9-aminomethyl minocycline compounds and use thereof

Abstract

To provide methods for treating bacterial infection of skin or skin structure.SOLUTION: Provided is a method for treating bacterial infection of skin or skin structure in a human subject in need thereof, the method comprising a step of orally administering to the subject 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof at a dose of about 450 mg per day for consecutive two days, then at a dose of about 300 mg per day for five days or longer.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Patent Application Nos. 62 / 370,527, filed August 3, 2016, 62 / 514,479, filed June 2, 2017, and 62 / 532,454, filed July 14, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] The development of tetracycline antibiotics was a direct result of the systematic screening of soil samples collected from numerous regions of the world for evidence that microorganisms were capable of producing bactericidal and / or bacteriostatic compositions. The first of these novel 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 provided an analytical basis for the production of the third member of this group, tetracycline, in 1952. A new family of minocycline compounds, lacking the methyl group attached to the ring present in the earlier tetracyclines, was prepared in 1957 and became publicly available in 1967, with minocycline being in use by 1972.

[0004] Subsequent research efforts have focused on developing novel tetracycline antibiotic compositions that are effective under a variety of therapeutic conditions and routes of administration. Novel tetracycline analogs have also been explored, and these analogs have been able to prove more effective than the originally introduced minocycline compound. 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- ceutically active tetracyclines and tetracycline analog compositions.

[0005] Historically, shortly after their initial development and introduction, tetracyclines were found to be quite pharmacologically effective against rickettsiae; several gram-positive and gram-negative bacteria; and the causative pathogens of lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Thus, tetracyclines became known as "broad-spectrum" antibiotics. With the subsequent establishment of their in vitro antibacterial activity, efficacy in experimental infections, and pharmacological properties, tetracyclines, as a class, rapidly became widely used for therapeutic purposes.

[0006] However, this widespread use of tetracyclines for both serious and minor illnesses and diseases has directly led to the development of resistance to these antibiotics, even among highly susceptible bacterial species that are both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise in tetracycline-resistant organisms has led to a general decline in the use of tetracyclines and tetracycline analogue compositions as antibiotics of choice. Additionally, other antibacterial agents have also been overused, generating multidrug-resistant (MDR) strains of bacteria.

[0007] Over the past decade, Gram-positive bacteria with multiple resistance to a wide range of antibiotics have emerged as a major treatment challenge. Two emergences have raised concerns that currently available antibiotics may not be of significant use in treating infections caused by Gram-positive organisms. The first is the emergence of vancomycin resistance in Enterococcus species and the subsequent transfer of such resistance elements to Staphylococcus aureus. Although vancomycin-resistant S. aureus has not become epidemiologically significant, its very existence is a concern because vancomycin has been the drug of choice for infections caused by resistant Gram-positive pathogens.

[0008] A second important development has been the emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA). These strains have become increasingly multi-drug resistant over time. In many parts of the world, MRSA infections are predominantly sporadic staphylococcal infections with community onset. These strains have also been associated with numerous outbreaks of localized (skin and skin structures) and invasive (bacteremic) infections.

[0009] In addition to the general need for effective antibacterial agents to treat bacterial infections, there is also a specific need for oral antibiotic therapy.

[0010] Compared to IV administration, oral antibiotic therapy can be advantageous as it may eliminate the need for a hospital visit and / or stay, thus reducing the overall cost of treatment, limiting the patient's exposure to secondary infections in the hospital environment, and increasing the availability of treatment in areas where hospitals are less accessible or not present, particularly in isolated or economically underdeveloped areas or regions of the world.

[0011] Unfortunately, with increasing antibiotic resistance, the use of older drugs can lead to increased hospital visits and, therefore, a greater chance of patients becoming infected with other bacteria.

[0012] Thus, there remains a need for new effective oral antibacterial agents, particularly oral-only dosing regimens, for treating bacterial skin or skin structure infections, such as ABSSSIs, which alone are responsible for over 750,000 hospitalizations per year (based on the most recent data from 2011), showing a 17.3% increase in hospitalized patients with ABSSSIs between 2005 and 2011. Summary of the Invention

[0013] One aspect of the invention provides a method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection comprising orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (also known as omadacycline or OMC) or a salt thereof, wherein a once daily oral dose of 450 mg or 600 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for five or more days.

[0014] In certain embodiments, the oral dose is 450 mg once daily administered for 5 or more consecutive days.

[0015] In certain embodiments, the oral dose is 600 mg once daily for 5 or more consecutive days.

[0016] A related aspect of the invention provides a method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein a once daily oral dose of 300 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for 5, 6, 7 or 8 consecutive days.

[0017] Another related aspect of the invention provides a method of treating a bacterial skin or skin tissue infection in a human subject in need of treatment, comprising orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein an oral loading dose is administered followed by a once daily oral dose of 300 to 600 mg (e.g., 300 mg, 450 mg or 600 mg) of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline for five or more days.

[0018] In certain embodiments, the oral loading dose consists essentially of / consists of a single oral dose of 600 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the first once daily oral dose of 300 mg, 450 mg or 600 mg.

[0019] In certain embodiments, the oral loading dose consists essentially of / consists of a single oral dose of 450 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the first once daily oral dose of 300 mg, 450 mg or 600 mg.

[0020] In certain embodiments, the oral loading dose consists essentially of / consists of two oral doses of 300 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

[0021] In certain embodiments, the oral loading dose consists essentially of / consists of two oral doses of 450 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

[0022] In certain embodiments, the oral loading dose consists essentially of / consists of two oral doses of 600 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

[0023] In certain embodiments, the oral loading dose consists essentially of / consists of two oral doses of 450 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

[0024] In another aspect, the present invention provides a method of treating a bacterial skin or skin tissue infection comprising orally administering to a human subject in need thereof an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, wherein 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered orally at a dose of about 450 mg per day for two consecutive days, then at a dose of about 300 mg per day for five or more days, such that said subject is treated.

[0025] In certain embodiments, the bacterial skin or skin tissue infection is a wound infection, cellulitis / erysipelas, large abscess, furuncle / boil, carbuncle, Staphylococcal scalded skin syndrome (SSSS), or ecthyma.

[0026] In certain embodiments, the bacterial skin or skin structure infection is an acute bacterial skin and skin structure infection (ABSSSI), such as a community-acquired ABSSSI.

[0027] In certain embodiments, an ABSSSI is greater than or equal to 75 cm2 of the total surface area of ​​adjacent associated tissue. 2 That's all.

[0028] In certain embodiments, ABSSSI includes wound infection, cellulitis / erysipelas, and / or large abscess.

[0029] In certain embodiments, the bacterial skin or skin tissue infection is the result of a skin injury, including but not limited to, trauma, surgical procedures, or IV drug use.

[0030] In certain embodiments, the bacterial skin or skin tissue infection is the result of vascular insufficiency or edema.

[0031] In certain embodiments, a human subject is administered 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline under fasting conditions.

[0032] In certain embodiments, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered once daily (eg, each oral dose is administered about 24 hours apart).

[0033] In certain embodiments, the subject is treated for up to about 14 days, inclusive, up to about 10 days, inclusive, up to about 9 days, inclusive, up to about 8 days, inclusive, or up to about 7 days, inclusive, up to about 5 days, inclusive.

[0034] In certain embodiments, subjects are treated for 7-10 days.

[0035] In certain embodiments, subjects are treated for 8 days.

[0036] In certain embodiments, the salt is a tosylate salt.

[0037] In certain embodiments, the bacterial skin or skin tissue infection is known or suspected to be caused by a gram-positive pathogen. For example, Gram-positive pathogens include Staphylococcus aureus, Staphylococcus lugdunensis, Streptococcus species, Streptococcus agalactiae, Streptococcus mitis, Enterococcus species (such as Enterococcus faecalis (VRE or VSE), or Enterococcus faecium (VRE or VSE)), Streptococcus anginosus group (S. anginosus, S. constellatus, and S. intermedius). The Streptococcus species may include S. intermedius (i.e. beta, alpha or non-hemolytic), Viridans group Streptococci (VGS), Clostridium perfringens, Finegoldia magna or combinations thereof. The Staphylococcus aureus may be Methicillin-resistant Staphylococcus aureus (MRSA) or Methicillin-susceptible Staphylococcus aureus (MSSA). The Streptococcus species may include Streptococcus anginosus group. The Streptococcus species may include beta-hemolytic Streptococcus or S. anginosus. The Streptococcus species may include non-hemolytic Streptococcus or S. intermedius. The Streptococcus species may include alpha-hemolytic Streptococcus or S. constellatus. The Enterococcus species may include Enterococcus faecalis (VSE). The genus and species of Streptococcus can include Streptococcus pyogenes.

[0038] In certain embodiments, the bacterial skin or skin tissue infection is known or suspected to be caused by a gram-negative pathogen, for example, the gram-negative pathogen can include Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Prevotella denticola, Prevotella melaninogenica, or a combination thereof.

[0039] In certain embodiments, the bacterial skin or skin tissue infection is known or suspected to be caused by any of the gram-positive and gram-negative pathogens listed above, or a combination thereof.

[0040] In certain embodiments, treatment-related gastrointestinal (GI) adverse events (AEs) are predominantly mild. In certain embodiments, treatment-related GI adverse events (AEs) do not lead to discontinuation of treatment.

[0041] In certain embodiments, the AUC after the first two doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof 0-24 is approximately 10,000 ng × hr / mL.

[0042] In certain embodiments, each dose of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is administered as a 150 mg tablet.

[0043] In certain embodiments, the method has a clinical success rate of about 70-100%. For example, the clinical success rate can be about 80-100%, about 79-98%, about 79-94%, about 84-98%, about 80-88%, or about 84-89%.

[0044] In certain embodiments, the clinical success rate is observed 48-72 hours after the first oral dose and is about 79-94%, or about 84-89%, or about 87.5%. In certain embodiments, the ABSSSI consists essentially of wound infection and the clinical success rate is about 84-94% or about 89%. In certain embodiments, the ABSSSI consists essentially of cellulitis / erysipelas and the clinical success rate is about 74-84% or about 79%. In certain embodiments, the ABSSSI consists essentially of large abscesses and the clinical success rate is about 90-98% or about 94%.

[0045] In certain embodiments, the clinical success rate is the overall clinical success rate observed about 7-14 days after the last dose of treatment and is about 79-98%, about 75-95%, about 79-89%, 84%, about 95-100%, or about 98%. In certain embodiments, the ABSSSI consists essentially of wound infections and the overall clinical success rate is about 80-85% or about 82-83%. In certain embodiments, the ABSSSI consists essentially of cellulitis / erysipelas and the overall clinical success rate is about 85-91%, about 87-88%, or about 88%. In certain embodiments, the ABSSSI consists essentially of large abscesses and the overall clinical success rate is about 80-88%, or about 84%.

[0046] In a related aspect, the present invention provides a method for treating bacterial skin or skin tissue infection, comprising administering to a human subject in need thereof an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered intravenously (iv) at a dose of about 150 mg per day for two consecutive days, and then orally at a dose of about 300 mg per day for five or more days. Due to the known bioequivalence established between oral and iv doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, an iv dose of 150 mg is considered bioequivalent to an oral dose of 450 mg. Thus, alternative embodiments of this aspect of the present invention are considered to be within the scope of the present invention.

[0047] It should be understood that any one embodiment may be combined with any one or more other embodiments, including those embodiments that are disclosed only in examples or only under one aspect of the invention, unless the combination is inappropriate or expressly excluded. [Brief description of the drawings]

[0048] [Figure 1] 1 is a graph showing plasma concentration-time curves for a single oral dose of 300 mg omadacycline. [Diagram 2] FIG. 1 shows PK data for a dosing regimen of 100 mg omadacycline given iv BID (twice a day, 12 hours apart) for 1 day, then 100 mg iv per day. [Diagram 3] FIG. 1 shows PK data for a dosing regimen of 450 mg omadacycline given po QD (once daily) for 2 days, followed by 300 mg per day po. [Figure 4] FIG. 1 shows PK data for a dosing regimen of 600 mg omadacycline given po QD (once daily) for 2 days, followed by 300 mg per day po. [Diagram 5] Graph showing plasma concentration versus time curves of omadacycline after oral administration. Mean (±SD) plasma concentrations of omadacycline versus time are shown by omadacycline dose (300, 450, or 600 mg) for the pharmacokinetic population. Oral omadacycline doses were administered at time 0 for each of 5 consecutive days of dosing in each of the three 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 the subjects received a particular dose. [Figure 6]Omadacycline demonstrated statistical non-inferiority (10% margin) to linezolid for early clinical response (ECR) in the mITT (modified intent to treat) population (see left pair of bars) (FDA primary endpoint), and for clinical success at PTE (post-treatment / treatment assessment) in both the mITT PTE population (see middle pair of bars) and the CE-PTE (clinically evaluable population in PTE) population (see right pair of bars) (EMA co-primary endpoints). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] 1. Overview Omadacycline (9-[(2,2-dimethyl-propylamino)-methyl]-minocycline) is highly active in vitro against most Gram-positive pathogens. For example, it has been shown to be effective in treating complicated skin and skin structure infections (see U.S. Pat. No. 9,265,740, incorporated herein by reference). Omadacycline also exhibits activity against atypical pathogens (e.g., Legionella spp.), as well as some anaerobic and Gram-negative pathogens. The drug is active against strains expressing both mechanisms of tetracycline resistance and strains resistant to currently available antibiotics, including methicillin, vancomycin, erythromycin, and ciprofloxacin. Omadacycline has also demonstrated activity against the most common ABSSSI pathogens, including isolates resistant to standard treatments.

[0050] Omadacycline has been developed in both iv and po (oral) dosage forms. To date, over 1000 subjects have received one or both formulations in completed clinical studies.

[0051] Completed phase 1 studies have studied single IV doses up to 600 mg and single PO doses up to 600 mg. Multiple IV doses of 100 mg once daily and 200 mg once daily for up to 14 and 7 consecutive days, respectively. Multiple PO doses of 200 mg once daily and 300 mg once daily for up to 10 consecutive days have been studied. Additionally, multiple PO doses of 450 mg once daily and 600 mg once daily for 5 consecutive days have also been studied.

[0052] In a phase 2 study, 219 subjects with complicated skin and skin structure infections (cSSSI) were treated with omadacycline (n=111) or linezolid (n=108). Treatment was initiated with iv administration (100 mg per day) and switched to po therapy (200 mg per day) at the investigator's discretion. In this study, the total duration of study treatment was a mean of 10 days and a maximum of 20 days.

[0053] In a sponsor-terminated phase 3 trial of similar design, 140 subjects with cSSSI were treated with omadacycline (n=68) or linezolid (n=72) for a mean of 10 days and a maximum of 20 days for omadacycline and 22 days for linezolid. Patients were initially treated with the investigational drug, omadacycline IV (100 mg per day), then switched to oral therapy (300 mg per day) at the investigator's discretion. The expectant duration of IV treatment was 4-7 days. The total expectant duration of treatment (IV and oral) was a maximum of 14 days. The study was double-blinded during the IV treatment phase and assessor-blinded during the oral treatment phase.

[0054] In a recently completed phase 3 study comparing omadacycline with linezolid for the treatment of adults with ABSSSI, subjects were initiated on treatment with omadacycline 100 mg iv every 12 hours (q12h) followed by 100 mg iv every 24 hours (q24h) or linezolid 600 mg iv q12h for two doses. Subjects could be switched to oral treatment (omadacycline 300 mg q24h or linezolid 600 mg q12h) after a minimum of 3 days of iv treatment. Total treatment duration was 7 to 14 days. Results showed that omadacycline was noninferior to linezolid. In the FDA's primary analysis population for omadacycline versus linezolid (defined as ITT subjects without a single gram-negative pathogen at screening, N=627 total), clinical success based on reduction in lesion size 48-72 hours after the first dose was 84.8% vs. 85.5% (95% confidence interval [CI]: -6.3, 4.9), respectively. Clinical success based on investigator assessment of clinical response 7-14 days after the last dose was 86.1% vs. 83.6% (CI: -3.2, 8.2). Omadacycline was well tolerated: treatment-emergent adverse events (TEAEs) were reported in 48.3% vs. 45.7%. Serious TEAEs occurred in 3.4% vs. 2.5% of omadacycline- and linezolid-treated subjects, respectively, and discontinuations due to TEAEs occurred in 1.9% vs. 2.2%.

[0055] However, in all of the above studies, part of the dosing regimen requires iv administration of omadacycline, thus requiring a hospital visit and / or stay, or time spent in an outpatient infusion facility. Thus, in an effort to develop an orally-only effective dosing regimen that eliminates hospital visits, particularly desirable for treating community-acquired bacterial skin or skin structure infections (e.g., ABSSSI or cSSSI), an initial oral-only dosing regimen was developed in which human subjects in need of treatment for bacterial skin or skin structure infections were orally administered omadacycline at a dose equivalent to that used in a recently completed Phase 3 study, i.e., about 300 mg BID (two doses per day, 300 mg each dose approximately 12 hours apart) for 1 day, followed by a dose of about 300 mg per day for a total of 7-14 days. Notably, a previous Phase 1 study demonstrated that a 300 mg oral dose using a tablet formulation of omadacycline was bioequivalent (based on serum AUC) to a 100 mg iv dose.

[0056] Omadacycline was found to have a significant food effect in that food consumption significantly affected the oral bioavailability of an orally administered 300 mg dose of omadacycline. See Example 1. PK studies in healthy volunteers showed that bioavailability was reduced by 15%-17% with a non-dairy meal 4 hours prior to dosing, 40%-42% with a non-dairy meal 2 hours prior to dosing, and 59%-63% with a dairy meal 2 hours prior to dosing compared to the fasted dose. Thus, the food effect was more pronounced when a high-fat meal was consumed closer to dosing and when dairy was included in the meal. Based on these results, oral omadacycline should be administered at least 6 hours after a meal to achieve maximum bioavailability for oral doses designed to achieve therapeutic efficacy.

[0057] This food effect imposes a significant burden on patient compliance, especially when two oral doses are to be administered in one day at the beginning of a dosing regimen.

[0058] Preliminary results from a Phase 1 study showed that the 300 mg (QD(q24h)) and 450 mg (QD(q24h)) oral dosing regimens have similar and favorable tolerability profiles. Furthermore, PK results and PK modeling indicate that the 450 mg (po, QD(q24h)) for two doses followed by 300 mg (po, QD(q24h)) regimen achieves nearly identical steady-state concentrations within the same time frame as a dosing regimen starting with 300 mg (po, q12h) for two doses followed by 300 mg (po, QD(q24h)). In both regimens, a total of 900 mg of oral omadacycline is administered over the first two days. See Example 2.

[0059] Thus, in one aspect, the invention provides a method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection.

[0060] In a first embodiment, the method includes orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, such that the subject is treated, wherein a once daily oral dose of 450 mg or 600 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for 5 days or more.

[0061] In a second embodiment, the method includes orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof, wherein a once daily oral dose of 300 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for 5, 6, 7, or 8 consecutive days such that the subject is treated.

[0062] In a third embodiment, the once daily oral dose of the first embodiment is 450 mg administered for 5 or more consecutive days.

[0063] In a fourth embodiment, the once daily oral dose of the first embodiment is 600 mg administered for 5 or more consecutive days.

[0064] In a fifth embodiment, the method includes orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated with an oral loading dose (e.g., greater than a once-daily oral dose of 300 mg) followed by a once-daily oral dose of 300-600 mg (e.g., 300 mg, 450 mg, or 600 mg) of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline for 5 or more days.

[0065] In a sixth embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of a single oral dose of 600 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to an initial once daily oral dose of 300, 450 or 600 mg.

[0066] In a seventh embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of a single oral dose of 450 mg of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to an initial once daily oral dose of 300, 450 or 600 mg.

[0067] In an eighth embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of two oral doses of 300 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

[0068] In a ninth embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of two oral doses of 450 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

[0069] In a tenth embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of two oral doses of 600 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

[0070] In an eleventh embodiment, the oral loading dose of the fifth embodiment consists essentially of / consists of two oral doses of 450 mg 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

[0071] In a twelfth embodiment, the method includes orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline (omadacycline) or a salt thereof such that the subject is treated, wherein 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is orally administered at a dose of about 450 mg per day for two consecutive days, followed by a dose of about 300 mg per day for five or more days, e.g., a total treatment period of 7 to 14 days.

[0072] As used herein, "bacterial skin and tissue infections" are infections of the skin and associated soft tissues, such as loose connective tissue and mucous membranes. The pathogens involved in bacterial skin and tissue infections are bacterial species. Such infections often require treatment with antibiotics, such as 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline.

[0073] In a thirteenth embodiment, the bacterial skin or skin tissue infection of any one of the first to twelfth embodiments is a wound infection, cellulitis / erysipelas, large abscess, furuncle / boil, carbuncle, Staphylococcal scalded skin syndrome (SSSS) or ecthyma.

[0074] In a fourteenth embodiment, the bacterial skin or skin structure infection of any one of the first to twelfth embodiments is an acute bacterial skin and skin structure infection (ABSSSI), which most commonly includes wound infections, cellulitis / erysipelas and large abscesses.

[0075] ABSSSIs account for nearly 10% of hospital admissions and 3.4 to 3.8 million emergency room visits annually in the U.S. Analysis of hospital discharge records indicates that 74% of hospitalizations for ABSSSIs include empirical treatment with antibiotics active against methicillin-resistant Staphylococcus aureus (MRSA).

[0076] In a fifteenth embodiment, the ABSSSI of the fourteenth embodiment is a community-acquired ABSSSI.

[0077] In a sixteenth embodiment, the community-acquired ABSSSI of the fifteenth embodiment is caused by a community-associated MRSA infection.

[0078] In a seventeenth embodiment, the ABSSSI of any one of the fourteenth to sixteenth embodiments is 75 cm2 in total surface area of ​​adjacent associated tissue. 2 That's all.

[0079] In an eighteenth embodiment, the ABSSSI of any one of the fourteenth to seventeenth embodiments includes wound infection, cellulitis / erysipelas, and / or large abscess.

[0080] In a nineteenth embodiment, the bacterial skin or skin structure infection (eg, ABSSSI) of the fourteenth embodiment develops or develops during hospitalization.

[0081] In a twentieth embodiment, the ABSSSI of any one of the first to nineteenth embodiments is a moderate to severe ABSSSI.

[0082] In a twenty-first embodiment, the bacterial skin or skin tissue infection of any one of the first to twentieth embodiments is the result of (or results from) skin damage, including but not limited to trauma, surgical procedures or IV drug use.

[0083] In a twenty-second embodiment, the bacterial skin or skin tissue infection of any one of the first to twentieth embodiments is a result of (or results from) vascular insufficiency or edema.

[0084] In a twenty-third embodiment, a human subject of any one of the first to twenty-second embodiments is orally administered 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline under fasting conditions.

[0085] For example, a human subject receiving omadacycline does not consume 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 prior to each dose. Additionally, the human subject does not consume food for 2 hours and does not consume dairy products, antacids, or multivitamins containing polyvalent cations (e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours after each dose.

[0086] In a twenty-fourth embodiment, the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline of any one of the first to twenty-third embodiments is administered once daily (e.g., each oral dose is administered about 24 hours apart). For example, a human subject can take an oral dose of omadacycline in the morning after an overnight fast of at least six hours.

[0087] In a twenty-fifth embodiment, a subject of any one of the first to twenty-fourth embodiments is treated for up to about 14 days (inclusive), up to about 13 days (inclusive), up to about 12 days (inclusive), up to about 11 days (inclusive), up to about 10 days (inclusive), up to about 9 days (inclusive), up to about 8 days (inclusive), or up to about 7 days (inclusive), up to about 6 days (inclusive), up to about 5 days (inclusive), or up to about 4 days (inclusive), such that the subject is treated.

[0088] In a twenty-sixth embodiment, the subject of the twenty-fifth embodiment is treated for 7 to 10 days.

[0089] In a twenty-seventh embodiment, the subject of the twenty-fifth embodiment is treated for eight days.

[0090] In a twenty-eighth embodiment, the salt of any one of the first to twenty-seventh embodiments is a tosylate salt of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline / omadacycline.

[0091] In a twenty-ninth embodiment, the bacterial skin or skin tissue infection of any one of the first to twenty-eighth embodiments is known or suspected to be caused by a gram-positive pathogen.

[0092] In a 30th embodiment, the Gram-positive pathogen of the 29th embodiment can include (but is not limited to) Staphylococcus aureus, Staphylococcus lugdunensis, Streptococcus spp., Streptococcus agalactiae, Streptococcus mitis, Enterococcus spp. (such as Enterococcus faecalis (VRE or VSE), or Enterococcus faecium (VRE or VSE)), Streptococcus anginosus group (S. anginosus, S. constellatus, and S. intermedius, i.e., beta, alpha, or non-hemolytic), Viridans Streptococcus group (VGS), Clostridium perfringens, Finegordia magna, or combinations thereof.

[0093] In a thirty-first embodiment, the Staphylococcus aureus of the thirtieth embodiment is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA).

[0094] In a thirty-second embodiment, the Streptococcus species of the thirty embodiment includes the Streptococcus anginosus group.

[0095] In a thirty-third embodiment, the Streptococcus species of the thirtieth embodiment includes beta-hemolytic streptococcus or S. anginosus.

[0096] In a thirty-fourth embodiment, the Streptococcus species of the thirtieth embodiment comprises non-hemolytic Streptococcus or S. intermedius.

[0097] In a thirty-fifth embodiment, the Streptococcus species of the thirtieth embodiment comprises alpha-hemolytic streptococcus or S. constellatus.

[0098] In a thirty-sixth embodiment, the Enterococcus species of the thirtieth embodiment includes Enterococcus faecalis (VSE).

[0099] In a thirty-seventh embodiment, the Streptococcus species of the thirtieth embodiment comprises Streptococcus pyogenes.

[0100] In a thirty-eighth embodiment, the bacterial skin or skin tissue infection of any one of the first to twenty-eighth embodiments is known or suspected to be caused by a gram-negative pathogen.

[0101] In a thirty-ninth embodiment, the gram-negative pathogen of the thirty-eighth embodiment can include Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Prevotella denticola, Prevotella melaninogenica, or a combination thereof.

[0102] In a fortieth embodiment, GI adverse events (AEs) associated with the treatment, if any, in any one of the first to thirty-ninth embodiments, are predominantly mild.

[0103] In a forty-first embodiment, GI adverse events (AEs) associated with the treatment, if any, in any one of the first to fortieth embodiments do not lead to discontinuation of therapy.

[0104] In a forty-second embodiment, the method of any one of the first to forty-first embodiments has a higher clinical success rate than linezolid (N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide), where 600 mg of linezolid is administered orally every 12 hours.

[0105] In a 43rd embodiment, in any one of the 1st to 42nd embodiments, a successful early clinical response (ECR) (e.g., 48-72 hours after the first dose) is achieved in a human subject, defined as survival with a 20% or greater reduction in lesion size compared to pre-treatment measurements (without any rescue antibacterial treatment).

[0106] In a 44th embodiment, in any one of the first to forty-third embodiments, a successful clinical response (CR) is achieved in a human subject after completion of treatment, where the successful clinical response is defined as survival with resolution or amelioration of one or more signs and symptoms of infection to the extent that further antibacterial treatment is not required.

[0107] In a forty-fifth embodiment, in any one of the first to forty-fourth embodiments, the AUC after the first two doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is 0-24 is about 9,000 ng×hr / mL, 9,500 ng×hr / mL, 10,000 ng×hr / mL or 10,500 ng×hr / mL, or between any two of the above numbers.

[0108] In a forty-sixth embodiment, in any one of the first to forty-fifth embodiments, each dose of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is administered as a 150 mg tablet, i.e., three tablets for a 450 mg oral dose and two tablets for a 300 mg oral dose.

[0109] In a 47th embodiment, the method of any one of the 1st to 46th embodiments has a clinical success rate of about 70 to 100%.

[0110] In the 48th embodiment, the clinical success rate of the 47th embodiment is about 80-100%, about 79-98%, about 79-94%, about 84-98%, about 80-88%, or about 84-89%.

[0111] In a 49th embodiment, the clinical success rate of the 47th or 48th embodiment is observed 48 to 72 hours after the first oral dose and is about 79 to 94%, or about 84 to 89%, or about 87.5%.

[0112] In a fiftieth embodiment, the ABSSSI of the forty-ninth embodiment consists essentially of wound infection and the clinical success rate is about 84-94%, or about 89%.

[0113] In a fifty-first embodiment, the ABSSSI of the forty-ninth embodiment consists essentially of cellulitis / erysipelas and the clinical success rate is about 74-84% or about 79%.

[0114] In a fifty-second embodiment, the ABSSSI of the forty-ninth embodiment consists essentially of a large abscess, and the clinical success rate is about 90-98% or about 94%.

[0115] In a 53rd embodiment, the clinical success rate of the 47th or 48th embodiment is an overall clinical success rate observed about 7-14 days after the last dose of treatment, which is about 79-98%, about 75-95%, about 79-89%, 84%, about 95-100% or about 98%.

[0116] In a fifty-fourth embodiment, the ABSSSI of the fifty-third embodiment consists essentially of wound infection and the overall clinical success rate is about 80-85% or about 82-83%.

[0117] In a fifty-fifth embodiment, the ABSSSI of the fifty-third embodiment consists essentially of cellulitis / erysipelas and the overall clinical success rate is about 85-91%, about 87-88%, or about 88%.

[0118] In a fifty-sixth embodiment, the ABSSSI of the fifty-third embodiment consists essentially of large abscesses, and the overall clinical success rate is about 80-88%, or about 84%.

[0119] In a fifty-seventh embodiment, in any one of the first to fifty-sixth embodiments, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof has greater efficacy than linezolid for treating bacterial skin or skin structure infections (e.g., ABSSSI). Linezolid is N-[[3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]methyl]acetamide, marketed under the trademark Zyvox™. In certain embodiments, linezolid is administered at 600 mg orally or 600 mg intravenously every 12 hours.

[0120] In a fifty-eighth embodiment, in any one of the first to fifty-seventh embodiments, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is administered with a pharma- ceutically acceptable carrier.

[0121] In a fifty-ninth embodiment, the pharma- ceutically acceptable carrier of the fifty-eighth embodiment is acceptable for oral administration.

[0122] In a sixtieth embodiment, in any one of the first to fifty-ninth embodiments, the method has a clinical success rate based, for example, on a reduction in lesion size of about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% or more 48 to 72 hours after the first dose.

[0123] In a sixty-first embodiment, in any one of the first to sixtieth embodiments, the method has a clinical success rate, e.g., 7 to 14 days (e.g., 7 to 10 days, or 7, 8, 9, 10 days) after the last dose, of about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or greater clinical success based on an investigator's assessment of the clinical response.

[0124] In a sixty-second embodiment, in any one of the first to sixty-first embodiments, the human subject is complicated with bacteremia.

[0125] In a sixty-third embodiment, in any one of the first to sixty-second embodiments, the human subject is obese (eg, has a BMI≧30).

[0126] In a sixty-fourth embodiment, in any one of the first to sixty-third embodiments, the human subject has mild to moderate renal impairment.

[0127] In a sixty-fifth embodiment, in any one of the first to sixty-fourth embodiments, the human subject has liver damage.

[0128] In a sixty-sixth embodiment, in any one of the first to sixty-fifth embodiments, the human subject is over 45 years old, over 50 years old, over 55 years old, over 60 years old, over 65 years old, over 70 years old, or over 75 years old.

[0129] In a sixty-seventh embodiment, in any one of the first to sixty-sixth embodiments, the human subject is an IV drug user.

[0130] Further details of various embodiments are provided below. 2.Definition

[0131] "ABSSSI" or "acute bacterial skin and skin structure infection" is also sometimes referred to as skin and soft tissue infection (SSTI). It is a type of infection of the skin and associated soft tissues, such as loose connective tissue and mucous membranes. The U.S. Department of Health, Food and Drug Administration (FDA) published a document entitled "Guidance for Industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment" (the "Guidance" which is incorporated herein by reference) in October 2013 to assist sponsors in the clinical development of drugs for the treatment of ABSSSI. The Guidance defines ABSSSI as an infection occurring within 75 cm of the skin or skin. 2 The guidelines define infections as cellulitis / erysipelas, wound infections and large subcutaneous abscesses with a measured surface area of ​​75 cm or greater. The guidelines include infections that require more complex treatment regimens such as less serious skin infections such as impetigo, as well as small subcutaneous abscesses and infections resulting from animal or human bites, necrotizing fasciitis, diabetic foot infections, decubitus ulcer infections, fungal necrosis and ecthyma gangrenosum, or infections that require treatment with antibiotics. 2 It does not address infections of less than 100%.

[0132] Thus, in certain embodiments, ABSSSI, as used herein, includes cellulitis / erysipelas, wound infection, and large subcutaneous abscess. In certain embodiments, cellulitis / erysipelas, wound infection, and / or large subcutaneous abscess is an abscess greater than or equal to about 75 cm 2 Lesion size can be measured by areas of redness, edema, or induration.

[0133] In certain embodiments, the area of ​​ABSSSI includes certain body surface areas, such as the face, or for infants who are suitable and eligible for Phase 3 clinical trials, the ABSSSI is within 75 cm 2 Smaller, for example about 70cm 2 , 65cm 2 , 60cm 2 , 55cm 2 , 50cm 2 , 45cm 2 Or about 40cm2 The lesion may include a lesion having a surface area of

[0134] In certain embodiments, the ABSSSI may involve certain body locations such as the face, near the eyes, or hands, where the lesion is located within 40 cm 2 It may even be smaller than 100 μg / kg, but still be treatable with antibiotics.

[0135] In certain other embodiments, the ABSSSI is 75 cm 2 The exclusion list does not include lesions with a surface area of ​​less than

[0136] The size of treatable skin and skin tissue infection can be measured by the total surface area of ​​adjacent related tissue.The methods of assessing lesion size generally include, but are not limited to: (1) manual measurement, which is the multiplication of length and perpendicular width; (2) digital surface measurement; and (3) computer-assisted tracing.For example, the total surface area of ​​adjacent related tissue can be calculated as the multiplication of maximum length (from head to tip) and maximum width (measured perpendicular to length), for example, by using a wound ruler.

[0137] In certain embodiments, ABSSSI, as used herein, refers to less serious skin infections such as cellulitis / erysipelas, wound infections, large subcutaneous abscesses, and impetigo, and small subcutaneous abscesses (e.g., less than 75 cm 2 In other embodiments, ABSSSIs include less serious skin infections, such as impetigo, and small subcutaneous abscesses.

[0138] "Involved tissue" is defined as tissue that shows evidence of one or more of the following: erythema, edema, or induration.

[0139] "Wound infection" includes infections characterized by purulent drainage from the wound accompanied by surrounding erythema, edema and / or induration, in certain embodiments, the surrounding erythema, edema and / or induration extends at least 5 cm from the peripheral edge of the wound.

[0140] "Cellulitis / erysipelas" includes diffuse skin infections characterized by spreading areas of erythema, edema and / or induration.

[0141] A "large abscess" includes an infection characterized by a collection of purulent fluid within the dermis or deeper, with surrounding erythema, edema, and / or induration, hi certain embodiments, the surrounding erythema, edema, and / or induration extends at least 5 cm from the peripheral edge of the abscess.

[0142] Common bacterial pathogens causing ABSSSI include, but are not limited to, Streptococcus pyogenes and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus; less common causes include other Streptococcus species, Enterococcus faecalis, or gram-negative bacteria.

[0143] In certain embodiments, the ABSSSI is a community-acquired ABSSSI, which (as opposed to a hospital-acquired ABSSSI) is acquired by individuals who have no or little contact with the health care system. In contrast, a hospital-acquired ABSSSI is acquired by individuals who reside in a long-term health care facility or who have recently visited a hospital or other health care facility.

[0144] "Adverse Event (AE)" includes any unexpected, undesired or unplanned occurrence in the form of a sign, symptom, disease, or laboratory or physiological observation that occurs in a human administered a dose or series of doses of a subject 9-aminomethyl minocycline compound (9-[(2,2-dimethyl-propylamino)-methyl]-minocycline) during treatment.

[0145] The term "effective amount" as used herein includes the amount of omadacycline required to treat a bacterial infection. For example, an effective amount describes a level effective enough to achieve a desired therapeutic effect by killing bacteria and / or inhibiting bacterial growth. Preferably, a bacterial infection is treated when the pathogen (e.g., bacteria) is eradicated.

[0146] "Fasted state" as used herein includes a condition in which the subject being treated is denied 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 prior to each dose, and 2 hours, and no food, dairy products, antacids, or multivitamins containing polyvalent cations (e.g., aluminum, magnesium, calcium, bismuth, iron, or zinc) for 4 hours after each dose.

[0147] A "furuncle / boil" involves a deep bacterial infection of the hair follicle.

[0148] "Carbuncle" includes the adhesion of multiple furuncles.

[0149] "Staphylococcal scalded skin syndrome (SSSS)" involves red, blistered skin caused by exotoxins derived from toxin-producing strains of the bacteria Staphylococcus aureus.

[0150] "Ecthyma" includes crusted sores or ulcers (a deeper form of impetigo) caused by Streptococcus pyogenes and / or Staphylococcus aureus.

[0151] "Clinical response" to ABSSSI can be based on the percentage reduction in lesion size at 48-72 hours, as measured in patients who did not receive rescue therapy and in surviving patients, compared to baseline. Patient clinical response in this time frame is generally defined as a percentage reduction in lesion size of 20 percent or more, compared to baseline.

[0152] Evidence of a systemic inflammatory response includes the following: an increase in white blood cell (WBC) count (e.g., >10,000 cells / mm 3 ≥ 4,000 cells / mm 3 or less); an increase in immature neutrophils (e.g., 15% or more banded morphology) regardless of total peripheral white blood cell (WBC) count; lymphocytic infiltrates, e.g., lymphangitis or lymphadenopathy proximal to and at a location suggestive of drainage due to a qualifying infection; fever or hypothermia evidenced by a temperature greater than approximately 38.0°C [100.4°F] or less than 36.0°C [95.5°F].

[0153] The term "treating" or "treatment" refers to the amelioration, eradication, or alleviation of one or more symptoms of a disorder, such as a bacterial skin or skin tissue infection (e.g., ABSSSI) being treated. In certain embodiments, the term disorder includes eradication of the bacteria associated with the infection being treated.

[0154] The term "prophylaxis" means preventing or reducing the risk of bacterial infection.

[0155] The terms "resistant" or "resistant" refer to antibiotic / biological standards as defined by the Clinical Laboratory Standards Institute (CLSI) and / or the Food and Drug Administration (FDA).

[0156] "Pharmaceutically acceptable carrier" includes substances that can be co-administered with 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or its salts, which allow the drug compound to perform its intended function, for example, to treat or prevent bacterial skin or skin tissue infections. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, various paraffins, flavor oils, fatty acid mono- and diglycerides, petroleum ether fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. Pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary substances that do not adversely react with the active compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavorings and / or aromatic substances, and the like.

[0157] In certain embodiments, the pharma- ceutically acceptable (inert) carrier is 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, and the like. Additionally, oral pharmaceutical compositions may be suitably sweetened and / or flavored. In general, the therapeutically effective omadacycline of the present invention is present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.

[0158] For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain silicate complexes, together with granular binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Similar types of solid compositions may also be used as fillers in gelatin capsules, and preferred materials in this connection also include lactose or milk sugar, and high molecular weight polyethylene glycols.

[0159] When aqueous suspensions and / or elixirs are desired for oral administration, 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.

[0160] In certain embodiments, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is formulated as a tablet with excipients including lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, crospovidone, colloidal silicon dioxide, sodium bisulfite, polyvinyl alcohol, titanium dioxide, talc, glycerol monocaprylocaprate, sodium lauryl sulfate, and / or iron oxide yellow.

[0161] In addition to treating human subjects, the therapeutic methods of the invention will 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, horses, and pets such as dogs and cats. Similarly, omadacycline and its salts may be used to treat non-animal subjects, such as plants.

[0162] With the invention generally described above, the following examples further illustrate (but do not limit) the invention described herein. EXAMPLES

[0163] [Example 1] Effect of food on the bioavailability of omadacycline in healthy volunteers. Omadacycline (OMC, 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). Omadacycline has demonstrated in vitro activity against a broad range of gram-positive and gram-negative aerobic bacteria, numerous anaerobic bacteria, and atypical pathogens including Legionella and Mycoplasma spp. (Macone et al., Antimicrob Agents Chemother. 58:1127-1135, 2014; Dubois et al., In vitro activity of omadacycline against Legionella pneumophila. Abstract presented at the 55th ICAAC Conference, September 17-21, 2015, San Diego, CA; Kim et al., Activity and efficacy of omadacycline against Clostridium difficile. Abstract presented at ECCMID, Amsterdam, The Netherlands, 2016). In patients with complicated skin and skin structure infections, omadacycline has demonstrated clinical efficacy and tolerability comparable to linezolid (Noel et al., Antimicrob Agents Chemother. 56:5650-5654, 2012; Noel et al., Safety and efficacy of PTK 0796(omadacycline) as treatment of complicated skin and soft tissue infection(cSSTI). Poster presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases, March 31-April 3, 2012, London, UK).

[0164] A phase 3 trial has been concluded with omadacycline as oral and intravenous (IV) monotherapy in patients with acute bacterial skin and skin structure infections (ABSSSI).

[0165] During the development process, oral omadacycline formulations have been evolved from the free base in capsules with a series of tablet and salt formulations to improve tolerability while simultaneously optimizing oral bioavailability. The current Phase 3 tablet formulation is the tosylate salt of omadacycline, which has been shown to have an absolute bioavailability of 34.5% when administered under fasting conditions. The primary objective of this study was to evaluate the relative bioavailability of a single 300 mg oral dose of omadacycline (administered as the Phase 3 tablet formulation) at various time points after consumption of food in healthy adult subjects.

[0166] The results of this study demonstrated that food consumption influenced the oral bioavailability of a single 300 mg dose of OMC.

[0167] Briefly, this study was a phase 1 randomized, four period, open-label crossover study. Subjects were randomized to one of four treatment sequences prior to dosing on Day 1 of Period 1 (see Table 1). On Day 1 of each period, subjects received a single oral dose of 300 mg omadacycline (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. A final study completion visit occurred 6-10 days after the last dose of omadacycline.

[0168] [Table 1]

[0169] 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, in accordance with Food and Drug Administration guidelines recommendations (FDA guidelines, 2002). These meals were to be consumed within 20 minutes. Dose administration for treatments B, C, and D was based on the time of completion of the meal. During all four treatment periods, subjects did not consume any 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.

[0170] A total of 32 subjects were enrolled and administered at least one treatment period. Overall mean age was 32.3 years, ranging from 21 to 50 years. 47% were male (Table 2). One subject was discontinued from the study and did not receive Treatments A and D due to a positive alcohol screen at baseline in Period 3. One subject asked to withdraw and did not receive Treatments B and C. PK data were available for 31 subjects for each treatment condition.

[0171] [Table 2]

[0172] Blood samples for pharmacokinetic (PK) assessment of omadacycline were collected pre-dose (pre-dose) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing for each period. PK parameters included the following: area under the plasma concentration-time curve (AUC) from 0 to 24 hours post-dose (AUC 0-24 ); AUC from time 0 to the last quantifiable concentration (AUC 0 -t); AUC extrapolated from time 0 to infinity (AUC 0-inf ); maximum (peak) observed plasma concentration (C max );C max Arrival time to max ); Terminal elimination half-life (T 1 / 2 ); terminal rate constant (λz);

[0173] 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 at 24 hours post-dose in each treatment period.

[0174] Regarding statistical analysis, individual PK parameters for omadacycline were summarized using descriptive statistics. AUC and C max The geometric mean of the mean mean was calculated. 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 for the geometric mean test-to-reference ratio (B / A, C / A, or D / A) was constructed as AUC 0-24 , AUC 0-t , AUC 0-inf and C max It was concluded that there was no effect of food when the mean values ​​were within the 80%–125% reference interval for T max A Wilcoxon signed rank test was performed for p < 0.05, and a statistically significant value was considered.

[0175] Linear mixed-effects models with treatment condition, sequence, and period as fixed effects, and subjects entered within sequence as a random effect, were fitted to natural log-transformed PK parameters for effect estimates and 90% confidence intervals (CIs) for the fed compared with fasted state.

[0176] [Table 3]

[0177] PK analysis revealed that for the 31 subjects included in this PK analysis, the AUC0-inf , AUC 0-t and AUC 0-24 were 10.2, 7.2, and 7.2 mcg × hr / mL, respectively, and C max The mean T was 0.6 mcg / mL over the entire treatment period. 1 / 2 The median T ranged from 13.5 to 13.8 hours. max The 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 3.

[0178] A significant reduction in systemic exposure to omadacycline was observed with all three treatments (Treatments B, C, and D) versus Treatment A (Figure 1 and Table 4).

[0179] [Table 4]

[0180] The food effect was more pronounced when a high-fat meal was consumed closer to dosing and when dairy components were included in the meal. Compared to fasting doses, omadacycline exposure (C max The AUC and AUC were decreased by 15% to 17% when a non-dairy meal was consumed 4 hours prior to dosing, by 40% to 42% when a non-dairy meal was consumed 2 hours prior to dosing, and by 59% to 63% when a dairy meal was consumed 2 hours prior to dosing. Inter-subject variability in systemic exposure to omadacycline was C max and AUC were similar for treatments A, B, and C (CV 22.4-29.2%). In contrast, for treatment D, the CV was 42.6-44.4% for these parameters.

[0181] Regarding safety and tolerability, two subjects experienced treatment-emergent AEs (one reported nausea and one reported drowsiness). Both events were mild in intensity and considered unrelated to study drug. No subjects discontinued the study due to AEs, and no subjects experienced serious AEs (SAEs). A slight increase from baseline in heart rate (median 8-10 bpm 4-6 hours after dosing) was observed in Treatment A (i.e., the group with the highest omadacycline exposure). Among 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 clinical laboratory tests.

[0182] These results indicate that a single oral dose of omadacycline was well tolerated. Administration of the 300 mg dose within 2-4 hours of food resulted in reduced bioavailability compared to the fasted state. Therefore, once-daily oral omadacycline should preferably be administered at least 6 hours after a meal.

[0183] [Example 2] A three-period, phase I, randomized, double-blind, crossover study to evaluate the safety, tolerability, and pharmacokinetics of multiple oral doses of omadacycline or placebo in healthy adult subjects

[0184] The primary objective of this study was to evaluate and compare the pharmacokinetics (PK) of oral omadacycline at doses of 300 mg, 450 mg, and 600 mg administered daily for 5 days. Secondary objectives of the study were to evaluate the safety and tolerability of multiple doses of omadacycline in healthy adult subjects.

[0185] Second, for the treatment of ABSSSI, the expected daily therapeutic oral dose (excluding any loading dose) was 300 mg. For possible future studies or for administration of a loading dose using an oral formulation, doses greater than 300 mg per day may be used to achieve sufficient omadacycline concentrations to treat the target bacteria in the organs / tissues of interest. One early clinical study evaluated single oral doses of omadacycline up to 600 mg, but no studies evaluated multiple doses greater than 300 mg per day. This study was designed to obtain data on the safety, tolerability, and pharmacokinetics (dose linearity and proportionality) of multiple oral doses of omadacycline at doses greater than 300 mg per day. A placebo group was included as a reference to minimize potential bias when evaluating tolerability.

[0186] In this study, multiple oral doses of 300, 450, and 600 mg per day of omadacycline or placebo were selected for administration. The lowest dose, 300 mg, was evaluated in the multiple dose study and was well tolerated. This daily dose was also examined in a Phase 3 study of ABSSSI. In one early clinical study, single oral doses of up to 600 mg in capsules were administered to healthy adult subjects and determined to have an acceptable safety profile. There was a somewhat increased incidence of GI AEs at oral doses of 400 mg and above, but the events were usually mild (none severe), and some of these events may have been related to the oral formulation. Multiple doses of up to 600 mg per day using the final optimized tablet formulation of omadacycline were expected to have an acceptable safety profile, but it was important to evaluate them in small, carefully controlled Phase 1 studies before evaluating these doses in larger clinical studies.

[0187] Briefly, the study was a three-period, phase 1, randomized, double-blind, crossover study in healthy adult subjects. The study 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 in period 3). There was a washout 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 released on day 6 of period 3, 24 hours after blood sampling, urine sampling, and safety assessments were completed. Subjects returned to the study site for a study completion visit 6-10 days after the last dose of study drug in period 3.

[0188] Target Selection Healthy, non-smoking male and female subjects were admitted to 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 (conducted within 21 days prior to dosing in Period 1) and at baseline (Day -1) for Period 1, and provided written informed consent. Health status was determined by past medical history, clinical laboratory tests, vital signs (oral body 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.

[0189] Subjects were excluded from participation in the study because of previous treatment with omadacycline, recent use of other investigational drugs; abnormal ECG; inability to tolerate oral medications; pregnancy or lactation; use of tobacco products, prescription drugs, herbal supplements, or over-the-counter drugs, or consumption of foods or beverages containing xanthines (e.g., caffeine) within the specified time frame prior to the start of the study; blood loss / blood donation; 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; evidence of liver disease or liver damage; serious illness within 2 weeks of the start of the study; any planned medical intervention that may interfere with the study; or a history of a disease or medical condition specified in the study protocol.

[0190] Study design On days 1-5 of each period, subjects received one of the following treatments (omadacycline or placebo) once daily after a 6-hour fast according to the randomization schedule: A. 300 mg of omadacycline (2 x 150 mg tablets) AP. Placebo (2 x placebo tablets) for 300 mg omadacycline B. 450 mg of omadacycline (3 x 150 mg tablets) BP. Placebo (3 × placebo tablets) to 450 mg omadacycline C 600 mg of omadacycline (4 x 150 mg tablets) CP. Placebo (4 x placebo tablets) for 600 mg of omadacycline

[0191] All doses of study medication were administered in the morning without food or beverages other than water for at least 6 hours prior to dosing. Subjects then did not consume food or beverages other than water for at least 2 hours after dosing, and did not consume dairy products, antacids, or multivitamins for 4 hours after dosing.

[0192] Prior to dosing, subjects underwent a screening assessment to determine eligibility within 21 days prior to dosing in 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 presented in the table below.

[0193] [Table 5]

[0194] Approximately 10 subjects were randomly assigned to each sequence. A placebo was administered to two subjects during each sequence as a measure to assess tolerability. Subjects assigned to omadacycline received omadacycline during all three periods and at all dose levels tested. Subjects assigned to placebo received placebo during all three periods. Investigators and subjects were blinded as to whether subjects were receiving omadacycline or placebo.

[0195] Consideration Assessment 1. Pharmacokinetics in plasma Serial blood samples for pharmacokinetic (PK) analysis of omadacycline were collected from designated time points up to 24 hours after dosing on Days 1 and 5 of each period. Specifically, blood samples for PK assessment of omadacycline were collected from all subjects at the following time points: pre-dose (pre-dose), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after dosing on Days 1 and 5 of each period. The 24-hour blood sample on Day 1 was collected pre-dose on Day 2 of each period.

[0196] Area under the plasma concentration versus time curve (AUC) from 0 to 24 hours post-dose (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 the maximum observed plasma concentration (T max ), terminal elimination half-life (T 1 / 2 ), terminal rate constant (λ z ) and AUC 0-24 and C. max Non-compartmental PK parameters, including accumulation factors (Rac) with and without seroconversion, were determined from plasma omadacycline concentrations and actual time data on days 1 and 5 of each period.

[0197] Subjects who took omadacycline and had at least one evaluable PK parameter were included in the PK analysis population. However, subjects who missed a dose, median T max Patients may be excluded from the PK population if they experience diarrhea or vomiting at or before twice the time equal to

[0198] 2. Urinary Pharmacokinetics Urine samples were collected from a subset of subjects on Day 5 of Period 2, and at specified intervals on Days 1 and 5 of Period: pre-dose, 0-4, 4-8, 8-12, and 12-24 hours post-dose. Urine samples at the 12-24 hour interval on Day 1 were collected pre-dose on Day 2. Urine samples were only collected from a subset of subjects because an amendment to the study protocol added urinary PK analysis after the study was already underway.

[0199] SAS version 9.2 was used to derive the following urinary omadacycline PK parameters from the urinary concentration and collection interval data: renal clearance (CLr), the percentage 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 administration (Aet1-t2 ) was determined. An additional parameter Ae 0-4 , Ae 4-8 , Ae 8-12 , Ae 12-24 and Ae 0-24 was also calculated.

[0200] 3. Safety and Tolerability Safety assessments included monitoring of adverse events (AEs), clinical laboratory test 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 system organ class using MedDRA version 17.1.

[0201] Safety and tolerability were assessed by monitoring and recording of AEs, clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital sign measurements (oral body temperature, systolic blood pressure, diastolic blood pressure, and HR), 12-lead electrocardiogram results, and physical examination findings.

[0202] Statistical analysis for pharmacokinetic studies: Individual plasma and urine concentration and time deviation data are presented in the data listing. Plasma and urine concentration data were summarized by day and time point or interval for each treatment 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 summary descriptive statistics of plasma and urine concentrations. Mean and individual plasma concentration versus time profiles are presented in the figures for both linear and semi-log scales.

[0203] 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 urinary 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.

[0204] For PK analysis, BLQ values ​​were treated as zero, except that BLQ values ​​between two quantifiable concentrations were set as unknown. From the PK parameter calculations, unknown concentrations were treated as unknown. In the terminal phase, if consecutive BLQ concentrations were followed by quantifiable concentrations, those concentrations after the BLQ concentrations were treated as unknown.

[0205] Individual PK parameters are presented in the data listing. Descriptive statistics (number of subjects, mean, SD, CV, median, minimum and maximum) were calculated for PK parameter estimates (e.g., plasma concentration to AUC 0-24 , AUC last , C max , T max , T 1 / 2 and Rac [only on the 5th day]; CLr, Fe from urinary concentrations 0-24 and Ae 0-24 ). AUC 0-24 , AUC last and C max Geometric means were included for

[0206] 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 within sequence as random effects, was used to estimate the effects and construct confidence intervals (CIs) for the PK parameter AUC normalized to natural log-transformed dose after dosing on days 1 and 5 of each period.0-24 / dose, AUC last / Dose, and C max The point estimates of differences and 90% CIs to the log scale were exponentiated to obtain estimates of the ratio of geometric means and respective 90% CIs to the original scale. No adjustment for multiplicity was made.

[0207] C of omadacycline after both day 1 and day 5 administration max , AUC last and AUC 0-24 Dose linearity across all three dose levels was assessed by fitting to an exponential 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.

[0208] For statistical analysis of omadacycline accumulation, a linear mixed-effects model with days as fixed effect and subjects as random effects was used to determine C max and AUC 0-24 to construct 90% CIs for day 5 compared with day 1 (separately for each dose level).

[0209] result Demographics, baseline characteristics, and predisposing factors of subjects studied 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 2-1) and across 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, ranging from 21 to 55 years.

[0210] [Table 6]

[0211] All 33 subjects who received at least one dose of study drug (omadacycline or placebo) 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). In addition, one omadacycline-treated subject was lost to follow-up. Thus, all 22 subjects received five doses of 300 mg, 450 mg, and 600 mg omadacycline, and all six subjects received five doses of placebo in periods 1, 2, and 3. These subjects were considered to have completed the study.

[0212] b. Plasma pharmacokinetics Preliminary results of the PK studies at the end of Days 1 and 5 are summarized below.

[0213] [Table 7] TIFF2025041903000008.tif92120

[0214] Pharmacokinetic data from this study and other Phase 1 studies were used to construct PK models for the following dosing regimens, the results of which are presented in Figures 2-4.

[0215] Specifically, FIG. 2 is a graph showing PK data for a dosing regimen, in this case 100 mg omadacycline administered iv BID (twice a day, 12 hours apart) for 1 day, followed by 100 mg iv / day.

[0216] FIG. 3 is a graph showing PK data for the dosing regimen, 450 mg omadacycline po QD (once a day) for 2 days, followed by 300 mg po / day.

[0217] FIG. 4 is a graph showing PK data for the dosing regimen: 600 mg omadacycline po QD (once a day) for 2 days, followed by 300 mg po / day.

[0218] AUC for the dosing regimens shown in Figures 2 and 3 0-24 It is clear that they were almost identical.

[0219] A more detailed data analysis is presented below.

[0220] At all dose levels of omadacycline tested, on both days 1 and 5 of each 5-day treatment period, mean plasma omadacycline concentrations peaked 2.5 hours post-dose (T max ), omadacycline was measurable in plasma for up to 24 hours after dosing (last sampling time) (Figure 5 and Table 2-2).

[0221] [Table 8]

[0222] As omadacycline dose was increased (300 vs. 450 vs. 600 mg) on ​​both days 1 and 5, total omadacycline exposure (AUC 0-24 and AUC last ) and peak concentration (C max ) increased and was higher on day 5 than on day 1 for the corresponding doses (Figure 5 and Table 2-2). 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 from 15.49 to 16.83 hours on day 5 (Table 2-2). Intersubject variability in systemic omadacycline exposure was low and similar across all three dose levels tested, with coefficients of variation (CV) of 0.01 to 0.05 on day 1 and 0.02 to 0.17 on day 5. max , AUC 0-24 and AUC last In the case of max , AUC 0-24 and AUC last In the case of , the rate was 25.0% to 27.1% (Table 2-2).

[0223] AUC of omadacycline 0-24 , AUC last and C max increased with increasing omadacycline dose, but the observed increase in exposure was less than dose-proportional on both analysis days (Tables 2-2 and 2-3).

[0224] [Table 9]

[0225] 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 (based on dose-proportionality) was 76% of that predicted if exposure was perfectly dose proportional (Table 2-3); at day 5, the observed increase in omadacycline exposure was 88% of that predicted (Table 2-3). max Analysis of values ​​similarly demonstrated that omadacycline concentrations were linear with dose, but less than dose proportional in this study (Tables 2-2 and 2-3).

[0226] Statistical analysis also revealed the accumulation of omadacycline in plasma after 5 consecutive days of once-daily dosing. Depending on the dose, the accumulation rate between day 5 and day 1 was as follows: AUC 0-24 In the case of 1.40 to 1.62, and Cmax In the case of omadacycline, the half-life ranged from 1.24 to 1.35 (data not shown). These findings are consistent with the long half-life of omadacycline in plasma.

[0227] The data above show that mean omadacycline concentrations peaked at 2.5 hours and remained measurable for up to 24 hours (the last time point tested) at all dose levels of omadacycline (300, 450, and 600 mg). On day 5, mean steady-state exposure (AUC 0-24 The AUC was 9267 ng·h / mL, which is consistent with previous results from a 300 mg oral dose. 0-24 and C. max Both increased with increasing dose and were approximately dose proportional, but somewhat less than expected (74%-88% of predicted). This was true for both days 1 and 5 of dosing. Omadacycline accumulated in plasma over the course of 5 consecutive days of dosing due to its relatively long half-life (mean = approx. 13 hours on day 1 and 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 again consistent with that observed after multiple dosing of omadacycline in early pharmacology studies, either once daily, IV or oral formulations.

[0228] With regard to systemic exposure, this study demonstrated that plasma concentrations of omadacycline on day 1 at the 450 mg dose were similar to those on day 5 at the 300 mg dose (mean AUC 0-24= 8976.5 and 9267.2 ng·h / mL). For indications where the treatment dosing regimen incorporates an oral dose of 300 mg per day, these data support the use of an initial oral "loading dose" of 450 mg once daily for 1 to 2 days, followed by oral dosing of 300 mg once daily. Such a strategy could potentially obviate the need for Phase IV of treatment and is currently being evaluated in an ongoing Phase 3 trial of oral-only omadacycline treatment in patients with ABSSSI (ClinicalTrials.gov ID, NCT02877927). C. Urinary pharmacokinetics

[0229] Urine sampling and PK analysis was added to the study by protocol amendment after the study was underway, so only 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). Although the sample size was too small to make meaningful comparisons between omadacycline dose groups, the results of this analysis provided a comprehensive indication of partial omadacycline renal clearance and urinary excretion.

[0230] For all omadacycline dose groups, 0–24 h post-dose (Fe 0-24 The mean percentage of the dose excreted unchanged in the urine 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 (Tables 2-4).

[0231] [Table 10]

[0232] Urinary KP 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. Since the absolute bioavailability of the tablet formulation used in this study 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. d. Safety and Tolerability

[0233] Overall, 12 of the 33 subjects in the safety population reported a total of 36 TEAEs during the study (Tables 2-5).

[0234] [Table 11]

[0235] 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 subjects in the 300 and 450 mg omadacycline dose groups and 16.7% of subjects in the 600 mg group. All of the TEAEs reported in this study were either mild or moderate in severity. There were no serious TEAEs (SAEs) reported during this study. Four subjects experienced TEAEs leading to study discontinuation, including one subject in each of the three omadacycline dose levels and one subject in the placebo group.

[0236] There were no clinically significant findings in the analysis of vital sign measurements, physical examinations, ECG results, hematology, or urinalysis parameters. Analysis of serum chemistry 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 receiving 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 the median aspartate aminotransferase (AST), bilirubin, or other serum chemistry parameters. The highest individual ALT value was 150 IU / L (2.7-fold higher than the upper limit of normal [ULN]), which occurred in a subject who first received 450 mg of omadacycline in period 1, then 300 mg in period 2, and then discontinued due to changes in liver enzymes. This subject's bilirubin levels remained within the normal range at all time points evaluated.

[0237] The plasma PK findings indicate that higher systemic drug exposure can be achieved by increasing the amount of omadacycline administered per dose during once-daily oral administration, but the benefit of exposure is not dose-proportional. Furthermore, increasing the dose of omadacycline beyond a certain point appears to have side 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%), but such events were more frequent at 600 mg (25.0%). Among the most frequent classes of TEAEs, GI disorders, nausea, occurred at a rate at least 9% higher at the 600 mg dose level than at lower doses, and diarrhea was reported in only two cases at the 600 mg dose. Furthermore, serum chemistry analysis showed a small but notable dose-dependent increase in median ALT concentrations. Although individual ALT values ​​did not exceed 3-fold above the ULN, the higher median ALT at 600 mg suggests an increased opportunity for more pronounced elevations in serum transaminase levels at this dose. In situations where oral doses above 300 mg may be beneficial, based on these findings, 450 mg was identified as the oral dose most likely to provide higher omadacycline exposure with favorable safety and tolerability.

[0238] In summary, this phase 1 study investigated the pharmacokinetics (PK) and safety / tolerability of multiple oral doses of omadacycline higher than 300 mg. Using a three-period crossover design, healthy adults were randomized to receive omadacycline (300 mg, 450 mg, and 600 mg in various sequences; n=26) or placebo (n=7) once daily for 5 consecutive days per period. In plasma, maximum and total exposures to omadacycline increased with increasing dose but were less than dose-proportional (74%-88% of predicted). The kinetics of omadacycline accumulation in plasma was similar between dose levels. Exposure on day 5 was approximately 50% higher than on day 1. Plasma concentrations of omadacycline at 450 mg on day 1 were similar to those at 300 mg on day 5. 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 omadacycline once daily as part of an oral-only dosing regimen, such as using 450 mg oral omadacycline once daily (1 or 2 doses) as a loading dose before reducing to 300 mg oral omadacycline once daily, or in a dosing regimen using 450 mg oral omadacycline once daily throughout treatment.

[0239] [Example 3] A multicenter, phase 3, randomized, double-blind study comparing the safety and efficacy of oral omadacycline with oral linezolid for treating adult subjects with acute bacterial skin and skin structure infections (ABSSSI)

[0240] The first aminomethylcycline antibiotic, 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline, otherwise known as omadacycline (OMC), is a semisynthetic derivative of the tetracycline class. As a class, the tetracyclines have been in use for about 70 years. They are well tolerated and have proven effective in treating a variety of bacterial infections.

[0241] Omadacycline has demonstrated activity against the most common ABSSSI pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Omadacycline was evaluated in a Phase 2 study of 219 subjects with complicated skin and skin structure infections (cSSSI) and in a sponsor-terminated Phase 3 study of 140 subjects with cSSSI. Omadacycline was well tolerated and demonstrated similar efficacy to an established comparator (linezolid).

[0242] In a recently completed global Phase 3 trial in 645 subjects comparing the safety and efficacy of intravenous (iv) and oral (po) omadacycline with iv and po linezolid in the treatment of adult subjects with ABSSSI, omadacycline was non-inferior to linezolid and well tolerated. I. Study design

[0243] This was a Phase 3 study designed to demonstrate the safety and efficacy of po omadacycline compared with po linezolid in the treatment of adult subjects with ABSSSI. Specifically, the study was designed to demonstrate that omadacycline administered orally (po) for 7 to 14 days was non-inferior (10%) to linezolid administered orally for 7 to 14 days in the treatment of adult subjects with ABSSSI known or suspected to be due to a Gram-positive pathogen. Additionally, the study was designed to demonstrate that omadacycline is safe in the treatment of adult subjects with ABSSSI and that the clinical responses observed are due to neutralization of the identified causative pathogen of the ABSSSI. Finally, the pharmacokinetics (PK) of oral omadacycline were evaluated in these adult subjects.

[0244] The study was designed as a randomized (1:1), double-blind, double-dummy, active comparator-controlled Phase 3 study comparing omadacycline with linezolid for the treatment of adult subjects with ABSSSI known or suspected to be due to a Gram-positive pathogen. Enrollment of subjects with large abscesses could be up to 30% of randomized subjects. Enrollment of subjects who had received a single dose of tolerated short-acting antibiotic within 72 hours prior to randomization was limited to less than 25% of randomized subjects. Subject randomization was stratified between treatment groups by type of infection (wound infection, cellulitis / erysipelas, or large abscess) and prior receipt of tolerated short-acting antibiotics (yes or no).

[0245] The study consisted of three protocol-defined phases: screening, double-blind treatment, and follow-up. All screening evaluations, except blood cultures, were completed within 24 hours prior to randomization. Blood cultures were completed within 24 hours prior to the first dose of test article. Subjects who met the inclusion criteria and those who did not meet the exclusion criteria were randomly assigned to a treatment group and received their first dose of test article (either omadacycline or rezoneride) at the site within 4 hours after randomization.

[0246] This study was designed in accordance with the US FDA and European Medicines Agency (EMA) guidelines for antibiotic development for the treatment of ABSSSIs, as well as the 2012 update from the Infectious Diseases Society of America (IDSA) and the National Institutes of Health Foundation Biomarker Consortium.

[0247] The comparator drug, linezolid, is approved worldwide to treat ABSSSIs caused by Gram-positive pathogens and has an acceptable, well-defined safety profile. Linezolid may be administered orally and has been approved by regulatory agencies to treat ABSSSIs caused by Gram-positive pathogens, including MRSA.

[0248] Subjects participated in the study for approximately 30 days. After screening, eligible subjects were randomly assigned to receive po treatment with either omadacycline or linezolid for 7 to 14 days. Follow-up office visits occurred approximately 7 to 14 days after the last dose of study article, and follow-up telephone contacts occurred approximately 30 to 37 days after the first dose of study article.

[0249] Other than informed consent, to be eligible for randomization in this study, eligible subjects met all of the following key criteria: (1) were male or female, aged 18 years or older; (2) had a qualifying skin and skin structure infection. For the purposes of the clinical trial, all eligible lesions were to be greater than or equal to 75 cm2 in total surface area of ​​adjacent involved tissue, calculated as the product of the maximal length (from head to tip) and the maximal width (measured perpendicular to the length), as measured by the investigator using a wound ruler. 2 Involved tissue was defined as tissue showing clear evidence of one or more of the following: erythema, edema, or induration; (3) Eligible infection categories were: wound infection, i.e., infection characterized by purulent drainage from the wound with surrounding erythema, edema, and / or induration extending at least 5 cm from the peripheral edge of the wound; cellulitis / erysipelas, i.e., diffuse skin infection characterized by spreading areas of erythema, edema, and / or induration; large abscess, i.e., infection characterized by a collection of purulent fluid within the dermis or deeper with surrounding erythema, edema, and / or induration extending at least 5 cm from the peripheral edge of the abscess; (4) had evidence of a systemic inflammatory response within the 24 hours prior to randomization, as indicated by one of the following: an increased white blood cell (WBC) count (10,000 cells / mm 3 ≥ 4,000 cells / mm 3or less); increased immature neutrophils (≥15% band morphology) regardless of total peripheral WBC count; lymphocytic infiltrates: lymphangitis or lymphadenopathy proximal to and at a location suggestive of drainage due to a qualifying infection; and fever or hypothermia documented by the investigator (temperature >38.0°C [100.4°F] or <36.0°C [95.5°F]).

[0250] During the screening phase, subject eligibility and baseline characteristics for each subject (based on comprehensive medical history and physical examination with particular attention to any history related to the infection under consideration) were established. Subjects were eligible for screening if they presented with signs and symptoms of ABSSSI. For example, at the time of screening evaluation, the type of ABSSSI: wound infection, cellulitis / erysipelas, or large abscess, as defined in the inclusion criteria, was recorded. To be eligible, subjects had to have 75 cm2 or more of wound infection in the total surface area of ​​adjacent involved tissue (i.e., surrounding erythema, edema, and / or induration). 2 It must be greater than or equal to this.

[0251] The anatomical location of the primary site of infection was also recorded. For subjects with multiple non-contiguous areas of infection, the most severely affected area was identified at screening and designated as the primary lesion site. The presence and nature of any foreign body (e.g., wood, metal, plastic, etc.) present at the site of infection was noted. The following information regarding the primary site of infection was recorded: presence of lymphadenopathy proximal to the primary lesion site; and presence of lymphangitis proximal to the primary lesion site; presence and description (serosous / serosanguineous, seropurulent, or purulent) of drainage from the primary lesion site. A semi-quantitative (none, mild, moderate, severe) description of infection for the following features was also obtained: tenderness, edema, erythema, and induration.

[0252] Screening assessment measurements of lesion size were collected within 4 hours prior to randomization. Lesion surface area was calculated by multiplying the maximum length and maximum width (perpendicular to the maximum length) of the entire lesion from head to tip, including adjacent involvement (erythema, edema, and / or induration). Investigator ruler measurements could be used to verify lesion size.

[0253] Additionally, each subject was asked to report certain outcomes or parameters related to disease status and treatment effectiveness, such as a numeric rating scale (0-10) of pain at the site of the primary ABSSSI lesion; the SF-36v2® Health Survey (also referred to as the General Health Survey because it can be used across ages (18 years and older), diseases, and treatment groups, as opposed to disease-specific health surveys that focus on a particular condition or disease). Additionally, a urine dipstick was performed at the site at screening.

[0254] Subjects who met the inclusion criteria and those who did not meet the exclusion criteria were randomly assigned to a treatment group and received their first dose of study article at the site within 4 hours after randomization.

[0255] Subjects were randomized (1:1) to one of two treatment groups:

[0256] Investigational treatment: omadacycline 450 mg po q24h for two doses, followed by 300 mg po q24h. Total treatment duration is 7-14 days. Standard treatment: Linezolid 600 mg po every 12 hours (q12h). Total treatment duration is 7-14 days.

[0257] The study used a double-blind, double-dummy design, using an omadacycline placebo comparator tablet matched in size and shape to the active omadacycline tablet, and an overencapsulated placebo and overencapsulated active linezolid tablet. To maintain double-blindness, subjects in both groups received the same number of tablets.

[0258] The double-blind treatment period was designed to be in accordance with the current study and lasted from 7 to 14 days. The following table summarizes the actual study drug exposure in the safety population:

[0259] [Table 12]

[0260] Percentage exposure was based on subjects who received at least one dose. Exposure duration of study drug in days = date of last dose - date of first dose + 1

[0261] All doses of test article were taken with water. Due to the effect of food on oral omadacycline, fasting was required to administer doses on odd-numbered days. These fasting requirements were taken into consideration when determining the day and time that subjects would take their dose. II. Effectiveness and Evaluation

[0262] Subjects were evaluated at two visits after completion of treatment, at a PTE (Post Treatment Evaluation) visit 7-14 days after the subject's last day on study treatment, and at a final follow-up assessment 30-37 days after the first dose of treatment. The final follow-up assessment could be conducted by telephone contact or by another interactive technique for subjects who were considered clinical successes at or after the PTE visit and had no noted AEs or clinically significant laboratory or ECG abnormalities. Otherwise, this assessment was conducted at an in-person study visit.

[0263] Efficacy analyses were based on the following list of critical assessments: Clinical assessment of the site of infection Assessment of lesion size Assessment of the need for adjunctive surgical procedures Microbiological assessment of infection Investigator assessment of clinical response All-cause mortality assessment

[0264] Each is described in further detail below. A. Clinical assessment of the site of infection

[0265] Clinical assessment of the site of infection was performed at screening and at each scheduled assessment except the final follow-up assessment. Clinical assessment of the site of infection was performed within 48-72 hours after the first dose. The primary site of infection was examined and the following information was recorded: presence and description (serosous / serosanguineous, seropurulent or purulent) of drainage from the primary lesion site; and a semiquantitative (none, mild, moderate, severe) description of the infection relative to the following characteristics (tenderness, edema, erythema and induration). b. Lesion size assessment

[0266] Ruler measurements of lesions were taken at screening and each scheduled evaluation except for the final follow-up assessment.

[0267] Lesion surface area was calculated by multiplying the maximum length from head to tip of the entire lesion, including adjacent involvement (erythema, edema, and / or induration), by the maximum width (perpendicular to the maximum length). Investigator ruler measurements were used to establish lesion size. C. Microbiological assessment of the site of infection

[0268] At the screening visit, material was collected from the infection site and submitted to the institution's on-site microbiology laboratory for Gram stain and culture. The type of specimen submitted was recorded. Laboratory reports on Gram stain included a semiquantitative description of the polymorphonuclear leukocyte count in a low-power field (i.e., 100×) and a description of the bacteria observed. Blood cultures were also performed to evaluate for concurrent bacteremia.

[0269] As the infected site responds to treatment, repeat cultures may not be clinically appropriate and / or there may be no material to culture. At the EOT and / or PTE visits, specimen cultures and Gram stains of the infected site were obtained only for subjects who had clinical failure and required alternative antimicrobial treatment for the infection under consideration.

[0270] All specimens submitted to the facility's on-site laboratory were evaluated for aerobic and, where appropriate, anaerobic cultures. Culture results included a semiquantitative description of the organisms on the primary culture plates and identification of all isolates to the genus and species level. Susceptibility testing to linezolid was performed on-site using standard methods selected by the laboratory. Results from this testing were used along with clinical findings to help guide treatment.

[0271] All bacterial isolates identified from specimens from infection sites or blood were submitted to a central laboratory for genus and species matching and standard minimum inhibitory concentration (MIC) testing against omadacycline, linezolid, and a panel of currently approved antibiotics.

[0272] Decisions to continue or discontinue study article and to modify antimicrobial regimens if there was evidence of gram-negative or anaerobic organisms, or organisms that were nonsusceptible to linezolid, were made based on the investigator's clinical judgment and recorded in source documentation. d. Assessment of Clinical Outcomes

[0273] Clinical outcome assessments were performed at Early Clinical Response Assessment (by program), EOT, and PTE, as described below. i) Evaluation of infections under study during Early Clinical Response Assessment

[0274] Formal determination of response to treatment during the Early Clinical Response Assessment (48-72 hours after the first dose of test article) was made programmatically using lesion measurements.

[0275] "Clinical success" at the time of the Early Clinical Response Assessment was defined as meeting all three of the following: the subject is alive; the primary lesion size has decreased by 20% or more compared to the screening measurement without any alternative (rescue) antimicrobial therapy; and the subject has not met any criteria for clinical failure or indeterminate (see below for definitions).

[0276] "Clinical failure" was defined as meeting any of the following criteria: the primary lesion did not decrease in size by 20% or more compared to the screening measurement; the test article was discontinued based on a determination that the infection had responded inadequately and required alternative (rescue) antimicrobial therapy; the subject received antimicrobial therapy for a variety of infections originating from a single organism during the study that could have been effective for the infection under study; the subject developed an AE prior to the Early Clinical Response Assessment that necessitated discontinuation of the test article and required alternative (rescue) antimicrobial therapy; or died prior to the Early Clinical Response Assessment.

[0277] "Indeterminate" was given when the clinical response to the study article could not be adequately inferred for the following reasons: the subject withdrew consent, did not appear for an early clinical response assessment, was lost to follow-up, or other reasons. ii) Clinical evaluation of the ongoing infection at EOT

[0278] At the EOT visit (on the day of the last dose of study article or within 2 days thereafter), a subinfectious clinical status was noted as detailed below.

[0279] "Clinical success" at the end of treatment (EOT) assessment was defined as satisfying the following: the subject survived; and the infection resolved sufficiently to not require further antimicrobial treatment (these subjects may have some residual changes related to the infection that require adjunctive (i.e., non-antibiotic) treatment, e.g., dressings on healing wounds, debridement (i.e., necrosis) of uninfected tissue).

[0280] Clinical failure was defined as meeting any of the following criteria, specifying the primary reason for clinical failure: the test article was discontinued based on a determination that the infection responded inadequately and would require alternative (rescue) antimicrobial therapy; the subject received antimicrobial therapy that could have been effective for the infection under study for a variety of infections originating from one bacteria during the study; or the subject developed an AE that necessitated discontinuation of the test article before completion of the planned test article regimen and required alternative (rescue) antimicrobial therapy; unplanned major surgical intervention (i.e., a procedure not typically performed at the bedside) for the infection under study; the subject died before evaluation; or other.

[0281] "Indeterminate" was given when the clinical response to the study article could not be adequately inferred. All that applies will be noted: subject withdrew consent, did not appear at EOT assessment, lost to follow-up, or other reasons. iii) Clinical evaluation of the infection under investigation at the time of PTE

[0282] At the post-treatment evaluation PTE visit (7–14 days after the subject's last day of study treatment), one of the following outcomes related to the primary infection under study was demonstrated:

[0283] "Clinical success" at the time of the post-treatment evaluation assessment was defined as satisfying the following: the subject survived; the infection resolved sufficiently to not require further antimicrobial treatment (these subjects may have some residual changes related to the infection that require adjunctive (i.e., non-antibiotic) treatment, e.g., dressings on healing wounds, debridement (i.e., necrosis) of uninfected tissue).

[0284] "Clinical failure" was defined as meeting any of the following criteria, specifying the primary reason for clinical failure: the infection required additional treatment with alternative (rescue) antimicrobial therapy; the subject received antimicrobial therapy between EOT and PTE that could have been effective for the infection under consideration, for a variety of infections originating from one bacterium during the study; unplanned major surgical intervention (i.e., a procedure not typically performed at the bedside) between EOT and PTE for the infection under consideration; the subject died before evaluation; and other.

[0285] "Indeterminate" was given when the clinical response to the study article could not be adequately inferred. All applicable were noted: subjects withdrew consent, did not appear for PTE assessment, lost to follow-up, and other reasons.

[0286] III. Pharmacokinetic studies PK data were analyzed using a population PK model. Blood samples for PK analysis were collected using a sparse sampling method for the population PK model. The number of samples and collection schedule varied for individual subjects. A maximum of four blood samples were collected per subject between days 2 and 3. For this purpose, blood was collected by fresh venipuncture or using only a cannula. All doses of test article and the date and time of PK sample collection were recorded. Subject identity, sample number, and time of sample collection to the nearest minute were immediately recorded on the collection tube. The tubes were centrifuged at 1500×g for 10 minutes. The separated plasma was transferred in two equal aliquots to pre-labeled tubes. The tubes were frozen at −70° C. within 60 minutes of collection. The time the samples were frozen was recorded to the nearest minute.

[0287] Omadacycline samples were analyzed using a specific, sensitive, validated liquid chromatography / tandem mass spectrometry (LC / MS / MS) method.

[0288] IV. Safety Monitoring An adverse event (AE) is any unexpected, unwanted or unplanned occurrence in the form of a sign, symptom, illness, or laboratory or physiological observation occurring in a human administered a test article or in a clinical study. An event does not require a causal relationship to the test article or clinical study. AEs include, but are not limited to: any clinically significant worsening of a pre-existing condition; AEs resulting from an overdose of the test article, whether accidental or intentional; an overdose is a dose exceeding the dose specified in the protocol; AEs resulting from abuse of the test article (e.g., use for non-clinical reasons); and AEs associated with discontinuation of the use of the test article.

[0289] The severity (or intensity) of AEs was classified using the following criteria:

[0290] Mild: These events were usually temporary, required minimal or no treatment, and did not interfere with the subject's daily activities.

[0291] Moderate: These events pose a low level of inconvenience or concern for therapeutic measures. Moderate events may result in some interference with normal functioning but do not pose a serious or permanent risk of damage.

[0292] Severe: These events interfere with the subject's normal daily activities and may require systemic medication or other treatment. Severe events were usually incapacitating.

[0293] Serious adverse events (SAEs) are AEs that result in death; are life-threatening (see below); require hospitalization or prolong an existing hospitalization (see below); result in permanent or serious disability or loss of function (see below); result in congenital malformation or birth defects. Additionally, a significant medical event that does not result in death, is not life-threatening, or does not require hospitalization may be considered an SAE if, based on appropriate medical judgment, the event endangers the subject and may require medical or surgical intervention to prevent any one of the outcomes listed above in this definition. Examples of such events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or seizures that do not result in hospitalization, or the development of drug dependence or abuse.

[0294] Life threatening means that there is an imminent risk of death if the event occurs to the reporter. Life threatening experiences do not include experiences that occur in a more severe form and thus have the potential to cause death, but that do not pose an immediate risk of death if they actually occur.

[0295] Hospitalization is a formal admission to a hospital. Hospitalization or prolonged hospitalization constitutes a criterion for whether an AE is serious, but is not, in itself, considered an SAE. In the absence of an AE, hospitalization or prolonged hospitalization was not reported as an SAE by the participating investigator. This is an example in the following situations: the hospitalization or prolonged hospitalization was necessary for a procedure required by the protocol; the hospitalization or prolonged hospitalization was part of a routine procedure and subsequently became central (e.g., stent removal after surgery); and hospitalization for a pre-existing condition that did not worsen.

[0296] An impairment is defined as a substantial disruption of a person's ability to perform normal life functions. If any doubt exists as to whether information constitutes an SAE, the information will be treated as an SAE.

[0297] Subject AEs and SAEs were reported from the time of signing the informed consent form until the time of the final follow-up assessment. Subjects were instructed to report AEs and SAEs during this period. Reports of deaths within 30 days after last contact with the subject were reported to the sponsor and additional information related to the cause of death was requested and documented.

[0298] Subjects were followed as medically necessary for all AEs and SAEs until the events subsided and the condition returned to baseline, or in the case of permanent disability, the condition stabilized.

[0299] AEs were based on signs or symptoms detected during the subject's physical examination and on clinical evaluation. Because AEs required surgical or diagnostic procedures, illnesses leading to these procedures were recorded as AEs, not the procedures themselves. Death was recorded as the outcome of an AE. Any unexpected risks to subjects were promptly reported.

[0300] All AEs and SAEs were assessed for relevance and causality (i.e., whether there was a reasonable possibility that the test article caused the event). Relevance was characterized using the following categories: Unrelated: The relationship suggested that there was no relationship between the test article and the reported event. The event could be explained by other factors, such as an underlying medical condition, concurrent treatment, or accident, and there was no possible temporal or biological relationship between the test article and the event. Related: This relationship suggested that there was a clear causal relationship between administration of the test product and the AE, or that there was a reasonable possibility that the event was caused by the study medicinal product, and that other conditions (concurrent illness, progression / development of a disease state, or response to a concomitant medication) did not appear to explain the event.

[0301] AEs and SAEs were also evaluated for their potential relationship to the protocol. Protocol-related adverse events are those not related to the test article, but 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 is participating in the study. For example, a protocol-related AE may be an unexpected event related to a medical procedure required by the protocol. The severity (or intensity) of the AEs was classified using the following criteria:

[0302] Mild: These events were usually temporary, required minimal or no treatment, and did not interfere with the subject's daily activities. Moderate: These events caused a low level of inconvenience or concern associated with therapeutic measures. Moderate events may result in some interference with normal functioning but do not pose a serious or permanent risk of damage. Severe: These events interfere with the subject's normal daily activities and may require systemic drug therapy or other treatment. Severe events were usually incapacitating.

[0303] Changes in the severity of AEs were documented as new events, allowing assessment of the duration of events at each level of intensity.

[0304] Results of protocol-defined safety laboratory tests were analyzed as part of the specific laboratory safety analyses. Results of additional laboratory tests at other time points may become available as part of standard clinical practice. Throughout this study, laboratory-related abnormalities were recorded as AEs only if they were deemed clinically significant outside the range of expected values ​​resulting from the subject's baseline assessment and clinical course and were not recognized as part of a separate AE diagnosis.

[0305] Skin infections for which subjects were eligible for enrollment in this study (qualifying "ABSSSI") were unique because data on progression of this infection were captured as part of the efficacy analysis. Thus, worsening or progression of a qualifying ABSSSI was recorded as a clinical failure rather than an AE (as part of the efficacy assessment) unless the worsening / progression also met the criteria for a serious AE (in which case the event was also reported as an SAE). In contrast, any new or secondary infection (e.g., secondary skin abscess in a different anatomical location) that the investigator considered distinct from a qualifying ABSSSI was reported as an AE in all cases, whether non-severe or severe.

[0306] V. Data Analysis All data analyses were in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-E9) and sponsor guidelines and standards. Statistical analyses were performed using statistical analysis software (SAS).

[0307] A SAP, incorporating the following sections, including a mock tables, figures, and lists (TFL) shell, was prepared prior to the start of the study. The plan specified the analysis population, the protocols for handling all data, and the statistical methods specified to be used to analyze safety and efficacy. As a result of different regulatory requirements for the selection of the primary efficacy outcome and statistical analysis, two separate SAPs were prepared (one each for the FDA and EMA). The following sections display the overall structure and analysis approach.

[0308] Inferential statistical analyses of primary and secondary outcomes were performed as outlined below. Descriptive statistics were provided for categorical variables and numbers, means, standard deviations (SD), medians, minimums and maximums for continuous variables. All comparisons were of omadacycline versus linezolid. Exploratory analyses were also performed. Listings of individual subject data were generated. Analysis population

[0309] Analysis populations of several subjects were defined to perform various efficacy and safety analyses as follows:

[0310] The intent-to-treat (ITT) population consisted of all randomized subjects.

[0311] The safety population consisted of all randomized subjects who received the study article.

[0312] The modified intent-to-treat (mITT) population consisted of all randomized subjects without a Gram-negative solely causative pathogen at screening.

[0313] The microbiologically modified intent-to-treat (micro-mITT) population consisted of subjects in the mITT population who had at least one Gram-positive causative pathogen at screening (e.g., a bacterial pathogen identified from a blood culture or from culture of a microbiological sample obtained from the site of the primary ABSSSI at baseline).

[0314] The clinically evaluable (CE) population (CE-PTE and CE-EOT) consisted of all mITT subjects who received at least one dose of study article, had no qualifying ABSSSI, no indeterminate clinical response at the PTE / EOT visit, an investigator assessment of clinical response, and met specific criteria related to required assessments.

[0315] The biologically evaluable (ME) population included subjects in the CE population who had at least one Gram-positive causative pathogen at screening (i.e., all subjects in both the micro-mITT and CE-PTE / EOT populations).

[0316] The various subject populations that participated in the study, as defined above, are summarized below.

[0317] [Table 13]

[0318] Subject disposition in the ITT population is summarized below:

[0319] [Table 14]

[0320] Subject disposition in the mITT population is summarized below:

[0321] [Table 15]

[0322] Subject disposition in the CE-PTE population is summarized below:

[0323] [Table 16]

[0324] The demographic and baseline characteristics of the safety population are summarized below.

[0325] [Table 17] TIFF2025041903000019.tif222149

[0326] The demographic and baseline characteristics of the mITT population are summarized below. [Table 18] TIFF2025041903000021.tif229146

[0327] The primary ABSSSI infection sites at baseline in the mITT population are summarized below.

[0328] [Table 19]

[0329] Baseline pathogenic organisms from ABSSSI sites or blood cultures by genus and species in the micro-mITT population are summarized below:

[0330] [Table 20]

[0331] In the above tables, percentages were based on the number of subjects in each treatment group. Subjects with the same pathogen isolated from multiple specimens were counted only once for that pathogen. Subjects with the same pathogen identified from both blood and primary ABSSSI cultures were counted only once. MRSA and MSSA were considered separate pathogens. VRE and VSE were considered separate pathogens. Where numbers per subject of Staphylococcus aureus are shown, subjects with both MRSA and MSSA were counted only once. Where numbers per subject of each Enterococcus species are shown, subjects with both VRE and VSE were counted only once. Only representative or most abundant genera / species are shown.

[0332] Primary efficacy analysis For all efficacy analyses, subject data were analyzed in the group to which subjects were randomized. For the primary analyses for both the FDA and EMA, subjects were analyzed in the strata to which subjects were randomized.

[0333] Early clinical responses can be clinical success, clinical failure, and indeterminate (as previously defined). Indeterminate responses were included in the denominator for calculating the percentage of subjects with clinical success in the mITT population, and therefore were essentially considered as clinical failures for purposes of the primary analysis for the FDA.

[0334] The investigator's assessment of clinical response in the PTE efficacy variable was defined as the investigator's assessment of clinical response at the PTE visit, with outcomes being clinical success, clinical failure, and indeterminate (as previously defined) in the mITT population, and clinical success and clinical failure in the CE population. Subjects with a response of clinical failure at the EOT were defined as clinical failures at the PTE. Indeterminate responses were included in the denominator for calculating the percentage of subjects with clinical success in the mITT population, and therefore were effectively considered clinical failures for the purposes of the primary analysis for the EMA.

[0335] To demonstrate that the efficacy of omadacycline is non-inferior to linezolid in the treatment of adult subjects with ABSSSI, the following hypotheses were evaluated by analysis of clinical success rates:

[0336] The null and alternative hypotheses for the early clinical response endpoint were evaluated in the mITT population as follows. H o :θ T -θ C ≦-Δ H ai :θ T -θ C >-Δ (where the clinical success rate of the omadacycline regimen is θT and the clinical success rate of linezolid is θC).

[0337] Δ is the non-inferiority (NI) margin, 0.10.

[0338] Similar null and alternative hypotheses can be set for the PTE endpoint with a delta of 0.10. For the early clinical response (FDA) endpoint, the approach to two-sided 95% confidence intervals (CIs) for the difference in clinical success rates (using the point estimate of the difference: omadacycline response rate - linezolid response rate) was used to test the NI of the omadacycline group compared to the linezolid group in the mITT population. The 95% CIs were calculated using the unhierarchical method proposed by Miettinen and Nurminen. Omadacycline is considered non-inferior to linezolid if the lower limit of the CI is greater than -0.10 (i.e., -10%).

[0339] For investigator assessment of clinical response in the PTE (EMA) primary efficacy analysis in both the mITT and CE populations, the NI of the omadacycline group compared with the linezolid group was tested using the two-sided 95% CI approach for the difference in clinical success rates (using the point estimate of the difference: omadacycline response rate - linezolid response rate). The 95% CI was calculated using the stratification (for randomization stratification factors) method proposed by Miettinen and Nurminen. Omadacycline is considered non-inferior to linezolid if the lower limit of the CI is greater than -0.10 (i.e., -10%).

[0340] Early clinical response in PTE and investigator assessment of clinical response were tested separately and were not co-primary endpoints. The probability of approving a drug without efficacy based on PTE efficacy was 2.5% regardless of the results for early clinical response endpoints and vice versa. Global approval with at least one endpoint attained would only require adjustment. Furthermore, co-primary efficacy endpoints for EMA (mITT and CE populations) do not require alpha adjustment since NI must be demonstrated in both populations to conclude NI. Therefore, there was no adjustment for multiple endpoints.

[0341] Early clinical response 48-72 hours after the first dose of study article (omadacycline or linezolid) in the mITT population is summarized below.

[0342] [Table 21]

[0343] In the above table, CI = confidence interval; the difference is the observed difference in early clinical success rates between the omadacycline and linezolid groups. 95% CI was constructed based on the unstratified Miettinen and Nurminen method. Percentages were based on the number of subjects in each treatment group.

[0344] The early clinical success rates (at 48-72 hours) in the mITT population for both omadacycline and linezolid are illustrated in Figure 6. See the left-most pair of bars. These data indicate that the observed 5.0% difference in clinical success rates is well within the 10% margin of statistical non-inferiority between -0.2% and 10.3% with a 95% CI (confidence interval), thus satisfying the primary efficacy point (for FDA approval).

[0345] Early clinical response 48-72 hours after the first dose of test article (omadacycline or linezolid) according to baseline pathogens from ABSSSI sites or blood cultures in the micro-mITT cohort is summarized below:

[0346] [Table 22] TIFF2025041903000026.tif37134

[0347] In the table above, N1 = number of subjects in the micro-mITT population in the treatment group with baseline pathogen; n = number of subjects in a particular category. Percentages are based on N1. Subjects with the same pathogen isolated from multiple specimens were counted only once for that pathogen. Subjects with the same pathogen identified from both blood and primary ABSSSI cultures were counted only once. Percentages are based on the number of subjects with the indicated pathogen. Only representative or most abundant genus / species is shown.

[0348] If the null hypothesis of inferiority is failed by early clinical response in the mITT population and the observed successful response rate to omadacycline is higher than that observed for linezolid, a formal statistical analysis of superiority will be performed. Omadacycline will be considered superior to linezolid if the lower limit of the two-sided 95% CI for the treatment difference is greater than 0%.

[0349] The primary efficacy outcome was assessed separately across the stratification factors of type of infection and receipt of acceptable antimicrobial therapy 72 hours prior to randomization stratification by treatment group. Two-sided 95% CIs for the observed differences in early clinical response rates for each type of infection strata and each previous antimicrobial therapy strata were calculated for the mITT population. Further subgroup analyses of the primary efficacy outcome can be performed as descriptive analyses.

[0350] The results of these individual assessments across stratification factors are summarized below.

[0351] Specifically, early clinical response by type of infection, 48-72 hours after the first dose of test article (omadacycline or linezolid) in the mITT population, is summarized below:

[0352] In the following tables, CI = confidence interval; difference is the observed difference in early clinical success rates between the omadacycline and linezolid groups. 95% CI within each type of infection was constructed based on the Miettinen and Nurminen method, without stratification. Percentages were based on the number of subjects in each treatment group within each type of infection. [1] Actual type of infection = type of infection recorded in the eCRF.

[0353] [Table 23]

[0354] Overall clinical responses at the PTE visit, based on investigator assessment in the mITT and CEPTE populations, are summarized below.

[0355] [Table 24]

[0356] CI = confidence interval; difference is the observed difference in overall clinical success rate in PTE between omadacycline and linezolid groups.[1] 95% CI was constructed based on Miettinen and Nurminen method without stratification.[2] 95% CI was adjusted for type of infection and previous antibiotic use based on Miettinen and Nurminen method with stratification using Cochran-Mantle-Haenszel weights as stratification weights.[2] For subgroups of previous antibiotic use were combined into one group. Type of infection was not combined. Overall clinical response in PTE was based on investigator assessment at EOT and PTE visits. Percentages were based on the number of subjects in each treatment group.

[0357] The overall clinical success / response rates at the PTE visit based on the investigator's assessment of the mITT PTE and CE-PTE populations for both omadacycline and linezolid are also illustrated in Figure 6. See the middle (mITT PTE) and rightmost (CE-PTE) pair of bars. These data show that the observed 3.3% difference in overall clinical response rate in the mITT PTE population is within the 10% margin of statistical non-inferiority between -2.2% and 9.0% (depending on stratification) in 95%CI (confidence interval), and the observed 2.3% difference in overall clinical response rate in the CE-PTE population is within the 10% margin of statistical non-inferiority between -0.5% and 5.8% (depending on stratification) in 95%CI (confidence interval). Thus, the co-primary efficacy point (for EMA approval) is also satisfied.

[0358] Overall clinical response at the PTE visit per investigator assessment by type of infection in the mITT population is summarized below.

[0359] [Table 25] CI = confidence interval; difference is the observed difference in overall clinical success rate in PTE between the omadacycline and linezolid groups. 95% CI within each type of infection was constructed based on the unstratified Miettinen and Nurminen method. Percentages were based on the number of subjects in each treatment group within each type of infection. [1] Actual type of infection = type of infection recorded on the eCRF.

[0360] Overall clinical success at the PTE visit, based on investigator assessment by baseline pathogens from ABSSSI sites or blood cultures in the micro-mITT population, is summarized below.

[0361] [Table 26] TIFF2025041903000031.tif41154

[0362] N1 = number of subjects in the micro-mITT population in the treatment group with baseline pathogen. n = number of subjects in a particular category. Percentages were based on N1. Subjects with the same pathogen isolated from multiple specimens were counted only once for that pathogen. Subjects with the same pathogen identified from blood and primary ABSSSI cultures were counted only once. Percentages were based on the number of subjects in each treatment group with the indicated pathogen.

[0363] Additional and sensitivity analyses of the primary efficacy outcomes (early clinical response and investigator assessment of clinical response at PTE) were performed (data not shown). Sensitivity analyses included performing an adjusted analysis of the primary efficacy outcome based on the randomized strata and alternatively based on the strata to which the subject actually belonged, as well as performing an analysis in which all subjects with an indeterminate response were considered clinical successes.

[0364] Secondary efficacy analyses The number and percentage of subjects classified as clinical success, clinical failure, and indeterminate (by the investigator's assessment at PTE, with subjects with indeterminate responses excluded from the CE population) in the mITT and CE populations were calculated for each treatment group. Two-sided unadjusted 95% CIs for observed differences in clinical success rates were constructed using the method of Miettinen and Nurminen. For the investigator's assessment of clinical response at PTE in the mITT and CE populations, the two-sided 95% CIs are for descriptive purposes only and no NI was concluded.

[0365] For the micro-mITT population, the number and percentage of subjects in each treatment group in each response category for early clinical response were presented. 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 for observed differences in clinical success rates were constructed using the method of Miettinen and Nurminen.

[0366] The number and percentage of subjects with successful early clinical response in PTE of clinical success by pathogen (including gram-negative causative pathogens and MRSA), and investigator assessment of clinical response were obtained in the micro-mITT and ME populations.

[0367] Analysis of further efficacy variables Further efficacy analyses were performed to support the efficacy findings for the primary and secondary outcomes. CIs were determined for descriptive purposes, but no NIs were concluded.

[0368] The numbers and percentages of subjects classified as early clinical success, clinical failure, and indeterminate 48-72 hours after the first dose of study article in the ITT population were calculated. Two-sided unadjusted 95% CIs for observed differences in clinical success rates were constructed using the method of Miettinen and Nurminen.

[0369] The number and percentage of subjects classified as clinical success, clinical failure, and indeterminate, as defined by the investigator's assessment at EOT in the mITT and CE populations (subjects with indeterminate responses were excluded from the CE population), were calculated for each treatment group. Two-sided unadjusted 95% CIs for observed differences in clinical success rates were constructed using the method of Miettinen and Nurminen.

[0370] Where appropriate, a narrative summary was provided including changes from baseline in clinical signs and symptoms (tenderness, edema, erythema, induration, and drainage), complete resolution of clinical signs and symptoms, temperature, measurements of ABSSSI lesions (absolute percentage reduction in lesion area, e.g., 0–<5%, 5–<10%, 10–<20%, ≥20%, etc.), and systemic signs by study visit.

[0371] All-cause mortality (ACM) at 15 and 30 days after the first dose of study article was summarized in the ITT population. Subjects lost to follow-up are considered dead for this analysis. Two-sided unadjusted 95% CIs for observed differences in mortality rates were calculated for ACM.

[0372] Per-subject and per-pathogen microbiological outcomes were obtained for the micro-mITT and ME populations at the EOT and PTE visits. Two-sided unadjusted 95% CIs for the difference in per-subject favorable microbiological outcome rates were obtained.

[0373] Concordance analyses of early clinical response and investigator assessment of clinical response at PTE in the mITT analysis set were presented.

[0374] Safety outcome measures Safety variables included AEs, changes in vital signs, ECG parameters, and laboratory test results obtained during the course of the study. For safety analyses, subjects were analyzed according to the treatment they actually received.

[0375] Summary tables present all treatment-emergent adverse events (TEAEs). A TEAE is defined as an AE with onset at or after the first dose of test article. AEs were coded using the Medical Dictionary of Clinical Practice (MedDRA) and summarized by system organ class (SOC) and preferred term (PT) to represent the number and percentage of subjects with TEAEs for each treatment group. Additional tables present summaries by SOC and PT of subjects who experienced SAEs, severe TEAEs, TEAEs judged to be related to the test article, TEAEs leading to discontinuation of the test article, and TEAEs of special interest.

[0376] An overview of AEs in the safety population is provided below:

[0377] [Table 27]

[0378] Percentages were based on the safety population. TEAEs are defined as AEs that occurred after the first dose of active test article.

[0379] A summary of treatment-emergent adverse events (TEAEs) leading to discontinuation of study drug in the safety population by organ system class and preferred term is presented below.

[0380] [Table 28]

[0381] Coding of organ system classes and preferred terms was based on MedDRA version 17.1. Percentages were based on the safety population. A TEAE is defined as an AE that occurred after the first dose of active test article. If a subject had two or more TEAEs coded to the same MedDRA class, the subject was counted only once.

[0382] In the safety population, a summary of the most common (≥2%) treatment-emergent adverse events (TEAEs) by preferred term is presented below.

[0383] [Table 29]

[0384] Preferred term coding was based on MedDRA version 17.1. Percentages were based on the safety population. TEAEs were defined as AEs that occurred after the first dose of active test article. If a subject had two or more TEAEs coded to the same MedDRA category, the subject was counted only once.

[0385] A summary of the most frequent GI procedure-emergent adverse events (TEAEs) in the safety population is presented below.

[0386] [Table 30]

[0387] Coding of system organ classes and preferred terms was based on MedDRA version 17.1. Percentages were based on the safety population. TEAEs were defined as AEs that occurred after the first dose of active test article. If a subject had two or more TEAEs coded to the same MedDRA class, the subject was counted only once at the highest severity. TEAEs with unknown severity were not displayed.

[0388] The following variables were analyzed descriptively: vital signs (systolic and diastolic BP, pulse rate, body temperature, respiratory rate), including change from screening by visit; clinically noteworthy vital signs by visit (meeting predefined criteria specified in the SAP). Subjects with noteworthy vital signs data were enumerated.

[0389] ECG data (RR interval, PR interval, QRS interval, QTc, QTc Bazett's formula [QTcB], and QTc Fridericia's formula [QTcF]) were summarized descriptively at each scheduled assessment with overall worst post-screening values. Changes from screening at each visit in which a 12-lead ECG was obtained were also obtained. Outlier analysis was performed based on worst post-screening values.

[0390] The following variables were analyzed descriptively: laboratory variables by visit; change from screening in laboratory variables by visit; and clinically noteworthy laboratory values ​​by visit (meeting predefined criteria specified in the SAP).

[0391] A listing of the test data for each subject was generated, and values ​​that met predefined criteria for being clinically noteworthy were flagged in the listing.

[0392] Pharmacokinetics Population PK analysis was performed to characterize PK parameters. A population PK data set, including subjects with one or more quantified omadacycline concentration determinations, is constructed from blood samples along with the dosing date and time, and all bioanalytical determinations and subject demographic information. If the actual date or time for the blood sample or dose was unknown, the associated biological determination of the PK concentration was excluded from all analyses. To calculate PK parameters, omadacycline concentrations below the limit of quantification were treated as missing data in summary statistics.

[0393] Variables including age (years), weight (kg), sex, and race / ethnicity were incorporated into the population PK database along with other covariates previously determined to be important. Descriptive summaries at screening for these variables were reported based on subjects in the population analysis data set. Outliers may be excluded from this analysis. These were determined by a scatter plot of observed concentrations versus reported post-dose time. The distribution of the number of samples contributing to the model-based analysis per subject was tabulated. Similarly, simple summary descriptive statistics for sample concentrations by study days or weeks were calculated.

[0394] Regarding population PK modeling, results from a phase 1 study showed that omadacycline PK was linear and that after intravenous infusion, the plasma concentration-time profile exhibited a three-compartment configuration. Therefore, the likely structural PK model appears to be a three-compartment model with zero order input for iv infusion and first order input for po administration. This PK model includes parameters clearance, volume of distribution, bioavailability, and absorption rate constant. The relevant population model is a nonlinear mixed-effects model. This population model adds random effects and covariates for the PK parameters to recognize individual differences and similarities across observations corresponding to the same subject. When modeling the population, previously reported structural PK models are considered first. A residual error model, combining additive and proportional errors, is considered first. If diagnostics for this model suggest false convergence, simplifications (e.g., fewer random effects or alternative residual error models) may be appropriate. As part of the model diagnostics, additional covariates are examined graphically (gender, race / ethnicity, age), some may be retained in the final model, and additional variables are retained in competing models, resulting in arguably non-significant effect estimates. Scatter plots of observed concentrations versus population and individual estimated concentrations are used as part of an overall assessment of the overall quality of the fit. During modeling, broad principles outlined by the FDA are followed.

[0395] Steady state (area under the curve [AUC] 0-24 , ss, time to peak plasma concentration [T max , ss], maximum plasma concentration [C max , ss]) are calculated and summarized.

[0396] The relationship between omadacycline exposure and response (efficacy and safety) will be examined data accordingly. A population PK model will be used to calculate the AUC for individual subjects and subsequent AUC / MIC breakpoints. The following are examples of embodiments of the present invention. [Embodiment 1] 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein a once daily oral dose of 450 mg or 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for five or more days. [Embodiment 2] 2. The method of embodiment 1, wherein the once daily oral dose is 450 mg administered for 5 or more consecutive days. [Embodiment 3] 2. The method of embodiment 1, wherein the once daily oral dose is 600 mg administered for 5 or more consecutive days. [Embodiment 4] 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 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 at an oral loading dose followed by a once daily oral dose of 300 to 600 mg (e.g., 300 mg, 450 mg, or 600 mg) for five or more days. [Embodiment 5] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of a single oral dose of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the initial once daily oral dose of 300 mg, 450 mg or 600 mg. [Embodiment 6] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of a single oral dose of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the initial once daily oral dose of 300 mg, 450 mg or 600 mg. [Embodiment 7] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 300 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before the first once daily oral dose of 300 mg, 450 mg, or 600 mg. [Embodiment 8] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before the first once daily oral dose of 300 mg, 450 mg, or 600 mg. [Embodiment 9] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before the first once daily oral dose of 300 mg, 450 mg or 600 mg. [Embodiment 10] The method of embodiment 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before the first once daily oral dose of 300 mg, 450 mg, or 600 mg. [Embodiment 11] 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 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 orally administered at a dose of about 450 mg per day for two consecutive days, then at a dose of about 300 mg per day for five or more days. [Embodiment 12] The method of any of the preceding embodiments, wherein the bacterial skin or skin structure infection is a wound infection, cellulitis / erysipelas, large abscess, furuncle / boil, carbuncle, Staphylococcal scalded skin syndrome (SSSS) or ecthyma. [Embodiment 13] 12. The method of any of embodiments 1-11, wherein the bacterial skin or skin structure infection is an acute bacterial skin and skin structure infection (ABSSSI). [Embodiment 14] The method of embodiment 13, wherein the ABSSSI is a community-acquired ABSSSI. [Embodiment 15] The method of embodiment 14, wherein the ABSSSI comprises wound infection, cellulitis / erysipelas, and / or large abscess. [Embodiment 16] The method of any of embodiments 1-15, wherein the bacterial skin or skin tissue infection is the result of a skin injury, including but not limited to, trauma, a surgical procedure, or IV drug use. [Embodiment 17] 16. The method of any one of the preceding embodiments, wherein the bacterial skin or skin tissue infection is a result of vascular insufficiency or edema. [Embodiment 18] 18. The method of any of the preceding embodiments, wherein the human subject is administered 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline under fasting conditions. [Embodiment 19] The method of any of embodiments 1 to 18, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered once daily (e.g., each oral dose is administered about 24 hours apart). [Embodiment 20] 20. The method of any of the preceding claims, wherein the subject is treated for up to about 14 days, inclusive, up to about 10 days, inclusive, up to about 9 days, inclusive, up to about 8 days, inclusive, or up to about 7 days, inclusive, up to about 5 days, inclusive. [Embodiment 21] The method of embodiment 20, wherein the subject is treated for 7 to 10 days. [Embodiment 22] The method of embodiment 20, wherein the subject is treated for 8 days. [Embodiment 23] 23. The method of any preceding embodiment, wherein the salt is a tosylate salt. [Embodiment 24] 24. The method of any of the preceding embodiments, wherein the bacterial skin or skin structure infection is known or suspected to be caused by a Gram-positive pathogen. [Embodiment 25] The Gram-positive pathogen is selected from the group consisting of Staphylococcus aureus, Staphylococcus lugdunensis, Streptococcus species, Streptococcus agalactiae, Streptococcus mitis, Enterococcus species (Enterococcus faecalis (e.g. VRE or VSE), or Enterococcus faecium (e.g. VRE or VSE)), Streptococcus anginosus group (S. anginosus, S. constellatus, and S. intermedius). 25. The method of embodiment 24, comprising the strain of Streptococcus intermedius (i.e. beta, alpha or non-hemolytic), Viridans group Streptococci (VGS), Clostridium perfringens, Finegoldia magna, or a combination thereof. [Embodiment 26] 26. The method of embodiment 25, wherein the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA). [Embodiment 27] 26. The method of embodiment 25, wherein the Streptococcus species comprises the Streptococcus anginosus group. [Embodiment 28] 26. The method of embodiment 25, wherein the Streptococcus species comprises beta-hemolytic streptococcus or S. anginosus. [Embodiment 29] 26. The method of embodiment 25, wherein the Streptococcus spp. comprises non-hemolytic streptococci or S. intermedius. [Embodiment 30] 26. The method of embodiment 25, wherein the Streptococcus species comprises alpha-hemolytic streptococcus or S. constellatus. [Embodiment 31] 26. The method of embodiment 25, wherein the Enterococcus species comprises Enterococcus faecalis (VSE). [Embodiment 32] 26. The method of embodiment 25, wherein said Streptococcus spp. comprises Streptococcus pyogenes. [Embodiment 33] 24. The method of any of the preceding embodiments, wherein the bacterial skin or skin structure infection is known or suspected to be caused by a gram-negative pathogen. [Embodiment 34] 34. The method of embodiment 33, wherein the gram-negative pathogen comprises Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Prevotella denticola, Prevotella melaninogenica, or a combination thereof. [Embodiment 35] The method of any of embodiments 1 to 34, wherein GI adverse events (AEs) associated with treatment are mostly mild. [Embodiment 36] The method of any of the preceding embodiments, wherein GI adverse events (AEs) associated with treatment do not lead to discontinuation of treatment. [Embodiment 37] AUC after the first two doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or its salts 0-24 37. The method of any preceding claim, wherein the IL-10 concentration is about 10,000 ng×hr / mL. [Embodiment 38] The method of any of the preceding embodiments, wherein each dose of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or salt thereof is administered as a 150 mg tablet. [Embodiment 39] 39. The method according to any one of the preceding claims, having a clinical success rate of about 70-100%. [Embodiment 40] The method according to embodiment 39, wherein the clinical success rate is about 80-100%, about 79-98%, about 79-94%, about 84-98%, about 80-88% or about 84-89%. [Embodiment 41] The method of embodiment 39 or 40, wherein the clinical success rate is observed 48 to 72 hours after the first oral dose and is about 79 to 94%, or about 84 to 89%, or about 87.5%. [Embodiment 42] The method of embodiment 41, wherein the ABSSSI consists essentially of wound infection and the clinical success rate is about 84-94% or about 89%. [Embodiment 43] The method of embodiment 41, wherein the ABSSSI consists essentially of cellulitis / erysipelas and the clinical success rate is about 74-84% or about 79%. [Embodiment 44] The method of embodiment 41, wherein the ABSSSI consists essentially of large abscesses and the clinical success rate is about 90-98% or about 94%. [Embodiment 45] The method of embodiment 39 or 40, wherein the clinical success rate is an overall clinical success rate observed about 7-14 days after the last dose of treatment and is about 79-98%, about 75-95%, about 79-89%, 84%, about 95-100%, or about 98%. [Embodiment 46] The method of embodiment 45, wherein the ABSSSI consists essentially of wound infection and the overall clinical success rate is about 80-85% or about 82-83%. [Embodiment 47] The method of embodiment 45, wherein the ABSSSI consists essentially of cellulitis / erysipelas and the overall clinical success rate is about 85-91%, about 87-88%, or about 88%. [Embodiment 48] The method of embodiment 45, wherein the ABSSSI consists essentially of large abscesses and the overall clinical success rate is about 80-88%, or about 84%.

Claims

1. 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof such that the subject is treated, wherein a once daily oral dose of 450 mg or 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered for five or more days.

2. 10. The method of claim 1, wherein the once daily oral dose is 450 mg administered for 5 or more consecutive days.

3. 10. The method of claim 1, wherein the once daily oral dose is 600 mg administered for 5 or more consecutive days.

4. 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 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 in an oral loading dose followed by a once daily oral dose of 300 to 600 mg (e.g., 300 mg, 450 mg, or 600 mg) for five or more days.

5. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of a single oral dose of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the initial once daily oral dose of 300 mg, 450 mg or 600 mg.

6. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of a single oral dose of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours prior to the initial once daily oral dose of 300 mg, 450 mg or 600 mg.

7. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 300 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before the initial once daily oral dose of 300 mg, 450 mg, or 600 mg.

8. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 12 hours and 24 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

9. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 600 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

10. 5. The method of claim 4, wherein the oral loading dose consists essentially of / consists of two oral doses of 450 mg of the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline administered 24 hours and 48 hours, respectively, before an initial once daily oral dose of 300 mg, 450 mg or 600 mg.

11. 1. A method of treating a human subject in need of treatment for a bacterial skin or skin tissue infection, comprising orally administering to the subject an effective amount of 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 orally at a dose of about 450 mg per day for two consecutive days, then at a dose of about 300 mg per day for five or more days.

12. 12. The method of any of claims 1 to 11, wherein the bacterial skin or skin tissue infection is a wound infection, cellulitis / erysipelas, large abscess, furuncle / boil, carbuncle, Staphylococcal scalded skin syndrome (SSSS) or ecthyma.

13. 12. The method of any one of claims 1 to 11, wherein the bacterial skin or skin structure infection is an acute bacterial skin and skin structure infection (ABSSSI).

14. The method of claim 13, wherein the ABSSSI is a community-acquired ABSSSI.

15. 15. The method of claim 14, wherein the ABSSSI comprises wound infection, cellulitis / erysipelas, and / or large abscess.

16. 16. The method of any of claims 1-15, wherein the bacterial skin or skin tissue infection is the result of a skin injury, including but not limited to, trauma, surgical procedures or IV drug use.

17. 16. The method of any of claims 1 to 15, wherein the bacterial skin or skin tissue infection is a result of vascular insufficiency or edema.

18. 18. The method of any of claims 1 to 17, wherein the human subject is administered 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline under fasting conditions.

19. 19. The method of any of claims 1-18, wherein the 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline is administered once daily (e.g., each oral dose is administered about 24 hours apart).

20. 20. The method of any of claims 1 to 19, wherein the subject is treated for up to about 14 days, inclusive, up to about 10 days, inclusive, up to about 9 days, inclusive, up to about 8 days, inclusive, or up to about 7 days, inclusive, up to about 5 days, inclusive.

21. The method of claim 20, wherein the subject is treated for 7 to 10 days.

22. 21. The method of claim 20, wherein the subject is treated for 8 days.

23. 23. The method of any one of claims 1 to 22, wherein the salt is a tosylate salt.

24. 24. The method of any of claims 1 to 23, wherein the bacterial skin or skin tissue infection is known or suspected to be caused by a gram-positive pathogen.

25. The Gram-positive pathogen is selected from the group consisting of Staphylococcus aureus, Staphylococcus lugdunensis, Streptococcus species, Streptococcus agalactiae, Streptococcus mitis, Enterococcus species (Enterococcus faecalis (e.g. VRE or VSE), or Enterococcus faecium (e.g. VRE or VSE)), Streptococcus anginosus group (S. anginosus, S. constellatus and S. intermedius), and the like.

25. The method of claim 24, comprising the following: Bacillus subtilis (i.e. beta, alpha or non-hemolytic), Viridans group Streptococci (VGS), Clostridium perfringens, Finegoldia magna or a combination thereof.

26. 26. The method of claim 25, wherein the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-sensitive Staphylococcus aureus (MSSA).

27. 26. The method of claim 25, wherein the Streptococcus species comprises the Streptococcus anginosus group.

28. 26. The method of claim 25, wherein the Streptococcus species comprises beta-hemolytic streptococcus or S. anginosus.

29. 26. The method of claim 25, wherein the Streptococcus species comprises non-hemolytic streptococci or S. intermedius.

30. 26. The method of claim 25, wherein the Streptococcus species comprises alpha-hemolytic streptococcus or S. constellatus.

31. 26. The method of claim 25, wherein the Enterococcus species comprises Enterococcus faecalis (VSE).

32. 26. The method of claim 25, wherein the Streptococcus species comprises Streptococcus pyogenes.

33. 24. The method of any of claims 1 to 23, wherein the bacterial skin or skin tissue infection is known or suspected to be caused by a gram-negative pathogen.

34. 34. The method of claim 33, wherein the gram-negative pathogen comprises Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Prevotella denticola, Prevotella melaninogenica, or a combination thereof.

35. 35. The method of any of claims 1 to 34, wherein treatment-related GI adverse events (AEs) are predominantly mild.

36. 36. The method of any of claims 1 to 35, wherein treatment-related GI adverse events (AEs) do not lead to discontinuation of treatment.

37. AUC after the first two doses of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or its salts 0-24 37. The method of any of claims 1 to 36, wherein the IL-10 concentration is about 10,000 ng x hr / mL.

38. 38. The method of any of claims 1-37, wherein each dose of 9-[(2,2-dimethyl-propylamino)-methyl]-minocycline or a salt thereof is administered as a 150 mg tablet.

39. 39. The method of any of claims 1 to 38, having a clinical success rate of about 70-100%.

40. 40. The method of claim 39, wherein the clinical success rate is about 80-100%, about 79-98%, about 79-94%, about 84-98%, about 80-88% or about 84-89%.

41. 41. The method of claim 39 or 40, wherein the clinical success rate is observed 48-72 hours after the first oral dose and is about 79-94%, or about 84-89%, or about 87.5%.

42. 42. The method of claim 41, wherein the ABSSSI consists essentially of wound infection and the clinical success rate is about 84-94% or about 89%.

43. 42. The method of claim 41, wherein the ABSSSI consists essentially of cellulitis / erysipelas and the clinical success rate is about 74-84% or about 79%.

44. 42. The method of claim 41, wherein the ABSSSI consists essentially of large abscesses and the clinical success rate is about 90-98% or about 94%.

45. 41. The method of claim 39 or 40, wherein the clinical success rate is an overall clinical success rate observed about 7-14 days after the last dose of treatment and is about 79-98%, about 75-95%, about 79-89%, 84%, about 95-100%, or about 98%.

46. 46. ​​The method of claim 45, wherein the ABSSSI consists essentially of wound infection and the overall clinical success rate is about 80-85% or about 82-83%.

47. 46. ​​The method of claim 45, wherein the ABSSSI consists essentially of cellulitis / erysipelas and the overall clinical success rate is about 85-91%, about 87-88%, or about 88%.

48. 46. ​​The method of claim 45, wherein the ABSSSI consists essentially of large abscesses and the overall clinical success rate is about 80-88%, or about 84%.

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