Patent Description:
The present invention relates to a treatment method for the treatment of an infection caused by Neisseria gonorrhoeae, comprising administering gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof, in accordance with a treatment regimen as defined in the claims.

Neisseria gonorrhoeae (NG) is gram negative bacteria that can infect male and female humans. Infections are most common in the urogenital tract (including the cervix, uterus, and fallopian tubes in women, and the urethra in women and men) - generally called "gonorrhoea" - but can also be anorectal, conjunctival, or pharyngeal. If left untreated, infections caused by NG can disseminate to other areas of the body, which commonly causes synovium and skin infections. Consequences of untreated gonococcal infections include pelvic inflammatory disease, infertility in women and men, ectopic pregnancy, tubo-ovarian abscess, neonatal conjunctivitis, and disseminated gonorrhoea.

Over the past few decades, NG has demonstrated the ability to develop 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 labeled drug-resistant NG with threat levels of urgent and high, respectively, and identified a critical need for new antibiotic treatments.

Treatment failures with cefixime or other oral cephalosporins have been reported in Asia, Europe, South Africa, and Canada. Ceftriaxone, in combination with 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, UK and Europe. Most gonococcal infections of the pharynx (site of resistance and decreased efficacy that also serves as a reservoir for contamination of other anatomical sites - see for example <NPL>) are asymptomatic. Gonococcal infections of the pharynx are more difficult to eradicate than are infections at urogenital and anorectal sites. Few antimicrobial regimens, including those involving oral cephalosporins, can.

reliably cure ><NUM>% of gonococcal pharyngeal infections. New oral antibiotics with favourable penetration properties at the pharyngeal site are urgently needed to address this major public health threat.

Gepotidacin is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor that is currently in development. <CIT> discloses generally the use of certain triazaacenaphthylene bacterial type II topoisomerase inhibitors, including gepotidacin, for the use in treating an infection caused by NG. In a phase <NUM> study completed in <NUM>, which evaluated the efficacy, safety, and tolerability of gepotidacin in the treatment of uncomplicated urogenital gonorrhea caused by NG, gepotidacin was found to be efficacious against urogenital infection caused by NG (see <NPL>).

There is still a need for an improved treatment for infection caused by NG, in view of the emergence of drug-resistant forms of NG. As gepotidacin is a novel mechanism antibacterial compound, appropriate dosages and dosage regimens with acceptable efficacy and safety profiles are required.

The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method of treatment of the human (or animal) body by therapy.

In the first aspect, the present disclosure provides 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 orally in two doses of <NUM> each, within one day and wherein the Neisseria gonorrhea is resistant to ciprofloxacin.

In an embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Neisseria gonorrhoeae in a human in need thereof, comprising administering the gepotidacin or a phramaceutically acceptable salt thereof to said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> each, within one day and wherein the Neisseria gonorrhea is resistant to ciprofloxacin.

In another embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Neisseria gonorrhoeae in a human in need thereof, comprising administering the gepotidacin or a pharmaceutically acceptable salt thereof to said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> at an interval of <NUM>-<NUM> hours.

As used herein, the term "antibiotic" is synonymous with "antibacterial" and "antimicrobial". Gepotidacin and its racemic form are disclosed in <CIT>.

Gepotidacin is (<NUM>R)-<NUM>-({<NUM>-[(<NUM>,<NUM>-Dihydro-<NUM>H-pyrano[<NUM>,<NUM>-c]pyridin-<NUM>-ylmethyl)amino]-<NUM>-piperidinyl}methyl)-<NUM>,<NUM>-dihydro-<NUM>H,<NUM>H-2a,<NUM>,8a-triazaacenaphthylene-<NUM>,<NUM>-dione:
<CHM>.

As used herein, the term "gepotidacin" may encompass gepotidacin free base, or a salt of gepotidacin. When a composition contains a salt of gepotidacin, the stated amount of gepotidacin in the composition refers to the amount of corresponding gepotidacin free base.

A lack of validated preclinical models for NG has prevented the establishment of the pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude predictive of gepotidacin efficacy in an infection caused by NG. In the Phase <NUM> randomized dose-ranging single-oral dose evaluation, reported by <NPL>, single oral doses of <NUM> and <NUM> of gepotidacin achieved ≥<NUM>% efficacy against urogenital infection caused by NG.

Surprisingly it has now been found that two <NUM> doses of gepotidacin administered within one day is a safe and efficacious treatment for infection caused by NG, with no increase in safety concerns. In particular, the present invention provides a treatment regimen of two <NUM> doses gepotidacin administered <NUM>-<NUM> hours apart, or <NUM>-<NUM> hours apart (total dose <NUM> within one day).

For the treatment of uncomplicated gonorrhea, both the CDC and WHO recommend a dual antibiotic regimen consisting of a single IM <NUM>-mg dose of ceftriaxone and a single oral <NUM>-g dose of azithromycin (<NPL>; and <NPL>). The present invention advantageously provides a more convenient single drug treatment regimen.

Thus in the first aspect, the present disclosure 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 said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> each, within one day and wherein the Neisseria gonorrhea is resistant to ciprofloxacin.

As would be understood by a skilled person, the two doses of <NUM> grams each provides a total dose of <NUM> in one day. "One day" is used herein to mean one period of <NUM> hours, which commences on taking the first dose. "Two doses within one day" is herein intended to mean the same as "bis in die" or "b.

In an embodiment, the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by NG, in a human in need thereof, comprising administering the gepotidacin or a phramaceutically acceptable salt thereof to said human wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> each within one day and wherein the Neisseria gonorrhea is resistant to cirpofloxacin.

This specification discloses 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 said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered in two doses of <NUM> each at an interval of <NUM>-<NUM> hours.

This specification describes 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 <NUM> each at an interval of <NUM>-<NUM> hours.

In one aspect, the present disclosure 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 said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> each at an interval of <NUM>-<NUM> hours.

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 in a human in need thereof, comprising administering the gepotidacin or a pharmaceutically acceptable salt thereof to said human wherein the gepotidacin or a pharmaceutically acceptable salt thereof is orally administered in two doses of <NUM> each at an interval of <NUM>-<NUM> hours.

As used herein, the phrase "infection caused by NG" may mean (<NUM>) that the skilled person suspects that the infection is caused by NG, for example due to clinical signs and symptoms, patient history or local epidemiology, or (<NUM>) that the skilled person proves or determines that the infection is caused by NG using standard methods such as culture results, or other information such as PCR, Gram stain or other stains. In one embodiment, in the method of the present invention, the infection is suspected to be caused by NG. In one embodiment, in the method of the present invention, the infection is proven to be caused by NG.

In one embodiment, for any aspect of the present invention, the gepotidacin is used for the treatment of an infection caused by a gepotidacin-susceptible isolate of NG.

As would be understood by the skilled person, "susceptible" means that an isolate of a microorganism is inhibited by the usually achievable concentration of an antimicrobial agent when the recommended dosage is used for the site of infection. Susceptibility to gepotidacin may be determined by the skilled person from an isolate recovered from a sample from an infected human, using standard methods as published by e.g. the <NPL> ("CLSI" - see for example <NPL>). or the European Union Committee on Antimicrobial Susceptibility Testing.

In one embodiment, "gepotidacin-susceptible isolate of NG "means that the gepotidacin MIC for an isolate of NG is <NUM>/L or less as measured by agar dilution according to CLSI guidelines. In one embodiment, it means that the MIC for the isolate is <NUM>/L or less as measured by agar dilution according to CLSI guidelines.

In one embodiment, for any aspect of the present invention, the human is aged <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> years old. In one embodiment, for any aspect of the present invention, the human is aged <NUM> years or above. In one embodiment, for any aspect of the present invention, the human is male. In one embodiment, for any aspect of the present invention, the human is female.

As used herein, an infection caused by NG in the urogenital area is termed "gonorrhea", which may include cervical and urethral gonorrhoea.

In one embodiment, for any aspect of the present invention, the infection caused by NG is a urogenital infection (also known as gonorrhea).

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

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

In one embodiment, for any aspect of the present invention, the infection caused by NG is a rectal infection.

In one embodiment, for any aspect of the present invention, the infection caused by NG is a pharyngeal infection. Infections of the pharynx caused by NG are more difficult to eradicate than infections at urogenital and anorectal sites. Gepotidacin has the advantage of favourable tissue distribution in the pharynx area in humans, as shown herein. Thus the present invention provides a method of treating a pharyngeal infection caused by NG in a human in need thereof, as defined herein.

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

In one embodiment, for any aspect of the present invention, the NG is drug resistant. As used herein, "drug resistant" is synonymous with "non-susceptible" and means that an isolate is not inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dosage is used for the site of infection. Drug resistance of a NG isolate may be suspected, for example through knowledge of the infected patient's medical history, e.g. recurrent urogenital infection, or may be proven through established techniques, which include phenotypic or genotypic determination. For example, a phenotypic test of drug resistance of a bacterium to an antibacterial agent may be performed by measuring susceptibility to the antibacterial agent, using standard methods and published breakpoints.

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

In one embodiment, for any aspect of the present 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.

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

In one embodiment, for any aspect of the present invention, the NG isolate is resistant to ciprofloxacin. In one embodiment, for any aspect of the present invention, the NG isolate is resistant to penicillin. In one embodiment, for any aspect of the present invention, the NG isolate is resistant to tetracycline.

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

In one embodiment, for any aspect of the present invention, the NG isolate causing the infection is resistant to ciprofloxacin, penicillin and tetracycline.

<CIT> discloses the preparation of the free base and the hydrochloride salt of gepotidaci n.

It will 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 of these. Thus by way of non-limiting example used here for illustrative purpose, "gepotidacin or a pharmaceutically acceptable salt thereof" may include a pharmaceutically acceptable salt of gepotidacin that is further present as a solvate.

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

Suitable pharmaceutically acceptable salts include those described by <NPL>.

Gepotidacin is a base (contains a basic moiety), and therefore a desired salt form may be prepared by any suitable method known in the art, including treatment of 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, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-<NUM>,<NUM>-dioates, hexyne-<NUM>,<NUM>-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-<NUM>-sulfonates and naphthalene-<NUM>-sulfonates.

Pharmaceutically acceptable salts of gepotidacin include the acid addition salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids.

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

In one embodiment, in any aspect of the present invention, the gepotidacin is gepotidacin free base.

In one embodiment, in any aspect of the present invention, the gepotidacin is gepotidacin methanesulphonate.

Pharmaceutical compositions and formulations acceptable and adaptable for use in methods and/or uses of the present invention are prepared using conventional art known pharmaceutical compositions, formulation or chemical materials, formulary excipients, preparation means, processes and/or methods and conventional techniques, etc..

In particular, gepotidacin or pharmaceutically acceptable salts, used in the present invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials/antitubercular compounds.

The pharmaceutical compositions used in the present disclosure may be formulated for administration by any route and include those in a form adapted for oral, topical or parenteral use and may be used in mammals including humans. According to the invention, gepotidacin or a pharmaceutically acceptable salt thereof is administered orally.

The compositions according to the disclosure 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.

In one embodiment, the gepotidacin or pharmaceutically acceptable salt thereof of the present invention is in a tablet or a capsule form. In one embodiment, it is in a tablet form. In one embodiment, the tablet is a <NUM> tablet.

Tablets and capsules for oral administration in the present invention may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, or wetting agents. The 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 for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories (not part of the claimed invention) will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration (not part of the claimed invention), fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied 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 being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Moreover, the quantity of the compound or pharmaceutical composition used in the present disclosure administered will vary depending on the patient and the mode of administration and can be any effective amount.

The compositions may contain from <NUM>% by weight, preferably from <NUM>-<NUM>% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from <NUM>-<NUM> of the active ingredient. Unless otherwise noted, the amount of the active ingredient (i.e., gepotidacin) refers to that of gepotidacin free base.

Conventional administration methods may be suitable for use in the present disclosure.

Depending upon the treatment being effected, the compounds, and/or or compositions of the present disclosure can be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Preferably, the composition is adapted for oral administration. For any aspect of the present invention, the gepotidacin or pharmaceutically acceptable salt thereof is administered orally.

The Examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present invention, which is as defined in the claims.

Gepotidacin exposures were assessed in plasma and other matrices, such as urine, saliva, epithelial lining fluid (ELF), Alveolar Macrophages (AM), cervix, rectum and pharynx, as follows:.

Plasma, Epithelial Lining Fluid (ELF) and Alveolar Macrophage (AM) PK were assessed following a single IV infusion of <NUM> gepotidacin over <NUM> hours. AM exposure was assessed by Cmax and AUC(<NUM>-<NUM>) and it was approximately <NUM>-fold and <NUM>-fold higher, respectively, than in ELF. AUC(<NUM>-<NUM>) ratio of AM and ELF to free plasma was <NUM> and <NUM>, respectively (gepotidacin free fraction equal to <NUM>). Concentrations in AM and ELF changed in a similar manner as in plasma over the <NUM>-hour sampling period.

Saliva, Urine and Plasma concentrations were determined after administration of gepotidacin <NUM> IV (healthy and renally impaired subjects) and <NUM> orally (healthy and hepatically impaired subjects, as well as uUTI patients). Saliva concentrations displayed a positive correlation to plasma concentrations in normal and renally impaired patients (R2 = <NUM>), as well as in normal and hepatic impaired subjects (R2= <NUM>). The ratio of saliva AUC to unbound plasma AUC was consistently close to unity (RAUC ≥ <NUM>). In uUTI patients, urine Ctau exposures ranged from <NUM> to <NUM>µg/mL from Day <NUM> onwards. The minimum gepotidacin urine concentrations remained above a Minimum Inhibitory Concentration (MIC) of <NUM>µg/mL over the <NUM>-hour dosing interval. Overall the gepotidacin urinary exposure (AUC[<NUM>-<NUM>]) in participants with moderate and severe hepatic impairment was approximately <NUM>-fold and <NUM>-fold greater than that observed in matched healthy controls, respectively.

In normal renal function subjects, <NUM>% of the gepotidacin dose was removed in the urine (fe%). As expected, the amount decreased to <NUM>% in moderate subjects and <NUM>% in End-Stage Renal Disease (ESRD) subjects not on hemodialysis. Less than <NUM>% of the gepotidacin dose was excreted in the urine for the ESRD subjects on hemodialysis.

Plasma, cervix, rectum and pharynx swabs were collected after administration of gepotidacin <NUM> BID to uUTI patients. The rank order of gepotidacin free-drug concentrations was highest in rectal tissue; followed by cervical tissue, which was similar to plasma concentrations; followed by pharyngeal tissue. PK results are shown in Table <NUM>.

In conclusion, gepotidacin displays enhanced intracellular penetration (high AM levels when compared to plasma), supporting the development of this new antibacterial for intracellular infections, such as gonorrhea.

Saliva exposures correlated well with plasma, indicating that saliva samples could be collected in cases of limited feasibility of plasma samples. In addition, the high saliva levels supports the use of gepotidacin for the treatment of oral gonorrhea.

As the hepatic function decreased, the gepotidacin levels in urine increase, while with the reduction in renal function, reduced urine levels are observed.

Gepotidacin concentrations were observed in cervical, rectal, and pharyngeal swabs and support the use of gepotidacin for infections caused by NG in these areas.

A set of duplicate <NUM>-day hollow fiber infection model studies was completed using an NG isolate from the Phase <NUM> clinical trial (as reported by Scangarella-Oman N et al. Antimicrob Agents Chemother <NUM>:e01221-<NUM>. https://doi. org/<NUM>/AAC. <NUM>-<NUM>), with a gepotidacin MIC of <NUM>µg/mL and a ParC D86N mutation, to determine the gepotidacin exposure needed to prevent amplification of a resistant subpopulation when a pre-existing single step mutation to gepotidacin was already present. The results were discussed in <NPL>.

The NG clinical isolate evaluated was known to be ciprofloxacin-resistant (minimum inhibitory concentration [MIC]= <NUM>/L), susceptible to ceftriaxone (MIC = <NUM>/L), and with a gepotidacin agar/broth MIC of <NUM>/<NUM>/L. The isolate was collected during the Phase <NUM> clinical study mentioned above, and contained the mutation, ParC D86N.

Gepotidacin, ciprofloxacin, and ceftriaxone MIC values were determined in triplicate using Gonococcal agar per CLSI guidelines (<NPL>). In order to evaluate the MIC of each challenge compound under the liquid conditions utilized in the HFIM, MIC values were determined using fastidious broth (FB) medium modified to lack agarose.

<NUM> of an initial bacterial density of <NUM><NUM> colony forming units (CFU)/mL was inoculated into the hollow-fiber cartridge (Fibercell Systems, Frederick, MD), utilizing modified FB medium.

Assuming a <NUM>-hour half-life for gepotidacin, human free-drug plasma concentration-time profiles were simulated following exposures observed after administration of <NUM> to <NUM> of gepotidacin as a single oral dose. Ciprofloxacin and ceftriaxone exposures were simulated (half-lives of <NUM> and <NUM> hours, respectively), using free-drug plasma profiles following administration of a <NUM> oral and <NUM> intramuscular dose, respectively. Samples were collected for observation of simulated pharmacokinetic profiles and enumeration of bacterial burden over the study duration. All bacterial samples were plated on drug-free and agar supplemented with <NUM> x the agar MIC value of each respective challenge compound. MIC values were determined in duplicate for isolates that were found upon the drug-supplemented agar plates.

The NG isolate grew well in the hollow fibre infection model, reaching a total bacterial burden ><NUM> log<NUM> CFU/mL by Day <NUM>. The ciprofloxacin and ceftriaxone controls performed as expected given that the isolate was resistant to ciprofloxacin and susceptible to ceftriaxone. The gepotidacin exposures evaluated provided a full exposure response from treatment failure to success, with doses ≥ <NUM> sterilizing the system over the seven-day period. The relationship between change in log<NUM> CFU/mL from bacterial burden of the gepotidacin-resistant subpopulation on Day <NUM> took on the form of an inverted-U, with doses ≥ <NUM> preventing amplification of resistance within the system. <FIG> shows the relationship between gepotidacin exposure (from <NUM> to <NUM>) and change in log<NUM> CFU/mL from baseline of the gepotidacin-resistant subpopulation on Day <NUM>.

In summary, total daily gepotidacin doses of equal to or greater than <NUM> (including <NUM> gepotidacin <NUM> doses, administered either <NUM> or <NUM> hours apart) prevented resistance amplification to gepotidacin for NG in the hollow fiber infection model.

Population PK modelling (see <NPL>) and simulation using available pharmacokinetic data was conducted. PK simulations were conducted to assess safety with the objective of limiting the occurrence of maximum plasma exposures, which is important from a safety perspective due to corrected QT interval (QTc) increases and acetylcholinesterase inhibition.

These simulations were conducted with the dose recommended for the treatment of gonorrhea. <FIG> and <FIG> were generated based on simulations of gepotidacin administered as two single oral <NUM>,<NUM>-mg doses, given either <NUM> or <NUM> hours apart (the dashed lines in <FIG> and <FIG> represent the Cmax value of potential clinical concern). These simulations demonstrate that the majority of the subjects (> <NUM>%) are below the level for the tested dosing intervals.

In conclusion, two <NUM> doses of gepotadicin, administered <NUM>-<NUM> hours apart, as opposed to the single <NUM>/<NUM> dose used in the aforementioned Phase <NUM> trial, were found to have the advantages of:.

Healthy adults and adolescents within the age ranges of <NUM>-<NUM> and <NUM>-<NUM> years old, respectively, participated in the study.

In Part <NUM> of the study, gepotidacin was administered with food to healthy adults (≥ <NUM> years) in period <NUM> (<NUM> oral single dose), followed by period <NUM> (<NUM> x <NUM> oral doses Q12h) and period <NUM> (<NUM> x <NUM> oral doses Q6h).

In Part <NUM> of the study, gepotidacin was administered with food to adolescents (<NUM> to < <NUM> years) at the same dose regimens as period <NUM> (<NUM> oral single dose) and period <NUM> (<NUM> x <NUM> oral doses Q6h).

In Period <NUM>, similar maximum concentration (Cmax) and slightly higher median area under the curve (AUC) exposures were observed for adolescents compared to adults. <NUM> was generally well tolerated by adults and adolescents with few mild gastro-intestinal-tract (GI) adverse events (AEs).

In Period <NUM>, the observed AUC0-t exposures following the first dose were similar in adults at the <NUM> dose level Q12 and Q6h. Higher accumulation ratios were observed in adults for Q6h as compared to Q12h.

In Period <NUM>, for the Q6h regimen following the second dose, the AUC was higher in adolescents, while Cmax was similar.

The shorter interval of Q6h resulted in higher accumulation ratios, as compared to Q12h, which led to a higher Cmax. The model had predicted <NUM>% and <NUM> % of subjects above the value of potential clinical concern following the second dose of <NUM> Q12h and Q6h, respectively. The present study verified that a higher percentage of the subjects were above this value (<NUM>% for adults Q12h, <NUM>% for adults Q6h and <NUM>% for adolescents Q6h). No observed safety issues related to QT or AchE-I were observed with subjects having higher Cmax.

Projection of ΔΔQTc values based on this data indicated that a longer dosing window of <NUM>-<NUM> hours would have the benefit of maintaining sufficient levels of gepotidacin in the body for efficacy, with no changes to the overall risk/benefit balance.

This ongoing Phase III study aims to evaluate oral gepotidacin compared to intramuscular (IM) ceftriaxone plus oral azithromycin, a currently recommended treatment regimen, for the treatment of uncomplicated urogenital infection caused by NG in adolescent and adult participants.

This is a Phase III, open-label (sponsor-blinded), parallel-group, multicenter, comparator-controlled, noninferiority study in adolescent and adult participants comparing the efficacy and safety of oral gepotidacin to IM ceftriaxone plus oral azithromycin in the treatment of uncomplicated urogenital gonorrhea caused by NG. Participants will be stratified by gender and sexual orientation and age; and will be randomly assigned to receive either oral gepotidacin or IM ceftriaxone plus oral azithromycin. Appropriate safety and microbiological assessments will be conducted at the Baseline (Day <NUM>) Visit and repeated at the TOC (Day <NUM> to <NUM>) and Follow-up (Day <NUM> to <NUM>) Visits. "Test-of-Cure" microbiological success will be defined by body site (i.e., urogenital and, as appropriate, pharyngeal and/or rectal) as culture-confirmed bacterial eradication of NG observed at the TOC (Day <NUM> to <NUM>) Visit.

Approximately <NUM> to <NUM> participants will be screened and randomized to achieve approximately <NUM> participants with culture-confirmed urogenital gonorrhea in the Microbiological Intent-to-Treat (micro-ITT) Population, for an estimated total of <NUM> participants per treatment group in the micro-ITT Population. Enrollment will continue until the target number of participants in the micro-ITT Population has been reached.

Participants will receive one of the following treatments:.

The study duration is approximately <NUM> days with <NUM> planned study visits: Baseline (Day <NUM>) Visit, TOC (Day <NUM> to <NUM>) Visit, and Follow-up (Day <NUM> to <NUM>) Visit.

In the Phase II study, both single oral doses of <NUM> and <NUM> gepotidacin were ≥<NUM>% efficacious (bacterial eradication) against urogenital NG with no unexpected safety signals at either dose. A total of <NUM> participants failed therapy at the urogenital body site (all with a baseline gepotidacin MIC of <NUM> pg/mL, which was among the highest MIC for gepotidacin), and analysis of the posttreatment cultures identified <NUM> isolates that had become resistant to gepotidacin (TOC gepotidacin MICs ≥<NUM>µg/mL). Further analysis revealed that both isolates also had a pre-existing D86N polymorphism in the topoisomerase IV gene at Baseline. Following treatment, both isolates showed a second mutation, an A92T substitution in the DNA gyrase enzyme, which resulted in reduced susceptibility to gepotidacin. Of the <NUM> participants in the study with D86N-positive baseline urogenital NG isolates, <NUM> were microbiological successes (bacterial eradication), including <NUM> that were infected with baseline organisms with the higher gepotidacin MIC of <NUM>µg/mL. These data suggest that the <NUM>-mg single dose may provide close to an effective exposure and that this genotype may be overcome with appropriate dosing. In the current study, gepotidacin will be administered as <NUM> oral <NUM>-mg doses.

Claim 1:
Gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Neisseria gonorrhoeae in a human in need thereof, comprising administering the gepotidacin or a pharmaceutically acceptable salt thereof to said human, wherein the gepotidacin or a pharmaceutically acceptable salt thereof is administered orally in two doses of <NUM> each within one day; and wherein the Neisseria gonorrhoeae isolate is resistant to ciprofloxacin.