Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to methods of treatment, pharmaceutical combinations or compositions, combination or resistance guided therapies and/or corresponding uses thereof for treating a bacterial infection caused by Staphylococcus saprophyticus, which comprises administration of gepotidacin or pharmaceutically acceptable salts thereof and vancomycin or pharmaceutically acceptable salts thereof.
• UTI urinary tract infections
• Staphylococcus saprophyticus which is estimated to be the causative agent in 5% to 15% of community-acquired UTIs.
• Vancomycin is a glycopeptide antibiotic which is active against aerobic and anaerobic Gram-positive bacteria. Vancomycin is often used for patients with UTIs caused by Grampositive bacterial infection. However, recent years have seen increasing bacterial resistance to vancomycin, particularly by enterococci, which presents a serious a medical and public health risk. To date, a variety of antibacterial drugs have been developed which have become clinically extremely important antimicrobial drugs. researchers at GlaxoSmithKline described a novel class of antibacterial agents that target type IIA topoisomerases [see Nature, Volume 466, pages 935-940 (19 August 2010) and Gibson et al.
• the present invention is directed to overcoming these and other problems encountered in the art.
• Gepotidacin has now been unexpectedly found to be synergistically effective against Staphylococcus saprophyticus when acting together with the antibiotic vancomycin, with no negative interaction.
• the present invention provides a method for treating an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention also provides vancomycin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection in a human caused by Staphylococcus saprophyticus by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof.
• the present invention also provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection in a human caused by Staphylococcus saprophyticus by co-administration with vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention also provides use of gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection in a human caused by Staphylococcus saprophyticus.
• the present invention also provides use of vancomycin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection in a human caused by Staphylococcus saprophyticus, by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof.
• the present invention also provides use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection in a human caused by Staphylococcus saprophyticus, by co-administration with vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention also provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, for use in the treatment of an infection in a human caused by Staphylococcus saprophyticus.
• the present invention also provides a pharmaceutical combination which comprises gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention also provides a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof, vancomycin or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient(s).
• Figures 1-5 show the bactericidal time-kill curves for each of the 5 isolates of Staphylococcus saprophyticus tested in the Example herein.
• A shows the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin;
• B shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• Figure 1 shows the bactericidal time-kill curves for Staphylococcus saprophyticus 1106006 (WT).
• Figure 1A shows the the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin.
• Figure IB shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• Figure 2 shows the bactericidal time-kill curves for Staphylococcus saprophyticus 1113726 (WT).
• Figure 2A shows the the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin.
• Figure 2B shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• Figure 3 shows the bactericidal time-kill curves for Staphylococcus saprophyticus 1115244 (WT).
• Figure 3A shows the the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin.
• Figure 3B shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• Figure 4 shows the bactericidal time-kill curves for Staphylococcus saprophyticus 1125669 (WT).
• Figure 4A shows the the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin.
• Figure 4B shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• Figure 5 shows the bactericidal time-kill curves for Staphylococcus saprophyticus 1129086 (WT).
• Figure 5A shows the the kill curves at l/4x MIC gepotidacin and l/2x MIC vancomycin.
• Figure 5B shows the kill curves at lx MIC gepotidacin and lx MIC vancomycin.
• antimicrobial refers to any natural or synthetic compound which kills or inhibits the growth of a microorganism.
• Antibiotic resistance occurs when bacteria change in response to the use of antibiotics, making them ineffective.
• vancomycin as used herein encompasses all forms of vancomycin including vancomycin hydrochloride.
• Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic with the ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, therefore providing the opportunity to address an unmet medical need.
• Gepotidacin and its racemic form is disclosed in WO 2008/128942 (herein incorporated in its entirety).
• Gepotidacin is (2/?)-2-( ⁇ 4-[(3,4-dihydro-2/Apyrano[2,3-c]pyridin-6- ylmethyl)amino]-l-piperidinyl ⁇ methyl)-l,2-dihydro-3//,8/A2a,5,8a-triazaacenaphthylene-3,8- dione:
• Combination therapy is a treatment in which a patient is given two or more drugs (or other therapeutic agents) for a single disease or when multiple diseases or pathogens are suspected or known to be present.
• Combination antibiotic therapy is used in patients due to widespread emergence of multidrug resistant (MDR) organisms.
• Multidrug resistance may be defined as lack of susceptibility to at least one agent in three or more antibiotic categories. Antimicrobials or antibacterials are frequently used in combination, so inhibitory drug interactions between the agents are undesirable.
• Combination therapy may have the advantages of broadening antibacterial spectrum, providing synergistic effects, and discouraging the emergence of resistance.
• the present invention provides a method for treating an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• terapéuticaally effective amount means a nontoxic but sufficient amount of the active ingredient to provide the desired effect.
• Staphylococcus saprophyticus may mean that Staphylococcus saprophyticus has been identified as being the cause of an infection, or part of the cause of an infection (i.e. associated with the infection); or it may mean that Staphylococcus saprophyticus is suspected or strongly suspected to be the cause of the infection, or part of the cause of the infection, due to identification of symptoms and other factors such as patient history or local epidemiology.
• the infection is urinary tract infection (UTI).
• Urinary tract infection is an infection of the bladder (also known as “cystitis”).
• the infection is uncomplicated UTI (uUTI), which is defined as “acute, sporadic or recurrent lower (uncomplicated cystitis) and/or upper (uncomplicated pyelonephritis) UTI, limited to non-pregnant women with no known relevant anatomical and functional abnormalities within the urinary tract or comorbidities" in the "Guidelines on Urological Infections" (European Urological Society), https://uroweb.org/guideline/urological- infections.
• Symptoms of uUTI can come on suddenly, and can include: frequent and strong urge to urinate even after emptying the bladder; dysuria, a painful or burning sensation when urinating; foul- or strong-smelling urine; cloudy urine; a sensation of pressure, bladder fullness, or cramping in the middle of the lower abdomen or back; a low-grade fever; chills; and/or the presence of blood in the urine.
• uUTI is generally seen in otherwise healthy subjects, mostly female, without relevant structural and functional abnormalities within the urinary tract, kidney diseases or comorbidity that could lead to more serious outcomes and require additional attention.
• the present invention provides a method for treating UTI in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention provides a method for treating UTI caused by Staphylococcus saprophyticus'm a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• the gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof may be administered sequentially (i.e. serial administration), concurrently (i.e. co-administration) or simultaneously (i.e. simultaneous administration) in separate or combined pharmaceutical formulations by any convenient route.
• the gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof are administered sequentially.
• vancomycin may follow recommended treatment guidelines.
• vancomycin or its pharmaceutically acceptable salt may be given orally 125 mg every 6 hours for 10 days; or 500 mg every 6 hours for 10 days.
• the length of period of vancomycin administration may be reduced from 10 days to, for example, 1, 2, 3, 4, 5, 6, 7, 8 or 9 days.
• the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days.
• the gepotidacin or a pharmaceutically acceptable salt thereof is administered at 1500 mg (measured as free base), b.i.d. (total daily dose 3000 mg measured as free base) for 5 days.
• the gepotidacin or a pharmaceutically acceptable salt thereof is administered at 3000 mg once.
• the gepotidacin or a pharmaceutically acceptable salt thereof is administered at two doses of 3000 mg each (measured as free base), 6-12 or 10-12 hours apart.
• the present invention provides a method for the treatment of an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to said human a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof followed by a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof.
• the human is administered vancomycin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days, followed by gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.
• the human is administered vancomycin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13 or 14 days, followed by gepotidacin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13 or 14 days.
• the present invention provides a method for the treatment of an infection caused by Staphylococcus saprophyticus in a human in need thereof, comprising administering to said human a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof followed by a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days, followed by vancomycin or a pharmaceutically acceptable salt thereof for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days.
• the human is administered gepotidacin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13 or 14 days, followed by vancomycin or a pharmaceutically acceptable salt thereof for 7, 8, 9, 10, 11, 12, 13 or 14 days.
• the total length of treatment is equal to or fewer than 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days.
• the present invention provides a method of treating an infection caused by Staphylococcus saprophyticus' ⁇ a human in need thereof, comprising administering to said human a pharmaceutical composition comprising (a) a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof and (b) a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention relates to a combination therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the infection is UTI. In another embodiment, the infection is ullTI.
• the present invention provides a combination therapy for treating UTI, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the present invention provides a combination therapy for treating UTI, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the present invention provides a combination therapy for treating UTI caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the present invention provides a combination therapy for treating UTI caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
• the vancomycin or a pharmaceutically acceptable salt thereof may be present in a corresponding pharmaceutical composition of vancomycin or a pharmaceutically acceptable salt thereof which comprises vancomycin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the gepotidacin or a pharmaceutically acceptable salt thereof may be present in a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
• the vancomycin or a pharmaceutically acceptable salt thereof may be present in a corresponding pharmaceutical composition of vancomycin or a pharmaceutically acceptable salt thereof which comprises vancomycin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient(s).
• the infection is UTI. In one embodiment, the infection is uUTI.
• resistance guided therapy means a course of therapy, the direction of which is guided by knowledge of the phenotypic or genotypic susceptibility of the microorganism to a given antibiotic, for example as described in Bradshaw et al, The Journal of Infectious Diseases, Volume 216, Issue suppl_2, 15 July 2017, Pages S412-S419.
• Detecting Staphylococcus saprophyticus ⁇ n an infection then detecting the resistance of the Staphylococcus saprophyticus strain to certain antibiotics, in advance or during the course of treatment, has the advantage of potentially reducing the patient's exposure to ineffective antibiotics that may lead to resistance.
• Identification of Staphylococcus saprophyticus may be performed by any suitable genotypic or phenotypic means, such as by NAAT.
• the present invention provides a resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, comprising administering a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof.
• the combination or resistance guided therapy of the present invention may be achieved by simultaneous administration, co-administration or serial administration of the two components.
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, where the bacterial infection is UTI.
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, where UTI is uUTI.
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, where each of the components are administered orally.
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, which comprises simultaneous administration, co-administration or serial administration of a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof; where use of vancomycin or a pharmaceutically acceptable salt thereof results in a synergistic effect; and/or also aids in protecting against development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering in its respective activity.
• the present invention relates to a combination or resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, which comprises simultaneous administration, co-administration or serial administration of a therapeutically effective amount of a pharmaceutical composition which comprises gepotidacin or a pharmaceutically acceptable salt thereof and at least one or more pharmaceutically acceptable excipient(s); and vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof; where use of vancomycin or a pharmaceutically acceptable salt thereof results in a synergistic effect; and/or also aids in protecting against development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering in its respective activity.
• the present invention relates to a combination or resistance guided therapy for treating UTI, which comprises administration of therapeutically effective amount of gepotidacin; and vancomycin or a pharmaceutically acceptable salt thereof to a human in need thereof; where use of vancomycin or a pharmaceutically acceptable salt thereof results in a synergistic effect; and/or also aids in protecting against development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering in their respective activities.
• the UTI is uUTI.
• the present invention relates to a combination or resistance guided therapy for treating UTI caused by Staphylococcus saprophyticus, which comprises administration of therapeutically effective amount of gepotidacin; and vancomycin or a pharmaceutically acceptable salt thereof to a human in need thereof; where use of vancomycin or a pharmaceutically acceptable salt thereof results in a synergistic effect; and/or also aids in protecting against development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering in their respective activities.
• the UTI is uUTI.
• the present invention relates to a resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus, which comprises administration of a therapeutically effective amount of gepotidacin or a pharmaceutically acceptable salt thereof to a human in need thereof; and vancomycin or a pharmaceutically acceptable salt thereof, to a human in need thereof; where use of vancomycin or a pharmaceutically acceptable salt thereof results in a synergistic effect; and/or also aids in protecting against development of resistance to either gepotidacin or a pharmaceutically acceptable salt thereof or vancomycin or a pharmaceutically acceptable salt thereof without interfering in their respective activity.
• the human is male.
• the human is female.
• the present invention provides vancomycin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Staphylococcus saprophyticus by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof.
• the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of an infection caused by Staphylococcus saprophyticus by co-administration with vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention provides use of gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus.
• the present invention provides vancomycin or a pharmaceutically acceptable salt thereof for use in the treatment of UTI caused by Staphylococcus saprophyticus by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof.
• the present invention provides gepotidacin or a pharmaceutically acceptable salt thereof for use in the treatment of UTI caused by Staphylococcus saprophyticus by co-administration with vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention provides use of vancomycin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus, by co-administration with gepotidacin or a pharmaceutically acceptable salt thereof.
• the present invention provides use of gepotidacin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an infection caused by Staphylococcus saprophyticus, by co-administration with vancomycin or a pharmaceutically acceptable salt thereof.
• gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
• the present invention provides a kit comprising gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.
• the present invention provides a pharmaceutical combination, which comprises gepotidacin or a pharmaceutically acceptable salt thereof; and vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention provides a pharmaceutical composition, which comprises gepotidacin or a pharmaceutically acceptable salt thereof, vancomycin or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient(s).
• the present invention provides a pharmaceutical combination of gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof.
• the present invention relates to a pharmaceutical combination, which comprises gepotidacin or a pharmaceutically acceptable salt thereof and vancomycin or a pharmaceutically acceptable salt thereof for use in combination or resistance guided therapy as described in the present invention.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof, vancomycin or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient(s) for use in combination or resistance guided therapy as described in the present invention.
• the present invention provides a combination of gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.
• the present invention provides a pharmaceutical composition comprising gepotidacin or a pharmaceutically acceptable salt thereof, and vancomycin or a pharmaceutically acceptable salt thereof, for use in the treatment of an infection caused by Staphylococcus saprophyticus.
• the present invention relates to a use of a pharmaceutical combination or a pharmaceutical composition as defined in the present invention for the manufacture of a medicament for treating an infection caused by Staphylococcus saprophyticus, such as UTI.
• the present invention relates to a use of a pharmaceutical combination according or a pharmaceutical composition as herein described for the manufacture of a medicament for treating UTI. In another aspect, the present invention relates to a use of a pharmaceutical combination according or a pharmaceutical composition as herein described for the manufacture of a medicament for treating UTI caused by Staphylococcus saprophyticus .
• the present invention relates to a use of a pharmaceutical combination or a pharmaceutical composition as herein described for the manufacture of a medicament for treating ullTI caused by Staphylococcus saprophyticus .
• the present invention relates to a use of a pharmaceutical combination or a pharmaceutical composition as defined in the present invention for resistance guided therapy for treating a bacterial infection caused by Staphylococcus saprophyticus in a human in need thereof.
• the present invention relates to a use of a pharmaceutical combination or a pharmaceutical composition as defined in the present invention for combination therapy for treating a bacterial infection caused by Staphylococcus saprophyticus in a human in need thereof.
• the present invention relates to a use as defined in the present invention, wherein the bacterial infection is UTI, such as uUTI.
• WO2008/128942 discloses the preparation of the free base and the hydrochloride salt of gepotidacin.
• 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.
• gepotidacin or a pharmaceutically acceptable salt thereof may include a pharmaceutically acceptable salt of gepotidacin that is further present as a solvate.
• vancomycin or a pharmaceutically acceptable salt thereof is intended to encompass vancomycin, a pharmaceutically acceptable salt of vancomycin, a solvate of vancomycin, or any pharmaceutically acceptable combination of these.
• vancomycin or a pharmaceutically acceptable salt thereof may include a pharmaceutically acceptable salt of vancomycin that is further present as a solvate.
• vancomycin or gepotidacin may be in any physical form thereof, including non-solid forms such as liquid or semi-solid forms, solid forms such as amorphous or crystalline forms, specific polymorphic forms and solvates including hydrates.
• Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J. Pharm.Sci (1977) 66, pp 1-19.
• 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
• 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- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenyl propionates, phenyl butrates, citrates, lactates, y-hydroxybutyrates, glycollates, tartrates mandelates,
• compositions 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 gepotidacin is gepotidacin free base or is gepotidacin methanesulphonate (mesylate).
• compositions of vancomycin 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 vancomycin is vancomycin hydrochloride.
• the present invention includes within its scope all possible stoichiometric and non- stoich iometric salt forms.
• 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.
• 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.
• compositions used in the present invention 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.
• 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.
• 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 750mg tablet.
• the vancomycin or a pharmaceutically acceptable salt thereof may be administered in any suitable form, including oral capsule (such as 125mg or 250mg), oral tablet, delayed or extended release oral tablet, delayed or extended release oral capsule, oral suspension (i.e. dry powder for reconstitution with water) or injectable solution.
• oral capsule such as 125mg or 250mg
• oral tablet such as 125mg or 250mg
• delayed or extended release oral tablet delayed or extended release oral capsule
• oral suspension i.e. dry powder for reconstitution with water
• injectable solution i.e. dry powder for reconstitution with water
• 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 O-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
• 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
• Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
• 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.
• the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
• agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
• 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.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• the quantity of the compound or pharmaceutical composition used in the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
• a "therapeutically effective amount" generally includes within its meaning a non-toxic but sufficient amount of the particular drug to which it is referring to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the patient's general health, the patient's age, etc.
• Treatment regimens for the administration of the compounds and/or pharmaceutical compositions used in the present invention can also be determined readily by those with ordinary skill in art.
• the quantity of the compound and/or pharmaceutical composition used in the present invention administered may vary over a wide range to provide in a unit dosage an effective amount based upon the body weight of the patient per day to achieve the desired effect.
• compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-1000 mg of the active ingredient. Unless otherwise noted, the amount of the active ingredient (i.e., gepotidacin) refers to that of gepotidacin free base.
• the dosage of the gepotidacin or a pharmaceutically acceptable salt as employed for adult human treatment in the present invention will preferably range from 100 or 6000 mg per day, or 100 to 3000 mg per day, for instance 1500 mg per day or 3000 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to about 100 or 50 mg/kg per day. Suitably the dosage is from 5 to 30 mg/kg per day. In one embodiment, the dosage is 1500 mg twice a day (i.e. 3000 mg per day). In one embodiment, the dosage is 3000 mg twice a day (i.e. 6000 mg per day).
• the compounds, and/or or compositions of the present invention can be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
• the composition is adapted for oral administration.
• the gepotidacin or a pharmaceutically acceptable salt thereof and the vancomycin or a pharmaceutically acceptable salt thereof are administered orally.
• the synergistic effect may help to shorten the patient's period of exposure to the first drug (which may be vancomycin or gepotidacin) to a few days, rather than a lengthy period, before switching to the other drug, or adding the other drug to the treatment regimen.
• This dual therapy may help protect gepotidacin from selection and/or spread of resistance as well as increase the potency of both compounds.
• the example herein describes synergy, indifference and antagonism interactions between gepotidacin and vancomycin determined using reference in vitro broth microdilution checkerboards.
• Recent clinical isolates of Enterococcus faeca/is and Staphylococcus saprophyticus (5 isolates per species) were tested against checkerboards of gepotidacin in combination with vancomycin.
• Synergy was observed for gepotidacin and vancomycin against 4 out of the 5 Staphylococcus saprophyticus isolates.
• Time-kill assays were performed when the observation of synergy was prevalent (>50% of isolates) for a species/drug combination.
• MIC values were determined in triplicate by Clinical and Laboratory Standards Institute (CLSI) M07 (2016) reference broth microdilution (BMD) using cation adjusted Mueller Hinton broth (CAMHB) to determine a consensus median baseline MIC value for each isolate and compound.
• CLSI M100 quality control (QC) strains Escherichia coii E. 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus 29213, and Enterococcus faecaiis ATCC 29212 were tested concomitantly with the clinical isolates. (QC data not shown).
• CAMHB Cation-adjusted Mueller-Hinton broth
• Time-kill concentration tubes were sampled at time 0 hours (TO), T2, T4, T8, and T24. Samples were serially diluted ten-fold up to 8 times in tubes with 0.15 mL of a 0.85% saline solution.
• a volume of 0.1 mL was then plated onto tryptic-soy agar with 5% sheep blood from the original sample and subsequent dilutions. Plates were incubated for 24 hours at 35°C before quantifying the viable cell count for each tube at the specified times (TO - T24).
• Antimicrobial interaction categorical characterization was defined as synergy in checkerboard assays when the fractional inhibitory concentration (FIC) index was ⁇ 0.5, indifferent when the FIC index was >0.5 to ⁇ 4.0, and antagonistic when the FIC index was >4.0. Interactions other than synergy or antagonism are referred to as indifferent or indeterminant. When the observation of synergy was prevalent for a species/drug combination (>50% of isolates tested for that species), time-kill assays were performed.
• FIC fractional inhibitory concentration
• bactericidal activity was defined as a 3-loglO decrease in CFU/mL below the starting inoculum that was maintained for 24 hours.
• Synergy via time-kill assays was defined as a >2 log 10 CFU/mL decrease between the combination and the most active agent alone at 24 hours.
• the number of surviving organisms in the presence of the combination was required to be >2 log 10 CFU/mL below the starting inocula and at least one of the drugs should not affect the growth curve of the tested organism.
• Indifference and antagonism were defined at 24 hours as a +/- 1 loglO to ⁇ 2 loglO kill compared to the most active agent alone and >1 loglO growth compared with the less active single agent, respectively.
• Table 1 MICs (ug/mL) and Fractional Inhibitor/ Concentration Indices (FICI) for gepotidacin and vancomycin against E. faecalis an S. saprophyticus All 5 S. saprophyticus isolates were further evaluated via the time-kill assay. Synergy between gepotidacin and vancomycin, as defined as a >2 log 10 CFU/mL decrease between the combination and the most active agent alone at 24 hours, was observed for all 5 isolates when both agents were tested at their respective lx MIC concentrations ( Figures 1 - 5).

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• 2023
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