Regimen for treating neisseria gonorrhoeae infection with gepotidacin

Abstract

To provide appropriate dosages and dosage regimens of gepotidacin, a novel mechanism antibacterial compound, having acceptable efficacy and safety profiles.SOLUTION: Provided is a method for treating an infection caused by Neisseria gonorrhoeae in a human in need of treatment, the method comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to the human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g each within one day.SELECTED DRAWING: None

Description

[Technical Field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under grant number HHSO100201300011C from the Assistant Secretary for Preparedness and Response, Department of Health and Human Services, Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, United States Of America Department of Health and Human Services. The government has certain rights in this invention.

[0002] Technical Field The present invention relates to a method for treating infections caused by Neisseria gonorrhoeae, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof according to the treatment regimen defined herein. [Background technology]

[0003] Neisseria gonorrhoeae (NG) is a gram-negative bacterium that can infect both men and women. It most commonly infects the urogenital tract (the cervix, uterus, and fallopian tubes in women, and the urethra in both men and women), commonly referred to as "gonorrhea," but it can also infect the anorectum, conjunctiva, or pharynx. If left untreated, infections caused by NG can disseminate to other parts of the body, commonly causing synovial and skin infections. Possible consequences of untreated gonococcal infection include pelvic inflammatory disease, female and male infertility, ectopic pregnancy, tubo-ovarian abscess, neonatal conjunctivitis, and disseminated gonorrhea.

[0004] Over the past few decades, NG has demonstrated the ability to acquire resistance to most antibiotics recommended or used for treatment, suggesting the possibility of untreatable gonorrhea in the future. The Centers for Disease Control and Prevention and the World Health Organization have designated drug-resistant NG as an "urgent" and "high" threat level, respectively, and noted the critical importance of new antibiotic treatments.

[0005] Treatment failures with cefixime and other oral cephalosporins have been reported in Asia, Europe, South Africa, and Canada. The combination of ceftriaxone and azithromycin is the last line of treatment recommended by CDC, EU, and AU guidelines, and treatment failures for pharyngeal infections have been reported in Australia, Japan, the UK, and Europe. The majority of gonococcal infections in the pharynx (a site of resistance and reduced efficacy that also serves as a reservoir for contamination of other anatomical sites; see, for example, Pharyngeal Clinical Infectious Diseases, Volume 49, Issue 12, 15 December 2009, Pages 1798-1800, https: / / doi.org / 10.1086 / 648428) are asymptomatic. Pharyngeal gonococcal infections are more difficult to eradicate than infections of the genitourinary and anorectal sites. Only a few antimicrobial regimens, including oral cephalosporins, can reliably cure more than 90% of gonococcal pharyngeal infections. Novel oral antibiotics with good pharyngeal penetration are urgently needed to address this major public health threat.

[0006] Gepotidacin is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor currently under development. International Patent Application Publication No. WO2016 / 027249 generally discloses the use of certain triazaacenaphthylene bacterial type II topoisomerase inhibitors, including gepotidacin, for use in treating infections caused by NG. A Phase II trial completed in 2017 evaluating the efficacy, safety, and tolerability of gepotidacin in the treatment of uncomplicated urogenital gonorrhea caused by NG found that gepotidacin was effective against urogenital infections caused by NG (see Taylor SN, Morris DH, Avery AK, et al. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. Clin Infect Dis. 2018;67(4):504-512. doi:10.1093 / cid / ciy145, which is incorporated herein by reference in its entirety).

[0007] Infections caused by NG still require improved treatments, given the emergence of drug-resistant forms of NG. Because gepotidacin is an antibacterial compound with a novel mechanism, appropriate use and administration regimens with acceptable efficacy and safety profiles are required. Summary of the Invention

[0008] In a first aspect, the present invention provides a method of treating an infection caused by Neisseria gonorrhoeae in a human in need thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to said human, wherein the gepotidacin or pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

[0009] In another aspect, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of infection caused by Neisseria gonorrhoeae, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

[0010] In another aspect, the present invention provides the use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of infection caused by Neisseria gonorrhoeae, wherein the gepotidacin or the pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows the relationship between gepotidacin exposure and change in NG log10 CFU / mL from baseline, as described in Example 2. [Figure 2] This shows a simulation of the PK curve of gepotidacin when orally administered twice at 3,000 mg each time, six hours apart. [Figure 3] This shows a simulation of the PK curve of gepotidacin when orally administered twice at 3,000 mg each time, 12 hours apart. DETAILED DESCRIPTION OF THE INVENTION

[0012] [Detailed Description of the Invention] As used herein, the term "antibiotic" is synonymous with "antibacterial agent" and "antimicrobial agent."

[0013] Gepotidacin and its racemate are disclosed in International Patent Application Publication No. WO 2008 / 1289422, which is incorporated herein by reference in its entirety. Gepotidacin is (2R)-2-({4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]-1-piperidinyl}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione.

[0014] [ka]

[0015] As used herein, the term "gepotidacin" can include gepotidacin free base or a salt of gepotidacin. When a composition contains a salt of gepotidacin, the amount of gepotidacin described in the composition refers to the amount of the corresponding gepotidacin free base.

[0016] Due to the lack of a validated preclinical model of NG, it was not possible to establish pharmacokinetic / pharmacodynamic (PK / PD) parameters and magnitudes predictive of gepotidacin efficacy in infections caused by NG. In a Phase II randomized, dose-ranging, single oral dose evaluation reported by Taylor SN et.al, Clin Infect Dis. 2018;67(4):504-512 (incorporated herein by reference in its entirety), single oral doses of 1.5 g and 3 g of gepotidacin achieved ≥95% efficacy against genitourinary infections caused by NG.

[0017] Surprisingly, it has now been found that administering 3 g of gepotidacin twice within one day is a safe and effective treatment for infections caused by NG without increasing safety concerns. In particular, the present invention provides a treatment regimen in which 3 g of gepotidacin is administered twice, 6 to 12 hours apart or 10 to 12 hours apart (for a total dose of 6 g within one day).

[0018] For the treatment of uncomplicated gonorrhea, both the CDC and WHO recommend a two-antibiotic regimen consisting of a single IM dose of ceftriaxone 250 mg and a single oral dose of azithromycin 1 g (Centers for Disease Control and Prevention (CDC), Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(No.RR-3):1-137; and World Health Organization (WHO), Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017). An advantage of the present invention is that it provides a more convenient single-drug treatment regimen.

[0019] [Treatment method] Accordingly, in a first aspect, the present invention provides a method of treating an infection caused by NG in a human in need thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to said human, wherein the gepotidacin or pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

[0020] As will be appreciated by those skilled in the art, two doses of 3 g each will result in a total daily dose of 6 g. As used herein, "daily" is used to mean a 24-hour period from the initial intake. As used herein, "two doses within one day" is intended to be synonymous with "bis in die" or "bid."

[0021] In a second aspect, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of infections caused by NG, wherein the gepotidacin or pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

[0022] In one embodiment, the present invention provides a method of treating an infection caused by NG in a human in need thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to the human, wherein the gepotidacin or pharmaceutically acceptable salt thereof is administered in two doses of 3 g, 6 to 12 hours apart.

[0023] In one embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by NG, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g, 6 to 12 hours apart.

[0024] In one embodiment, the present invention provides a method for treating an infection caused by NG in a human in need thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to the human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g, 10 to 12 hours apart.

[0025] In one embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by NG, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g, 10 to 12 hours apart.

[0026] As used herein, the phrase "infection caused by NG" can mean either (1) that one of skill in the art suspects that an infection is caused by NG, for example, by clinical signs or symptoms, patient history, or local epidemiology, or (2) that one of skill in the art proves or determines that an infection is caused by NG, for example, using standard methods such as culture results, PCR, Gram stain, or other staining, or other information. In one embodiment, in the methods of the invention, the infection is suspected to be caused by NG. In one embodiment, in the methods of the invention, the infection is proven to be caused by NG.

[0027] In one embodiment, in any aspect of the invention, gepotidacin is used for the treatment of infections caused by gepotidacin-susceptible isolates of NG.

[0028] As will be understood by those skilled in the art, "susceptible" means that the microbial isolate is inhibited by a commonly achievable concentration of the antimicrobial agent when the recommended dosage is applied to the site of infection. Susceptibility to gepotidacin can be determined by those skilled in the art from isolates recovered from infected human samples using standard methods published, for example, by the U.S. Food and Drug Administration (Antibacterial Susceptibility Test Interpretive Criteria), the Clinical and Laboratory Standards Institute (CLSI) (see, for example, Performance Standards for Antimicrobial Susceptibility Testing. Vol. 29 CLSI Supplement M100. (Wayne, PA: Clinical and Laboratory Standards Institute; 2019, incorporated herein by reference in its entirety), or the European Union Committee on Antimicrobial Susceptibility Testing.

[0029] In one embodiment, "gepotidacin-susceptible isolates of NG" means that the MIC of gepotidacin for the NG isolate is 2 mg / L or less as determined by the agar dilution method according to CLSI guidelines. In one embodiment, the MIC for the isolate is 1 mg / L or less as determined by the agar dilution method according to CLSI guidelines.

[0030] In one embodiment, in any aspect of the invention, the human is 12, 13, 14, 15, 16, or 17 years old.

[0031] In one embodiment, in any aspect of the invention, the human is 18 years of age or older.

[0032] In one embodiment, in any aspect of the invention, the human is male.

[0033] In one embodiment, in any aspect of the invention, the human is a female.

[0034] As used herein, infections caused by NG in the urogenital area are referred to as "gonorrhea" and include cervical gonorrhea and urethral gonorrhea.

[0035] In one embodiment, in any aspect of the invention, the infection caused by NG is a urogenital infection (also called gonorrhea).

[0036] In one embodiment, in any aspect of the invention, the infection caused by NG is a urethral infection or cervical infection (also known as urethral or cervical gonorrhea).

[0037] In one embodiment, in any aspect of the invention, the urogenital infection caused by NG is an uncomplicated urethral infection or cervical infection (also known as uncomplicated urethral gonorrhea or cervical gonorrhea).

[0038] In one embodiment, in any aspect of the invention, the infection caused by NG is a rectal infection.

[0039] In one embodiment, in any aspect of the present invention, the infection caused by NG is a pharyngeal infection. Pharyngeal infections caused by NG are more difficult to eradicate than infections in the urogenital and anorectal regions. As shown herein, gepotidacin has the advantage of good tissue distribution in the pharyngeal region of humans. Thus, the present invention provides a method for treating a pharyngeal infection caused by NG, as defined herein, in a human in need thereof.

[0040] In one embodiment, in any aspect of the invention, the human has failed at least one prior line of treatment for the infection, such as ceftriaxone or ciprofloxacin.

[0041] In one embodiment, in any aspect of the invention, the NG is drug-resistant. As used herein, "drug-resistant" is synonymous with "non-susceptible" and means that the isolate is not inhibited by normally achievable concentrations of an antimicrobial agent when applied to the site of infection at the recommended dose. Drug resistance in NG isolates may be suspected based on a patient's history of infection, e.g., recurrent urogenital infections, or may be proven by established techniques, including phenotyping or genotyping. For example, phenotyping of bacterial drug resistance to antimicrobial agents can be performed by measuring susceptibility to antimicrobial agents using standard methods and published breakpoints.

[0042] In one embodiment, in the present invention, "resistant" means resistance as defined by the CLSI breakpoint. In one embodiment, "resistant" is as defined by the relevant breakpoint in the M100 CLSI.

[0043] In one embodiment, in any aspect of the invention, the NG isolate causing the infection is resistant to an antibacterial agent selected from the group consisting of ciprofloxacin, azithromycin, tetracycline, penicillin, ceftriaxone, cefixime, gentamicin, and spectinomycin.

[0044] In one embodiment, in any aspect of the invention, the NG isolate causing the infection is resistant to at least one antibacterial agent selected from ciprofloxacin, penicillin, and tetracycline.

[0045] In one embodiment, in any aspect of the invention, the NG isolate is resistant to ciprofloxacin. In one embodiment, in any aspect of the invention, the NG isolate is resistant to penicillin. In one embodiment, in any aspect of the invention, the NG isolate is resistant to tetracycline.

[0046] In one embodiment, in any aspect of the invention, the NG isolate causing the infection is resistant to two antibacterial agents selected from ciprofloxacin, penicillin, and tetracycline.

[0047] In one embodiment, the NG isolate causing the infection in any aspect of the invention is resistant to ciprofloxacin, penicillin and tetracycline.

[0048] Compounds of the Invention International Patent Application Publication No. WO 2008 / 128942 discloses the preparation of the free base and hydrochloride salt of gepotidacin.

[0049] It should be understood that the phrase "gepotidacin or a pharmaceutically acceptable salt thereof" is intended to encompass gepotidacin, a pharmaceutically acceptable salt of gepotidacin, a solvate of gepotidacin, or any pharmaceutically acceptable combination thereof. Thus, as a non-limiting example used herein for illustrative purposes, "gepotidacin or a pharmaceutically acceptable salt thereof" may include a pharmaceutically acceptable salt of gepotidacin that further exists as a solvate.

[0050] As used herein, the term "compound of the invention" refers to gepotidacin in any form, i.e., any salt or non-salt form (e.g., the free base or a pharmaceutically acceptable salt thereof), and any of its physical forms (e.g., including non-solid forms (e.g., liquid or semi-solid forms) and solid forms (e.g., amorphous or crystalline forms, particular polymorphic forms, solvates including hydrates)), as well as mixtures of various forms.

[0051] Suitable pharmaceutically acceptable salts include those described in Berge, Bighley and Monkhouse J. Pharm. Sci (1977) 66, pp. 1-19.

[0052] Gepotidacin is a base (contains a basic moiety), and therefore the desired salt form may be prepared by any suitable method known in the art, including treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate. , benzoates, chlorobenzoates, methyl benzoate, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenyl acetate, phenyl propionate, phenyl butyrate, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, mandelates, and sulfonates such as xylene sulfonates, methane sulfonates, propane sulfonates, naphthalene-1-sulfonate, and naphthalene-2-sulfonate.

[0053] Pharmaceutically acceptable salts of gepotidacin include acid addition salts, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, or salts with organic acids such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, or tartaric acid.

[0054] The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0055] In one embodiment, in any aspect of the invention, the gepotidacin is gepotidacin free base.

[0056] In one embodiment, in any aspect of the invention, the gepotidacin is gepotidacin methanesulfonate.

[0057] Pharmaceutical Compositions and Formulations Pharmaceutical compositions and formulations acceptable and adapted for use in the methods and / or uses of the present invention are prepared using pharmaceutical compositions, formulations or chemicals, formulary excipients, preparation means, processes and / or methods known in the art, and conventional techniques, etc.

[0058] In particular, gepotidacin or a pharmaceutically acceptable salt used in the present invention may be formulated for administration by any convenient method used in human or veterinary medicine, similar to other antibacterial / antitubercular compounds.

[0059] The pharmaceutical compositions used in the present invention may be formulated to be administered by any route, including those in forms adapted for oral, topical or parenteral use, and may be used in mammals, including humans.

[0060] The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, creams, or liquid preparations such as oral or sterile parenteral solutions or suspensions.

[0061] In one embodiment, gepotidacin or a pharmaceutically acceptable salt thereof of the present invention is in the form of a tablet or capsule. In one embodiment, it is in the form of a tablet. In one embodiment, the tablet is a 750 mg tablet.

[0062] Tablets or capsules for oral administration of the present invention may be in the form of unit dose formulations and may contain conventional excipients, such as binding agents, fillers, tableting lubricants, disintegrants, or wetting agents. Tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, for example, suspending agents such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents such as lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include, for example, edible oils) such as almond oil, oily esters such as glycerin, propylene glycol or ethyl alcohol, preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid, and conventional flavorings or colorings, if desired.

[0063] Suppositories contain conventional suppository bases such as cocoa butter or other glycerides.

[0064] For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle (preferably water).The compound can be suspended or dissolved in the vehicle depending on the vehicle and the concentration used.For preparing a liquid, the compound can be dissolved in water for injection, and can be filter sterilized before being filled into a suitable vial or ampoule and sealed.

[0065] Advantageously, agents such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. To improve solubility, the composition can be frozen after filling into the vial, and the water can be removed under vacuum. The lyophilized dry powder can then be sealed in the vial, and an accompanying vial of water for injection can be provided to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of dissolved, and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

[0066] Furthermore, the dosage of the compounds or pharmaceutical compositions used in the present invention varies depending on the patient and the mode of administration, and can be any effective amount.

[0067] The composition may contain from 0.1% by weight to preferably 10-60% by weight of the active substance, depending on the method of administration. When the composition contains dosage units, each unit preferably contains 50-1000 mg of the active ingredient. Unless otherwise specified, the amount of active ingredient (i.e., gepotidacin) refers to the amount of gepotidacin free base.

[0068] Conventional methods of administration may be suitable for use in the present invention.

[0069] Depending on the treatment being performed, the compounds and / or compositions of the present invention may be administered orally, intravenously, intraperitoneally, subcutaneously, intramuscularly, or topically. Preferably, the compositions are adapted for oral administration. In one embodiment, in any aspect of the present invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

[0070] The examples set forth below are illustrative of the present invention and are not intended to limit the scope of the invention in any way. [Example]

[0071] [Example 1] Gepotidacin exposure was assessed in plasma and other matrices, such as urine, saliva, epithelial lining fluid (ELF), alveolar macrophages (AM), cervix, rectum, and pharynx, as follows:

[0072] [1. Plasma, epithelial lining fluid (ELF) and alveolar macrophage (AM) samples] A study was conducted to evaluate the plasma and pulmonary pharmacokinetics (PK) of gepotidacin following intravenous administration in healthy adult subjects (see M Hossain, EF Dumont. Population Pharmacokinetic Modeling of Plasma and Epithelial Lining Fluid Data for a Novel Antimicrobial Compound. 54th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting, 5-9 September 2014, Washington, DC, USA, which is incorporated herein by reference in its entirety).

[0073] [2. Saliva, urine, and plasma samples] a. A single-dose study evaluating the PK of oral gepotidacin in male and female adult participants with varying degrees of hepatic impairment and in matched-control study participants with normal liver function (J. Hands et al. Pharmacokinetics of Gepotidacin in Subjects with Hepatic Impairment. ID Week, 2-6 October 2019, Washington, DC, USA, which is incorporated herein by reference in its entirety). b. A single-dose study to evaluate the PK of gepotidacin in adult subjects with varying degrees of renal impairment and in matched-control study subjects with normal renal function

[0074] [3. Urine, plasma, cervical, rectal, and throat swabs] A phase IIa, single-center, single-arm, open-label study (Overcash et al., Open Forum Infectious Diseases, Volume 6, Issue Supplement 2, October 2019, Page S539, https: / / doi.org / 10.1093 / ofid / ofz360.1343, incorporated herein by reference in its entirety) conducted in the United States from July 2018 to January 2019 enrolled 22 female participants with uncomplicated urinary tract infections (uUTIs) and evaluated pharmacokinetics (PK), safety, and clinical efficacy. Participants were isolated in the clinic from baseline (pre-dose day 1–1) through treatment (days 1–5) and returned as outpatients for assessment of cure (TOC, days 10–13) and follow-up (day 28 ± 3). Participants received gepotidacin 1,500 mg orally twice daily (BID) for 5 days. Two participants (9%) were lost to follow-up and withdrew from the study due to family reasons, but no participants discontinued due to adverse events (AEs). Most participants were Caucasian, aged 19 to 60 years, and had a body mass index of 20.9 to 37.9 kg / m. 2 Among participants, the number of previous uUTI episodes in the past 12 months ranged from 0 to 10, with the majority reporting two or fewer. The mean total clinical symptom score at baseline was 7.9 points (range: 4-12). All participants reported urinary frequency and urgency, and all but one (5%) reported dysuria. Gepotidacin exposure in the urine, cervix, rectum, and pharynx was assessed.

[0075] [result] PK assessments were performed in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) after a single 1,000 mg gepotidacin infusion over 2 hours. AM exposure, assessed by Cmax and AUC(0-12), was approximately 120- and 97-fold higher than ELF, respectively. The AUC(0-12) ratios to free plasma for AM and ELF were 178 and 1.84, respectively (gepotidacin free fraction = 0.67). AM and ELF concentrations varied similarly in plasma over the 12-hour sampling period.

[0076] Gepotidacin was administered intravenously (IV) at 750 mg (healthy and renal-impaired subjects) and orally at 1,500 mg (healthy and hepatically-impaired subjects, as well as patients with uUTI), and saliva, urine, and plasma concentrations were measured. Saliva concentrations were positively correlated with plasma concentrations in healthy subjects and patients with renal impairment (R2 = 0.82), and also in healthy and hepatically-impaired subjects (R2 = 0.76). Furthermore, the ratio of saliva AUC to plasma AUC of unbound drug was consistently close to 1 (RAUC ≥ 0.75). Urinary Ctau exposure in patients with uUTI ranged from 322 to 352 μg / mL from day 3 onward. The lowest urinary concentration of gepotidacin remained above the minimum inhibitory concentration (MIC) of 4 μg / mL throughout the 12-hour dosing interval. Additionally, the total urinary exposure (AUC[0-48]) of gepotidacin in participants with moderate and severe hepatic impairment was approximately 3.2-fold and 3.9-fold, respectively, compared with that observed in matched healthy controls.

[0077] In subjects with normal renal function, 37.4% of the administered dose of gepotidacin was excreted in urine (fe%). As expected, this amount decreased to 22.1% in subjects with moderate renal function and 7.9% in subjects with end-stage renal disease (ESRD) not undergoing hemodialysis. In ESRD subjects undergoing hemodialysis, less than 2% of the administered dose of gepotidacin was excreted in urine.

[0078] Patients with uUTI were administered gepotidacin 1,500 mg twice daily (BID), and plasma, cervical, rectal, and pharyngeal swabs were collected. Gepotidacin free drug concentrations were highest in rectal tissue, followed by cervical tissue (similar to plasma concentrations), and pharyngeal tissue. PK results are shown in Table 1.

[0079] Table 1: Summary of gepotidacin concentration-time data in the cervix, rectum, pharynx, and free plasma (μg / mL) (pharmacokinetic population)

[0080] [Table 1]

[0081] In conclusion, gepotidacin exhibits enhanced intracellular penetration (higher AM levels compared with plasma), supporting the development of this new antibacterial agent against intracellular infections such as gonorrhea.

[0082] Salivary exposure correlated well with plasma, indicating that saliva samples can be collected when plasma samples are difficult to obtain, and the high levels in saliva support the use of gepotidacin for the treatment of oral gonorrhea.

[0083] It was observed that gepotidacin levels increased in urine with decreased liver function, while urinary levels decreased with decreased renal function.

[0084] Gepotidacin concentrations observed in cervical, rectal, and pharyngeal swabs support the use of gepotidacin for infections caused by NG at these sites.

[0085] Example 2: PK / PD Modeling (a) Hollow fiber infection model An identical set of 7-day hollow fiber infection studies was completed using the NG isolate from the Phase II clinical trial (with a gepotidacin MIC of 1 μg / mL and the ParC D86N mutation) (as reported by Scangarella-Oman N et al., 2018. Antimicrob Agents Chemother 62:e01221-18. https: / / doi.org / 10.1128 / AAC.01221-18, incorporated herein by reference in its entirety) to determine the amount of gepotidacin exposure required to prevent amplification of resistant subpopulations in the presence of pre-existing single-step mutations conferring resistance to gepotidacin. These results are described in VanScoy BD et al., A Hollow-Fiber Infection Model to Evaluate the Prevention of On-Therapy Resistance of Neisseria gonorrhoeae to Gepotidacin. 2018 STD Prevention Conference, 26-30 August 2018, Washington DC, USA, which is incorporated herein by reference in its entirety.

[0086] [method] The clinical NG isolate evaluated was known to be ciprofloxacin-resistant (minimum inhibitory concentration [MIC] = 2 mg / L), ceftriaxone-susceptible (MIC = 0.004 mg / L), and had a gepotidacin agar / broth MIC = 1 / 0.5 mg / L. This isolate was collected in the phase II clinical trial described above and contained the ParC D86N mutation.

[0087] MIC values ​​of gepotidacin, ciprofloxacin, and ceftriaxone were determined in triplicate using gonococcal agar according to CLSI guidelines (CLSI (2012) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard, 9th edition. CLSI document M07, Wayne, PA). To evaluate the MIC of each challenge compound under the liquid conditions used in HFIM, MIC values ​​were determined using Fastidious broth (FB) medium modified to contain no agarose.

[0088] Modified FB medium was used, with an initial bacterial density of 10 6 Ten milliliters of colony-forming units (CFU) / mL were inoculated into hollow fiber cartridges (Fibercell Systems, Frederick, MD).

[0089] Human plasma free drug concentration-time profiles were simulated from exposure after single oral doses of 0.75 to 12 g of gepotidacin, assuming a half-life of 7 hours. Ciprofloxacin and ceftriaxone exposures were simulated using plasma free drug profiles after oral administration of 0.5 g and intramuscular administration of 0.25 g, respectively (half-lives of 3 and 7.5 hours). Samples were collected throughout the study period for observation of the simulated pharmacokinetic profiles and for enumeration of bacterial load. All bacterial samples were inoculated onto agar supplemented with twice the agar MIC value of each challenge compound or onto unsupplemented agar. MIC values ​​were measured in duplicate for isolates detected on the supplemented agar plates.

[0090] [result] NG isolates grew well in the hollow fiber infection model, with total bacterial loads >8 log on day 1. 10CFU / mL. The ciprofloxacin and ceftriaxone control groups performed as expected, as the isolates were resistant to ciprofloxacin and susceptible to ceftriaxone. Gepotidacin exposure was assessed, and doses of 4.5 g or higher demonstrated system sterilization over 7 days, providing a sufficient exposure response from treatment failure to success. The bacterial load and log 10 The relationship between the change in CFU / mL was inverted U-shaped, and administration of 4.5 g or more suppressed the amplification of resistance in the system. Figure 1 shows the logarithm of the gepotidacin-resistant subpopulation from baseline on day 7 as a function of gepotidacin exposure (750 mg to 12 g). 10 The relationship between the change in CFU / mL is shown.

[0091] In summary, in the hollow fiber infection model, a total daily dose of gepotidacin of 4,500 mg or more (including two doses of 3 g of gepotidacin administered at 8- or 12-hour intervals) was able to suppress the amplification of NG resistance to gepotidacin.

[0092] (b) PK modeling Population PK modeling (see Hossain M et al, Population Pharmacokinetic Modeling of First-Time-in-Human Data of GSK2140944, a Novel Antimicrobial Agent. 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting, 10-13 September 2013, Denver, CO, USA, incorporated herein in its entirety) and simulations were performed using available pharmacokinetic data. PK simulations were performed to assess safety with the goal of minimizing the occurrence of safety-critical peak plasma exposures due to increased corrected QT interval (QTc) and acetylcholinesterase inhibition.

[0093] These simulations were performed at doses recommended for the treatment of gonorrhea. Figures 2 and 3 were generated based on simulations of gepotidacin administered orally twice at a dose of 3,000 mg, 6 or 12 hours apart (the dashed lines in Figures 2 and 3 represent Cmax values ​​of potential clinical concern). These simulations showed that the majority of subjects (>97%) had Cmax values ​​below this level for the dosing intervals tested.

[0094] In conclusion, the following advantages were observed when gepotidacin was administered in two 3-g doses 6–12 hours apart, as opposed to the single 1.5g / 3g dose used in the aforementioned phase II study: -Providing a 2-fold higher systemic exposure to cover NG isolates with high gepotidacin MICs. -Reducing the risk of emergence of clinically resistant isolates. -Maintain peak plasma concentrations below levels that pose safety concerns (related to Cmax-dependent changes in QTc interval and acetylcholinesterase activity).

[0095] Example 3: Safety and Pharmacokinetics (PK) of Gepotidacin in Healthy Adults and Adolescents Healthy adults and adolescents (aged 19-64 years and 12-17 years, respectively) participated in the study.

[0096] In Part 1 of the study, healthy adults (aged 18 years or older) received gepotidacin with meals in Period 1 (1,500 mg orally in a single dose), followed by Period 2 (3,000 mg orally twice daily, 12 hours apart) and Period 3 (3,000 mg orally twice daily, 6 hours apart).

[0097] In the second part of the study, adolescents (12 to <18 years of age) received gepotidacin in the same dose regimen with meals in period 1 (1,500 mg orally as a single dose) and period 3 (3,000 mg orally twice daily, Q6h).

[0098] During Period 1, maximum concentrations (Cmax) in adolescents were comparable to those in adults, and median area under the curve (AUC) exposure was slightly higher compared to adults. The 1,500 mg dose was generally well tolerated in adults and adolescents, with few mild gastrointestinal (GI) adverse events (AEs).

[0099] In adults, the AUC0-t exposures observed after the first dose at the 3,000 mg dose level were similar in Q12 and Q6 during Period 2. A higher accumulation ratio was observed in adults at Q6h compared with Q12h.

[0100] In period 3, AUC was higher but Cmax was similar in adolescents on the Q6h regimen after the second dose.

[0101] The shorter dosing interval with Q6h compared with Q12h resulted in a higher accumulation ratio and therefore a higher Cmax. The model predicted that 0.3% and 2.85% of subjects would experience clinically significant increases after the second 3,000 mg dose with Q12h and Q6h, respectively. This study confirmed that the proportion of subjects exceeding these limits was higher (15% for adult Q12h, 46% for adult Q6h, and 58% for adolescent Q6h). No QT- or AchE-I-related safety issues were observed in subjects with high Cmax.

[0102] Projections of ΔΔQTc values ​​based on this data suggest that a relatively long dosing window of 10-12 hours may offer the advantage of maintaining sufficient levels of gepotidacin in the body for efficacy, without changing the overall risk-benefit balance.

[0103] Example 4: A Phase III, Randomized, Multicenter, Open-Label Study Comparing the Efficacy and Safety of Gepotidacin Versus Ceftriaxone Plus Azithromycin in Adolescent and Adult Participants to Treat Uncomplicated Urogenital Gonorrhea Caused by NG (BTZ116577) This ongoing phase III study aims to investigate oral gepotidacin compared with the currently recommended treatment regimen, intramuscular (IM) ceftriaxone plus oral azithromycin, for the treatment of uncomplicated urogenital infections caused by NG in adolescents and adults.

[0104] [Overall design] This is a phase III, open-label (sponsor-blinded), parallel-group, multicenter, controlled, non-inferiority trial comparing the efficacy and safety of oral gepotidacin with oral ceftriaxone (IM) plus azithromycin for the treatment of uncomplicated urogenital gonorrhea caused by NG in adolescent and adult participants. Participants will be stratified by sex, sexual orientation, and age and randomly assigned to receive either oral gepotidacin or oral ceftriaxone (IM) plus azithromycin. Appropriate safety and microbiological assessments will be performed at the baseline (day 1) visit and repeated at the time of conception (days 4-8) and follow-up (days 14-21) visits. Microbiological success at Test-of-cure (TOC) is defined by culture-confirmed clearance of NG by body site (i.e., genitourinary tract, and pharynx and / or rectum, as appropriate) at the TOC (Days 4-8) visit.

[0105] [Number of participants] Approximately 500-600 participants will be screened and randomized to yield approximately 400 participants with culture-confirmed urogenital gonorrhea in the microbiological intent-to-treat (micro-ITT) population, for a total of 200 potential participants per treatment group in the micro-ITT population. Enrollment will continue until the target number of participants in the micro-ITT population is reached.

[0106] [Treatment group and period] Participants will receive one of the following treatments: 1. Gepotidacin: 3,000 mg orally administered at the study site at the baseline (Day 1) visit, followed by a second 3,000 mg orally self-administered dose as an outpatient 6-12 hours after the first dose (optimal administration time is 8-10 hours after the first dose, except for participants weighing less than 50 kg or with moderate renal impairment, where the second dose should be administered approximately 12 hours after the first dose). 2. Ceftriaxone + azithromycin: A single dose of ceftriaxone 500 mg (IM) and a single dose of azithromycin 1 g (oral) were administered at the study site at the baseline (Day 1) visit.

[0107] The study duration is approximately 21 days, with three study visits planned: a baseline (day 1) visit, a TOC (days 4-8) visit, and a follow-up (days 14-21) visit.

[0108] [Dosage Justification] In a phase II study, single oral doses of 1,500 mg and 3,000 mg of gepotidacin demonstrated >95% efficacy (bacterial eradication rate) against urogenital NG, with no unexpected safety signals observed at either dose. A total of three participants experienced treatment failure at urogenital body sites (all with baseline gepotidacin MICs of 1 μg / mL, the highest gepotidacin MIC), and post-treatment culture analysis identified two isolates that had acquired resistance to gepotidacin (TOC gepotidacin MIC ≥ 32 μg / mL). Furthermore, both isolates harbored a pre-existing D86N polymorphism in the topoisomerase IV gene at baseline. After treatment, both isolates displayed a second mutation, the A92T substitution in the DNA gyrase enzyme, resulting in reduced susceptibility to gepotidacin. In this study, of eight participants with baseline urogenital NG isolates positive for D86N, five achieved microbiological success (bacterial eradication), two of whom were infected with organisms with baseline gepotidacin MICs as high as 1 μg / mL. These data suggest that a single 3,000 mg dose may provide a near-effective exposure and that appropriate dosing may be able to overcome this genotype. In this study, gepotidacin was administered orally at 3,000 mg twice. By administering two 3,000 mg doses 6–12 hours apart, we anticipated a two-fold higher systemic exposure compared with the single 3,000 mg dose used in the Phase II study. This could potentially provide coverage for NG isolates with higher gepotidacin MICs, as would be expected in this global Phase III study, and potentially reduce the risk of resistance.

[0109] All publications and references cited in this application are incorporated herein by reference in their entirety.

Claims

1. 1. A method for treating an infection caused by Neisseria gonorrhoeae in a human in need thereof, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

2. 10. The method of claim 1, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered at intervals of 6 to 12 hours.

3. 10. The method of claim 1, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered at 10-12 hour intervals.

4. 4. The method of any one of claims 1 to 3, wherein the gepotidacin is gepotidacin free base.

5. 4. The method of any one of claims 1 to 3, wherein the gepotidacin is gepotidacin methanesulfonate.

6. 6. The method of any one of claims 1 to 5, wherein the human is 12, 13, 14, 15, 16 or 17 years old.

7. 6. The method of any one of claims 1 to 5, wherein the human is 18 years of age or older.

8. 8. The method of any one of claims 1 to 7, wherein the human is a male.

9. 8. The method of any one of claims 1 to 7, wherein the human is a female.

10. 10. The method according to any one of claims 1 to 9, wherein the infection caused by Neisseria gonorrhoeae is a urogenital infection.

11. 11. The method of claim 10, wherein the infection caused by Neisseria gonorrhoeae is an infection of the urethra or cervix.

12. 12. The method of claim 11, wherein the urogenital infection caused by Neisseria gonorrhoeae is an uncomplicated urethral or cervical infection.

13. 10. The method according to any one of claims 1 to 9, wherein the infection caused by Neisseria gonorrhoeae is a rectal infection.

14. 10. The method according to any one of claims 1 to 9, wherein the infection caused by Neisseria gonorrhoeae is an infection of the pharynx.

15. 15. The method of any one of claims 1 to 14, wherein the human has failed at least one previously selected treatment for the infection.

16. 15. The method of any one of claims 1 to 14, wherein the gonococcal isolate is resistant to an antibacterial agent selected from the group consisting of ciprofloxacin, azithromycin, tetracycline, penicillin, ceftriaxone, cefixime, gentamicin and spectinomycin.

17. 17. The method of any one of claims 1 to 16, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

18. 1. Gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of infections caused by Neisseria gonorrhoeae, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

19. 19. The method of claim 18, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered at intervals of 6 to 12 hours.

20. 19. The method of claim 18, wherein gepotidacin or a pharmaceutically acceptable salt thereof is administered at intervals of 10 to 12 hours.

21. 1. Use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of infections caused by Neisseria gonorrhoeae, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of 3 g within one day.

22. 22. The use according to claim 21, wherein the two administrations are given 6 to 12 hours apart.

23. 23. The use according to claim 22, wherein the two administrations are administered 10 to 12 hours apart.

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