplicity.

[0458] Dose linearity across all three dose levels was evaluated for omadacycline C after both day 1 and day 5 doses. max , AUC last and AUC 0-24 was assessed by fitting to the power model (10): ln(PK)=a+b×ln(dose)+error, where PK is the PK parameter, a is the intercept, and b is the slope. Estimates of the slope, b, are reported with the corresponding two-sided 90% CI.

[0459] For statistical analysis of omadacycline accumulation, a linear mixed-effects model with day as a fixed effect and subject as a random effect was used to determine natural log-transformed C max and AUC 0-24 The 90% CI for day 5 compared to day 1 was constructed (separately for each dose level) by fitting to

[0460] result Demographics, baseline characteristics and disposition of study subjects Of the 33 subjects enrolled in the study, 26 were assigned to receive omadacycline and 7 were assigned to receive placebo. Demographic and baseline characteristics were generally similar between the omadacycline and placebo treatment groups (Table 4-1) and across all omadacycline treatment sequences (data not shown). The majority of subjects in the study were white (57.6%) and male (81.8%). The overall mean age of subjects was 36.9 years, with a range of 21 to 55 years.

[0461] [Table 31] TIFF2025041746000046.tif61166

[0462] All 33 subjects received at least one dose of study drug (omadacycline or placebo) and were included in the safety analysis population. Twenty-five of the 26 omadacycline-treated subjects (96.2%) were included in the PK analysis population (one subject was excluded from this population due to post-dose vomiting). Four omadacycline-treated subjects (15.4%) and one placebo-treated subject (14.3%) discontinued the study. These early discontinuations were due to treatment-emergent adverse events (TEAEs) in four subjects (see below), and one additional omadacycline-treated subject was lost to follow-up. Thus, in periods 1, 2, and 3, 22 subjects received all five doses of 300-, 450-, and 600-mg omadacycline and six subjects received all five doses of placebo. These subjects were considered to have completed the study.

[0463] B. Plasma pharmacokinetics At all omadacycline dose levels tested on both days 1 and 5 of each 5-day treatment period, mean plasma omadacycline concentrations peaked 2.5 hours after dosing (T max), omadacycline was measurable in plasma for up to 24 hours after dosing (last sampling time) (Figure 5 and Table 4-2).

[0464] [Table 32] TIFF2025041746000048.tif171166

[0465] Omadacycline total exposure (AUC 0-24 and AUC last ) and peak concentration (C max ) increased with increasing omadacycline dose (300 vs. 450 vs. 600 mg) on ​​both days 1 and 5 and was higher on day 5 than on day 1 for the corresponding doses (Figure 5 and Table 4-2). The mean half-life of omadacycline in plasma (T 1 / 2 ) were similar across the three dose levels tested, ranging from 13.03 to 13.66 hours on day 1 and 15.49 to 16.83 hours on day 5 (Table 4-2). Intersubject variability in systemic omadacycline exposure was low and similar across all three dose levels tested, with C max , AUC 0-24 and AUC last About 23.2% to 26.6% and C on the 5th day max , AUC 0-24 and AUC last The coefficients of variation (CV) ranged from 25.0% to 27.1% (Table 4-2).

[0466] Omadacycline AUC 0-24 , AUC last and C max increased with increasing omadacycline dose, but the observed increases in exposure were less than dose-proportional on both days of analysis (Tables 4-2 and 4-3).

[0467] [Table 33] TIFF2025041746000050.tif96166

[0468] Statistical analysis showed that increasing the dose from 300 mg to 600 mg significantly increased omadacycline exposure on day 1 (dose-normalized AUC 0-24 The results showed that the observed increase in omadacycline exposure was 76% of that predicted if exposure was perfectly dose proportional (Table 4-3), and at 5 days the observed increase in omadacycline exposure was 88% of that predicted (Table 4-3). max Analysis of the values ​​also demonstrated that omadacycline concentrations were dose-linear, but less than dose-proportional, in this trial (Tables 4-2 and 4-3).

[0469] Statistical analysis also demonstrated the accumulation of omadacycline in plasma after once-daily dosing for 5 consecutive days. Depending on the dose, the accumulation ratio between day 5 and day 1 was AUC 0-24 About 1.40~1.62 and C max The mean half-life of omadacycline in plasma ranged from 1.24 to 1.35 (data not shown). These findings are consistent with the long half-life of omadacycline in plasma.

[0470] The data above showed that mean omadacycline concentrations peaked at 2.5 hours and remained measurable for up to 24 hours (the last time point tested) at all omadacycline dose levels (300, 450, and 600 mg). On day 5, mean steady-state exposure (AUC 0-24 ) was 9267 ng·h / mL, which is consistent with previous clinical trials using a 300 mg oral dose. AUC 0-24 and C maxBoth increased with increasing dose and were approximately dose proportional, but somewhat less (74%-88% of that predicted). This was the case on both days 1 and 5 of dosing. Omadacycline accumulated in plasma over the course of dosing on 5 consecutive days due to its relatively long half-life (mean = approx. 13 hours on day 1, approx. 16 hours on day 5). Thus, at all dose levels tested, systemic exposure on day 5 was approximately 50% higher than on day 1. This degree of accumulation is also consistent with that observed following multiple once-daily dosing of IV or oral formulations of omadacycline in early pharmacology trials.

[0471] In terms of systemic exposure, this study demonstrated that omadacycline plasma concentrations on day 1 of the 450-mg dose were similar to those on day 5 of the 300-mg dose (mean AUC 0-24 = 8976.5 and 9267.2 ng·h / mL). For indications where the treatment regimen incorporates a daily oral dose of 300 mg, these data support a strategy of using an initial oral "loading dose" of 450 mg once daily for 1 to 2 days, followed by a once daily oral dose of 300 mg. Such a strategy could potentially eliminate the need for Phase IV treatment.

[0472] C. Urinary pharmacokinetics A protocol amendment added urine sample collection and PK analysis to the study after the trial was ongoing, so a limited number of samples were evaluated (samples from 9 subjects on day 5 of period 2 and samples from 8 subjects on days 1 and 5 of period 3). The sample size was too small to allow meaningful comparisons between omadacycline dose groups, but the results of the analysis provided an overall indication of partial omadacycline renal clearance and urinary excretion.

[0473] For all omadacycline dose groups, the mean percentage of dose excreted unchanged in urine 0 to 24 hours after dosing (Fe 0-24) ranged from about 5% to about 7% on day 1 and from about 7% to about 9% on day 5. Renal clearance (CLr) ranged from 2.8 to 4.2 L / h on day 1 and from 2.4 to 3.3 L / h on day 5 (Table 4-4).

[0474] [Table 34] TIFF2025041746000052.tif45166

[0475] Urinary PK analysis in a subset of subjects provided a preliminary indication of partial renal clearance and urinary excretion of omadacycline. On day 5, depending on dose level, approximately 7% to approximately 9% of the administered oral dose was excreted unchanged in the urine over 24 hours. As the absolute bioavailability of the tablet formulation used in this trial was found to be 35%, this represents approximately 20% to 25% of the absorbed dose. The presence of unchanged omadacycline in the urine suggests that it may be useful in urinary tract infections, an indication currently being investigated.

[0476] d. Safety and Tolerability Overall, 12 of 33 subjects in the safety population reported a total of 36 TEAEs during the study (Tables 4-5).

[0477] [Table 35] TIFF2025041746000054.tif104166

[0478] TEAEs were reported by 38.5% of subjects receiving omadacycline and 28.6% of subjects receiving placebo. The highest percentage of TEAEs were classified as gastrointestinal (GI) disorders. The most frequently reported TEAE was nausea, which occurred in ≦7.7% of the omadacycline 300 and 450 mg dose groups and 16.7% of the 600 mg group. All of the TEAEs reported in this study were either mild or moderate in severity. No serious TEAEs (SAEs) were reported during the study. Four subjects experienced TEAEs leading to study discontinuation, including one subject at each of the three omadacycline dose levels and one subject in the placebo group.

[0479] There were no clinically significant findings in the analysis of vital sign measurements, physical examinations, ECG results, hematology or urinalysis parameters. Serum chemistry analyses showed that the median changes in alanine aminotransferase (ALT) concentrations between baseline and day 5 of each dosing period were -2.0, 5.0 and 19.5 IU / L in subjects dosed with 300, 450 and 600 mg of omadacycline, respectively. Corresponding changes in the placebo group ranged from -5.0 to -1.0 IU / L. No substantial changes were noted in median aspartate aminotransferase (AST), bilirubin or other serum chemistry parameters. The highest individual ALT value was 150 IU / L (2.7-fold above the upper limit of normal [ULN]) in a subject who initially received 450 mg omadacycline in period 1, then 300 mg in period 2, and then discontinued due to liver enzyme changes; this subject's bilirubin values ​​remained within the normal range at all time points evaluated.

[0480] Plasma PK findings indicate that higher systemic drug exposure can be achieved with increasing amounts of omadacycline administered per dose during once-daily oral dosing, but the exposure benefit is not dose-proportional. Furthermore, escalating omadacycline dosing beyond a certain point is found to have adverse effects in terms of safety and tolerability. Multiple doses of 300, 450, and 600 mg were all generally well tolerated in this study (all TEAEs were either mild or moderate in severity), although there were some differences between doses. The frequency of treatment-related TEAEs did not increase with increasing omadacycline dose from 300 to 450 mg (15.4% vs. 8.3%), although such events were more frequent with 600 mg (25.0%). Within the most frequent class of TEAEs, GI disorders, nausea occurred at a prevalence at least 9% higher for the 600 mg dose level than for the lower doses, with only two reports of diarrhea occurring with 600 mg. Furthermore, serum chemistry analysis showed a small but significant dose-dependent increase in median ALT concentrations. Although individual ALT values ​​did not exceed the ULN by more than 3-fold, the higher median ALT at 600 mg suggests a greater increase in the change in serum transaminase levels, which were more significantly elevated, with this dose. Based on these findings, for situations in which an oral dose above 300 mg may be beneficial, 450 mg was identified as the oral dose most likely to provide higher omadacycline exposure with favorable safety and tolerability.

[0481] In summary, this phase 1 trial investigated the pharmacokinetics (PK) and safety / tolerability of multiple oral omadacycline doses higher than 300 mg. Using a three-period crossover design, healthy adults were randomized to receive omadacycline (300-, 450-, and 600-mg in variable sequence, n=26) or placebo (n=7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentrations and total exposure increased with increasing dose but were less than dose-proportional (74%-88% of expected). The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was approximately 50% higher than on day 1. Omadacycline plasma concentrations on day 1 of the 450 mg dose were similar to those on day 5 of the 300 mg dose. Urinary PK analysis showed partial renal clearance and urinary excretion of unchanged omadacycline. All doses were generally well tolerated. These results support the use of 450-mg oral omadacycline once daily (1 or 2 doses) as part of an oral-only dosing regimen, e.g., as a loading dose before decreasing to 300-mg oral omadacycline once daily, or in a dosing regimen using 450-mg oral omadacycline once daily throughout treatment.

Claims

1. 1. A pharmaceutical composition comprising 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof for use in a method for treating community-acquired bacterial pneumonia (CABP) in a subject in need thereof, said method comprising administering to said subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof by administering to said subject the following: (1) three oral doses of about 300-450 mg each, 12 hours apart, followed by (2) optionally, orally administering one or more doses of about 300-600 mg each, each dose being administered 24 hours after the immediately preceding oral administration; A pharmaceutical composition comprising administering the compound according to the dosage regimen.

2. The administration regimen is such that the subject is treated: (2) administering one or more oral doses of about 300 to 600 mg each, each dose being administered 24 hours after the immediately preceding oral administration.

2. The pharmaceutical composition of claim 1, comprising:

3. The administration regimen (2) orally administering one or more doses of about 300 mg each, each dose being administered 24 hours after the immediately preceding oral administration; 2. The pharmaceutical composition of claim 1, comprising:

4. The pharmaceutical composition of claim 1, wherein each oral dose is about 300 mg.

5. The pharmaceutical composition of claim 1, wherein each oral dose in step (1) is about 300 mg.

6. A pharmaceutical composition described in claim 1 or 5, wherein each oral dose in step (2) is about 300 mg.

7. 5. The pharmaceutical composition of claim 1 or 4, 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.

8. 10. The pharmaceutical composition of claim 1, wherein the steps are completed within 7 to 14 days; within 7 to 10 days; within 11 to 14 days; within 11 to 14 days; or within 10 days.

9. 5. The pharmaceutical composition of claim 1, wherein the 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.

10. 10. The pharmaceutical composition of claim 9, wherein the Streptococcus pneumoniae is penicillin-resistant Streptococcus pneumoniae (PRSP), macrolide-resistant Streptococcus pneumoniae, cephalosporin-resistant Streptococcus pneumoniae, or multidrug-resistant Streptococcus pneumoniae (MDRSP).

11. 5. The pharmaceutical composition of claim 1, wherein the CABP is caused by an intracellular pathogen, such as Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, or a combination thereof.

12. 5. The pharmaceutical composition of claim 1, wherein the CABP is caused by Haemophilus parainfluenzae.

13. The pharmaceutical composition of claim 1 or 4, wherein the subject is a human.

14. 10. The pharmaceutical composition of claim 1 or 4, wherein each of the oral doses is administered independently as two 150 mg tablets.

15. A pharmaceutical composition described in claim 1 or 4, wherein the dosage regimen has a clinical success rate that is within a 10% (or 12.5%) margin of non-inferiority compared to the clinical success rate of a dosage regimen of intravenous administration of 400 mg of moxifloxacin once every 24 hours for three or more days, followed by one or more oral administrations of 400 mg of moxifloxacin once every 24 hours.

16. 5. The pharmaceutical composition of claim 1, wherein the subject experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea on days 3 to 5 after step (1), wherein the symptoms are rated on a 4-point scale of none, mild, moderate, and severe, and the improvement is an improvement of at least one level from baseline to the rating on days 3 to 5 (e.g., from severe to moderate, moderate to none, or mild to none).

17. 5. The pharmaceutical composition of claim 1, wherein the subject experiences improvement in at least two symptoms selected from chest pain, cough frequency or severity, sputum volume, and dyspnea, with no worsening of any of the symptoms selected therefrom, and improvement in at least one vital sign selected from body temperature, blood pressure, heart rate, and respiratory rate, from day 3 to day 5 after step (1).

18. 10. The pharmaceutical composition of claim 1 or 4, wherein the subject fasts overnight and has not consumed food or beverages other than water for at least 6 hours immediately prior to dosing in step (3), if any, and the subject continues to fast after dosing in step (3), has not consumed food for 2 hours, and has not consumed dairy products for 4 hours.

19. 5. The pharmaceutical composition of claim 1, wherein the salt is a tosylate salt.

20. 10. The pharmaceutical composition of claim 1 or 4, having a clinical success rate of about 70% to 100%.

21. 21. The pharmaceutical composition of claim 20, wherein the 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%.

22. 22. The pharmaceutical composition of claim 21, wherein the clinical success rate is about 75-85% observed about 72-120 hours after administration of the first intravenous dose.

23. 23. The pharmaceutical composition of claim 22, wherein the clinical success rate is about 80-82%, or about 80% or about 81%.

24. 22. The pharmaceutical composition of claim 21, wherein the clinical success rate is observed about 5 to 10 days after the last dose of treatment (e.g., corresponding to the time of post-treatment assessment in a clinically evaluable population or CE-PTE, or in an ITT population).

25. 25. The pharmaceutical composition of claim 24, wherein the clinical success rate is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96% or about 97%.

26. 5. The pharmaceutical composition of claim 1 or 4, wherein the subject has CABP classified as PORT risk class II.

27. 27. The pharmaceutical composition of claim 26, having 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%.

28. 28. The pharmaceutical composition of claim 27, wherein the clinical success rate is about 75-85% or about 90-100% observed about 5-10 days after the last dose of treatment.

29. 29. The pharmaceutical composition of claim 28, wherein the clinical success rate is about 82% or about 95%.

30. 5. The pharmaceutical composition of claim 1 or 4, wherein the subject has CABP classified as PORT risk class III.

31. 31. The pharmaceutical composition of claim 30, having a clinical success rate of about 80-100%, about 85-95%, about 90-95%, about 90-91%, or about 93-94%.

32. 32. The pharmaceutical composition of claim 31, wherein the clinical success rate is about 85-100% observed about 5-10 days after the last dose of treatment.

33. 33. The pharmaceutical composition of claim 32, wherein the clinical success rate is about 90-91% or about 93-94%.

34. 5. The pharmaceutical composition of claim 1 or 4, wherein the subject has CABP classified as PORT risk class IV.

35. 35. The pharmaceutical composition of claim 34, having a clinical success rate of about 70-100%, about 75-95%, about 80-95%, about 83-85%, or about 90-91%.

36. 36. The pharmaceutical composition of claim 35, wherein the clinical success rate is about 80-95% observed about 5-10 days after the last dose of treatment.

37. 37. The pharmaceutical composition of claim 36, wherein the clinical success rate is about 83-85% or about 90-91%.

38. 5. The pharmaceutical composition of claim 1 or 4, wherein the subject has CABP classified as PORT risk class III or IV.

39. 39. The pharmaceutical composition of claim 38, having a clinical success rate of about 75-100%, about 85-95%, about 85-90%, about 88-89%, about 90-95%, or about 92-93%.

40. 40. The pharmaceutical composition of claim 39, wherein the clinical success rate is about 85-95% observed about 5-10 days after the last dose of treatment.

41. 41. The pharmaceutical composition of claim 40, wherein the clinical success rate is about 88-89% or about 92-93%.

42. 10. The pharmaceutical composition of claim 1 or 4, wherein the gastrointestinal (GI) adverse events (AEs) associated with the treatment of the subject are mild.

43. 10. The pharmaceutical composition of claim 1 or 4, wherein a GI adverse event (AE) associated with treatment of the subject does not result in discontinuation of therapy with the method.

44. 10. The pharmaceutical composition of claim 1 or 4, wherein treatment of the subject (1) does not result in an increased risk of C. difficile (e.g., C. difficile colitis and Pseudomembranous colitis) infection in the subject, or (2) does not substantially disrupt the gut microbiome in the subject.

45. 45. The pharmaceutical composition of claim 44, wherein the subject is at risk of or predisposed to developing a C. difficile infection.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the subject has recently been treated with one or more antibiotics (e.g., broad-spectrum antibiotics), has undergone gastrointestinal surgery, has a colon disease (e.g., inflammatory bowel disease or colorectal cancer), has kidney disease, has a weakened immune system, is undergoing chemotherapy, has previously had a C. difficile infection, is 65 years of age or older, is taking a proton pump inhibitor, or lives in an environment that predisposes the subject to developing a C. difficile infection (e.g., a hospital, nursing home, or assisted living facility).

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