Use of a helicase-primase inhibitor in a method of treatment of a herpes virus infection

Abstract

The present invention relates to methods for treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection. In particular, provided are certain methods for treatment of a herpes virus infection, particularly a recurrent genital herpes infection associated with HSV-2, in a human subject, comprising oral administration of 2-(3-(2',5'-difluoro-[1, 1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)yl)-4-methylthiazole-5-sulfonamide (also referred to herein as 'Compound T).

Description

HGF Ref. P387157WO1METHODS OF TREATMENTFIELD OF THE INVENTION

[0001] Provided herein are methods for treating and / or inhibiting the development, progression, or transmission, of diseases or disorders caused by, or associated with, herpes virus infection. In particular, provided herein are certain methods for treatment of a herpes virus infection, particularly a recurrent genital herpes infection associated with HSV-2, in a human subject, comprising oral administration of 2-(3-(2',5'-difluoro-[1 , 1 biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (also referred to herein as ‘Compound T).BACKGROUND OF THE INVENTION

[0002] Human herpes viruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing life-long infections in humans. This is accomplished by their ability to exist in the host either as a symptom free latent infection, where the virus lies dormant or, following activation, as a lytic infection with associated symptoms. These viral infections have widespread, worldwide prevalence and it is notable that over 90% of all humans are chronically infected with more than one human herpes virus.

[0003] Human herpes viruses are classified into three subfamilies (a, and y) based upon their biological characteristics and the family consists of eight members, i.e. , Herpes Simplex Virus subtype type 1 and 2 (HSV1 , HSV2), Varicella Zoster Virus (VZV), Epstein- Barr virus (EBV), Cytomegalovirus (CMV), and Human Herpes Viruses 6-8 (HHV 6-8).

[0004] HSV1 and 2 infections can cause disease in immune competent individuals. Both subtypes cause cutaneous genital / anal and oro-labial / nasal cavity (cold sore) lesions, although HSV2 is more commonly associated with the former and HSV1 the latter. It is believed that >80% of genital infections are caused by HSV2. Globally, over 500 million people have genital herpes infections and approximately 50 to 80% of the world’s population have oro-labial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1 , can also cause lesions on the fingers (Whitlows) and other areas of the skin.

[0005] The vast majority of HSV infected individuals will not experience any noticeable symptoms. However, some will experience recurrent (and often severe) outbreaks of infection. In the USA, 20 to 40% of the population will get recurrent labial HSV lesions. Significantly, oro-labial cold sores and Whitlow’s provide a very easy route for transmission of the virus to other individuals which can lead to rarer but much more serious HSV-relatedHGF Ref. P387157WO2 pathologies. For example, HSV-related ocular keratitis is a major cause of blindness and HSV can also cause encephalitis in neonates, which is a life-threatening condition. Other disorders believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis and possibly Bell's palsy.

[0006] Primary infection with, or reactivation of an existing herpes virus infection, can be a major cause of disease in immunocompromised individuals. Key at-risk populations include patients undergoing solid organ or stem cell transplantation, patients undergoing cancer treatment, individuals with HIV / AIDS, and ICU patients.

[0007] HSV-2 initially infects epithelial cells in the skin or mucosa and then establishes latency in the sensory nerve root ganglia, resulting in lifelong infection. The course of infection is manifested by periodic viral shedding episodes with clinical recurrence after latent HSV reactivates in the neurons and is transported via the peripheral nerves to epithelial cells on the mucosal or skin surface (James et al. ‘Herpes simplex virus: global infection prevalence and incidence estimates, 2016’ Bulletin of the World Health Organization (2020) 98(5):315-329). Lesions may occur at the site of the initial infection but also at proximal or distal sites depending on which axonal branches the virus transits (Gupta et al. Lancet (2007), 370(9605)). While reactivation rates may be higher in the year following initial infection compared to subsequent years, the median number of recurrences has been reported to be 4 times per year among individuals who reported symptomatic genital herpes (Tronstein et al. Journal of the American Medical Association. (2011), 305(14), 1441-1449). In addition to the pain associated with the genital lesions, individuals with a history of recurrent genital herpes suffer from significant psychological stress as a result of the condition and have an increased risk of acquiring human immunodeficiency virus type 1 (HIV-1) infection (Gupta et al. Lancet (2007), 370(9605); Schiffer & Corey, Current Infectious Disease Reports (2009) 11 :457-464).

[0008] Genital herpes is a chronic viral infection that can result in painful genital lesions, serious psychological and social impacts, and an increased risk of acquiring human immunodeficiency virus (HIV). Approximately 50% of individuals with initial symptomatic genital herpes infection have three or more recurrences per year, including over four million people in the United States and France, Germany, Italy, Spain and the United Kingdom. While genital herpes can be caused by either HSV type 1 (HSV-1) or HSV type 2 (HSV-2), recurrences are more likely to be experienced by individuals infected by HSV- 2. The current standard of care for recurrent genital herpes is nucleoside analogues given as daily chronic suppressive therapy; however, these are only partially effective in preventing recurrences and in reducing transmission of the virus. No new drugs have been approved in the United States or Europe to treat genital herpes for more than 25 years.HGF Ref. P387157WO3

[0009] Presently, there is no cure for HSV. Medicines have been developed that can to some degree reduce the occurrence and / or shorten the length of outbreaks, but there is a need for improved therapies.

[0010] Currently, nucleoside analogues, such as acyclovir and its prodrugs, e.g., valacyclovir and famciclovir, are used as agents against herpes viruses such as HSV. In order to exert their effects, these nucleoside analogues must be phosphorylated by viral thymidine kinase (TK) and subsequently converted by cellular kinases to the nucleoside triphosphate, which inhibits the activity of the viral DNA polymerase. If the virus has no functionally active TK, as is the case, for example, with resistant HHV1 mutants or with TK-negative viruses, the nucleoside analogues are unable to exert their effects.

[0011] Nucleoside analogues are clinically administered at very high doses, e.g., doses as high as several hundred milligrams to several grams are typically administered per day. Even at these high doses, which are often administered over long treatment durations, these drugs are unable to completely prevent recurrent outbreaks of symptoms from HSV infection. Nucleoside analogues also do little to address the issue of viral shedding, which can asymptomatically facilitate the transmission of HSV to more individuals. Certain nucleoside analogues, particularly when used at high doses, also give rise to safety concerns. For example, since these agents can incorporate into the genome DNA of a host via the host DNA polymerase, their mutagenicity is of concern, as documented for the nucleoside analogue, ganciclovir (Aoki, Chapter 45 in Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases (Eighth Edition) 2015).

[0012] Given the inadequacy of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments.

[0013] One class of compounds currently being investigated are the helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex consisting of helicase, primase, and cofactor subunits, which have functions that are essential for viral DNA replication. These agents are not nucleoside analogues and do not require phosphorylation by TK to inhibit HSV replication and they are therefore potentially active against TK-deficient HSV, which as described above, is a major mechanism of resistance to nucleoside analogues.

[0014] Two examples of helicase-primase inhibitors are BILS-179 BS (Crute et al., (2002) Nature Medicine 8, p. 386-391) and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p. 201-206).HGF Ref. P387157WO

[0015] Another example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative with the chemical name N-Methyl-N-(4-methyl-5-sulfamoyl-1 ,3-thiazol-2-yl)-2- [4-(pyridin-2-yl)phenyl]acetamide. The compound has been disclosed in WO 2001 / 47904.

[0016] Efforts to improve therapy with the small molecule based antiviral therapeutics, e.g. to try and further reduce or prevent HSV shedding and viral reactivation, have largely focussed on using high oral drug doses and frequent dosing, e.g., multiple daily dosing.

[0017] There is still an ongoing need for novel and improved methods for treating HSV infections, including HSV-2 infections such as recurrent genital herpes, and the present invention was devised with the foregoing in mind.SUMMARY OF THE INVENTION

[0018] In a first aspect, the present invention provides a method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months.

[0019] It has been surprisingly found that when Compound 1 , or a pharmaceutically acceptable salt thereof, is administered orally to a human subject, a single dose provides plasma concentrations of Compound 1 at therapeutically effective levels for unexpectedly long periods. The human half-life of Compound 1 has been found to be approximately 500 hours (20 days) over the dose range evaluated, and remarkably a single dose of Compound 1 may provide therapeutically effective coverage over at least 28 days. Moreover, it has also been found that when administered orally to a human subject using a once weekly dosage regimen, Compound 1 can provide significant reductions in viral shedding rate and genital lesion rate in participants seropositive for HSV-2 with recurrent genital herpes. The rate of samples with high viral load (i.e. , >104copies / mL HSV DNA), a potential surrogate for HSV-2 transmission, is also significantly reduced.HGF Ref. P387157WO5

[0020] The above-mentioned benefits offer the possibility for much less frequent dosing and / or the use of low doses. This is an unexpected finding. As described above, efforts to improve therapy for small molecule based antiviral therapeutics have largely focussed on increasing oral drug doses and using more frequent drug dosing regimens (e.g. multiple daily dosing).

[0021] The present invention satisfies a need for a novel treatment approach for HSV infections which can provide improvements in efficacy and / or safety and / or patient use.

[0022] In a second aspect of the invention, there is provided Compound 1 represented by:or a pharmaceutically acceptable salt thereof, for use in the treatment of a herpes virus infection in a human subject in need thereof, wherein the treatment comprises orally administering Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months.

[0023] In a third aspect of the invention, there is provided a method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject wherein the method comprises the steps of: a. administering to the human subject a loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, for a first period of time of one or twoHGF Ref. P387157WO6 weeks, wherein the loading dose is from about 50 mg to 200 mg, and the loading dose is administered once weekly; and b. after said first period of time, administering a maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, wherein the maintenance dose is from about 10 mg to 300 mg and the maintenance dose is administered once a week, or once a month.

[0024] In a fourth aspect of the invention, there is provided Compound 1 represented by:or a pharmaceutically acceptable salt thereof, for use in the treatment of a herpes virus infection in a human subject in need thereof, wherein the treatment comprises the steps of: a. orally administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, for a first period of time of one or two weeks, wherein the loading dose is from about 50 mg to 200 mg, and the loading dose is administered once weekly; and b. after said first period of time, orally administering a maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, wherein the maintenance dose is from about 10 mg to 300 mg and the maintenance dose is administered once a week, or once a month.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed compositions and methods, there are shown in the drawings exemplary embodiments of the compositions and methods; however, the compositions and methods are not limited to the specific embodiments disclosed. In the drawings:

[0026] FIG. 1 shows the mean plasma concentration-time profiles of Compound 1 for the Phase 1A study subject cohorts described in Example 4 up to (A) 24 hours; (B) 168 hours (7 days); and (C) 1680 hours (71 days) after dosing [circles = 10 mg fasted cohort; triangles = 30 mg fasted cohort; squares = 100 mg fasted cohort; diamonds = 30 mg fed cohort].HGF Ref. P387157WO7

[0027] FIG. 2 shows the mean plasma concentration-time profiles of Compound 1 for the Phase 1A study subject cohorts described in Example 4 for (A) days 1-8; and (B) days 1- 36; for the 10 mg, 30 mg, 100 mg, and 350 mg cohorts [circles = 350 mg fasted cohort; triangles = 100 mg fasted cohort; squares = 30 mg fasted cohort; diamonds = 10 mg fasted cohort],

[0028] FIG. 3 shows the mean plasma concentration-time profiles of Compound 1 from the Phase 1 B study subject described in Example 5 for the (A) 150 / 30 mg cohort, in which subjects (under fasted conditions) were dosed with a loading dose of 150 mg of Compound 1 on Day 1 followed by once weekly dosing of 30 mg of Compound 1 on Days 8, 15, 22, and 29; and (B) the 350 mg cohort, in which subjects (also under fasted conditions) were dosed with 350 mg of Compound 1 weekly on Days 1 , 8, 15, 22, and 29 [circles = 350 mg weekly fasted cohort; and squares = 150 / 30 mg fasted cohort],DETAILED DESCRIPTION OF THE INVENTION

[0029] The disclosed methods and compositions used in the methods, may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.Definitions

[0030] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0031] Reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

[0032] It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.HGF Ref. P387157WO8

[0033] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0034] As used herein, Cmax refers to the geometric mean maximum concentration of the active agent. This may be measured in vivo following administration of a composition of the invention to a subject and measuring the plasma levels of the drug at various timepoints after dosing.

[0035] As used herein, AUC refers to the area under the curve and is the definite integral of the concentration of the active agent in blood plasma as a function of time.

[0036] As used herein, the term “amorphous” refers to a solid material having no long- range order in the position of its molecules. Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, / .e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern ( / .e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.

[0037] As used herein, the term “dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle or carrier). The size of the dispersed phase can vary considerably (e.g., single molecules or colloidal particles of nanometer dimension up to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include: an amorphous drug in an amorphous polymer; an amorphous drug in a crystalline polymer; a crystalline drug in an amorphous polymer; or a crystalline drug in crystalline polymer. Herein, a solid dispersion can include an amorphous drug in an amorphous polymer, an amorphous drug in a crystalline polymer, or a crystalline drug in an amorphous polymer. In some embodiments, a solid dispersion includes the matrix polymer constituting the dispersed phase, and the drug or compound constitutes the continuous phase. Alternatively, a solid dispersion includes the drug constituting the dispersed phase, and the matrix polymer constitutes the continuous phase or carrier. Conveniently, the solid dispersion of the present invention comprises a dispersed phase, which comprises Compound 1 or a pharmaceutically acceptable salt thereof, and a continuous phase, which comprises the at least one matrix polymer. More conveniently, the solid dispersion comprises amorphousHGF Ref. P387157WOCompound 1 or a pharmaceutically acceptable salt thereof in an amorphous matrix polymer.

[0038] As used herein, “matrix polymer” refers to a polymer suitable for use in a solid dispersion according to the present invention and comprises inert, pharmaceutically acceptable polymers. Suitable matrix polymers include linear, branched or cyclic, natural or synthetic homopolymers (e.g., polysaccharides) and copolymers (e.g., block copolymers).

[0039] As used herein, the term “HPMCAS” refers to hydroxypropylmethylcellulose acetate succinate (CAS 71138-97-1). HPMCAS was first introduced by Shin-Etsu Chemical Co., Ltd., Japan, with three substitution levels designated according to the content of acetyl substituents as L, M, or H (e.g., Shin-Etsu AQOAT® LF, MF, HF, LG, MG and HG) The dissolution pH of HPMCAS ranges from about 5.5 (L) to about 6.5 (H) depending on the buffer type used for dissolution. Dow Chemical also markets HPMCAS (e.g., Dow AFFINISOL® 716, 912 and 126) as well as Ashland Chemical (e.g., AQUASOLVE® L, M and H grades). In contrast to HPMC, where substitution levels are specified by the monographs, the range for HPMCAS is not limited to the three commercially available subranges. Manufacturer’s specs for these products are shown below in Tables A-C.Table A: Manufacturer’s Specs for AQOAT® HPMCAS by Shin-EstuTable B: Manufacturer’s Specs for AFFINISOL® HPMCAS products by Dow*viscosity determined as a 2% solution in NaOH solutionHGF Ref. P387157WOTable C: Manufacturer’s Specs for AQUASOLVE® HPMCAS products by Ashland*measured for a 2% solution at 20 °C.

[0040] The properties of HPMCAS may be affected in particular by the acetyl and succinoyl contents of the polymer. Determination of the % w / w acetyl and succinoyl contents may be carried out by ester group hydrolysis of a weighed amount of polymer with 1M NaOH, followed by determination of the acetyl and succinoyl contents in the hydrolysed solutions by reverse-phase liquid chromatography against standard calibration solutions; this methodology is described in detail in Chen et al., Journal of AOAC International (2002), 85(4), 824-831 , the contents of which are incorporated by reference.

[0041] It is to be appreciated that references to “treating” or “treatment” include prevention as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e. , arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. As used herein, “treating” and like terms may specifically include reducing the severity and / or frequency of HSV induced symptoms, eliminating HSV induced symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of HSV induced symptoms and / or their underlying cause, delaying, preventing and / or slowing the progression of HSV induced conditions, and improving or remediating damage caused, directly or indirectly, by HSV infections. The term "preventing," as used herein with respect to an HSV infection or HSV-related disorder, refers to reducing the likelihood of HSV infection. In one embodiment, “treating” or “treatment” of a state, disorder or condition means inhibiting the state, disorder or condition, i.e., arresting, reducing orHGF Ref. P387157WO11 delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e. , causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. Conveniently, “treating” and like terms mean reducing the severity and / or frequency of HSV induced symptoms, eliminating HSV induced symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of HSV induced symptoms and / or their underlying cause, delaying, preventing and / or slowing the progression of HSV induced conditions, and / or improving or remediating damage caused, directly or indirectly, by HSV infections.

[0042] A “therapeutically effective amount” or “therapeutically effective dose” means the amount of a compound that, when administered to a patient or subject for treating a disease, is sufficient to effect such treatment for the disease. As used herein, the phrase “therapeutically effective dose” or “therapeutically effective amount” may specifically refer to the amount of Compound 1 , or a pharmaceutically acceptable salt thereof, dosed to a patient or subject, as described herein, which is effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and / or regression of conditions caused by, or associated with, HSV or prevention of the development of conditions caused by, or associated with, HSV, as determined by any means suitable in the art.

[0043] When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. Further, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0044] The term “about” when used in reference to numerical ranges, cut-offs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term “about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1 % or less, variations of ± 0.5% or less, or variations of ± 0.1 % or less from the specified value.HGF Ref. P387157WO12

[0045] At various places in the present specification, values are disclosed in groups or in ranges. It is specifically intended that the description include all individual subcombination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0046] The use of any and all examples, or exemplary language herein, for example, “such as,” “including,” or “for example,” is intended merely to illustrate better the present teachings and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present teachings.Compound 1

[0047] Compound 1 is a potent helicase-primase inhibitor having the following chemical structure:

[0048] The compound shown above is 2-(3-(2',5'-difluoro-[1 , 1 '-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide. The compound is disclosed as Compound 5 (with its synthesis described at Example 22) in WO 2024 / 049760.

[0049] Compound 1 has an in-vitro EC50 value of approximately 0.019 iM against HSV- 1 and 0.011 iM against HSV-2. The in-vitro EC50 value against HSV-1 and / or HSV-2 can be determined in accordance with methods known to the skilled person, such as those disclosed in Field et al. (2013, Antiviral Res. 100, p. 297-299). The in-vitro EC50 value can also be determined in accordance with the assays described in the Examples section of the present application.

[0050] Compound 1 of the present invention comprises both a parent compound and any pharmaceutically acceptable salt of the parent compound. It is to be understood thatHGF Ref. P387157WO13Compound 1 may exhibit polymorphism, and that the invention encompasses all such forms (including anhydrous / non-solvated forms, solvates and hydrates).

[0051] Throughout the specification, unless specified otherwise, references to the amount of Compound 1 will be understood to refer to the amount of Compound 1 on a free form basis, even if the compound is present as a pharmaceutically acceptable salt of Compound 1. Purely by way of example, reference to 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof, will be understood to refer to 10 mg of the free form, or a pharmaceutically acceptable salt of Compound 1 with 10 mg of free form equivalent.Treatment Methods of the Invention

[0052] In a first aspect, the present invention provides a method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months.

[0053] It has been discovered that Compound 1 , or a pharmaceutically acceptable salt thereof, when administered orally to human subjects in a single dose provides plasma concentrations of Compound 1 at therapeutically effective levels for unexpectedly long periods. The human half-life of Compound 1 has been found to be approximately 500 hours (20 days) over the dose range evaluated, and remarkably a single dose of Compound 1 may provide therapeutically effective coverage over at least 28 days. Moreover, it has also been found that when administered orally to a human subject using a once weekly dosage regimen, Compound 1 is able to provide significant reductions in viral shedding rate and genital lesion rate in participants seropositive for HSV-2 with recurrent genital herpes. The rate of samples with high viral load (i.e. , >104copies / mL HSV DNA), a potential surrogate for HSV-2 transmission, is also significantly reduced.HGF Ref. P387157WO14

[0054] Therefore, a dose administered to the human subject of from about 5 mg to 1200 mg may be useful to maintain the Compound 1 plasma concentrations at therapeutically effective levels.

[0055] In an embodiment, the dose of Compound 1 is administered no more than once every 7 days. In an embodiment, the dose of Compound 1 is administered no more than once a month. In an embodiment, the dose of Compound 1 is administered no more than once every three months.

[0056] In an embodiment, the dose of Compound 1 is administered once a week, once every two weeks, once a month, once every two months, or once every three months. In a convenient embodiment, the dose of Compound 1 is administered once a week, or once a month. In a convenient embodiment, the dose of Compound 1 is administered once every 7 days (once a week). In a convenient embodiment, the dose of Compound 1 is administered once a month.

[0057] In an embodiment, the dose of Compound 1 is from about 5 mg to 1000 mg, about 5 mg to 900 mg, about 5 mg to 800 mg, about 5 mg to 700 mg, about 5 mg to 600 mg, about 5 mg to 500 mg, or about 5 mg to 400 mg. Conveniently, the dose of Compound 1 is from about 10 mg to 300 mg, such as about 10 mg to 250 mg, or yet more conveniently about 10 mg to 200 mg or 25 mg to 200 mg. In a convenient embodiment, the dose of Compound 1 is from about 10 mg to 100 mg, such as about 10 mg to 50 mg; conveniently the dose is from about 10 mg to 40 mg, such as about 20 mg to 40 mg, about 25 mg to 35 mg, or about 30 mg. In a convenient embodiment, the dose of Compound 1 is from about 50 mg to 200 mg, such as about 100 mg to 150 mg; conveniently the dose is about 100 mg or about 150 mg.

[0058] In an embodiment, the dose of Compound 1 is from about 10 mg to 100 mg administered once a week, such as about 10 mg to 50 mg; conveniently the dose is from about 10 mg to 40 mg, such as about 20 mg to 40 mg, about 25 mg to 35 mg, or about 30 mg. In an embodiment, the dose of Compound 1 is from about 30 mg to 100 mg administered once a week, such as about 30 mg once weekly, about 50 mg once weekly, about 80 mg once weekly, or about 100 mg once weekly.

[0059] In an embodiment, the dose of Compound 1 is from about 25 mg to 200 mg administered once a week, such as about 50 mg to 200 mg administered once a week; conveniently the dose is from about 100 mg to 150 mg, such as about 100 mg or about 150 mg, administered once a week. In an embodiment, the dose of Compound 1 is from about 50 mg to 750 mg administered once a month, such as about 100 mg to 500 mg; conveniently the dose is from about 150 mg to 500 mg, such as about 150 mg to 300 mg.HGF Ref. P387157WO15Conveniently the dose is from about 120 mg to 300 mg once monthly. In an embodiment, the dose of Compound 1 is about 120 mg once monthly, about 150 mg once monthly, about 180 mg once monthly, about 240 mg once monthly, about 270 mg once monthly, or about 300 mg once monthly.

[0060] In an embodiment, the dose of Compound 1 is from about 400 mg to 800 mg administered once a month, such as about 400 mg to 700 mg; conveniently the dose is from about 400 mg to 600 mg administered once a month. Conveniently the dose is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg, administered once a month. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg, administered once a month.

[0061] In an embodiment, the dose of Compound 1 is from about 300 mg to 1200 mg administered once every three months, such as about 300 mg to 1000 mg; conveniently the dose is from about 350 mg to 900 mg. Conveniently the dose is from about 350 mg to 600 mg once every three months.

[0062] It is to be understood that a dose of Compound 1 , or a pharmaceutically acceptable salt thereof, can be administered as a single administration or it can be divided into more than one administration on the same day. For example, a dose of 100 mg of Compound 1 could be administered as two smaller 50 mg doses on the same day. Conveniently, the smaller divided amounts are administered within approximately 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes, of each other. More conveniently, the smaller divided amounts are administered simultaneously. In a convenient embodiment, the dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered in a single administration.

[0063] In an embodiment, the dose of Compound 1 achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 500 ng / mL for at least 80% of the dosing interval, conveniently at least 800 ng / mL for at least 80% of the dosing interval, more conveniently at least 1100 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 1200 ng / mL for at least 80% of the dosing interval.

[0064] In an embodiment, the method further comprises a step of administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, prior to the administration of the dose described in any of the above embodiments. A loading dose may be beneficial to achieve higher initial plasma concentrations of Compound 1 , with the subject being subsequently administered the maintenance dose over a longer time period to maintain the Compound 1 plasma concentrations at therapeutically effective levels.HGF Ref. P387157WO16

[0065] In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 50 mg to 500 mg, conveniently from about 50 mg to 400 mg, or about 50 mg to 300 mg, and yet more conveniently from about 50 mg to 200 mg. In a convenient embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 100 mg to 200 mg, such as from about 130 mg to 170 mg, conveniently about 150 mg.

[0066] In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once daily for a period of 1 to 28 days, conveniently 1 to 14 days, more conveniently 1 to 7 days.

[0067] In another embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once weekly for a period of one to four weeks, such as one week, two weeks, three weeks or four weeks. Conveniently, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once weekly for a period of one or two weeks, such as for one week.

[0068] In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 50 mg to 200 mg administered once daily for a period of 1 to 7 days. In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 100 mg to 300 mg administered once weekly for a period of one or two weeks. In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 50 mg to 200 mg administered once weekly for a period of one or two weeks. In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 150 mg administered once daily for a period of 7 days. In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 150 mg administered once weekly for a period of one or two weeks.

[0069] In a second aspect of the invention, there is provided Compound 1 represented by:or a pharmaceutically acceptable salt thereof, for use in the treatment of a herpes virus infection in a human subject in need thereof, wherein the treatment comprises orally administering Compound 1 , or a pharmaceutically acceptable salt thereof, to the humanHGF Ref. P387157WO17 subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months.

[0070] All of the above embodiments described in relation to the first aspect, apply equally to the second aspect of the invention.

[0071] In a third aspect of the invention, there is provided a method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject wherein the method comprises the steps of: b. administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, for a first period of time of one or two weeks, wherein the loading dose is from about 50 mg to 200 mg, and the loading dose is administered once weekly; and c. after said first period of time, administering a maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, wherein the maintenance dose is from about 10 mg to 300 mg and the maintenance dose is administered once a week, or once a month.

[0072] In an embodiment, the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 100 mg to 200 mg, such as about 150 mg.

[0073] In an embodiment, the maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 30 mg to 100 mg, such as about 30 mg.

[0074] In an embodiment, the first period of time is one week.

[0075] In an embodiment, the maintenance dose is administered once a week. Conveniently, the maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 30 mg once a week.HGF Ref. P387157WO18

[0076] In an embodiment, the maintenance dose is administered once a month. Conveniently, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 150 mg to 300 mg once a month.

[0077] In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 150 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg once a week.

[0078] In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 150 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 150 mg to 300 mg once a month.

[0079] In an embodiment, the maintenance dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 500 ng / mL for at least 80% of the dosing interval, conveniently at least 800 ng / mL for at least 80% of the dosing interval, more conveniently at least 1100 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 1200 ng / mL for at least 80% of the dosing interval.

[0080] In a fourth aspect of the invention, there is provided Compound 1 represented by:or a pharmaceutically acceptable salt thereof, for use in the treatment of a herpes virus infection in a human subject in need thereof, wherein the treatment comprises the steps of: b. orally administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, for a first period of time of one or two weeks, wherein the loading dose is from about 50 mg to 200 mg, and the loading dose is administered once weekly; and c. after said first period of time, orally administering a maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, wherein the maintenance dose is from about 10 mg to 300 mg and the maintenance dose is administered once a week, or once a month.

[0081] All of the above embodiments described in relation to the third aspect, apply equally to the fourth aspect of the invention.HGF Ref. P387157WO19Pharmaceutical Compositions

[0082] In the methods and treatments according to the first, second, third, or fourth aspects of the invention, Compound 1 , or a pharmaceutically acceptable salt thereof, may be formulated as a pharmaceutical composition, wherein the pharmaceutical composition comprises an amorphous solid dispersion.

[0083] In an embodiment, the pharmaceutical composition comprises a solid dispersion comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and at least one matrix polymer, wherein the Compound 1 or a pharmaceutically acceptable salt thereof is stabilised within the solid dispersion, for example in a substantially amorphous (or fully amorphous) form. Conveniently, Compound 1 or a pharmaceutically acceptable salt thereof is stabilised within the pharmaceutical composition in an amorphous form.

[0084] In an embodiment, the solid dispersion comprises about 5 wt % to about 60 wt % of Compound 1 , or a pharmaceutically acceptable salt thereof. Conveniently, the solid dispersion comprises about 10 wt % to about 30 wt % of Compound 1 , or a pharmaceutically acceptable salt thereof. Conveniently, the solid dispersion comprises about 20 wt % of Compound 1 , or a pharmaceutically acceptable salt thereof.

[0085] In an embodiment, the solid dispersion comprises about 40 wt % to about 95 wt % of at least one matrix polymer, such as about 70 wt % to about 90 wt of at least one matrix polymer. In a convenient embodiment, the solid dispersion comprises about 80 wt % of at least one matrix polymer.

[0086] In an embodiment, the at least one matrix polymer is selected from a copovidone polymer, poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol), hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate.

[0087] In a convenient embodiment, the at least one matrix polymer is selected from hydroxypropyl methylcellulose acetate succinate, EUDRAGIT® L 100, EUDRAGIT® E 100, PVP-VA64, HPMC E3 and Soluplus®. In a convenient embodiment, the at least one matrix polymer is selected from hydroxypropyl methylcellulose acetate succinate, EUDRAGIT® L 100, PVP-VA64, HPMC E3 and Soluplus®. Conveniently, the at least one matrix polymer is selected from hydroxypropyl methylcellulose acetate succinate and Soluplus®.

[0088] In a convenient embodiment, the at least one matrix polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0089] In an embodiment, the at least one matrix polymer is HMPCAS-L, HPMCAS-M or HPMCAS-H. Conveniently, the at least one matrix polymer is HPMCAS-M. Conveniently,HGF Ref. P387157WO20 the at least one matrix polymer is HPMCAS-L. More conveniently, the at least one matrix polymer is HPMCAS-H. In an embodiment, the HPMCAS has a weight-average molecular weight of about 15,000 to 25,000, such as about 17,000 to 20,000.

[0090] The pharmaceutical composition is in a unit dosage form suitable for oral administration. In an embodiment, the pharmaceutical composition is in a unit dosage form selected from the group consisting of a granule, a pellet, a tablet, a particle, a capsule, a suspension and a mini-tablet.

[0091] It is to be understood that a dose of Compound 1 , or a pharmaceutically acceptable salt thereof, can be administered using one or more unit dosage forms, e.g. one or more tablets. For example, a dose of 100 mg of Compound 1 could be administered in two unit dosage forms, e.g. two tablets, each containing 50 mg of Compound 1 , or a pharmaceutically acceptable salt thereof. Conveniently, when a dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered using more than one unit dosage form, e.g. two or more tablets, the unit dosage forms are administered within approximately 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 5 minutes, of each other. More conveniently, the unit dosage forms are administered simultaneously.

[0092] Conveniently, the dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered in a single unit dosage form, e.g., in a single tablet.

[0093] Conveniently, the pharmaceutical composition is formulated as a tablet for oral administration. Tablets may include pills, caplets, mini-tablets, micro-tablets and / or orally disintegrating tablets. Tablets can be any shape or size. In an embodiment, the pharmaceutical composition is a tablet with a total weight of 50-1000 mg, such as less than 1000 mg, such as less than 900 mg, 50-150 mg, 100-300 mg, or 750-950 mg. In an embodiment, the pharmaceutical composition is a tablet with a total weight of 250-500 mg, conveniently 300-500 mg, such as about 400 mg.

[0094] In an embodiment, the tablet comprises 50-70 wt % of a solid dispersion comprising Compound 1 , or a pharmaceutically acceptable salt thereof. Conveniently, the tablet comprises 55-65 wt % of the solid dispersion according.

[0095] In an embodiment, the pharmaceutical composition is a tablet comprising about 5 mg to about 100 mg of Compound 1 , or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition is a tablet comprising about 50 mg of Compound 1 , or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition is a tablet comprising about 5 mg to about 40 mg of Compound 1 , or a pharmaceutically acceptable salt thereof.HGF Ref. P387157WO21Treatment of Herpes Virus Infections

[0096] The methods of the present invention provide for the treatment of a herpes virus infection in a human subject in need thereof.

[0097] In an embodiment, the herpes virus infection being treated in the human subject is a herpes simplex virus (HSV) infection. In one embodiment, the herpes virus infection being treated is HSV1. In one embodiment, the herpes virus infection being treated is HSV2. In yet a further embodiment, both herpes virus HSV1 and HSV2 are being treated.

[0098] In an embodiment, the methods of the present invention provide for the treatment of a disease or disorder caused by, or associated with, a herpes virus infection in a human subject. In an embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s), herpes genitalis, HSV-related keratitis, HSV-related encephalitis, pneumonia, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis, and Bell's palsy. In a particular embodiment, the disease or disorder caused by, or associated with, HSV infection, is selected from herpes labialis (oro-labial cold sores or Whitlow’s), or genital herpes. In one embodiment, the disease or disorder is recurrent herpes labialis, or recurrent genital herpes. Individuals with a history of multiple recurrences of herpes labialis or genital herpes (e.g. HSV which recurs six times or more annually) may be regarded as having recurrent HSV.

[0099] In a further embodiment, the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes (RGH).

[0100] In one embodiment, the herpes virus being treated is resistant to nucleosidic antiviral therapy. In one embodiment, the nucleosidic antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.

[0101] In one embodiment, the herpes virus infection being treated is resistant to nucleosidic antiviral therapy, e.g., acyclovir-resistant mucocutaneous HSV infection. In a further embodiment, the HSV infection being treated is a mucocutaneous HSV infection resistant to therapy with antiviral therapy with nucleoside analogues, such as acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir.

[0102] In a particular embodiment, the subject in need of the methods disclosed herein, is immunocompromised. The subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation, chronic glucocorticoid use or a genetic immunodeficiency.HGF Ref. P387157WO22

[0103] In a particular embodiment, the subject in need of the methods disclosed herein, is a neonate or an infant.

[0104] In a particular embodiment, the subject is a herpes-positive patient.

[0105] In a particular embodiment, the subject in need of the methods disclosed herein, has acyclovir-resistant mucocutaneous HSV infection. This subject may have been diagnosed with this condition on the basis of clinical failure, e.g., no improvement after oral or iv doses for at least 7 days with approved doses of acyclovir.

[0106] In a particular embodiment, the subject in need of the methods disclosed herein, has a primary genital HSV-related herpes infection. In one embodiment, the subject in need of the methods disclosed herein, has severe or progressive genital HSV-related herpes infection.

[0107] In a particular embodiment, the methods according to the invention can reduce recurrence of HSV infections (i.e., provide a suppressive therapy) causing diseases or disorders, such as herpes labialis or genital herpes.

[0108] In an embodiment, the methods of the invention method suppresses recurrence of HSV symptoms or outbreaks in a human subject. In one embodiment, the reduction in the number of recurrences of lesions over a period of one year can be reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the rate of lesions over one year can be reduced by 90% or more.

[0109] In a particular embodiment, the methods according to the invention can reduce the duration of recurrent episodes of HSV infection, e.g., by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days.

[0110] In a particular embodiment, the methods according to the invention can reduce time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from HSV infections in diseases or disorders, such as herpes labialis or genital herpes. The time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.

[0111] In one embodiment, the methods according to the invention can reduce pain or pain intensity (for example, at a lesion site) caused as a consequence of HSV infections in diseases or disorders, such as herpes labialis or genital herpes.

[0112] In a particular embodiment, the methods according to the invention can reduce viral shedding, or reduce the rate of viral shedding, in individuals with recurrent HSV, e.g.,HGF Ref. P387157WO23 genital HSV2. For example, a within-subject genital HSV mucocutaneous shedding rate can be measured by taking swabs of skin and mucosa for HSV detection, e.g. by analysing samples for HSV DNA with a real-time, quantitative, fluorescent polymerase-chain- reaction (PCR) assay. The frequency of HSV2 detection (the viral shedding rate) can be defined as the number of days with a genital swab that was positive for HSV divided by the total number of days on which genital swabs were obtained. Alternatively, the frequency of HSV2 detection (the viral shedding rate) can be defined as the number of positive HSV-2 anogenital swabs divided by the total number of swabs collected during a period. Reduction in the HSV shedding rate among subjects receiving the compositions of the invention relative to the shedding rate among subjects receiving placebo or other treatments can be compared. The quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes can also be monitored.

[0113] In a particular embodiment, methods according to the invention reduce (or substantially supress or eliminate) break-through HSV shedding in a subject in need thereof.

[0114] In a particular embodiment, methods according to the invention prevent the transmission of HSV, or an infectious disease caused by HSV. The terms “prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. The term “prevention” or “preventing” also encompasses carrying out the methods described herein post-exposure of the subject to the virus, but before the appearance of symptoms of the disease, and / or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectible levels in the blood. It also encompasses carrying out the methods described herein to prevent perinatal transmission of viral infection from mother to baby, by carrying out the treatment method as described herein on the mother before giving birth, and on the child within the first days of its life.Particular methods of the invention

[0115] In a particular embodiment, there is provided a method for treating a herpes virus infection in a human subject in need thereof, wherein the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weeklyHGF Ref. P387157WO24 dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg.

[0116] In a particular embodiment, there is provided a method for reducing recurrence of HSV2 episodes (e.g., providing a suppressive therapy) in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg. Conveniently, the reduction in the number of recurrences of HSV2 episodes over a period of one year can be reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the rate of HSV2 episodes over one year can be reduced by 90% or more.

[0117] In a particular embodiment, there is provided a method for reducing genital lesion rate in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg. Conveniently, the lesion rate is reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the lesion rate is reduced by 90% or more. The genital lesion rate can be calculated as the number of days with genital lesions present divided by the total number of days assessed, e.g. over a period of one year.

[0118] In a particular embodiment, there is provided a method for reducing the duration of recurrent episodes of HSV infection treating a herpes virus infection in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the onceHGF Ref. P387157WO25 weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg. Conveniently, the duration of recurrent episodes of HSV infection is reduced by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days.

[0119] In a particular embodiment, there is provided a method for reducing time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from an herpes virus infection in a human subject in need thereof, wherein the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg. Conveniently, the time to healing of lesions is reduced by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days. The time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.

[0120] In a particular embodiment, there is provided a method for reducing HSV2 viral shedding, or reducing the rate of viral shedding, in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg. A within-subject genital HSV mucocutaneous shedding rate can be measured by taking swabs of skin and mucosa and for HSV detection, e.g. by analysing samples for HSV DNA with a real-time, quantitative, fluorescent polymerase-chain- reaction (PCR) assay. The frequency of HSV2 detection (the viral shedding rate) can be defined as the number of days with a genital swab that was positive for HSV divided by the total number of days on which genital swabs were obtained. Alternatively, the frequency of HSV2 detection (the viral shedding rate) can be defined as the number of positive HSV-2 anogenital swabs divided by the total number of swabs collected during a period. Reduction in the HSV shedding rate among subjects receiving the compositions ofHGF Ref. P387157WO26 the invention relative to the shedding rate among subjects receiving placebo or other treatments can be compared. The quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes can also be monitored.

[0121] In a particular embodiment, there is provided a method for reducing HSV2 viral shedding, or reducing the rate of viral shedding, in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, and wherein the subject has a high viral load (i.e., >104copies / mL HSV DNA), the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg.

[0122] In a particular embodiment, there is provided a method for reducing or preventing the transmission of HSV2 from a human subject in need thereof, wherein the subject has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. Conveniently, the once weekly dose of Compound 1 is from about 50 mg to about 200 mg; more conveniently the once weekly dose is from about 75 mg to 200 mg, yet more conveniently the once weekly dose is from about 100 mg to 150 mg. Conveniently, the once weekly dose of Compound 1 is about 100 mg or about 150 mg.

[0123] In a particular embodiment, there is provided a method for treating a herpes virus infection in a human subject in need thereof, wherein the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg.HGF Ref. P387157WO27

[0124] In a particular embodiment, there is provided a method for reducing recurrence of HSV2 episodes (e.g., providing a suppressive therapy) in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg. Conveniently, the reduction in the number of recurrences of HSV2 episodes over a period of one year can be reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the rate of HSV2 episodes over one year can be reduced by 90% or more.

[0125] In a particular embodiment, there is provided a method for reducing genital lesion rate in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg. Conveniently, the lesion rate is reduced by 20, 30, 40, 50, 75, 90 or 95% or more. Conveniently, the lesion rate is reduced by 90% or more. The genital lesion rate can be calculated as the number of days with genital lesions present divided by the total number of days assessed, e.g. over a period of one year.

[0126] In a particular embodiment, there is provided a method for reducing the duration of recurrent episodes of HSV infection treating a herpes virus infection in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose ofHGF Ref. P387157WO28Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg. Conveniently, the duration of recurrent episodes of HSV infection is reduced by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days.

[0127] In a particular embodiment, there is provided a method for reducing time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from an herpes virus infection in a human subject in need thereof, wherein the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg. Conveniently, the time to healing of lesions is reduced by one or more days, e.g., at least 2, 3, 4, 5, 14, 21 or 28 days. The time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.

[0128] In a particular embodiment, there is provided a method for reducing HSV2 viral shedding, or reducing the rate of viral shedding, in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg. A within-subject genital HSV mucocutaneous shedding rate can be measured by taking swabs of skin and mucosa and for HSV detection, e.g. by analysing samples for HSV DNA with a real-time, quantitative, fluorescent polymerase-chain- reaction (PCR) assay. The frequency of HSV2 detection (the viral shedding rate) can be defined as the number of days with a genital swab that was positive for HSV divided by the total number of days on which genital swabs were obtained. Alternatively, the frequency of HSV2 detection (the viral shedding rate) can be defined as the number ofHGF Ref. P387157WO29 positive HSV-2 anogenital swabs divided by the total number of swabs collected during a period. Reduction in the HSV shedding rate among subjects receiving the compositions of the invention relative to the shedding rate among subjects receiving placebo or other treatments can be compared. The quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes can also be monitored.

[0129] In a particular embodiment, there is provided a method for reducing HSV2 viral shedding, or reducing the rate of viral shedding, in a human subject in need thereof, wherein the subject in need of the treatment has HSV2 recurrent genital herpes, and wherein the subject has a high viral load (i.e., >104copies / mL HSV DNA), the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg.

[0130] In a particular embodiment, there is provided a method for reducing or preventing the transmission of HSV2 from a human subject in need thereof, wherein the subject has HSV2 recurrent genital herpes, the method comprising orally administering a dose of from about 400 mg to about 800 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. Conveniently, the once monthly dose of Compound 1 is from about 400 mg to about 700 mg; more conveniently the once monthly dose is from about 400 mg to 600 mg. Conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 700 mg. More conveniently, the once monthly dose of Compound 1 is about 400 mg, about 450 mg or about 500 mg.

[0131] It is to be understood that the monthly dose of Compound 1 , or a pharmaceutically acceptable salt thereof, can be administered as a single administration or it can be divided into more than one administration on the same day. For example, a monthly dose of 400 mg of Compound 1 could be administered as two smaller 200 mg doses on the same day. Conveniently, the smaller divided amounts are administered simultaneously. In a convenient embodiment, the monthly dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered in a single administration.HGF Ref. P387157WO

[0132] In the methods and treatments described above, Compound 1 , or a pharmaceutically acceptable salt thereof, may be formulated as a pharmaceutical composition, wherein the pharmaceutical composition comprises an amorphous solid dispersion.Combinations

[0133] In an aspect of the present invention, the methods of treating a herpes virus infection comprise the treatment regimen as described herein, wherein Compound 1 is administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.

[0134] Therefore, contemplated in this aspect are methods that include administering a second active agent. For example, in addition to being infected with HSV, a subject or patient can further have HSV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HSV. In an embodiment, the second active agent has previously been shown to treat these HSV-infection-related conditions. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of Compound 1 according to methods described herein, and the second active agent.

[0135] Therefore, provided herein is a method for treating a herpes virus infection in a human subject in need thereof, the method comprising (i) orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months; and (ii) coadministering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0136] In an embodiment, the additional therapeutic agent is selected from one or more of the following agents:HGF Ref. P387157WO31 i. nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir and ganciclovir; ii. pyrophosphate polymerase inhibitors, such as foscarnet; iii. saturated aliphatic alcohols, such as docosanol; iv. agents such as idoxuridine, trifluridine and vidarabine; v. a corticosteroid; and vi. other helicase-primase inhibitors, such as amenamevir.

[0137] In some cases, the methods of the present invention may be carried out as part of a combination therapy in conjunction with one or more antiviral agents, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir, or the respective prodrugs valacyclovir or famciclovir.

[0138] Therapeutically effective amounts of Compound 1 , or a pharmaceutically acceptable salt thereof, and an antiviral agent may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same, or different, routes of administration. In some instances, it may be advantageous to initiate administration of Compound 1 first, for example one or more days or weeks prior to initiation of administration of the antiviral agent. Moreover, additional drugs may be given in conjunction with the above combination therapeutic method.

[0001] All of the above embodiments disclosed in relation to methods of treating herpes virus infections and combination treatments apply equally to the first, second, third, or fourth aspects of the invention. The invention is illustrated below by the following nonlimiting examples.EXAMPLESEXAMPLE 1 : Synthesis of Compound 1HGF Ref. P387157WO1A Int. 1ASynthesis of 1-(4-methylthiazol-2-yl) tetrahydropyrimidin-2(1H)-one (1-2)

[0139] A mixture of 2-amino-4-methylthiazole (compound 1-1 ; 6 g, 52.632 mmol) and 1- chloro-3-isocyanatopropane (6.26 g, 52.632 mmol) in THF (60 mL) was heated at 70 °C for 6 h. To the resulting solution, TBAB (1.7 g, 5.263 mmol) and K2CO3 (18.15 g, 131.58 mmol) were added portion wise maintaining the same temperature and stirring continued at 70 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 60-70% EtOAc in heptane) to afford the title compound 1-2 (5.1 g, 49.22%) as an off-white solid. TLC: 70% EtOAc / heptane (Rf: 0.5). MS calcd. for Chemical Formula: C8H11 N3OS: 197.06; Found: 198.17 [M + 1]+. 1 H NMR (400 MHz, DMSO-d6) 5 7.30 (s, 1 H), 6.60 (s, 1 H), 3.99 (t, J = 5.4 Hz, 2H), 3.20 - 3.19 (m, 2H), 2.28 (s, 3H), 1.99 - 1.89 (m, 2H).Synthesis of 1-(2',5'-difluoro-[1,1,-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl) tetrahydropyrimidin-2(1 H)-one (1 -3)

[0140] To a stirred solution of compound 1-2 (5 g, 25.380 mmol) in 1 ,4-dioxane (100 mL) were added Int. 1A (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol) followed by Cui (0.96 g, 5.076 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture, 1 ,2-Dimethylethylenediamine (0.9 g, 10.152 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 120 °C for 24 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through Celite® bed and washed with ethyl acetate. The filtrate was diluted with water and,HGF Ref. P387157WO33 extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to afford the title compound 1-3 (4.1 g, 41.96%) as an off-white solid. TLC: 50% EtOAc / Heptane (Rf: 0.5). MS calcd. for Chemical Formula: C20H17F2N3OS: 385.11 ; Found: 385.90 [M + 1]+.1H NMR (400 MHz, DMSO-ds) 5 7.61 (d, J = 7.8 Hz, 2H), 7.54 - 7.35 (m, 4H), 7.35 - 7.21 (m, 1 H), 6.70 (s, 1 H), 4.17 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 4.9 Hz, 2H), 2.26 (s, 3H), 2.24 - 2.21 (m, 2H).Synthesis of 2-(3-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonic acid (1-4)

[0141] To a stirred solution of compound 1-3 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0 °C in an inert atmosphere, chlorosulfuric acid (2.07 mL, 31.168 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The obtained solid was filtered off and dried in vacuo to afford the title compound 1- 4 (3.35 g, crude) as an off-white solid. TLC: 100% EtOAc (Rf: 0.2). MS calcd. for Chemical Formula: C20H17F2N3O4S2: 465.06; Found: 466 [M + 1]+.Synthesis of 2-(3-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonamide (Compound 1)

[0142] A stirred solution of compound 1-4 (3.3 g, 7.096 mmol) in POCI3 (33 mL) was allowed to stir at 90 °C for 5 h. The reaction mixture was concentrated under reduced pressure to dryness. The resulting residue obtained was dissolved in THF (66 mL), and aqueous ammonia (33 mL) was added at -5 °C and stirring continued at room temperature for another 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 100% EtOAc) to afford the desired product Compound 1 (1.1 g, 44.64%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 5 7.65-7.59 (m, 2H), 7.55 (br s, 2H), 7.53-7.48 (m, 2H), 7.48-7.36 (m, 2H), 7.31-7.25 (m, 1 H), 4.17 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.29-2.18 (m, 2H).Synthesis of 4'-bromo-2,5-difluoro-1,1 '-biphenyl (Int. 1A)

[0143] To a stirred solution of 4-bromo-iodobenzene (5 g, 17.674 mmol) in 1 ,4 dioxane: H2O (50:5 mL) were added (2,5-difluorophenyl) boronic acid (3.07 g, 19.441 mmol) and K3PO4 (7.5 g, 35.348 mmol) and the reaction mixture was purged under nitrogen for 10HGF Ref. P387157WO34 min. To this resulting solution PdCI2(dppf) (1.29 g, 1.767 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 80 °C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 100% heptane) to afford the title compound Int. 1A (2.3 g, 48.62%) as an off-white solid. TLC: 100% heptane (Rf: 0.5). 1 H NMR (400 MHz, CDCI3) 5 7.58 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.15-7.06 (m, 2H), 7.05-6.97 (m, 1 H). difluoro-[1,1,-bi-4-vl)-2--5-sulfonamideCell culture

[0144] Vero cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% foetal bovine serum and 100 units / mL penicillin and streptomycin. The cells were passaged 2-3 times per week to maintain sub-confluent densities.HSV-1 antiviral

[0145] Vero cells were seeded into 96-well plates at a density of 2.5 x 103cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DMEM supplemented with 2% foetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 80 TCID50 HSV-1 was added to the cells and incubated at 37°C for 4 days. After the incubation, the plates were equilibrated to room temperature, the media was removed, and 60 of a 1 :1 dilution of Cell titer glow and phosphate buffered saline was added to the cells. Following a 5-minute incubation, cell viability was quantified by measuring luminance using a Tecan Infinite M1000 Pro plate reader.HSV-2 antiviral

[0146] Vero cells were seeded into 96-well plates at a density of 1.0 x 104cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DM EM supplemented with 2% foetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSOHGF Ref. P387157WO35 concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 160 TCID50 HSV-2 G strain was added to the cells and incubated at 37°C for 5 days. After the incubation, 10 pL / well of WST-8 chromogenic reagent was added and the plates incubated at 37°C for 3 hours. Following the incubation, cell viability was quantified by measuring the absorbance at 460 nm and 620 nm using a Tecan Infinite M1000 Pro plate reader.

[0147] In the HSV-1 antiviral assay, Compound 1 had an EC50 of 0.019 pM (n=22). In the HSV-2 antiviral assay, Compound 1 had an EC50 of 0.011 pM (n=35).EXAMPLE 3: Preparation of Compound 1 Tablet compositions Preparation of solid dispersion for use in tablet formulation

[0148] A solid dispersion of Compound 1 in hypromellose acetate succinate HG grade (HPMCAS HG; Shin-Etsu, AQOATO-HG) was manufactured using a commercial scale spray dryer. Preparation conditions are described in Table 1.Table 1 : Spray Drying Conditions

[0149] The solid dispersion was characterised for drug loading and purity and the results from this characterisation work are shown in Table 2.Table 2: Solid Dispersion CharacterisationHGF Ref. P387157WO36Preparation of tablet composition

[0150] A tablet composition using the solid dispersion was manufactured using a dry granulation method. The composition of the tablet formulations is given in Table 3.Table 3: Tablet Composition

[0151] The tablet formulation was prepared as follows. The SDD amount was correct based on actual drug loading and mixed with the intra-granular excipients described in Table 3. Roller compaction was utilized to granulate the mixture. Extra-granular components were then added and blended. The final blend was compressed into tablets. The tablet formulation was characterised and the results from this characterisation are given in Table 4.Table 4: Tablet CharacterisationHGF Ref. P387157WO37EXAMPLE 4: Phase 1a Study to evaluate safety, tolerability and PK of Compound 1

[0152] A randomized, blinded and placebo-controlled Phase 1a clinical study of Compound 1 was carried out to evaluate the safety, tolerability and PK following single ascending dose administration in healthy participants, as well as the potential effect of food on Compound 1.Inclusion Criteria

[0153] Subjects must have met all of the following inclusion criteria in order to be eligible for the study:1 . Subject is willing and able to provide informed consent prior to Screening.2. Subject is male or female > 18 and < 60 years of age at Screening.3. Subject has a body mass index (BMI) between > 18.0 and < 32.0 kg / m2at Screening.4. Subject is in good health (as determined by the Investigator) based on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory results. Medical history and physical examination must be without major or clinically significant findings.5. Subject has serum chemistry, hematology, coagulation, and urinalysis values within the respective reference range or has values outside the reference range, which are deemed not clinically significant (as determined by the Investigator) during the Screening period.6. Subject must be willing to discontinue herbal / dietary supplements (eg, vitamins, St. John’s Wort, ginkgo biloba, garlic supplements), over-the-counter (OTC) medications (except for paracetamol), or any prescription medications beginning 14 days or 5 half-lives prior to the Day 1 dosing, whichever is longer, and through EOS.7. Female subjects of childbearing potential must be non-pregnant, non-lactating, and have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1 or Day 1 , obtained prior to dosing.8. Subject agrees to comply with protocol-specified contraceptive requirements.9. Male subjects must agree not to donate sperm from Screening through at least 90 days after EOS.HGF Ref. P387157WO3810. Subject must be able to take oral medication and in the opinion of the Investigator, be willing to comply with the clinical trial protocol and procedures.Exclusion Criteria

[0154] Subjects who met any of the following exclusion criteria were not eligible for the study:1 . Subject has a current infection of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), acute hepatitis A virus (HAV), or acute hepatitis E virus (HEV).2. Female subjects who are pregnant, lactating, or plan to become pregnant from Screening through end of study (EOS).3. Subject has a clinically significant medical, behavioral, or mental condition, or pharmacologic or surgical treatment that, in the opinion of the Investigator or the Sponsor, may interfere with safety assessments, or the absorption, distribution and / or elimination of the study drug, or make the subject unsuitable for study participation.4. Subject has a history of malignancy in the last 5 years, with the exception of nonmetastatic basal cell, squamous cell carcinoma of the skin, or localized carcinoma of the cervix that has been successfully resected or otherwise resolved.5. Subject has had an illness within 5 days before receiving the first dose of study drug (“illness” is defined as a recent nonserious condition such as the flu, the common cold, or Coronavirus disease 2019 [COVID-19]).6. Subject has hypersensitivity or history of idiosyncratic reaction to any components or excipients of the study drug (Compound 1 or placebo).7. Subject has a history of any significant (as determined by the Investigator) drug- related allergic reactions such as anaphylaxis, Stevens-Johnson syndrome, urticaria, or multiple drug allergies.8. Subject has a history of persistent alcohol abuse (alcohol consumption exceeding2 standard drinks per day on average [1 standard drink =14 grams of alcohol]) or a history of persistent illicit substance / drug use within 3 years prior to Screening.9. Subject is unwilling to abstain from alcoholic beverage consumption 48 hours prior to Day 1 dosing through Day 28.10. Subject is unwilling to abstain from use of marijuana from Screening through EOS.11. Subject is unwilling to abstain from illicit substance use from Screening through EOS.12. Subject has a smoking habit, uses, or has used tobacco or nicotine-containing products (eg, including but not limited to cigarettes, e-cigarettes, pipes, cigars, chewingHGF Ref. P387157WO39 tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 90 days before Day 1 dosing and is unwilling to abstain from tobacco or nicotine-containing products through discharge from the study site.13. Subject is unwilling to abstain from consumption of grapefruit, pomelo, or Seville oranges whole fruits or juices for 7 days prior to Day 1 dosing through discharge from the study site.14. Subject is unwilling to abstain from caffeine in any form, including coffee, tea, cola, chocolate, and other caffeinated beverages 48 hours prior to Day 1 dosing through discharge from the study site.15. Subject has received an investigational agent within 30 days or 5 half-lives before Screening, whichever is longer.16. Subject has donated or lost more than 1 unit of blood (500 mL) within 60 days prior to Screening, or donated plasma within 7 days prior to Screening, or plans to donate blood or plasma through EOS.Study Design

[0155] Subjects remained confined to the study site from Day-1 until Day 8, with subsequent outpatient follow-up visits scheduled. Since this is a first-in-human study, a sentinel dosing approach was utilized for the ascending dose cohorts. Using this approach, when a higher dose was evaluated which had not been studied previously, then 2 subjects in that cohort were initially dosed (one receiving Compound 1 and one receiving placebo). These sentinel subjects were observed for a minimum of 3 days post dose to ensure acceptable safety and tolerability of the study drug, before dosing of the remaining subjects within the cohort proceeded.Study Drug

[0156] The drug product was a tablet containing approximately 10 mg or 50 mg of Compound 1 formulated in a solid dispersion which was produced by spray drying a solution of Compound 1 with HPMCAS HG, according to the tablet formulation described in Example 3.

[0157] Matching placebo tablets containing equivalent excipients, and having the same appearance as the Compound 1 tablets, were manufactured.Study Treatment

[0158] Subjects underwent 28 days of screening, followed by 1 day of treatment and 100 days of follow-up. The cohorts studied comprised 8 subjects each, split 6:2 between Compound 1 and placebo:HGF Ref. P387157WO40 a) 10 mg Compound 1 or placebo, oral, single dose, fasted; b) 30 mg Compound 1 or placebo, oral, single dose, fasted; c) 100 mg Compound 1 or placebo, oral, single dose, fasted; d) 350 mg Compound 1 or placebo, oral, single dose, fasted; e) 30 mg Compound 1 or placebo, oral, single dose, fed.

[0159] In the fasted cohorts, single doses of study drug were administered in the morning of Day 1 after an overnight fast of at least 10 hours. All subjects continued fasting for 4 hours after dosing, and received a standardized lunch, afternoon snack, dinner, and an evening snack at approximately 4 hours, 7 hours, 10 hours, and 12 hours after dosing, respectively. On all non-dosing inpatient days (Days 2 through 7), subjects received a standardized breakfast at approximately the same time as dosing time on dosing days, and lunch, afternoon snack, dinner, and an evening snack approximately 4 hours, 7 hours, 10 hours, and 12 hours later, respectively.

[0160] In the 30 mg fed cohort, after an overnight fast of at least 10 hours, 30 minutes prior to dosing on Day 1 the subjects received a high fat (approximately 50% calories from fat), high-calorie (800 to 1000 calories) test meal, which must have been completely consumed. They then continued fasting for 4 hours after dosing and received a standardized lunch, afternoon snack, dinner, and an evening snack at approximately 4 hours, 7 hours, 10 hours, and 12 hours after dosing, respectively. On all non-dosing inpatient days (Days 2 through 7), subjects received a standardized breakfast at approximately the same time as dosing time on dosing days, and lunch, afternoon snack, dinner, and an evening snack approximately 4 hours, 7 hours, 10 hours, and 12 hours later, respectively.

[0161] Subjects were required to comply with the following restrictions (in addition to restrictions noted in the inclusion / exclusion criteria) during study participation:• Subjects were not to engage in strenuous exercise beyond their accustomed daily level of activity from Day 1 dosing through EOS.• Subjects were advised to take measures to minimize exposure to ultraviolet light from Day 1 through Day 7, as an initial assessment of Compound 1 for the potential for phototoxicity has not yet been conducted.• Subjects must have been fasting for at least 8 hours before chemistry assessments.Subject AssessmentsHGF Ref. P387157WO41

[0162] Subjects underwent physical examination, vital sign measurements, 12-lead ECG tests, urinalysis, and blood chemistry testing during the screening, treatment and / or followup periods of the study.

[0163] Blood sampling for Compound 1 PK determination was carried out on day 1 and throughout the inpatient and outpatient follow-up periods. Urine and faeces PK sampling was also carried out on day 1 and during the follow-up period.

[0164] Any adverse events were monitored and recorded throughout the study period and the severity assessed according to the following guidelines:• Grade 1 (Mild): Mild symptoms causing no or minimal interference with usual social and functional activities with intervention not indicated.• Grade 2 (Moderate): Moderate symptoms causing greater than minimal interference with usual social & functional activities with intervention indicated.• Grade 3 (Severe): Severe symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated (NB: the term “severe” does not necessarily equate to “serious”).• Grade 4 (Life-Threatening): Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death.Summary of ResultsPharmacokinetic (PK) Data

[0165] The Compound 1 blood plasma concentrations after single dosing on Day 1 are shown in Figure 1 for the 10 mg fasted, 30 mg fasted, 100 mg fasted, and 30 mg fed cohorts for 24 hours (Fig. 1A), seven days (Fig. 1 B), and up to 71 days / 1680 hrs (Fig. 1C), post-administration.

[0166] The Compound 1 blood plasma concentrations after single dosing on Day 1 are shown in Figure 2 for the 10 mg fasted, 30 mg fasted, 100 mg fasted, and 350 mg fasted cohorts for days 1-8 (Fig. 2A), and days 1-36 (Fig. 2B).

[0167] Across the cohorts evaluated Compound 1 unexpectedly had a mean half-life of approximately 20 days when dosed orally. Furthermore, the pharmacokinetic data indicates that high plasma concentrations were achieved and maintained following administration for a prolonged period. The data indicates that once-weekly, or even once- monthly dosing of Compound 1 , would provide therapeutic levels expected for antiviral activity. No significant difference in the PK data was seen between the 30 mg fasted andHGF Ref. P387157WO4230 mg fed cohorts, indicating that there may be minimal impact of food on Cmax or AIIC24 at this dose level.Safety Data

[0168] The Phase 1a results show that Compound 1 was well-tolerated and showed a favourable safety profile with exposure of up to 70 days due to its extended pharmacokinetic (PK) profile.

[0169] In summary, single doses of Compound 1 at dose levels tested in Phase 1a surpassed projected target plasma concentrations, and support the Phase 1 b study evaluating the treatment of patients with recurrent genital herpes with once-weekly and once-monthly dosing of Compound 1.EXAMPLE 5: Phase 1 b Study to evaluate Compound 1 in patients seropositive for herpes simplex virus type 2 (HSV-2) with Recurrent Genital Herpes (RGH)

[0170] A randomized, blinded and placebo-controlled Phase 1b clinical study of Compound 1 is carried out to evaluate the safety and PK profile of Compound 1 following multiple dose administration in subjects with RGH along with proof-of-concept (POC) for antiviral activity.Inclusion Criteria

[0171] Subjects must have met all of the following inclusion criteria in order to be eligible for the study:1 . Subject is willing and able to provide informed consent prior to Screening.2. Subject is male or female > 18 and < 60 years of age at Screening.3. Subject has a BMI between > 18.0 and < 32.0 kg / m2 at Screening.4. Other than HSV infection, the subject is in good health (as determined by the Investigator) based on medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory results. Medical history and physical examination must be without major or clinically significant findings.5. Subject has serum chemistry, haematology, coagulation, and urinalysis values within the respective reference range or has values outside the reference range, which are deemed not clinically significant (as determined by the Investigator) during the Screening period.6. Subject must be willing to discontinue: a. prohibited concomitant medications (strong CYP3A4 inhibitors / inducers, or drugs with narrow therapeutic window (e.g. warfarin, digoxin or phenytoin)HGF Ref. P387157WO43 beginning 14 days or 5 half-lives prior to the Day 1 dosing, whichever is longer, and through EOS. b. treatment (systemic and topical) for genital herpes beginning 7 days prior to Day 1 dosing through Day 36.7. Female subjects of childbearing potential must be nonpregnant, non-lactating, and have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 , obtained prior to dosing.8. Subject agrees to comply with protocol-specified contraceptive requirements.9. Male subjects must agree not to donate sperm from Screening through at least 90 days after EOS.10. Subject is HSV-2 seropositive as determined by HSV Western Blot.11. Subject has a history of RGH, with 4-9 clinical episodes in the last year or if currently on suppressive therapy, 4-9 times a year prior to suppressive therapy.12. Subject is willing to obtain required anogenital swabs during the study.13. Subject is willing to maintain a diary for anogenital symptoms and swabs during the study.14. Subject must be able to take oral medication and in the opinion of the Investigator, be willing to comply with the clinical trial protocol and procedures.Exclusion Criteria

[0172] Subjects who meet any of the following exclusion criteria will not be eligible for the study:1 . Subject has a current co-infection with HIV, HBV, HCV, acute HAV, or acute HEV.2. Female subjects who are pregnant, lactating, or wish to become pregnant from Screening through EOS.3. Subject has a clinically significant medical, behavioral, or mental condition, or pharmacologic or surgical treatment that, in the opinion of the Investigator or the Sponsor, may interfere with safety assessments, or the absorption, distribution and / or elimination of the study drug, or make the subject unsuitable for study participation.4. Subject has a history of malignancy in the last 5 years, with the exception of nonmetastatic basal cell, squamous cell carcinoma of the skin or localized carcinoma of the cervix that has been successfully resected or otherwise resolved.5. Subject has had an illness within 5 days before receiving the first dose of study drug (“illness” is defined as a recent nonserious condition such as the flu, the common cold, or COVID-19).6. Subject has hypersensitivity or history of idiosyncratic reaction to any components or excipients of the study drug (Compound 1 or placebo).HGF Ref. P387157WO447. Subject has a history of any significant (as determined by the Investigator) drug- related allergic reactions such as anaphylaxis, Stevens-Johnson syndrome, urticaria, or multiple drug allergies.8. Subject has a history of significant drug-related macular or maculopapular skin reactions (exanthema or eruption).9. Subject is known to have other genital tract disorders or sexually transmitted diseases that may interfere with the assessment of study drug efficacy.10. Subject has an acute episode of genital herpes on Day 1 prior to dosing.11. Subjects with demonstrated poor clinical response or tolerability to any HPI, such as pritelivir.12. Subject is known to be immunosuppressed.13. Subject has a history of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per day on average [1 standard drink =14 grams of alcohol]) or a history of persistent illicit substance / drug use within 3 years prior to Screening.14. Subject is unwilling to abstain from alcoholic beverage consumption 48 hours prior to Day 1 dosing through EOT.15. Subject is unwilling to abstain from use of marijuana from Screening through EOS.16. Subject is unwilling to abstain from illicit substance use from Screening through EOS.17. Subject is unwilling to abstain from consumption of grapefruit, pomelo, or Seville orange whole fruits or juices for 7 days prior to Day 1 dosing through EOT.18. Subject has had treatment with long-term (i.e. , >14 days) systemic steroids or other immunomodulating agents within 6 months prior to Screening.19. Subject has had treatment with pritelivir, or any other investigational HPI within 12 months prior to Screening.20. Subject has participated in a clinical study involving administration of either an investigational agent / device or a marketed drug used in an investigational manner within 30 days or 5 half-lives prior to Screening, whichever is longer.21. Subject has donated or lost more than 1 unit of blood (500 mL) within 60 days prior to Screening, or plasma donation within 7 days prior to Screening, or plans to donate blood or plasma through EOS.

[0173] The study period is up to 172 days with up to 45 days of screening, 29 days of treatment and up to 98 days of follow-up. Subjects will be randomised to one of four cohorts (B1-B4), with 25 subjects in each cohort split 20:5 between Compound 1 and placebo.HGF Ref. P387157WO45

[0174] Cohort B1 subjects are dosed with a loading dose of 150 mg of Compound 1 on Day 1 , followed by once weekly dosing of 30 mg of Compound 1 on Days 8, 15, 22, and 29.

[0175] Subsequently, dosing in Cohorts B2, B3, and B4 are staggered with subjects receiving once weekly or once monthly doses of study drug over 29 days (i.e. , dosing on Days 1 , 8, 15, 22, and 29 for once weekly dosing, or dosing on Days 1 and 29 for once monthly dosing). Dosing regimens in all Cohorts B2, B3, and B4 may or may not include loading doses.

[0176] The dose levels and frequency for Cohorts B2-B4 are determined based on reviews of study information including safety data from a minimum of 10 subjects through at least Day 15 and available PK data for the present cohort, and all available safety, PK, and antiviral activity data from preceding cohorts. PK modelling / simulation may also be used to support dose selection. In no case would the exposure from an individual dose escalation be greater than 3.5-fold compared with the exposure from the highest dose from a previous cohort that was considered safe and well tolerated.

[0177] Study drug dosing will occur at the study site in the morning under fasted conditions. On Days 1 and 29, subjects remain at the study site for approximately 8 hours after dosing for PK sample collection.

[0178] The drug product is a tablet containing approximately 10 mg or 50 mg of Compound 1 formulated in a solid dispersion produced by spray drying a solution of Compound 1 with HPMCAS HG, according to the tablet formulation described in Example 3.

[0179] Matching placebo tablets containing equivalent excipients, and having the same appearance as the Compound 1 tablets, are manufactured.Study Treatment

[0180] In the B1-B4 cohorts, all study drug doses are administered at the study site in the morning after an overnight fast of at least 10 hours. All subjects will continue fasting for 4 hours after dosing and on Days 1 and 29 will receive a standardized lunch and afternoon snack at approximately 4 hours and 7 hours after dosing, respectively, as applicable (depending on duration of clinic stay). Subjects will have approximately 30 minutes to consume the meals.

[0181] Subjects are required to comply with the following restrictions (in addition to restrictions noted in the inclusion / exclusion criteria) during study participation:HGF Ref. P387157WO46• Subjects will not engage in strenuous exercise beyond their accustomed daily level of activity from Day 1 dosing through EOS.• Subjects will be advised to take measures to minimize exposure to ultraviolet light from Day 1 through Day 7, as an initial assessment of Compound 1 for the potential for phototoxicity has not yet been conducted.• Subjects must be fasting for at least 8 hours before chemistry assessments.Subject Assessments

[0182] Subjects will undergo physical examination, vital sign measurements, 12-lead ECG tests, urinalysis, and blood chemistry testing during the screening, treatment and / or follow-up periods of the study.

[0183] Blood sampling for Compound 1 PK determination is carried out on day 1 and throughout the inpatient and outpatient follow-up periods.

[0184] Examination of the anogenital area will be performed as part of physical examination. This assessment would determine whether an anogenital lesion(s) was observed or not. If no lesions were observed, then the anogenital examination would be complete. If one or more lesions were observed, then each lesion would be scored separately by the Investigator according to the scale presented in Table 5.Table 5: HSV Lesion scoring tool during Phase 1b studyHGF Ref. P387157WO47

[0185] Subjects will receive specific training on the swabbing procedure to be completed during the study. The subject’s initial training on this procedure will take place during the Day 1 study visit, with follow-up training during the Day 8 study visit. On Day 1 , while implementing the procedure under trained site supervision, the subject will collect anogenital swabs as directed. All swabs collected during the study will be analyzed at a central laboratory for the detection and quantification of HSV DNA. In addition to the twice daily swabbing of the anogenital region described above, swabs will also be collected by the subject from the site(s) of anogenital lesion(s) each time they occur. Should anogenital lesions occur, the subject will be instructed to attend the clinical site for an unscheduled visit within 48 hours, if possible, after first appearance of the lesion(s). At this unscheduled visit, the Investigator will collect a swab from the lesion site(s) in addition to those being collected by the subject. HSV DNA extracted from genital swab samples will be analyzed in a quantitative real-time PCR assay to measure HSV-1 and HSV-2 DNA. HSV-2 DNA levels will be reported for all subjects at all timepoints tested; HSV-1 DNA levels will be reported for any subject that is also HSV-1 seropositive.

[0186] Any adverse events (AEs) will be monitored and recorded throughout the study period and the severity assessed according to the following guidelines:• Grade 1 (Mild): Mild symptoms causing no or minimal interference with usual social and functional activities with intervention not indicated.• Grade 2 (Moderate): Moderate symptoms causing greater than minimal interference with usual social & functional activities with intervention indicated.• Grade 3 (Severe): Severe symptoms causing inability to perform usual social and functional activities with intervention or hospitalization indicated (NB: the term “severe” does not necessarily equate to “serious”).• Grade 4 (Life-Threatening): Potentially life-threatening symptoms causing inability to perform basic self-care functions with intervention indicated to prevent permanent impairment, persistent disability, or death.

[0187] For Grade 1 or Grade 2 AEs, the study drug may be continued at the discretion of the Investigator. For Grade 3 or Grade 4 AEs, the study drug may be continued ifHGF Ref. P387157WO48 considered to be unrelated to the study drug, while for a Grade 3 or Grade 4 AE that is considered to be related to the study drug, the study drug should be discontinued.

[0188] RGH episodes (i.e., a lesion with a morphology score other than 4 - see Table 5) will not be documented as adverse events and will be captured as part of the RGH condition.Objectives and Endpoints

[0189] A first primary objective is to assess the safety and tolerability of Compound 1 following single and multiple dose administration; the relevant endpoints are the proportion of subjects with AEs, premature treatment discontinuation due to AEs, and abnormal laboratory results.

[0190] A further primary objective is to characterize the PK of Compound 1 in plasma following single and multiple dose administration; the relevant endpoints are noncompartmental plasma PK parameters including AUC, Cmax, Tmax, Cmin, t1 , CL / F, Vz / F, dose normalized ALICs and Cmax, and accumulation ratios, as applicable.

[0191] A secondary objective is to evaluate the plasma PK of loading doses administered as part of the multiple dose regimens, in terms of a comparison of plasma PK profiles and parameters with and without loading doses.

[0192] A further secondary objective is to evaluate the antiviral effect of Compound 1 ; the relevant endpoints are: the difference in viral shedding rate across treatments; the difference in mean and median HSV-2 DNA copies / mL for swab samples positive for HSV- 2 DNA across treatments; the difference in the proportion of swab samples with HSV-2 DNA >4 log copies / mL across treatments; the difference in the number and duration of shedding episodes during the swabbing period across treatments; the difference in subclinical shedding rate across treatments; the difference in lesion rate and duration during the swabbing period across treatments; and the difference in recurrence rate across treatments.Summary of Interim Results from Phase 1b Clinical Study of Helicase-Primase inhibitor Compound 1

[0193] Interim results from the Phase 1 b clinical study of long-acting helicase-primase inhibitor, Compound 1 showed reductions in viral shedding rate and genital lesion rate in participants seropositive for HSV type 2 (HSV-2) with recurrent genital herpes.

[0194] As described in more detail below, the study showed a 94% reduction in HSV-2 shedding rate and a 98% reduction in high viral load shedding rate, both statisticallyHGF Ref. P387157WO49 significant, observed in the cohort evaluating 350 mg weekly oral dose compared to placebo over 29-day evaluation period.

[0195] The study also showed 94% reduction in genital lesion rate, also statistically significant, observed with the 350 mg weekly oral dose compared to placebo over same period.

[0196] Favourable safety and tolerability profiles were observed in the first two cohorts evaluating weekly oral doses of Compound 1.Brief Study Overview

[0197] As described above, the Phase 1b study was conducted in participants seropositive for HSV-2 with recurrent genital herpes. The study evaluates weekly and monthly oral dose regimens over a 29-day dosing period in up to four cohorts randomized 20:5 between Compound 1 and placebo with a pooled placebo analysis.

[0198] In addition to assessing safety, tolerability and PK, the study also evaluates antiviral activity by measuring changes in viral parameters including shedding rate, quantification of HSV-2 DNA levels obtained from anogenital swab samples, and clinical parameters including genital lesion rate and duration. Due to the long half-life of Compound 1 , the safety follow-up period for participants extends for 98 days after dosing, with safety data available as of the data cutoff date through at least Day 56 for all participants from these cohorts that completed the evaluation period.

[0199] The Compound 1 Phase 1b study uses pooled data from placebo recipients across cohorts as a control. As additional placebo, recipients are enrolled in later cohorts, the sample size for the pooled placebos will change, which is expected to result in adjustments to both the observed effect sizes compared to placebo and the tests of statistical significance for those observed effects.Interim Results - Antiviral Activity

[0200] The Phase 1 b interim analysis reported here includes data from cohort B1 , evaluating a loading dose of 150 mg and weekly doses of 30 mg (the 150 / 30 mg cohort), and cohort B2, evaluating a loading dose and weekly doses of 350 mg (the 350 mg cohort).

[0201] A total of 50 participants were enrolled in the 150 / 30 mg and 350 mg cohorts; 40 assigned to Compound 1 (20 participants in each cohort) and 10 assigned to placebo (five in each cohort). 45 participants from these cohorts completed the 29-day evaluation period while five discontinued treatment; one due to an adverse event (described below), three withdrew consent and one withdrew for recurrence of genital herpes.HGF Ref. P387157WO

[0202] For the powered antiviral endpoint, HSV-2 shedding rate, highly potent antiviral activity was observed with a 94% reduction compared to placebo (p<0.01) over the 29-day evaluation period in the cohort evaluating a 350 mg weekly dose. For a secondary clinical endpoint of genital lesion rate, a 94% reduction compared to placebo (p<0.01) was observed with the 350 mg weekly dose. The rate of samples with high viral load (i.e. , >104copies / mL HSV DNA), a potential surrogate for HSV-2 transmission and a secondary endpoint, was reduced by 98% compared to placebo (p<0.05) in this cohort.

[0203] Antiviral activity and clinical outcomes by treatment arm are summarized in Table 6 below.Table 6: Antiviral activity and clinical outcomesPBO=placebo; QW=once weekly; SD=standard deviation; High viral load = >104 HSV DNA copies / mL. All outcomes measured over evaluation period.aHSV-2 shedding rate calculated as the number of positive HSV-2 anogenital swabs divided by the total number of swabs collected.bHigh viral load shedding rate calculated as the number of positive HSV-2 anogenital swabs with HSV-2 >104copies / mL divided by the total number of swabs collected.cGenital lesion rate calculated as the number of days with genital lesions present divided by the total number of days assessed.

[0204] Statistically significant reductions were observed in the viral shedding rate, high viral load shedding rate and genital lesion rate for the 350 mg cohort compared to placebo as summarized in Table 7 below.Table 7: Rate Reductions Compound 1 350 mg once weekly vs placeboPBO=placebo; QW=once weekly; High viral load = >104HSV DNA copies / mLaStatistical analysis conducted using Poisson regression models and the corresponding p-values estimated accordingly.

[0205] No viral shedding of >104HSV DNA copies / mL, a potential surrogate for HSV-2 transmission, was observed in the absence of lesions for the 350 mg cohort.HGF Ref. P387157WO51Pharmacokinetic (PK) Data

[0206] Across the 150 / 30 mg and 350 mg cohorts, Compound 1 demonstrated a PK profile that continues to be supportive of once-weekly and potentially once-monthly dosing. The mean Compound 1 blood plasma concentrations after weekly dosing for the cohort dosed with a loading dose of 150 mg of Compound 1 on Day 1 followed by once weekly dosing of 30 mg of Compound 1 on Days 8, 15, 22, and 29, and the cohort dosed with 350 mg of Compound 1 weekly on Days 1 , 8, 15, 22, and 29 (both cohorts dosed under fasted conditions) are shown in Figure 3.

[0207] Safety Data

[0208] Compound 1 was observed to be well-tolerated at oral doses up to 350 mg weekly in the study population of participants seropositive for HSV-2 with recurrent genital herpes.

[0209] Overall, the proportion of participants reporting treatment-emergent adverse events (TEAEs) was similar between Compound 1 (90%) and placebo (90%) recipients. Of the TEAEs reported, the majority were grade 1 or grade 2. One grade 3 adverse event was reported, hypertriglyceridemia, in a participant with relevant medical history who had grade 4 elevated triglycerides pre-dose on Day 1. This adverse event resulted in study discontinuation but was not considered treatment related.

[0210] The proportion of participants reporting treatment-emergent laboratory abnormalities was higher in placebo (90.0%) than in Compound 1 (67.5%) recipients, with the majority of observed abnormalities being grade 1 or grade 2. There were three participants with treatment-emergent grade 3 laboratory abnormalities, all considered unrelated to assigned treatment: an exercise-associated elevation in creatine kinase, a decrease in neutrophils and an elevation of cholesterol in the follow-up period in a participant that had a grade 2 elevation at baseline. There did not appear to be a doseresponse relationship in either the frequency or severity of TEAEs or laboratory abnormalities. There have been no serious adverse events reported to date.

[0211] In summary, Compound 1 dosed using a weekly dosage regimen as described above has been found to provide significant reductions in viral shedding rate and genital lesion rate in participants seropositive for HSV type 2 (HSV-2) with recurrent genital herpes. Moreover, the rate of samples with high viral load (i.e. , >104copies / mL HSV DNA), a potential surrogate for HSV-2 transmission, was also significantly reduced.

Claims

HGF Ref. P387157WOCLAIMS1. A method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 5 mg to 1200 mg, wherein the dose is administered no more than once every 7 days, no more than once a month, or no more than once every three months.

2. The method of claim 1 , wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week.

3. The method of claim 1 , wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a month.

4. The method of any one of claims 1 to 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 5 mg to 400 mg, conveniently 10 mg to 300 mg, yet more conveniently 10 mg to 200 mg.

5. The method of any one of claims 1 to 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to 50 mg, conveniently from about 10 mg to 40 mg.

6. The method of any one of claims 1 to 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg.

7. The method of claim 2, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 25 mg to about 200 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, and wherein the dose is administered once a week.

8. The method of claim 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 400 mg to about 800 mg of Compound 1, or a pharmaceutically acceptable salt thereof, and wherein the dose is administered once a month.HGF Ref. P387157WO539. The method of any one of claims 1 to 8, wherein the dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 500 ng / mL for at least 80% of the dosing interval, conveniently at least 800 ng / mL for at least 80% of the dosing interval, more conveniently at least 1100 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 1200 ng / mL for at least 80% of the dosing interval.

10. The method of any one of claims 1 to 9, wherein the method further comprises a step of administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, prior to the administration of the dose according to claim 1 .

11. The method of claim 10, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is from about 50 mg to 500 mg, conveniently from about 50 mg to 300 mg, and yet more conveniently from about 50 mg to 200 mg.

12. The method of claim 10, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 150 mg.

13. The method of any one of claims 10 to 12, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once daily for a period of 1 to 28 days, conveniently 1 to 14 days, more conveniently 1 to 7 days.

14. The method of any one of claims 10 to 12, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered once weekly for a period of one to four weeks, conveniently once weekly for a period of 1 or 2 weeks.

15. A method for treating a herpes virus infection in a human subject in need thereof, the method comprising orally administering a therapeutically effective amount of Compound 1 represented by:or a pharmaceutically acceptable salt thereof, to a human subject wherein the method comprises the steps of: a. administering to the human subject a loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, for a first period of time of one or twoHGF Ref. P387157WO54 weeks, wherein the loading dose is from about 50 mg to 200 mg, and the loading dose is administered once weekly; and b. after said first period of time, administering a maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, wherein the maintenance dose is from about 10 mg to 300 mg and this maintenance dose is administered once a week, or once a month.

16. The method of claim 15, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 150 mg and the maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 30 mg once a week.

17. The method of claim 15, wherein the loading dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 150 mg and the maintenance dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is about 100 mg to 300 mg once a month.

18. The method of any one of claims 15 to 17, wherein the maintenance dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 500 ng / mL for at least 80% of the dosing interval, conveniently at least 800 ng / mL for at least 80% of the dosing interval, more conveniently at least 1100 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 1200 ng / mL for at least 80% of the dosing interval.

19. The method of any one of claims 1 to 18, wherein the Compound 1 , or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, wherein the pharmaceutical composition comprises an amorphous solid dispersion.

20. The method of claim 19, wherein the pharmaceutical composition is a tablet comprising about 5 mg to about 100 mg of Compound 1 , or a pharmaceutically acceptable salt thereof, such as about 50 mg of Compound 1 , or a pharmaceutically acceptable salt thereof.

21. The method of claim 19, wherein the pharmaceutical composition is a tablet comprising about 5 mg to about 40 mg of Compound 1 , or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1 to 21 , wherein the herpes virus infection being treated in the human subject is a HSV infection.

23. The method claim 22, wherein the HSV infection is HSV2.HGF Ref. P387157WO5524. The method claim 23, wherein the HSV infection is HSV2 with recurrent genital herpes.

25. The method of any one of claims 22 to 24, wherein the method suppresses recurrence of HSV symptoms or outbreaks in a human subject.

26. The method of any one of claims 22 to 25, wherein the method reduces viral shedding, or reduces the rate of viral shedding in a human subject with recurrent HSV, such as genital HSV2.

27. The method of any one of claims 22 to 26, wherein the method prevents or reduces the transmission of HSV, or an infectious disease caused by HSV.

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