Compositions and methods of treatment of a herpes virus infection

Abstract

The present disclosure relates to compositions and 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 (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as 'Compound 1'). Also provided herein are certain oral pharmaceutical compositions comprising (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as 'Compound 1'), or a pharmaceutically acceptable salt thereof; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament and for the treatment of diseases or disorders caused by, or associated with, herpes virus.

Description

HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOCOMPOSITIONS AND METHODS OF TREATMENTCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No 63 / 760,284, filed on February 19, 2025, and United States Provisional Application No 63 / 849,526, filed on July 23, 2025, each of which is incorporated by reference herein in its entirety.FIELD

[0002] Provided herein are compositions and 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 (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as ‘Compound 1’). Also provided herein are certain oral pharmaceutical compositions comprising (R)-5-fluoro-2-methyl-1-(( / ?)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide (also referred to herein as ‘Compound 1’), or a pharmaceutically acceptable salt thereof; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament and for the treatment of diseases or disorders caused by, or associated with, herpes virus.BACKGROUND

[0003] 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.

[0004] Human herpes viruses are classified into three subfamilies (a, p 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).

[0005] 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,HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOwhich 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.

[0006] 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-related 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.

[0007] 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.

[0008] 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).

[0009] 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 beHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOexperienced 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.

[0010] 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.

[0011] 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.

[0012] 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).

[0013] Given the inadequacy of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments.

[0014] 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0015] 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).

[0016] 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 PCT publication WO 2001 / 47904.

[0017] 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 drug doses and frequent dosing, e.g., multiple daily dosing.

[0018] 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 disclosure was devised with the foregoing in mind.SUMMARY

[0019] In a first aspect, the present disclosure 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: / NH2(R)or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, no more than once every 7 days, no more than once a month, or no more than once every three months.

[0020] 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 90 hours after a single oral dose, and remarkably a single oral dose of Compound 1 may provide therapeutically effective coverage over at least 7 days. Moreover, it has been found that a single dose delivered using compositions of the disclosure provides high oral bioavailability and / or low inter-subject variability in pharmacokinetic plasma concentrations of Compound 1 following oral administration. It has also been found that when administered orally to a human subject using a once weekly dosageHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOregimen, Compound 1 can provide significant reductions in viral shedding rate and virologically confirmed 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.

[0021] 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).

[0022] The present disclosure satisfies a need for a novel treatment approach for HSV infections which can provide improvements in efficacy and / or safety and / or patient use.

[0023] In a second aspect of the disclosure, 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 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, no more than once every 7 days, no more than once a month, or no more than once every three months.

[0024] In a third aspect of the disclosure, 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:HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOa. 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 days, wherein the loading dose is from about 10 mg to about 300 mg, and the loading dose is administered once daily; andb. 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 1 mg to about 100 mg administered once a week or from about 100 mg to about 2000 mg administered once a month.

[0025] In a fourth aspect of the disclosure, 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 days, wherein the loading dose is from about 10 mg to about 300 mg, and the loading dose is administered once daily; andb. 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 1 mg to about 100 mg administered once a week or from about 100 mg to about 2000 mg administered once a month.

[0026] In a fifth aspect of the disclosure, there is provided an oral pharmaceutical composition comprising Compound 1 represented by:HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOor a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition comprises from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0027] In a sixth aspect of the disclosure, there is provided a method for forming an oral pharmaceutical composition according to the fifth aspect.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] 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:

[0029] FIG. 1 shows the XRPD pattern for Compound 1 Form I.

[0030] FIG. 2 shows the XRPD pattern for Compound 1 Mesylate Form I.

[0031] FIG. 3 shows the mean plasma concentration-time profiles of Compound 1 for the PK study described in Example 4.

[0032] FIG. 4 shows the mean plasma concentration-time profiles of Compound 1 for the PK study described in Example 5.

[0033] FIG. 5a shows the dissolution data for the 50 mg tablets after being stored at 3 months at 25°C / 60% RH.

[0034] FIG. 5b shows the dissolution data for the 50 mg tablets after being stored at 3 months at 40°C / 75% RH.

[0035] FIG. 6a shows the dissolution data for the 250 mg tablets after being stored at 3 months at 25°C / 60% RH.

[0036] FIG. 6b shows the dissolution data for the 250 mg tablets after being stored at 3 months at 40°C / 75% RH.

[0037] FIG. 7a shows the mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively) over 96 hours.

[0038] FIG. 7b shows the mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively) over 240 hours.

[0039] FIG. 8a shows the plasma concentration-time profiles for six individual subjects after single dosing of Compound 1 at 100 mg.

[0040] FIG. 8b shows the plasma concentration-time profiles for six individual subjects after single dosing of Compound 1 at 300 mg.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0041] FIG. 9 shows the mean plasma concentration-time profiles of Compound 1 in for the PK study described in Example 9, wherein Compound 1 is formulated in a capsule.

[0042] FIG. 10a shows the mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively), 50 mg (cohort A3), and 50 mg Fed and Fasted (cohort A7) over 24 hours (y-axis is linear scale).

[0043] FIG. 10b shows the mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively), 50 mg (cohort A3), and 50 mg Fed and Fasted (cohort A7) over 11 days (y-axis is logarithmic scale).

[0044] FIG. 11 shows the mean plasma concentration-time profiles after weekly dosing of Compound 1 at 50 mg (cohort B1). On days 1 and 29, plasma samples were taken every couple of hours during the day. On days 8, 15 and 22, two plasma samples were taken; one pre-dose and one postdosing (ranging from a couple of minutes to a couple of hours after dosing).

[0045] FIG. 12 shows the mean plasma concentration-time profiles after weekly dosing of Compound 1 at 20 mg (cohort B2). On days 1 and 29, plasma samples were taken every couple of hours during the day. On days 8, 15 and 22, two plasma samples were taken; one pre-dose and one post-dosing (ranging from a couple of minutes to a couple of hours after dosing).DETAILED DESCRIPTION

[0046] 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

[0047] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0048] 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.

[0049] 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 methodsHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOthat are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0050] As used herein, the singular forms “a,” “an,” and “the" include the plural.

[0051] As used herein, C™x refers to the geometric mean maximum concentration of the active agent. This may be measured in vivo following administration of a composition of the disclosure to a subject and measuring the plasma concentration of the drug at various timepoints after dosing.

[0052] 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.

[0053] 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.

[0054] It is to be appreciated that references to “treating” or “treatment” include prevention as well as the alleviation of established symptoms of a condition. “T reating” 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 or delaying the development ofHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOthe 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. In some embodiments, “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.

[0055] 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.

[0056] 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.

[0057] 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 ±HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO10% 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.

[0058] 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 sub-combination 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.

[0059] 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 base basis, even if the compound is present as a 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 base, ora pharmaceutically acceptable salt of Compound 1 with 10 mg of free base equivalent.

[0060] The use of any and all examples, or exemplary language herein, for example, “such as,” “including,” or “for example,” is intended merely to illustrate betterthe present teachings and does not pose a limitation on the scope of the disclosure 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

[0061] The compound referred to herein as ‘Compound T is (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide and is a potent helicase-primase inhibitor. The compound is disclosed as Example 35 in WO2023 / 225162A1 (PCT Application No. PCT / US2023 / 022679).

[0062] Compound 1 is a potent helicase-primase inhibitor and has an in-vitro mean EC₅₀ value of approximately 1 nM against both HSV-1 and 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 ECso value can also be determined in accordance with the assays described in the Examples section of the present application.

[0063] Compound 1 shows no or low levels of carbonic anhydrase inhibition, such as inhibition of carbonic anhydrase I and / or carbonic anhydrase II. Carbonic anhydrase inhibition can be measured using a carbonic anhydrase I assay as described in Katritzky et al. (J. Med. Chem.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO1987, 30:2058) and a carbonic anhydrase I assay as described in Iyer et a / . (J. Biomol. Screen 2006, 11:782).

[0064] In some embodiments, a pharmaceutically acceptable salt of Compound 1 is used. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of Compound 1 and typically is not biologically active or otherwise undesirable.

[0065] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic group such as an amine with a suitable acid affording a physiologically acceptable anion.

[0066] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, aspartic acid, glutamic acid, glucuronic acid, glycolic acid, and other acids known to persons skilled in the art.

[0067] It is to be understood that Compound 1, or pharmaceutically acceptable salts of Compound 1, may exhibit polymorphism, and that the disclosure encompasses all such forms (including anhydrous / non-solvated forms, solvates and hydrates).

[0068] Compound 1, or a pharmaceutically acceptable salt thereof, may be present in any suitable solid form, such as an amorphous form, or an anhydrate, hydrate or solvate crystalline form(s).

[0069] In an embodiment, Compound 1, or a pharmaceutically salt thereof, is a crystalline solid. The crystalline solid may be present in any suitable form, such as an anhydrate, hydrate or solvate form(s). It is also to be understood that Compound 1, or a pharmaceutically salt thereof, may be pure, essentially pure, or have a purity level greater than 75%, such as greaterthan 85%, greater than 90%, greaterthan 95%, greaterthan 97%, greaterthan 98%, or greaterthan 99% with respect to other crystalline or amorphous forms (for example as measured by X-Ray powder diffraction).

[0070] In certain embodiments, Compound 1 is in the form of Compound 1 Form I, which may also referred to as Compound 1 Free Base Form I.

[0071] In a convenient embodiment, Compound 1 is in the form of a mesylate salt. Conveniently, the mesylate salt form of Compound 1 is a crystalline solid. In some embodiments, Compound 1 is in the form of a mesylate salt. In some embodiments, the mesylate salt form of Compound 1 is a crystalline solid. It has been found that certain crystalline solid forms ofHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOCompound 1 are particularly suited to oral administration and the oral compositions of the present disclosure. Conveniently, Compound 1 is in the form of crystalline Compound 1 mesylate salt Form I, as described in the Examples. In some embodiments, Compound 1 is in the form of crystalline Compound 1 mesylate salt Form I, as described in the Examples.

[0072] Compound 1 mesylate salt Form I may also be referred to as Compound 1 mesylate Form I or Compound 1 Mesylate Form I or Compound 1 MSA salt Form I.

[0073] In some embodiments, Compound 1 mesylate salt Form I is characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising five or more peaks selected from the peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 2θ (± 0.2° 2θ).

[0074] In some embodiments, Compound 1 mesylate salt Form I is characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 2θ (± 0.2° 2θ). In some embodiments, Compound 1 mesylate salt Form I is characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 2θ (± 0.1° 2θ).

[0075] In some embodiments, Compound 1 mesylate salt Form I is characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising peaks at 7.2, 11.6, 14.3, 17.3 and 18.5° 2θ (± 0.2° 2θ) and further comprising at least two, five, ten, fifteen, twenty or twenty-five specific peaks selected from 8.9, 12.8, 16.1, 16.4, 18.1, 19.1, 19.5, 20.2, 20.6, 20.9, 20.9, 21.4, 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 25.7, 26.1, 26.8, 27.7, 29.6, 31.0, 31.5, 32.4, 34.0, 35.4, 35.9, 36.3, 37.2, and 37.9° 2θ (± 0.2° 2θ).

[0076] In some embodiments, Compound 1 Mesylate Form I is characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) substantially as shown in Figure 2.Treatment Methods

[0077] In a first aspect, the present disclosure 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:HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOor a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, no more than once every 7 days, no more than once a month, or no more than once every three months.

[0078] 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 was found to be approximately 90 hours after a single oral dose. The mean elimination half-life across different cohorts of the human clinical study described in Example 7 ranged from approximately 88.1 to 127 hours. Remarkably, the data suggests that a single dose of Compound 1 may provide therapeutically effective coverage over at least 7 days. Moreover, it has been found that a single dose delivered using compositions of the disclosure provides high oral bioavailability and / or low inter-subject variability in pharmacokinetic plasma concentrations of Compound 1 following oral administration. 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 virologically confirmed 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.

[0079] Therefore, a dose orally administered to the human subject of from about 1 mg to about 2000 mg may be useful to maintain the Compound 1 plasma concentrations at therapeutically effective levels for a prolonged period of time.

[0080] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered no more than once every 7 days. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered no more than once a month. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered no more than once every three months.

[0081] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, is administered once a week, or once a month. In a convenient embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a month. In a more convenient embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once every 7 days (once a week). In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week, or once a month. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a month. In an embodiment, theHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOdose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once every 7 days (once a week).

[0082] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1 mg to about 100 mg administered once a week, such as from about 1 mg to about 50 mg; conveniently the dose is from about 5 mg to about 50 mg administered once a week, such as from about 5 mg to about 40 mg, from about 10 mg to about 40 mg, from about 20 mg to about 40 mg, or about 30 mg administered once a week. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1 mg to about 100 mg administered once a week, such as from about 1 mg to about 50 mg; or the dose is from about 5 mg to about 50 mg administered once a week, such as from about 5 mg to about 40 mg, from about 10 mg to about 40 mg, from about 20 mg to about 40 mg, or about 30 mg administered once a week. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 35 mg administered once a week, such as from about 10 mg to about 20 mg, or about 15 mg once weekly. In yet another embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 75 mg administered once a week, such as about 20 mg to about 50 mg administered once a week; or the dose is about 20 mg, or about 30 mg, or about 50 mg administered once a week. In one embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg administered once a week. In one embodiment, the dose of Compound 1 is about 50 mg administered once a week.

[0083] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 100 mg to about 2000 mg administered once a month, such as from about 300 mg to about 2000 mg; conveniently the dose is from about 500 mg to about 2000 mg administered once a month, such as from about 750 mg to about 2000 mg, from about 1000 mg to about 2000 mg, from about 1500 mg to about 2000 mg, from about 1750 mg to about 2000 mg, administered once a month. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 100 mg to about 2000 mg administered once a month, such as from about 300 mg to about 2000 mg; or the dose is from about 500 mg to about 2000 mg administered once a month, such as from about 750 mg to about 2000 mg, from about 1000 mg to about 2000 mg, from about 1500 mg to about 2000 mg, from about 1750 mg to about 2000 mg, administered once a month. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1750 mg once monthly, about 1800 mg once monthly, about 1850 mg once monthly, or about 1900 mg once monthly.

[0084] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 100 mg to about 1000 mg administered once a month, such as from about 500 mg to about 1000 mg; conveniently the dose is from about 750 mg to about 1000 mgHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOadministered once a month. In an embodiment, the dose of Compound 1, ora pharmaceutically acceptable salt thereof, is from about 100 mg to about 1000 mg administered once a month, such as from about 500 mg to about 1000 mg; or the dose is from about 750 mg to about 1000 mg administered once a month. In an embodiment, the dose of Compound 1, ora pharmaceutically acceptable salt thereof, is about 700 mg once monthly, about 800 mg once monthly, or about 900 mg once monthly.

[0085] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 2000 mg administered once every three months, such as from about 750 mg to about 2000 mg; conveniently the dose is from about 1000 mg to about 2000 mg administered once every three months. Conveniently the dose is from about 1750 mg to about 2000 mg administered once every three months. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 2000 mg administered once every three months, such as from about 750 mg to about 2000 mg; or the dose is from about 1000 mg to about 2000 mg administered once every three months. In an embodiment, the dose is from about 1750 mg to about 2000 mg administered once every three months.

[0088] 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, or a pharmaceutically acceptable salt thereof, could be administered as two smaller 50 mg doses on the same day. In some embodiments, 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. In some embodiments, the smaller divided amounts are administered simultaneously. In another embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single administration.

[0087] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, conveniently at least 300 ng / mL for at least 80% of the dosing interval, more conveniently at least 500 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 600 ng / mL for at least 80% of the dosing interval. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, or at least 300 ng / mL for at least 80% of the dosing interval, or at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0088] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 200 ng / mL for at least 80% of the dosing interval.

[0089] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 300 ng / mL for at least 80% of the dosing interval.

[0090] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 600 ng / mL for at least 80% of the dosing interval.

[0091] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of between about 200 ng / mL and about 600 ng / mL for at least 80% of the dosing interval.

[0092] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, 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 1000 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. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, 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, or at least 800 ng / mL for at least 80% of the dosing interval, or at least 1000 ng / mL for at least 80% of the dosing interval, or at least 1200 ng / mL for at least 80% of the dosing interval.

[0093] Compound 1 is subject to plasma protein binding. Dependent on the extent of the plasma protein binding, the free fraction (unbound active agent) may be low relative to the protein bound fraction. In an embodiment, the plasma concentrations referred to above refer to the total (unbound and protein bound) plasma concentrations. Therefore, in an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a (unbound and protein bound) plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, conveniently at least 300 ng / mL for at least 80% of the dosing interval, more conveniently at least 500 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 600 ng / mL for at least 80% of the dosing interval. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a (unbound and protein bound) plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, or at least 300 ng / mL for at least 80% of the dosing interval, or at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0094] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a (unbound and protein bound) plasma concentration in the human subject of Compound 1 of at least 200 ng / mL for at least 80% of the dosing interval, such as at least 250 ng / mL for at least 80% of the dosing interval, at least 300 ng / mL for at least 80% of the dosing interval, at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.

[0095] Advantageously, certain compositions of the disclosure, containing relatively low doses of Compound 1, or a pharmaceutically acceptable salt thereof, may exhibit high oral bioavailability and low inter-subject variability in pharmacokinetic plasma concentrations of Compound 1 following oral administration.

[0096] 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 a maintenance dose over a longer time period to maintain the Compound 1 plasma concentrations at therapeutically effective levels.

[0097] In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 300 mg, conveniently from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg, and yet more conveniently from about 200 mg to about 300 mg. In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 300 mg, or from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg, or from about 200 mg to about 300 mg. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg.

[0098] In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily over one or two days, conveniently over one day. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily over one or two days, or over one day.

[0099] In a second aspect of the disclosure, there is provided Compound 1 represented by:OHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOor 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 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, no more than once every 7 days, no more than once a month, or no more than once every three months

[0100] All of the above embodiments described in relation to the first aspect, apply equally to the second aspect of the disclosure.

[0101] In a third aspect of the disclosure, 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 two days, wherein the loading dose is from about 10 mg to about 300 mg, and the loading dose is administered once daily; andb. 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 1 mg to about 100 mg administered once a week or about 100 mg to about 2000 mg administered once a month.

[0102] In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 50 mg to about 300 mg, such as about 300 mg.

[0103] In an embodiment, the first period of time is one day.

[0104] In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week. Conveniently, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1 mg to about 50 mg administered once a week. In an embodiment, the maintenance dose of Compound 1, or aHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOpharmaceutically acceptable salt thereof, is from about 1 mg to about 50 mg administered once a week. Conveniently, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 5 mg to about 50 mg administered once a week, such as from about 5 mg to about 40 mg, from about 10 mg to about 40 mg, from about 20 mg to about 40 mg, or about 30 mg administered once a week. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 5 mg to about 50 mg administered once a week, such as from about 5 mg to about 40 mg, from about 10 mg to about 40 mg, from about 20 mg to about 40 mg, or about 30 mg administered once a week. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 35 mg administered once a week, such as from about 10 mg to about 20 mg, or about 15 mg once weekly. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 50 mg administered once a week, or about 30 mg once weekly. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 50 mg once weekly.

[0105] In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a month. Conveniently, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 2000 mg administered once a month. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 300 mg to about 2000 mg administered once a month. Conveniently, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 500 mg to about 2000 mg administered once a month, such as from about 750 mg to about 2000 mg, from about 1000 mg to about 2000 mg, from about 1500 mg to about 2000 mg, from about 1750 mg to about 2000 mg, administered once a month. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 500 mg to about 2000 mg administered once a month, such as from about 750 mg to about 2000 mg, from about 1000 mg to about 2000 mg, from about 1500 mg to about 2000 mg, from about 1750 mg to about 2000 mg, administered once a month. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1750 mg once monthly, about 1800 mg once monthly, about 1850 mg once monthly, or about 1900 mg once monthly.

[0106] In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 100 mg to about 1000 mg administered once a month, such as from about 500 mg to about 1000 mg; conveniently the dose is from about 750 mg to about 1000 mg administered once a month. In an embodiment, the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 100 mg to about 1000 mg administered once a month, such as from about 500 mg to about 1000 mg; or the dose is from about 750 mg to about 1000 mg administered once a month. In an embodiment, the maintenanceHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOdose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg once monthly, about 800 mg once monthly, or about 900 mg once monthly.

[0107] In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg once a week. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg once a week.

[0108] In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 15 mg once a week. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 15 mg once a week.

[0109] In a convenient embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1750 mg to 2000 mg once a month. In an embodiment, the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1750 mg to 2000 mg once a month.

[0110] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, conveniently at least 300 ng / mL for at least 80% of the dosing interval, more conveniently at least 500 ng / mL for at least 80% of the dosing interval, yet more conveniently at least 600 ng / mL for at least 80% of the dosing interval. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, or at least 300 ng / mL for at least 80% of the dosing interval, or at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.

[0111] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 200 ng / mL for at least 80% of the dosing interval.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0112] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 300 ng / mL for at least 80% of the dosing interval.

[0113] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 600 ng / mL for at least 80% of the dosing interval.

[0114] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, achieves and maintains a plasma concentration in the human subject of Compound 1 of between about 200 ng / mL and about 600 ng / mL for at least 80% of the dosing interval.

[0115] In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, 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 1000 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. In an embodiment, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, 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, or at least 800 ng / mL for at least 80% of the dosing interval, or at least 1000 ng / mL for at least 80% of the dosing interval, or at least 1200 ng / mL for at least 80% of the dosing interval.

[0116] In an embodiment, the plasma concentrations referred to above refer to the total (unbound and protein bound) plasma concentrations.

[0117] In a fourth aspect of the disclosure, 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 days, wherein the loading dose is from about 10 mg to about 300 mg, and the loading dose is administered once daily; andHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOb. 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 1 mg to about 100 mg administered once a week or from about 100 mg to about 2000 mg administered once a month.

[0118] All of the above embodiments described in relation to the third aspect, apply equally to the fourth aspect of the disclosure.Pharmaceutical Compositions

[0119] In the methods and treatments according to the first, second, third, or fourth aspects of the disclosure, Compound 1, or a pharmaceutically acceptable salt thereof, may be formulated as an oral pharmaceutical composition, wherein the pharmaceutical composition is selected from the group consisting of a granule, a pellet, a tablet, a particle, a capsule, a suspension and a mini-tablet.

[0120] 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. In some embodiments, 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. In some embodiments, the unit dosage forms are administered simultaneously.

[0121] In some embodiments, 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.

[0122] In one embodiment, the pharmaceutical composition is a tablet comprising from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition is a tablet comprising from about 1 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, conveniently from about 1 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition is a tablet comprising from about 1 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or from about 1 mg to about 60 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition is a tablet comprising from about 20 mg to about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or from about 30 mg to about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In someHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOembodiments, the pharmaceutical composition is a tablet comprising about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0123] In a further embodiment, the pharmaceutical composition is a tablet comprising from about 1 mg to about 40 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0124] Conveniently, the oral pharmaceutical composition is formulated as a tablet for oral administration. In some embodiments, the oral 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. In an embodiment, the pharmaceutical composition is a tablet with a total weight of 250-500 mg, or 300-500 mg, such as about 400 mg.

[0125] In a fifth aspect of the disclosure, there is provided an oral pharmaceutical composition comprising Compound 1 represented by:or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition comprises from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the oral pharmaceutical composition is selected from the group consisting of a granule, a pellet, a tablet, a particle, a capsule, or a suspension.

[0127] In one embodiment, the oral pharmaceutical composition comprises Compound 1 mesylate salt. Conveniently, Compound 1 is in the form of crystalline Compound 1 mesylate salt Form I, as described in the Examples. In one embodiment, Compound 1 is in the form of crystalline Compound 1 mesylate salt Form I, as described in the Examples.

[0128] Conveniently, the oral pharmaceutical composition is a tablet unit dosage form comprising from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof. More conveniently, the pharmaceutical composition is a tablet comprising from about 1 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, and yet more conveniently, the pharmaceutical composition is a tablet comprising from about 1 mg toHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOabout 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, such as from about 1 mg to about 40 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the oral pharmaceutical composition is a tablet unit dosage form comprising from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition is a tablet comprising from about 1 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is a tablet comprising from about 1 mg to about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, such as from about 1 mg to about 40 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0130] Conveniently, the oral pharmaceutical composition is a tablet comprising about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof. Conveniently, the oral pharmaceutical composition is a tablet comprising about 15 mg or about 30 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0131] In one embodiment, the oral pharmaceutical composition is a tablet comprising about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In one embodiment, the oral pharmaceutical composition is a tablet comprising about 15 mg or about 30 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0132] The oral pharmaceutical composition comprises one or more pharmaceutically acceptable excipients.

[0133] In one embodiment, the oral pharmaceutical composition is a tablet comprising one or more pharmaceutically acceptable excipients selected from the group consisting of a surfactant, a filler or diluent, a binder, a lubricant, a disintegrant, a drying agent, a pH modifier, a complexing agent and a glidant.

[0134] Conveniently, the oral pharmaceutical composition comprises a surfactant. In one embodiment, the oral pharmaceutical composition comprises a surfactant. As demonstrated in the Examples, compositions containing the surfactant sodium lauryl sulfate provided beneficial pharmacokinetic performance, including high oral exposure, and low inter-subject variability in AUC0-72hrWhen compared to certain other tablet formulations tested.

[0135] In an embodiment, the surfactant is a non-ionic surfactant. In an embodiment, the surfactant is an ionic surfactant. In an embodiment, the surfactant is selected from benzylalkonium chloride, benzethonium chloride, cetylpyridinium chloride, poloxamer 188, poloxamer 407, polyoxyl stearate, Cremophor, Solutol, Vitamin E TPGS, polysorbates, sodium lauryl sulfate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate. In anHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOembodiment, the surfactant is sodium lauryl sulfate. In an embodiment, the pharmaceutical composition comprises 0.1 to 5.0 wt % (such as 0.5 to 2.0 wt %, or about 1.0 wt %) of a surfactant. Conveniently, the surfactant is sodium lauryl sulfate. In an embodiment, the surfactant is sodium lauryl sulfate.

[0136] Examples of pharmaceutically acceptable fillers or diluents include lactose, sugar, maize-starch, microcrystalline cellulose, mannitol, calcium phosphate, sorbitol and glycine. In an embodiment, the filler or diluent is selected from lactose, microcrystalline cellulose and mannitol; conveniently microcrystalline cellulose and lactose. In an embodiment, the filler or diluent is selected from lactose, microcrystalline cellulose and mannitol; or microcrystalline cellulose and lactose. In an embodiment, the composition comprises 15-60 wt % of one or more fillers / diluents. In an embodiment, the tablet comprises 30-50 wt % of one or more fillers / diluents.

[0137] Examples of pharmaceutically acceptable binders include hydroxy propyl cellulose, hydroxypropylmethylcellulose, povidone, starch, methylcellulose, gelatin, pregelatinized starch, and xanthan gum; conveniently the binder is hydroxypropylmethylcellulose. In an embodiment, the binder is selected from hydroxy propyl cellulose, hydroxypropylmethylcellulose, povidone, starch, methylcellulose, gelatin, pregelatinized starch, and xanthan gum; or the binder is hydroxypropylmethylcellulose. In an embodiment, the tablet comprises 0.1 to 10.0 wt % (such as 2.5 to 7.5 wt %, or about 5.0 wt %) of a binder. In an embodiment, the tablet comprises 0.1 to 10.0 wt % (such as 2.5 to 7.5 wt %, or about 5.0 wt %) of hydroxypropylmethylcellulose.

[0138] Examples of pharmaceutically acceptable disintegrants include crospovidone, croscarmellose, sodium starch glycolate and low substituted hydroxypropyl cellulose; conveniently the disintegrant is croscarmellose sodium. In an embodiment, the pharmaceutically acceptable disintegrant is selected from crospovidone, croscarmellose, sodium starch glycolate, and low substituted hydroxypropyl cellulose; or the disintegrant is croscarmellose sodium. In an embodiment, the tablet comprises 0.1 to 10.0 wt % (such as 2.5 to 7.5 wt %, or about 5.0-6.0 wt %) of a disintegrant. In an embodiment, the tablet comprises 0.1 to 10.0 wt % (such as 2.5 to 7.5 wt %, or about 5.0-6.0 wt %) of croscarmellose sodium.

[0139] Examples of pharmaceutically acceptable lubricants include magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, sodium stearyl fumarate, mineral oil, hydrogenated vegetable oil and polyethylene glycol; conveniently the lubricant is magnesium stearate. In an embodiment, the pharmaceutically acceptable lubricant is selected from magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, sodium stearyl fumarate, mineral oil, hydrogenated vegetable oil, and polyethylene glycol; or the lubricant is magnesium stearate. In an embodiment, the tablet comprises 0.1 to 2.0 wt % (such as 0.5 to 1.5 wt %) of a lubricant. In an embodiment, the tablet comprises 0.1 to 2.0 wt % (such as 0.5 to 1.5 wt %) of magnesium stearate.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0140] Examples of pharmaceutically acceptable glidants include colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch and talc; conveniently the glidant is colloidal silicon dioxide. In an embodiment, the pharmaceutically acceptable glidant is selected from colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch, and talc; or the glidant is colloidal silicon dioxide. In an embodiment, the tablet comprises 0.1 to 2.0 wt % (such as 0.1 to 0.5 wt %, or about 0.25 wt %) of a glidant. In an embodiment, the tablet comprises 0.1 to 2.0 wt % (such as 0.1 to 0.5 wt %, or about 0.25 wt %) of colloidal silicon dioxide

[0141] In an embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, wherein one or more of the following apply: the filler or diluent is microcrystalline cellulose and / or lactose; the binder is hydroxypropylmethylcellulose; the surfactant is sodium lauryl sulfate; the disintegrant is croscarmellose sodium; the lubricant is magnesium stearate; and the glidant is colloidal silicon dioxide.

[0142] It is to be understood that in the present context the “wt %’’ or “% by weight" values specified herein for tablet dosage forms refer to the percentage by weight of an ingredient in the core tablet, thus excluding any exterior coatings or films.

[0143] Advantageously, certain oral pharmaceutical compositions are chemically and physically stable. In one embodiment, certain oral pharmaceutical compositions comprising Compound 1 mesylate salt Form I are chemically and physically stable, for example, there is minimal to zero chemical degradation of Compound 1 mesylate salt Form I and / or no change in appearance and / or no change in dissolution at ambient and / or accelerated storage conditions, such as when stored for at least three months at 25°C and 60% relative humidity (RH) or 40°C and 75% RH.

[0144] The oral pharmaceutical composition according to the fifth aspect can be used in a method disclosed in any one of the embodiments described in relation to the first, second, third, or fourth aspects of the disclosure.Preparation of the Compositions

[0145] In a sixth aspect, the present disclosure provides a method for forming an oral pharmaceutical composition according to the fifth aspect.

[0146] In an embodiment, the oral pharmaceutical composition of the present disclosure is a tablet. In an embodiment, a process for the preparation of the tablet comprises the steps of: a. providing a mixture of Compound 1, or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptably filler or diluent, at least one pharmaceutically acceptable binder, and a granulation solvent;b. blending the mixture to obtain a wet granulate;c. drying the wet granulate;HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOd. optionally, milling the dried granulate;e. optionally, mixing the dried granulate from step c. or step d. with other pharmaceutically acceptable excipients;f. compressing the dried granulate from step c., step d., or step e. into tablets;g. optionally, coating (i.e., film coating) the tablets from step f.

[0147] In one embodiment, the granulation solvent comprises water, isopropyl alcohol, acetone, ethanol or mixtures thereof.Treatment of Herpes Virus Infections

[0148] The methods of the present disclosure provide for the treatment of a herpes virus infection in a human subject in need thereof.

[0149] In an embodiment, the herpes virus infection being treated in the human subject is a herpes simplex virus (HSV) infection. In one embodiment, the herpesvirus infection being treated is HSV1. In one embodiment, the herpes virus infection being treated is HSV2. In yet a further embodiment, both herpes viruses HSV1 and HSV2 are being treated.

[0150] In an embodiment, the methods of the present disclosure 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.

[0151] 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).

[0152] 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.

[0153] 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 withHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOantiviral therapy with nucleoside analogues, such as acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir.

[0154] 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 and a genetic immunodeficiency.

[0155] In a particular embodiment, the subject in need of the methods disclosed herein, is a neonate or an infant.

[0156] In a particular embodiment, the subject is a herpes-positive patient.

[0157] 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.

[0158] 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.

[0159] In a particular embodiment, the methods according to the disclosure can reduce recurrence of HSV infections (i.e., provide a suppressive therapy) causing diseases or disorders, such as herpes labialis or genital herpes.

[0160] In an embodiment, the methods of the disclosure suppress 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. In an embodiment, the rate of lesions over one year can be reduced by 90% or more.

[0161] In a particular embodiment, the methods according to the disclosure can reduce the duration of recurrent episodes of HSV infection, e.g., by one or more days, e.g., at least by 2, 3, 4, 5, 14, 21 or 28 days.

[0162] In a particular embodiment, the methods according to the disclosure 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0163] In one embodiment, the methods according to the disclosure 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.

[0164] In a particular embodiment, the methods according to the disclosure can reduce viral shedding, or reduce the rate of viral shedding, in individuals with recurrent HSV, e.g., 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. Reduction in the HSV shedding rate among subjects receiving the compositions of the disclosure 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.

[0165] In a particular embodiment, methods according to the disclosure reduce (or substantially supress or eliminate) break-through HSV shedding in a subject in need thereof.

[0166] In a particular embodiment, methods according to the disclosure 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 priorto 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

[0167] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. InHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOsome embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg.

[0168] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg. In some embodiments, 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. In some embodiments, the rate of HSV2 episodes over one year can be reduced by 90% or more.

[0169] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg. In some embodiments, the lesion rate is reduced by 20, 30, 40, 50, 75, 90 or 95% or more. In some embodiments, 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.

[0170] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceuticallyHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOacceptable salt thereof is about 30 mg or about 50 mg. In some embodiments, 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.

[0171] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg. In some embodiments, 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.

[0172] 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 5 mg to about 100 mg of Compound 1, ora pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 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. Reduction in the HSV shedding rate among subjects receiving the compositions of the disclosure 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0173] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg.

[0174] 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 5 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once every week. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 20 mg to about 75 mg; or the once weekly dose is from about 20 mg to 50 mg, or the once weekly dose is from about 30 mg to 50 mg. In some embodiments, the once weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg.

[0175] It is to be understood that the weekly 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 weekly dose of 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof, could be administered as two smaller 25 mg doses on the same day. In some embodiments, the smaller divided amounts are administered simultaneously. In another embodiment, the weekly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered in a single administration.

[0176] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable saltHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOthereof is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg.

[0177] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg. In some embodiments, 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. In some embodiments, the rate of HSV2 episodes over one year can be reduced by 90% or more.

[0178] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg. In some embodiments, the lesion rate is reduced by 20, 30, 40, 50, 75, 90 or 95% or more. In some embodiments, 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.

[0179] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceuticallyHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOacceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg. In some embodiments, 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.

[0180] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg. In some embodiments, 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.

[0181] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 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. Reduction in the HSV shedding rate among subjects receiving the compositions of the disclosure 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0182] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg.

[0183] 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 100 mg to about 2000 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to the human subject, wherein the dose is administered once a month. In some embodiments, the once monthly dose of Compound 1 is from about 600 mg to about 2000 mg; or the once monthly dose is from about 1000 mg to 2000 mg. In some embodiments, the once monthly dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 700 mg, about 800 mg, about 900 mg, about 1750 mg, about 1800 mg, about 1850 mg, or about 1900 mg.Combinations

[0184] In an aspect of the present disclosure, the methods of treating a herpes virus infection comprise the treatment regimen as described herein, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved byway of simultaneous, sequential or separate administration of the individual components of the treatment.

[0185] 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, or a pharmaceutically acceptable salt thereof, according to methods described herein, and the second active agent.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0186] 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 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, no more than once every 7 days, no more than once a month, or no more than once every three months; and (ii) co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0187] in an embodiment, the additional therapeutic agent is selected from one or more of the following agents: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; andvi. other helicase-primase inhibitors, such as amenamevir.

[0188] In some cases, the methods of the present disclosure 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.

[0189] 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0190] 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 disclosure. The disclosure is illustrated below by the following non-limiting examples.EXAMPLES

[0191] The following abbreviations are used within this specification:aq.: AqueousDCM: DichloromethaneDMSO: Dimethyl sulfoxideEOS: End of Studyeq / equiv: EquivalentsESI: Electrospray ionizationEtOAc: Ethyl acetateHr / h: HoursHP-BCD Hydroxypropyl-beta-cyclodextrinHPLC: High Performance Liquid ChromatographyLCMS: Liquid-Chromatography Mass-Spectrometrymin: minutesMRM: multiple reaction monitoringMTBE: Methyl tert-butyl etherNaBH₃CN: Sodium cyanoborohydrideNaH: Sodium hydridemin: Minutesm / z Mass to charge ratioNa2SO4: Sodium sulfateNMR: Nuclear magnetic resonance spectroscopyPK: PharmacokineticRT: Room Temperature (~22°C)SFC Supercritical Fluid ChromatographyTCFH: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphateTBD: To be determinedTFA: Trifluoroacetic acidTHF: TetrahydrofuranTLC: Thin Layer chromatographyUPLC: Ultra-performance liquid chromatographyVol / V: VolumeXRPD: X-Ray Powder DiffractionHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOEXAMPLE 1: Synthesis of (R)-5-fluoro-2-methyl-1-(( / ?)-5-(Pyridin-2-yl)-2,3-dihvdro-1H-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1)

[0192] Compound 1 was prepared according to the procedures described in Example 35 in WO2023 / 225162A1 (PCT Application No. PCT / US2023 / 022679) and the procedures described in WO2025 / 104687, each of which are incorporated by reference herein in its entirety.Preparation of Intermediate 2: 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acidIntermediate 2.1 Intermediate 2.2Intermediate 2

[0193] Preparation of Intermediate 2.1: To a stirred suspension of 60% NaH (22.72 g, 2 equiv) in THF (1000 mL) at 0 °C was added diethyl carbonate (86 mL, 1.5 equiv). To this was added 5-bromo-indan-1-one (100 g, 473.1 mmol) portion wise at this temperature. The reaction mixture continued to stir at this temperature until gas evolution subsided. The reaction mixture was slowly heated to 50 °C and maintained stirring for 2h. Progress of the reaction was monitored by TLC, and after consumption of starting material, the reaction mixture was allowed to cool to RT. The reaction was diluted with EtOAc (10V). To this was added 3N aq HCI dropwise. Both layers were separated. Aqueous layer was extracted with EtOAc (2 x 5V). The combined organic layer was washed with brine solution (5V), dried (Na2SO4) and evaporated to obtain the crude, which was purified by column chromatography on silica gel to afford Intermediate 2.1. LCMS: 283.0 [M+H],

[0194] Preparation of Intermediate 2.2: To a solution of Intermediate 2.1 (56 g, 197.9 mmol) in TFA (280 mL) at 0°C was added triethyl silane (224 mL) dropwise and the reaction mixtureHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOwas stirred at RT for 24 h. Progress of the reaction was monitored by TLC. After consumption of starting materials, the reaction mixture was evaporated to dryness under reduced pressure to obtain the crude. The crude was purified by column chromatography on silica gel to obtain Intermediate 2.2. LC / MS: 269.0 [M+H],

[0195] Preparation of Intermediate 2.3: A stirred solution of Intermediate 2.2 (40 g, 148.7 mmol) and 2-tributylstannylpyridine (57.5 g, 1.05 equiv) in 1,4 dioxane (400 mL) was degassed for 10 min using argon, at which time Pd(PPh3)4(8.6 g, 5 mol%) was added and again degassed for another 10 min. The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was filtered through Celite pad and the Celite pad was washed with ethyl acetate twice. The combined filtrate was evaporated to dryness to obtain crude. The crude was purified by column chromatography on silica gel to afford Intermediate 2.3. LC / MS: 268.1 [M+H],

[0196] Preparation of Intermediate 2: To a stirred solution of Intermediate 2.3 (35 g, 131.1 mmol) in methanol (350 mL) at 0°C was added 2N aq NaOH solution (140 mL, 2.2 equiv) and the reaction mixture was stirred at rt for 4h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 100 mL. The residue was diluted with water (10V) and the aqueous layer washed with ethyl acetate (2 x 2V). The aqueous phase was neutralized with 2N aq HCI solution and extracted with 10% Methanol / DCM (3 x 5V). The organic layer was dried over sodium sulfate and concentrated to afford the crude. Then the crude was taken with 10% isopropanol / toluene (10V) solution and treated with activated carbon. The solvent was then removed under reduced pressure. The residue was taken in 30% toluene / hexane, stirred for 30 min and filtered, and then dried under vacuum. This process was repeated two additional times to afford Intermediate 2. LC / MS: 238.1 [M-H],Preparation of Intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid.Intermediate 19

[0197] Intermediate 19 was obtained as the first eluent of SFC purification of Intermediate 2 using a Chiralpak AD-H column with 20% methanol as co-solvent. LC / MS: 238.1 [M-H],HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOPreparation of Intermediate 21:Intermediate 21.1 Intermediate 21.2Intermediate 21.3 Intermediate (R)-21 Intermediate (S)-21

[0198] Preparation of intermediate 21.1: 5-fluoro-2-methylindoline (40 g, 268 mmol, 1 eq) was taken up in acetic acid (200 mL, 5V). NaBH3CN (50 g, 815 mmol, 3 eq) was added portion-wise while maintaining the temperature below 10° C. The resulting solution was warmed to RT and stirred for 3 h, at which time the reaction was diluted with ice-cold water (500 mL). The reaction was then extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over Na2SO4and concentrated in vacuo. The crude Intermediate 21.1 was isolated as a thick yellow oil and used in the next step without further purification. LC / MS: 151.2 [M+H],

[0199] Preparation of Intermediate 21.2: To a stirred solution of Intermediate 21.1 (35 g, 86.6 mmol) in DCM (300 mL) was added triethylamine (35 mL, 1 vol) followed by acetyl chloride (35mL, 1 vol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The residue was quenched with cold water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (750 mL), dried over Na2SO4and concentrated in vacuo. The crude residue was purified by column chromatography (100-200 silica gel, eluted 8% EtOAc-Hexane) to afford Intermediate 21.2. LC / MS: 193.2 [M+H],

[0200] Preparation of Intermediate 21.3: To a stirred solution of Intermediate 21.2 (35 g, 0.011 mol) in chlorosulfonic acid (250 mL, 10 V) at 0 °C under nitrogen and the reaction mixture was stirred at 50 °C for 3h. Upon completion of the reaction, the mixture was diluted with ice-cold water. The precipitate was filtered, taken up in dichloromethane (50 mL), and added to a solution of concentrated ammonium hydroxide (20 mL). After vigorous stirring for 15 minutes at RT, the solvent was removed under pressure and the resulting solid was filtered and rinsed with water to afford Intermediate 21.3. LC / MS: 272.3 [M+H],

[0201] Preparation of Intermediates fRJ-21 and SJ-21: A racemic mixture of Intermediate 21.3 (30 g, 110 mmol, 1 equiv) in 500 mL of 2N sodium hydroxide was heated at 100°C for 3 hours. The reaction was cooled to RT and the pH was adjusted to 7 with acetic acid. The precipitate was filtered, washed with water, and dried under vacuum. The resulting de-acetylatedHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOracemic mixture was then subjected to chiral SFC purification using a ChiralPak IG 240 x 4.6 mm column with a mobile phase consisting of 70:20: 10 hexane: methanol: MTBE. Intermediate (R)- 21 was collected as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H], Intermediate (SJ-21 was collected as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H],Preparation of Compound 1:Intermediate (R)-21 b Compound 1

[0202] Intermediate fR)-21 was taken up in THF (10 V) and dimethylformamide dimethyl acetal (1.2 equiv) was added at once. The solution was stirred at RT for 30 minutes and the solvent was then removed under reduced pressure to afford the crude residue intermediate (7?)-21a (LC / MS: 286.1 [M+H]) which was used directly in the next step without further purification.

[0203] Intermediate (RJ-21a was taken up in acetonitrile (10 V). Intermediate 19 (1 equiv) was added, followed by TCFH (2 equiv). The suspension was placed in a RT water bath and N-methylimidazole (5 equiv) was added dropwise. The solution stirred at RT for 1 hour, at which time LC / MS analysis indicated complete conversion to Intermediate F? J-21b (LC / MS: 507.2 [M+H]). Hydrazine hydrate (50 equiv) was then added at once and allowed to stir at RT for 30 minutes, after which time water was added (5 V). The resulting precipitate was filtered and dried under reduced pressure to afford Compound 1.1H NMR (400 MHz, DMSO-d6) 58.69 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 6.6 Hz, 1H), 8.10 - 7.84 (m, 4H), 7.58 (s, 2H), 7.51 -7.24 (m, 3H), 4.90 (t, J = 7.5 Hz, 1H), 3.77 (p, J = 8.2 Hz, 1H), 3.46 (ddt, J = 34.0, 17.5, 8.7 Hz, 3H), 3.20 (ddd, J = 59.1, 16.3, 8.3 Hz, 2H), 2.80 (d, J = 16.9 Hz, 1H), 1.30 (d, J = 6.2 Hz, 3H). LC / MS: 452.1 [M+H], EXAMPLE 2: Biological assay data for (R)-5-fluoro-2-methyl-1-((R)-5-(pyridin-2-vi)-2,3-dihydro-1 H-indene-2-carbonyl)indoline-6-sulfonamide (Compound 1 )HSV-2 Cellomics Assay

[0204] Compound 1 was tested for its ability to inhibit HSV-2 replication by monitoring the expression of the HSV protein gD using a high-throughput immunofluorescence-based assay.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO10-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 0.2 or 2 mM in 100% DMSO. 250 nl_ of compounds were spotted in quadruplicates onto black collagen-coated 384-well microplates with clear bottom (Greiner cat# 781956) using a Labcyte ECHO acoustic dispenser. The final starting concentration in the assay was either 1 or 10 pM. DMSO (no compound) and pritelivir were included on each microplate as negative and positive controls, respectively.

[0205] ARPE-19 cells (ATCC cat# CRL-2302) were maintained DMEM / F-12 Glutamax medium (Thermo Fisher Scientific cat# 10565018) supplemented with 10% FBS (Corning cat# 35-011-CV) and 1% Penicillin-Streptomycin (cat# 30-002-CI). Prior to confluence, cells were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium (DMEM / F-12 Glutamax, 2% FBS, 1% Penicillin-Streptomycin) and counted. Cell density was adjusted to 150,000 cells / mL and infected with HSV-2 virus (MS strain, ATCC cat# VR-540) at a MOI of 0.06 in a 50 mL conical tube for 1 hour under constant rocking. Cells were then spun for 5 minutes at 1000 rpm and the media replaced with assay medium containing either 2% FBS or 10% human serum (EMD Millipore cat# S1-100ML). 50 pL of the infection suspension were added into microplate wells that were pre-spotted with compounds (7,500 cells per well). Plates were incubated for 16 hours at 37°C.

[0206] Cell culture medium was aspirated using a Biomek Fx and 50 pL of a paraformaldehyde solution (Electron Microscopy Sciences cat# 15712-S) diluted to 4% in DPBS (Corning cat# 21-031 -CM) were added per well. After a 30-minute incubation at room temperature, plates were washed 4 times with 100 pL / well of PBS using a Biotek plate washer. A 1:500 solution of primary antibody (anti-HSV gD, Virusys cat# P1103) was prepared in permeabilization buffer (Invitrogen cat# 00-8333-56) and 50 pLwere added into wells. After a 1 -hour incubation at room temperature, 50 pL of a 1:1000 solution of secondary antibody (Alexa Fluor 488 goat anti-mouse, Thermo Fisher Scientific cat# A11001) and DAPI (Thermo Fisher Scientific cat# 62248) in permeabilization buffer were added into wells and plates were incubated in the dark at room temperature for 1 hour. Plates were washed 4 times again and 50 pL of DPBS were added to all wells prior to sealing the plates with a black adhesive seal. Fluorescence was measured on a Cellomics plate reader.

[0207] Data analysis was carried out using the Thermo Scientific HCS Studio software. Briefly, cells were identified using the DAPI nuclear stain and thresholds were set to filter cells out based on shape and size. A second threshold based on green fluorescence intensity (detection of HSV-2 gD) was set to identify HSV-2 infected cells. Data was reported as the average fluorescence intensity of HSV-2 infected cells. EC50 values were defined as the compound concentration that caused a 50% decrease in the average fluorescence intensity and was calculated using aHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOsigmoidal dose-response model to generate curve fits. EC50 for pritelivir in this assay was 150 nM. Data for Compound 1 is reported in Table 1.Table 1: Biological assay data for Compound 1Compound EC50-HSV2-FBS (nM) EC50-HSV2-10% CC50-MT4 (nM)Human Serum (nM)Compound 1 7.0 57.5 24000MT-4 CC50 Assay

[0208] Compounds were tested in 384-well plates: 18 compounds in duplex. Compounds were diluted in 7 points, 3-fold with DMSO by Bravo. Assay plate, which contains 20 pL medium with compounds, was seeded 2000 MT-4 cells in 20 pL / well by Multi-drop to start the assay. The plate was incubated at 37°C for 5 days. On 6th day, the CellTiter Gio 40 pL was added in each well. Luminescence was read by Victor II. CC50 values are defined as the compound concentration that causes a 50% decrease in luminescence signal, and were calculated using a sigmoidal dose-response model to generate curve fits. Data for Compound 1 is reported in Table 1 above.HSV qPCR Assay

[0209] HSV replication in the presence or absence of compounds was measured by qPCR according to the following procedure: DMSO stock compound solutions (1-10 mM) were serially diluted (2.5-fold) in DMSO in clear round bottom 96-well plates. Compounds were then diluted 1:20 in assay medium (DMEM / F12 Glutamax + 2% Fetal bovine serum + 1% Penicillin Streptomycin) and 10 pL of these dilutions were added to 96-well tissue culture plates for final starting concentrations between 0.5 and 5 pM.

[0210] ARPE-19 cells (ATCC cat # CRL-2302) that were maintained in growth medium (DMEM / F12 Glutamax + 10% FBS + 1% Penicillin streptomycin) were transferred to a centrifuge tube and spun for 5 minutes at 1000 rpm. Cells were resuspended in assay medium, counted, and cell density was adjusted to 2.8E+05 cells / mL with assay medium. Cells were then infected with HSV-1 (KOS strain, ATCC cat# VR-1493) or HSV-2 virus (MS strain, ATCC cat# VR-540) at a MOI 0.05 in a 50-mL conical tube for 1 hour under constant rocking. 90 pL of the infection suspension (25,000 cells) were added to assay plates in which compounds were already added. After an overnight incubation at 37°C, cell culture medium was removed, and cell lysis was performed using the prepGEM Universal kit (MicroGEM cat# PUN 1000). Specifically, 100 pL of prepGEM master mix (94.75 pL Water, 5 pL buffer, 0.25 pL enzyme stock) were added to each well and plates were incubated at room temperature for 15 minutes, with the 5 last minutes on aHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOplate shaker. The cell lysates were then transferred to a 96-well PCR compatible microplate (Applied Biosystems, Cat #N8010560). Plates were sealed with a heat resistant plastic sealer and heated on a thermal cycler using the following conditions: 75°C for 10 min, 95°C for 5 minutes. Finally, plates were cooled down to room temperature with light shaking before proceeding to the qPCR setup.

[0211] qPCR reactions were carried out in a total reaction volume of 20 pL, using the QuantiNova multiplex PCR kit (Qiagen Cat #208456). 15 pL of reagent mix (5pL of 4X QuantiNova Master Mix, 0.1 pL of QN Rox reference dye, 1 pL of 20X HSV primer / probe mix and 8.9 pL PCR grade water) and 5 pL of cell lysate were added to wells of a 96-well fast optical microplate (Applied Biosystems cat# 4246906). Plates were sealed with a clear sealer, spun down, and qPCR reactions were performed in an Applied Biosystems Quantstudio 7 Flex instrument using the following conditions: 95°C for 2 minutes, then 40 cycles alternating between 95°C for 5 seconds and 60°C for 30 seconds.

[0212] Analysis was performed using dCT method where dCT = CT (test)- CT (DMSO). Fold change was calculated using the 2-dCTequation. This fold change was then converted to percentage relative to DMSO control (no drug). EC50S were determined by non-linear regression analysis using GraphPad Prism software.

[0213] EC50for both pritelivir and amenamevir in this assay were 14 nM. EC5o for acyclovir was 1250 nM. Data for Compound 1 is reported in Table 2.Table 2: Biological assay data for Compound 1Compound EC50-HSV2-qPCR (nM) IC50-hCAII (nM) IC50-hCAI (nM) Compound 1 1.1 2900 35300Carbonic anhydrase (esterase) biochemical assay

[0214] Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit the human carbonic anhydrase (hCA)-mediated hydrolysis of 4-nitrophenyl acetate (4NPA) (Verpoorte et al, JBC, 1967). 10-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 10 mM in 100% DMSO. 200 nL of compounds were then spotted in quadruplicates onto clear 384-well microplates (Perkin Elmer cat# 6007640) using a Labcyte ECHO acoustic dispenser. Final starting concentration in the assay was 50 pM. DMSO (no compound) and acetazolamide were included on each microplate as negative and positive controls, respectively.

[0215] A 1.5 pM solution of hCAI (R& D systems cat# 2180-CA) or a 1 pM solution of hCAII (Genscript cat# U3256FL150-4 / P5GA002) was prepared in assay buffer (25 mM Tris (pH 7.5),HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO100 mM NaCI, 1% DMSO) and 20 pL were added to compounds using a Biotek Micro Flo. Following a preincubation at room temperature for 15 minutes, 20 pL of a 4 mM solution of 4NPA substrate (Sigma cat# N8130) in assay buffer were added to start the reaction. Microplates were incubated at room temperature for 60 min after which absorbance at 405 nM was read on an Envision plate-reader. IC5o values were defined as the compound concentration that caused a 50% decrease in absorbance signal and were calculated using a sigmoidal dose-response model to generate curve fits. ICso of acetazolamide was 0.04 pM in the hCAII assay and 1.1 pM in the hCAI assay. Data for Compound 1 is reported in Table 2 above.Plasma Stability Assay

[0216] The test compound was incubated at 2 pM in either rat or human plasma (BiolVT, Westbury, NY) up to 4 hours at 37°C. At specified time points, an aliquot from the incubation was quenched by addition of 9 volumes of 100% acetonitrile containing internal standard. Following the last collection, samples were centrifuged at 4500 rpm for 10 min and supernatants were transferred to a new plate containing an equal volume of water for analysis by liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS / MS). The percentage of test compound remaining (analyte to internal standard peak area ratio) in plasma after incubation was plotted versus incubation time and plasma half-life (t1 / 2) was calculated from the linear fit of the natural logarithm of the curve.Stability Assay in Cryopreserved Hepatocytes

[0217] Test compound was incubated at 1 pM with either rat or human cryopreserved hepatocytes (BiolVT, Westbury, NY) up to 6 hours at 37°C in a 24-well plate format (1x106cells / mL per well). At specified time points, samples were transferred to a 96-well plate and quenched with 2 volumes of a solution containing 90% acetonitrile 10% methanol 0.1% formic acid and internal standard. Sample plate was centrifuged at 3200 rpm for 15 min and supernatants transferred to a new plate containing half volume of water. The resulting solution was analyzed by LC-MS / MS. Data (analyte to internal standard peak area ratio) was plotted on a semi-log scale and fitted using an exponential fit. Assuming first order kinetics, the half-life (t1 / 2) and rate of metabolism were determined. Predicted hepatic clearance was calculated from the half-life using the well-stirred model. Data for Compound 1 is reported in Table 3 below.Table 3: Hepatocyte stability assay data for Compound 1Compound Predicted human hepatic clearance (L / hr / kg)Compound 1 0.055HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOEXAMPLE 3: Preparation of Compound 1 Form I and Compound 1 mesylate salt Form I Compound 1 Form I

[0218] Solid forms of Compound 1 may be prepared by the procedures described in WO2025 / 104687, which is incorporated by reference herein in its entirety.

[0219] Compound 1 (5.61 kg) is dissolved in acetone (30V) at 45 - 50 °C. The solution is concentrated to 5 V and ethanol (12 V) is added over 3 hours at 45 °C. After aging for 2h, the slurry is cooled to -10 °C over 3h. After aging for 2h, the slurry is filtered and washed with ethanol (1.5 V). The product is dried at 50 °C to afford 4.95 kg Compound 1 Form I (88% yield, 99.9% area purity). The polymorphic form was confirmed by XRPD (see Figure 1).

[0220] A mixture of Compound 1 (4.90 kg) in acetone (31.5 V) is heated to 45 - 55 °C for 2h. The resulting solution is filtered through a cartridge filter, rinsed with acetone (2 V) and Compound 1 mesylate Form I seed (0.014X) is charged. After aging the mixture for 0.5h at 45 - 55 °C, a solution of methanesulfonic acid (1.03 eq) in acetone (2.1 V) is slowly added over 2h. Rinse with acetone (2 V). The mixture is aged for 2h and cooled to 15 - 25 °C over 2h and aged for 2h. The resulting slurry is filtered, and the cake is washed with acetone (3.9 V). The product is dried at 50 °C, then sieved to afford 5.76 kg Compound 1 mesylate Form I (96% yield, 99.9% area purity). The polymorphic form was confirmed by XRPD (see Figure 2) measured using Cu Ka radiation (1.5419 A). Positions of the peaks in the XRPD for Compound 1 Mesylate Form I are presented in Table 4.Table 4: XRPD peak list of Compound 1 Mesylate Form INo. Pos. [°2Th.] Rel. Int. [%]1 7.2 242 8.9 63 11.6 234 12.8 85 14.3 196 16.1 9HGF Ref. P393744WOSMRH Ref: 37JD-434629-WONo. Pos. [°2Th.] Rel. Int. [%]7 16.4 108 17.3 209 18.1 3710 18.5 10011 19.1 5912 19.5 3213 20.2 2314 20.6 3015 20.9 5916 20.9 6417 21.4 1018 22.2 2019 22.5 1220 23.2 1921 24.0 7122 24.7 2323 25.4 1424 25.7 2325 26.1 1326 26.8 9127 27.7 1528 29.6 2929 31.0 830 31.5 1831 32.4 1132 34.0 533 35.4 1034 35.9 1235 36.3 1336 37.2 737 37.9 8Mesylate Form I Seed preparation.

[0221] To a 4 mL vial equipped with a Teflon coated magnetic stir bar, about 50 mg of Compound 1 Form I was stirred with 1 equivalent of methanesulfonic acid in 0.5 mL of MeCN at about 22 °C. After stirring for 4 hours, XRPD analysis of the wet solids showed a new pattern, which was unchanged after drying at 50 °C under vacuum. The salt was designated as Compound 1 mesylate Form I.

[0222] This form may also be obtained from other solvents such as MeCN, EtOH, IPA, acetone, MEK, MIBK, DCM, THF, MeTHF, EtOAc, IPAc, MTBE, and toluene.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOEXAMPLE 4: Dog PK study of Prototype Tablet FormulationsPreparation of Prototype Tablet Formulations

[0223] Compositional details of five prototype tablet formulations are presented in Table 5.

[0224] All the tablet components except magnesium stearate were screened with a 20-mesh sieve and blended well. The mixture was then blended with pre-screened (30-mesh) magnesium stearate and compressed into tablets.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 5: Compositional details of prototype table formulationsF1 F2 F3 F4 F5 Component Functionmg / unit % mg / unit % mg / unit % mg / unit % mg / unit % Compound 1 FreeActive 50.00 40.00 50.00 33.33 50.00 33.33 0.00 0.00 0.00 0.00 Base Form ICompound 1 MSAActive 0.00 0.00 0.00 0.00 0.00 0.00 60.98 48.78 60.98 48.78 Salt Form IAvicel pH 102 Filler 35.94 28.75 35.63 23.75 35.63 23.75 31.07 24.86 30.45 24.36 Lactose anhydrous Filler 29.69 23.75 28.12 18.75 28.12 18.75 24.82 19.86 24.19 19.36 CroscarmelloseDisintegrant 6.25 5.00 7.50 5.00 7.50 5.00 6.25 5.00 6.25 5.00 SodiumSodium LaurylSurfactant 1.25 1.00 1.50 1.00 1.50 1.00 0.00 0.00 1.25 1.00 SulfateComplexingHP-BCD 0.00 0.00 25.00 16.67 0.00 0.00 0.00 0.00 0.00 0.00 agentTartaric acid Acid 0.00 0.00 0.00 0.00 25.00 16.67 0.00 0.00 0.00 0.00 Colloidal SiliconGlidant 0.63 0.50 0.75 0.50 0.75 0.50 0.63 0.50 0.63 0.50 DioxideMagnesium Stearate Lubricant 1.25 1.00 1.50 1.00 1.50 1.00 1.25 1.00 1.25 1.00 Core tablet total 125.00 100.00 150.00 100.00 150.00 100.00 125.00 100.00 125.00 100.00HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOPK StudyDosing

[0225] Adult male Beagle dogs with 8-10 kg body weight were used for the PK study (n=3). All dogs received an oral dose of Compound 1 tablet of 50 mg / dog via oral gavage, to ensure the complete oral dose was received; a small quantity of water (50 mL) was flushed down the gavage immediately after administration.

[0226] Further details are presented in Table 6.Table 6: Dog PK study detailsStomach pHFormulation Pre-treatment Route Dose Level before dosingF1F2Fasted, Pentagastrin- 50F3 1.00-2.50 POIM-6 pg / kg (80 pL / kg) mg / animalF4F5Sampling

[0227] At each timepoint, approximately 0.5 mL was collected via cephalic vein into K2EDTA tubes. Blood sample was put on ice and centrifuged at 4°C to obtain plasma sample within 15 minutes. Plasma samples were stored at approximately -80 °C until analyzed by LC-MS.Measurement of stomach pH

[0228] A feeding tube is inserted through the mouth into the stomach of the dog, and a syringe is attached to the outlet of the feeding tube for gastric juice extraction. The gastric juice removed is dropped onto pH test paper, and the corresponding pH value is read by comparing with the standard colour card after waiting for 30 seconds to 1 minute.LC-MS AnalysisTable 7: LC-MS detailsInstrument UPLC-MS / MS-33 (Triple Quad™ 6500+)Matrix Male Beagle Dog plasmaInternal standard(s) propranololMS conditions Positive ion, ESIMRM detectionHPLC conditions Mobile phase:Mobile phase A: H2O-0.025%FA-1mM NH4OACHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOMobile phase B: MeOH-0.025%FA-1mM NH4OACTime (min) Mobile Phase B (%)Initial 100.20 101.00 902.00 902.01 102.50 StopColumn: ACQUITY UPLC-BEH C18 (2.1*50mm,1,7pm)Flow rate: 0.60 mL / minColumn temperature: 50 °CFor non-diluted plasma samples:An aliquot of 20 pL sample was added to 200 pL acetonitrile containing 100 ng / mL propranolol (IS). The mixture was shaken for 10 minutes and centrifuged at 5,800 rpm for 10 minutes at 4 °C. Then 0.2 pL of mixture was injected into LC-MS / MS.Sample preparationFor 10-fold diluted plasma samples:An aliquot of 2 pL sample was diluted with 18 pL blank plasma sample, resulting in the dilution factor of 10. The subsequent procedure was the same as non-diluted plasma samples.Calibration curve 1.0-3,000 ng / mL for Compound 1 in dog plasmaResults

[0229] Following single oral dosing of Compound 1 with 5 different tablet formulations to dogs, mean PK parameters are described in Table 8 and plasma-concentration time profiles are shown in Figure 3.

[0230] As demonstrated by the pharmacokinetic results, initial plasma concentrations for the mesylate salt tablet formulations were higher than the free base containing compositions. Moreover, tablet formulations containing the surfactant, sodium lauryl sulfate, provided high oral exposure, as evidenced by the plasma concentrations and AUC0.72hr post-administration. Formulations containing sodium lauryl sulfate also exhibited lower inter-subject variability in AUC072hrWhen compared to other tablet formulations tested. The mesylate salt tablet formulation containing the surfactant, sodium lauryl sulfate (F5), provided the highest AUC0-72hr.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 8: PK ResultsParameter F1 F2 F3 F4 F5Tl / 2 7.3 hr 11.2 hr 6.5 hr 6.4 hr 5.9 hr (CV%) (11.2%) (43.8%) (9.1%) (N / A) (24.7%) Cmax 7.55 pM 9.58 pM 9.06 pM 15.33 pM 15.58 pM (CV%) (54.9%) (40.7%) (68.9%) (91.9%) (39.5%)100.91 AUC0-72hr 51.26 hr*pM 46.53 hr*pM 44.88 hr*pM 80.86 hr*pMhr*pM (CV%) (23.5%) (53.2%) (78.0%) (91.8%)(30.2%)EXAMPLE 5: PK study of Engineering Batch Tablet FormulationsPreparation of Engineering Batch Tablet Formulations

[0231] All the intra-granulation components were blended. High shear wet granulation was used to prepare granules. The granules were dried with a fluid bed dryer, co-milled and then mixed with extra-granulation components, except magnesium stearate. The mixture was then blended with magnesium stearate and compressed into tablets. The core tablets were then film coated. The tablet composition, characterization and equipment used are summarized in Tables 9-11. Analytical testing results (assay / impurity and dissolution) are also summarized (see Tables 12-13).Table 9: Engineering Batch Tablet CompositionComponent Function mg / unit %Intra- Compound 1 MSA Salt Active 60.64 34.65 granulation Form IAvicel pH 101 Filler 40.42 23.10 Lactose monohydrate Filler 43.75 25.00 Croscarmellose Sodium Disintegrant 5.25 3.00 Sodium Lauryl Sulfate Surfactant 1.75 1.00 HPMC E5 Binder 7.00 4.00 Extra- Avicel PH 102 Filler 7.88 4.50 granulation Croscarmellose Sodium Disintegrant 5.25 3.00Colloidal Silicon Dioxide Glidant 0.44 0.25 Magnesium Stearate Lubricant 2.62 1.50 Core tablet weight 175.00 100.00 OPADRY®TF FILM COATING Coating 5.25 3.00 Coated tablets 180.25 103.00HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 10: EquipmentName Model Manufacture NanTong Beite Pharmaceutical Machinery Bin blender HBD-200Co., Ltd.Table Mixer Granulator TMG1 / 6 Glatt, Dresden, Germany Glatt Powder Coater & GPCG 2Glatt, Binzen, Germany Granulator LabSystemComil U5 QuadroRotary Tablet Press XL 100 KorschGMPC II MultiTablet Coating GLATT, Pratteln SwitzerlandLabTable 11: Tablet CharacterizationItem ResultsMean Core Tablet Weight 175 mgTablet Weight RSD 0.43%Thickness -3.50 mmHardness -9.50 kpDisintegration Time 7-8 minutesFriability 0.03%Table 12: Analytical testing - assay / impurityName Assay (%) Avg. Assay (%) Total Impurity% Sample-1 98.598.8 0.07Sample-2 99.0Table 13: Analytical testing - dissolutionDissolution condition: (pH 2.0 HCI, 900 mL, paddle, 75 rpm)Time point 5min 10min 15min 20min 30min 45min 60min 75min Tablet 1 29 71 92 97 99 101 101 102 Tablet 2 30 75 92 96 98 100 100 101 Tablet 3 35 78 92 97 98 99 99 100 Mean 31 75 92 97 98 100 100 101 Max 35 78 92 97 99 101 101 102 Min 29 71 92 96 98 99 99 100 % RSD 10 5 0.3 0.3 0.8 0.8 1 0.8HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOPK StudyDosing

[0232] Adult male Beagle dogs with 8-10 kg body weight were used for the PK study (n=3). All dogs received an oral dose of Compound 1 tablets of 150 mg / dog or 50 mg / dog via oral gavage. To ensure the complete oral dose was received, a small quantity of water (50 ml_) was flushed down the gavage immediately after administration. Further details are presented in Table 14. Table 14: PK study detailsStomach pHGroup Pre-treatment before oral Route Dose Level dosingGroup 1 Fasted,150 mg / dog Pentagastrin- IM- 2.00 - 3.00 POGroup 2 6 pg / kg (80 pL / kg) 50mg / dogSampling

[0233] At each point, approximately 0.5 ml_ was collected via cephalic vein into K2EDTA tubes. Blood sample was put on ice and centrifuged at 4°C to obtain plasma sample within 15 minutes. Plasma samples were stored at approximately -80 °C until analyzed by LC-MS.Measurement of stomach pH

[0234] A feeding tube is inserted through the mouth into the stomach of the dog, and a syringe is attached to the outlet of the feeding tube for gastric juice extraction. The gastric juice removed is dropped onto pH test paper, and the corresponding pH value is read by comparing with the standard colour card after waiting for 30 seconds to 1 minute.LC-MS AnalysisTable 15: LC-MS detailsInstrument UPLC-MS / MS-33 (Triple Quad™ 6500+)Matrix Male Beagle Dog plasmaInternalGlipizidestandard(s)MS conditions Positive ion, ESIHPLC conditions Mobile phase:Mobile phase A: H2O-0.025%FA-1mMN H4OACMobile phase B: MeOH-0.025%FA-1mM NH4OACTime (min) Mobile Phase B (%)Initial 10HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO0.20 101.00 952.00 952.01 102.50 StopColumn: Xbridge BEH C1 8(2.1*50mm 2.5pm)Flow rate: 0.60 mL / minColumn temperature: 60 °CFor non-diluted plasma samples:An aliquot of 20 pL sample was added to 200 pL acetonitrile containing 100 ng / mL Glipizide (IS). The mixture was shaken for 10 minutes and centrifuged at 5,800 rpm for 10 minutes at 4 °C.Then 0.1 pL of mixture was injected into LC-MS / MS.Samplepreparation For 10-fold diluted plasma samples:An aliquot of 2 pL sample was diluted with 18 pL blank plasma sample, resulting in the dilution factor of 10. The subsequent procedure was the same as non-diluted plasma samples.Calibration curve 5.00-10,000 ng / mL for Compound 1 in dog plasmaResults

[0235] Mean PK parameters are listed in Table 16 and Figure 4.

[0236] As demonstrated by the pharmacokinetic results, plasma concentrations and AUCo^hr for the mesylate salt tablet formulation at both doses are high and exhibit low inter-subject variability.Table 16: PK ResultsGroupl: 150Group 2: 50 mg / dogmg / dogTl / 2 11.3 hr 5.3 hr(CV%) (28.0%) (8.6%)Cmax 46.9 pM 28.0 pM(CV%) (12.6%) (24.3%)AUCo-24hr 291.0 hr‘pM 123.7 hr‘pM(CV%) (25.8%) (15.6%)HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOEXAMPLE 6: Tablet Formulation used in Phase 1a / 1b Studies

[0237] All the intra-granulation components were blended using a bin blender. High shear wet granulation was used to prepare granules. The granules were dried with a fluid bed dryer, comilled and then mixed with extra-granulation components except magnesium stearate. The mixture was then blended with magnesium stearate and compressed into tablets. The core tablets were then film coated. The tablet composition, characterization and equipment used are summarized in Tables 17-19. Analytical testing results (assay / impurity and dissolution) for the 50 mg and 250 mg strength tablets are also summarized in Tables 20-22.Table 17: Tablet Compositional Details for 50 mg and 250 mg strength tablets mg / TabletComponent %50 mg Strength 250 mg StrengthIntra GranulationCompound 1 Mesylate Salt,60.64 303.19 34.65 Form IMicrocrystalline Cellulose PH- 40.42 202.12 23.10 101Lactose Monohydrate 43.75 218.75 25.00 Croscarmellose Sodium 5.25 26.25 3.00 Sodium Lauryl Sulfate 1.75 8.75 1.00 Hydroxypropyl Methylcellulose 7.00 35.00 4.00 Extra GranulationMicrocrystalline Cellulose PH- 8.75 43.75 5.00 102Croscarmellose Sodium 5.25 26.25 3.00 Colloidal Silicon Dioxide 0.44 2.19 0.25 Magnesium Stearate 1.75 8.75 1.00 Core tablet weight (mg) 175.00 875.00 100.00 OPADRY® TF FILM COATING5.25 26.25 3.00 SystemCoated tablets (mg) 180.25 901.25 103.00HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 17a: Tablet Compositional Details for 10 mg strength tabletsmg / TabletComponent %10 mg StrengthIntra GranulationCompound 1 Mesylate Salt,12.13 6.93 Form IMicrocrystalline Cellulose PH- 66.62 38.07 101Lactose Monohydrate 66.50 38.00 Croscarmellose Sodium 5.25 3.00 Sodium Lauryl Sulfate 1.75 1.00 Hydroxypropyl Methylcellulose 7.00 4.00 Extra GranulationMicrocrystalline Cellulose PH- 8.75 5.00 102Croscarmellose Sodium 5.25 3.00 Colloidal Silicon Dioxide 0.44 0.25 Magnesium Stearate 1.31 0.75 Core tablet weight (mg) 175.00 100.00 OPADRY® TF FILM COATING5.25 3.00 SystemCoated tablets (mg) 180.25 103.00Table 18: EquipmentName Model Manufacture High Shear Granulator TMG1 / 6 GLATTFluid Bed Dryer GPCG 2 Glatt Mill U5 QUADRO Engineering, Canada Tablet Press XM12 Korsch AG Bin blender HTD-200 Nantong BEITE Pan Coating Machine MultiLab GC GlattHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 19: Tablet CharacterizationsItem 50mg Strength 250mg StrengthMean Core Tablet Weight 175 mg 875 mg Tablet Weight RSD -0.7% -0.3%Thickness -3.50 mm -6.30 mmHardness -9.0 kp -24.0 kp Disintegration Time -4-5 minutes -5-6 minutesFriability 0.04% 0.04%Table 20: Analytical results50 mg Strength 250 mg StrengthAssay 98.7% 102.2%Total Impurity 0.12% 0.10% Uniformity AV: 2.0 AV: 2.0 Water Content 2.3% 2.4%Table 21: Analytical testing - dissolution resuits for 50 mg tabletsDissolution condition: (pH 2.0 HCI, 900 mL, paddle, 75 rpm) Time Point (min) 50 mg Dissolution (%)5 10 15 20 30 45 60 75 Tablet 1 28 73 94 98 100 101 101 101 Tablet 2 26 71 95 99 101 102 102 102 Tablet 3 37 84 94 96 98 98 99 99 Tablet 4 35 83 95 98 99 100 101 101 Tablet 5 23 63 94 101 104 105 105 105 Tablet 6 25 66 93 98 100 101 101 101 Max 37 84 95 101 104 105 105 105 Min 23 63 93 96 98 98 99 99 Mean 29 73 94 98 100 101 101 102 RSD 20.4 12.2 0.8 1.8 2.0 2.1 2.1 2.1HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 22: Analytical testing - dissolution results for 250 mg tabletsDissolution condition: (pH 2.0 HCi, 900 mL, paddle, 75 rpm) Time Point (min) 250 mg Dissolution (%)5 10 15 20 30 45 60 75 Tablet 1 27 70 91 97 99 101 101 101 Tablet 2 31 73 91 97 100 101 101 101 Tablet 3 23 60 87 95 99 100 101 101 Tablet 4 32 72 91 97 100 101 101 101 Tablet 5 27 69 90 96 99 100 101 101 Tablet 6 30 70 90 96 99 100 101 101 Max 32 73 91 97 100 101 101 101 Min 23 60 87 95 99 100 101 101 Mean 28 69 90 96 99 100 101 101 RSD 11.7 6.7 1.9 0.7 0.2 0.2 0.2 0.1Stability studies

[0238] A stability study was conducted. The 50 mg and 250 mg tablets were packaged in HDPE bottles with desiccant and stored under long term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions.

[0239] The tablets were evaluated at different time points for physical and chemical stability by appearance, assay and impurities by HPLC, water content and dissolution.

[0240] At the 3-month time point, no significant changes were observed compared to the initial timepoint. The tablets were found to be chemically and physically stable.

[0241] Analytical stability data is provided in Tables 23 and 24, and dissolution profiles are shown in Figures 5a, 5b, 6a, and 6b.Table 23: Stability data for 50 mg tabletsTest Parameters Initial 25°C / 60% RH 40°C / 75% RHT=0 3 months 1 month 3 months Appearance Yellow film- Yellow film- Yellow film- Yellow film- coated round coated round coated round coated round tablets tablets tablets tablets Assay (% LC) 98.7 99.1 98.3 98.8HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTotal Impurities 0.12 0.10 0.08 0.10 Water Content (%) 2.3 1.8 2.3 1.8Table 24: Stability data for 250 mg tabletsTest Parameters Initial 25°C / 60% RH 40°C / 75% RHT=0 3 months 1 month 3 months Appearance Yellow film- Yellow film- Yellow film- Yellow film- coated round coated round coated round coated round tablets tablets tablets tablets Assay (% LC) 102.2 100.2 103.2 101.8 Total Impurities 0.10 0.10 0.09 0.10 Water Content (%) 2.4 1.8 2.2 1.9EXAMPLE 7: Phase 1a study to evaluate safety, tolerability and PK of Compound 1 (Part l

[0242] A randomized, blinded and placebo-controlled Phase 1a clinical study of Compound 1 (Part A) 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

[0243] 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, 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO6. Subject must be willing to discontinue herbal / dietary supplements (e.g., 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, whichever is longer, prior to the Day 1 dosing 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.10. 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

[0244] 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), or acute hepatitis A virus (HAV).2. Female subjects who are pregnant, lactating, or plan to become pregnant from Screening through EOS.3. Subject has a clinically significant medical, behavioural, 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 gastroesophageal reflux disease requiring treatment with acid reducing agents.5. 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.6. 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]).7. Subject has hypersensitivity or history of idiosyncratic reaction to any components or excipients of the study drug (Compound 1 or placebo).8. 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO9. Subject has a history of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per day on average [1 standard drink =14 gram of alcohol]) or history of persistent illicit substance / drug use within 3 years prior to Screening.10. Subject is unwilling to abstain from alcoholic beverage consumption 48 hours prior to Day 1 dosing through EOS.11. Subject is unwilling to abstain from use of marijuana from Screening through EOS. 12. Subject is unwilling to abstain from illicit substance use from Screening through EOS.13. Subject has a smoking habit, uses, or has used tobacco or nicotine-containing products (e.g., including but not limited to cigarettes, e-cigarettes, pipes, cigars, chewing 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 EOS.14. 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 EOS.15. 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 EOS.16. Subject has received an investigational agent within 30 days or 5 half-lives, whichever is longer, before Day 1 dosing.17. 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

[0245] Part A of the study to enrol up to 5 fasted cohorts (Cohorts A1-A5) and 1 cohort to evaluate the potential for food effect (either Cohort A6 [with subjects from a previous fasted cohort] or A7 [a 2-period crossover design with new subjects, fasted and fed]) in healthy subjects.

[0246] The first cohort of Part A (Cohort A1) evaluates a single dose of 100 mg of Compound 1. Dose levels for subsequent cohorts are determined based on interim cohort review performed by an unblinded Data Review Committee (DRC) between the SAD cohorts. For each interim cohort review, the DRC review study information including safety data for Day 1 through at least Day 5 and available PK data for the present cohort, and all available safety and PK data from preceding cohort(s). In no case would an individual dose / exposure escalation be greater than 3.5-fold compared with the highest dose / exposure for a previous cohort that was considered safe and well tolerated. PK modelling / simulation will be utilized to predict exposures for each dose level to be evaluated. Once a dose level is determined to be safe, lower dose cohorts can be conducted in parallel to dose escalation cohorts.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0247] Cohort A6: Subjects who completed participation in the selected dose cohort will be asked to return to the study site to be enrolled in this food effect cohort (i.e., Cohort A6). Returning subjects will retain their original subject number and randomized treatment assignment. After a minimum 10-day washout period from their first dose of study drug, a second dose will be administered 30 minutes after the start of a high fat meal (containing approximately 50% calories from fat), which must be completely consumed.

[0248] Cohort A7: If there is an insufficient number of subjects from previous fasted SAD cohorts (i.e., Cohorts A1-A5) who are willing to participate in Cohort A6, then a separate Cohort A7 may be enrolled, comprising 6 new subjects meeting the study eligibility criteria, who will all receive Compound 1. Cohort A7 will involve a two-period crossover assessment of food effect (i.e., Period 1: dosing under fasted or high fat-fed [as described for Cohort A6] conditions; Period 2: dosing under conditions opposite of Period 1), with a minimum 10-day washout period between dosing in Period 1 and Period 2, and a 10-day post dose follow-up in Period 2.

[0249] Note: Dosing in Cohort A6 or A7 may proceed in parallel with another SAD cohort if the A6 or A7 dose is at least 2-fold lower compared with the parallel SAD cohort or compared with the highest dose for a previous cohort that was considered safe and well tolerated, whichever is higher.

[0250] Based on emergent data, some prespecified cohorts may not be enrolled.Study Treatments• Cohort A1: 100 mg Compound 1 or placebo, oral (PO), single dose, fasted• Cohort A2: 300 mg Compound 1 or placebo, PO, single dose, fasted• Cohort A3: 50 mg Compound 1 or placebo, PO, single dose, fasted• Cohort A4: TBD mg Compound 1 or placebo, PO, single dose, fasted• Cohort A5: TBD mg Compound 1 or placebo, PO, single dose, fasted• Cohort A6: Food Effect Cohort (in subjects from a previous fasted cohort), TBD mg Compound 1 or placebo, PO, single dose, fed, OR• Cohort A7: Food Effect Cohort (if needed with new subjects) 50 mg Compound 1, PO, single dose, 2-period crossover (fasted and fed)

[0251] The dose level for Cohort A1 is 100 mg. The dose levels for subsequent cohorts in Parts A are selected based on evaluation of safety, tolerability, and available PK data from the previous cohorts. In no case would an individual dose / exposure escalation be greater than 3.5-fold compared with the highest dose / exposure from a previous cohort that was considered safe and well tolerated. Based on emergent data, some prespecified cohorts may not be enrolled.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0252] In the present study, a separate cohort A7 was used to evaluate the potential for a food effect on Compound 1 safety and pharmacokinetics at a dose to 50 mg, since an insufficient number of subjects from previous fasted SAD cohorts were available to participate in Cohort A6. A total of 6 new participants were enrolled in Cohort A7 and the study was conducted in a 2-period crossover design. Each participant received a single dose of Compound 1 both with and without consumption of a high-fat meal in a randomized manner with a 28-day washout between the 2 periods.Duration of Treatment

[0253] Part A (SAD, healthy subjects): 1 dayDuration of Study

[0254] Part A (SAD, healthy subjects): Up to 39 days, including up to 28 days of screening, 1 day of treatment, and 10 days of follow-up. The duration of the study will be longer for subjects in the food effect cohort(s) by at least 11 days depending on the washout period.Study Drug

[0255] The investigational medicinal products to be used in this study are Compound 1 and matching placebo.

[0256] The drug product is a tablet containing the mesylate salt of Compound 1 (equivalent to approximately 50 mg or 250 mg of Compound 1 free base) as described in Example 6. The active tablets were manufactured in accordance with Good Manufacturing Practices (GMP).

[0257] Matching placebo tablets contain standard compendial excipients and are manufactured in conformance with GMP. Matching PBO tablets have the same appearance as the Compound 1 active tablets.Dosages and Administration

[0258] All study drug doses for subjects in Part A are administered with 240 mL of water in the morning at the study site under supervision. Subjects will remain in an upright or sitting position for at least 30 minutes after ingestion unless a supine position is required for ECGs or vital signs. Liquids, other than the 240 mL water for drug administration, will be restricted for 1 hour before and 1 hour after each PO dose. Following study drug administration, site personnel will perform a hand and mouth check to verify that the prescribed dose was swallowed.Fasting Requirements; Cohorts A1-A5 and A7 (Fasting Period)

[0259] In Part A (healthy subjects), single doses of study drug will be administered in the morning after an overnight fast of at least 10 hours. All subjects will continue fasting for 4 hours after dosing, and will receive a standardized lunch, afternoon snack, dinner, and an evening snack at approximately 4 hours, 7 hours, 10 hours, and 12 hours after dosing, respectively. OnHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOall non-dosing in-patient days (Days 2 through 7 for Cohorts A1-A5), subjects will receive 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. Subjects will have approximately 30 minutes to consume the meals. Meals on the day of discharge (Day 5 for Cohorts A1-A5) are optional.Fasting Requirements; Cohorts A6 or A7 (fed period)

[0260] Subjects in Part A, Cohort A6 or Cohort A7 (fed period) will fast for at least 10 hours until 30 minutes before dosing on Day 1 when they will receive a high-fat, high-calorie test meal and will then continue fasting for 4 hours after dosing. Subjects will then receive a standardized lunch, afternoon snack, dinner, and an evening snack at approximately 4 hours, 7 hours, 10 hours, and 12 hours after dosing, respectively. Subjects will have approximately 30 minutes to consume the meals. On all non-dosing inpatient days (Days 2 through 4), subjects will receive a standardized breakfast at approximately the same time as the dosing time on dosing days, and then a lunch, afternoon snack, dinner, and an evening snack at approximately 4 hours, 7 hours, 10 hours, and 12 hours later, respectively. Subjects will have approximately 30 minutes to consume the meals. Meals on Day 5 are optional due to discharge from the clinic.Dietary and Lifestyle Restrictions

[0261] 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 Assessments

[0262] Subjects underwent 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.

[0263] Blood sampling for Compound 1 PK determination was carried out on day 1 and throughout the inpatient and outpatient follow-up periods. Urine PK sampling was also carried out on day 1 and during the follow-up period.

[0264] Any adverse events were monitored and recorded throughout the study period and the severity assessed according to the following guidelines:HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO* 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.Objectives and Endpoints

[0265] A first primary objective is to assess the safety and tolerability of Compound 1 following single dose administration; the relevant endpoints are the proportion of subjects with AEs, premature treatment discontinuation due to AEs, and abnormal laboratory results.

[0266] A further primary objective is to characterize the PK of Compound 1 in plasma following single dose administration; the relevant endpoints are non-compartmental plasma PK parameters including AUC, Cmax, Tmax, Cmin, t½, CL / F, Vz / F, dose normalized AUCs and Cmax, and accumulation ratios, as applicable.

[0267] A secondary objective is to evaluate the effect of food on plasma PK of Compound 1 following single dose administration; the relevant endpoints are comparison of plasma AUC and Cmax between fasted and fed treatments.

[0268] An exploratory objective is to evaluate the PK of Compound 1 in urine following single dose; the relevant endpoints are noncompartmental urine PK parameters including Ae, CL, %Fe administration.

[0269] Another exploratory objective is to assess the potential for Compound 1 to affect electrocardiogram (ECG) parameters (via Holter data collection) following single dose administration; the relevant endpoints are Pharmacodynamic (PD) relationship between changes from Baseline in corrected QT interval using Fridericia’s correction (QTcF) and plasma concentrations of Compound 1.Summary of ResultsPharmacokinetic (PK) Data

[0270] The mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively) over 96 and 240 hours are shown in Figures 7a and 7b respectively, while individual plasma concentration-time profiles after single dosing ofHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOCompound 1 at 100 and 300 mg (cohorts A1 and A2 respectively) are shown in Figures 8a and 8b respectively.

[0271] The mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively), 50 mg (cohort A3), and 50 mg Fed and Fasted (cohort A7) over 24 hours are shown in Figure 10a (y-axis is linear scale).

[0272] The mean plasma concentration-time profiles after single dosing of Compound 1 at 100 and 300 mg (cohorts A1 and A2 respectively), 50 mg (cohort A3), and 50 mg Fed and Fasted (cohort A7) over 11 days are shown in Figure 10b (y-axis is logarithmic scale).

[0273] In the present study, a separate Cohort A7 was used to evaluate the potential for a food effect on Compound 1 safety and pharmacokinetics at a dose to 50 mg, since an insufficient number of subjects from previous fasted SAD cohorts were available to participate in Cohort A6. A total of 6 new participants were enrolled in Cohort A7 and the study was conducted in a 2- period crossover design. Each participant received a single dose of Compound 1 both with and without consumption of a high-fat meal in a randomized manner with a 28-day washout between the 2 periods.

[0274] A summary of the pharmacokinetic parameters is provided in Table 25 and Table 25A.

[0275] Across the cohorts evaluated, Compound 1 unexpectedly had a long half-life when dosed orally. Furthermore, the pharmacokinetic data indicates that high plasma concentrations were achieved and maintained following administration fora prolonged period. The data indicates that once-weekly, or even once-monthly dosing of Compound 1, would provide therapeutic levels expected for antiviral activity. Based on the data, plasma trough concentrations following weekly dosing are projected to be in multiple-fold excess of the in-vitro protein-adjusted half-maximal effective concentration (EC50) values for HSV replication at all dose levels.

[0276] As shown in Figures 8a and 8b, compositions of the disclosure, exhibited high oral exposure with low inter-subject variability in pharmacokinetic plasma concentrations of Compound 1 following oral administration.

[0277] As shown in Figures 10a and 10b and Tables 25 and 25A, Compound 1 was rapidly absorbed and compositions of the disclosure exhibited high oral exposure with low inter-subject variability in pharmacokinetic plasma concentrations of Compound 1 following oral administration. Consumption of a high-fat meal did not appear to change Compound 1 pharmacokinetic exposures at the 50 mg dose level (Table 25A and Figures 10a and 10b).HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 25: Summary of the pharmacokinetic parametersDose AUC0-last AUC0-24hr AUC0-96hr AUC0-inf Cmax Tmax kel t1 / 2 (mg) Cohort Food (h*ng / mL) (h*ng / mL) (h*ng / mL) (h*ng / mL) (ng / mL) (h) (1 / h) (h)N 6 6 6 5 6 6 6 6 Mean 557800 99630 329700 626600 5377 3.667 0.008383 86.03 SD 57843 12456 13468 64816 860.53 0.81650 0.0018428 18.967 CV% 10.4 12.5 4.1 10.3 16.0 22.3 22.0 22.0 100 A1 Fasted Min 505000 89400 308000 568000 4440 3.00 0.00583 59.9Median 541300 93660 329100 596000 5145 3.500 0.008182 84.71 Max 648000 120000 350000 724000 6720 5.00 0.0116 119 GeometricMean 555400 99020 329500 624000 5322 3.595 0.008219 84.34 Geometric CV% 10.2 12.0 4.1 10.1 15.7 21.7 22.1 22.1 N 6 6 6 NC 6 6 5 5 Mean 854100 247800 854100 NC 13450 11.17 0.008116 123.2 SD 149580 61978 149580 NC 3668.7 13.527 0.0048853 95.906 CV% 17.5 25.0 17.5 NC 27.3 121.1 60.2 77.9 300 A2 Fasted Min 723000 180000 723000 NC 10700 3.0 0.00239 43.9Median 796900 223600 796900 NC 11450 3.500 0.006907 100.3 Max 1080000 329000 1080000 NC 18600 36.0 0.0158 289 GeometricMean 843700 241600 843700 NC 13070 6.419 0.006878 100.8Geometric CV% 17.0 24.7 17.0 NC 26.1 152.2 77.0 77.0HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOTable 25A: Summary of the pharmacokinetic parametersDose T max Ti / 2 Cmax AUCo-24hr AUCo iast Cpay7(mg) Cohort Food (h) (h) (ng / mL) (h*ng / mL) (h*ng / mL) (ng / mL)N 6 5 6 6 6 6Median 1.050 A3 Fasted Range 1.0-4.0Mean 127.0 3037 52800 302200 1038CV% 48.3 19.5 13.4 23.7 35.5N 6 6 6 6 6 3Median 1.550 A7 Fasted Range 0.5-3.0Mean 98.5 3797 63010 254400 915CV% 22.8 16.5 12.9 22.8 17.5N 6 6 6 6 6 3Median 5.050 A7 Fed Range 0.5-5.0Mean 110 3193 59330 268500 1189CV% 13.9 25.0 16.7 43.6 37.6AUC0-24hr, area under the plasma concentration-time curve from time zero to 24 hours post-dose; AUC0-last, area under the concentration-time curve from the time of dosing to the time of last measurable concentration; CDay7, Compound 1 concentration on Day 7; Cmax, maximum plasma concentration; CV, coefficient of variation; T1 / 2, apparent terminal elimination half-life; Tmax, time when Cmax is observed.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOSafety Data

[0278] The Phase 1a results show that Compound 1 was well-tolerated and showed a favourable safety profile.

[0279] In summary, single doses of Compound 1 at dose levels tested in Phase 1 a surpassed projected target plasma concentrations, and support the Phase 1 b study evaluating the treatment of patients with recurrent genital herpes.EXAMPLE 8: Phase 1b Study (Part B) to evaluate Compound 1 in patients seropositive for herpes simplex virus type 2 (HSV-2) with Recurrent Genital Herpes (RGH)

[0280] A randomized, blinded and placebo-controlled Phase 1b clinical study of Compound 1 (Part B) 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.Study Population

[0281] Male or female subjects seropositive for HSV-2 with a history of recurrent episodes of genital herpes 4-9 times in the last year or if currently on suppressive therapy, 4-9 times a year prior to suppressive therapy.

[0282] Part B (subjects with RGH): Up to approximately 100 subjects (25 subjects / cohort) Inclusion Criteria

[0283] Subjects must meet all 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 / m2at 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 as described below beginning 14 days or 5 half-lives, whichever is longer, prior to the Day 1 dosing and through EOS.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOb. treatment (systemic and topical) for genital herpes beginning 7 days prior to Day 1 dosing through Day 35.7. 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 the HSV Western Blot conducted at University of Washington.11. Subject has a history of RGH, with 4-9 clinical episodes in the last 1 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 PO medication and in the opinion of the Investigator, be willing to comply with the clinical trial protocol and procedures.Exclusion Criteria

[0284] 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 hepatitis E virus (HEV).2. Female subjects who are pregnant, lactating, or wish to become pregnant from screening through EOS.3. Subject has a clinically significant medical, behavioural, 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 gastroesophageal reflux disease requiring treatment with acid reducing agents.5. 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO6. 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).7. Subject has hypersensitivity or history of idiosyncratic reaction to any components or excipients of the study drug (Compound 1 or placebo).8. 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.9. Subject has a history of significant drug-related macular or maculopapular skin reactions (exanthema or eruption).10. Subject is known to have other genital tract disorders or sexually transmitted diseases that may interfere with assessment of the study drug efficacy.11. Subject has an acute episode of genital herpes on Day 1 prior to dosing.12. Subjects with demonstrated poor clinical response or tolerability to any HPI, such as pritelivir.13. Subject is known to be immunosuppressed.14. 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.15. Subject is unwilling to abstain from alcoholic beverage consumption 48 hours prior to Day 1 dosing through EOT.16. Subject is unwilling to abstain from use of marijuana from screening through EOS. 17. Subject is unwilling to abstain from illicit substance use from screening through EOS.18. 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.19. Subject has had treatment with long-term (i.e., >14 days) systemic steroids or other immunomodulating agents within 6 months prior to Screening.20. Subject has had treatment with pritelivir, or any other HPIs within 12 months prior to Screening.21. 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, whichever is longer, prior to Day 1 dosing.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO22. 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.Study Design

[0285] Part B of the study will enrol up to 4 cohorts (Cohorts B1-B4) in subjects with RGH. Dosing in Part B (Cohort B1) may commence prior to completion of all Part A cohorts at a weekly dose level / exposure which is not higher than the highest Part A dose level / exposure that has been evaluated and deemed safe and well tolerated. PK modelling / simulation will be utilized to predict exposures for each dose level to be evaluated. Subjects in Cohort B1 will receive once weekly doses of study drug over 29 days (i.e., dosing on Days 1, 8, 15, 22, and 29). Subsequently, once weekly dosing over a 29-day period in Cohorts B2, B3, and B4 will be staggered as described below. Dosing regimens in all Part B cohorts may or may not include loading doses.

[0286] The dose level in Cohort B1 will be determined based on emergent safety, tolerability, and available PK data from completed cohorts in Part A. Dose levels for subsequent cohorts in Part B (Cohorts B2-B4) will be determined based on DRC reviews of study information including safety data from a minimum of 10 subjects for Day 1 through at least Day 15 and available PK and antiviral activity data for the present cohort, and all available safety, PK and antiviral activity data from preceding cohorts. In no case would an individual dose / exposure escalation be greater than 3.5-fold compared with the highest dose / exposure from a previous cohort that was considered safe and well tolerated.

[0287] Each of the Cohorts B1-B4 will enrol 25 subjects with RGH who will be randomized in a 4:1 ratio to receive multiple PO doses of the study drug, i.e., Compound 1 (20 subjects) or PBO (5 subjects) for 29 days, with a post-treatment follow-up period of 28 days after the last dose.

[0288] The study drug will be administered at the study site on the mornings of Days 1, 8, 15, 22 and 29. Dosing will occur under fasted or fed conditions, depending on the results from the food effect cohort in Part A (Cohort A6 or A7), as it becomes available. On Days 1 and 29, subjects will remain at the study site for approximately 8 hours after dosing for PK sample collection. Subjects will be instructed to collect anogenital swabs twice daily on Days 8 to 35.

[0289] Based on emergent data, some prespecified cohorts may not be enrolled.

[0290] Subjects will receive specific training on the swabbing procedure to be completed during the study.

[0291] HSV DNA extracted from anogenital swab samples will be analyzed.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOStudy Treatments

[0292] As previously described in Example 7, the starting dose of 100 mg for Part A, Cohort A1, is based on Compound 1 nonclinical safety findings and regulatory guidelines forthe selection of starting doses for FIH studies. For all subsequent parts of the study described below, the decision to enrol a cohort and its respective dose level will be based on the assessment of available data.

[0293] Based on emergent data, some prespecified cohorts may not be enrolled.* Cohort B1: TBD mg Compound 1 or PBO, PO, multiple doses once weekly over 29 days * Cohort B2: TBD mg Compound 1 or PBO, PO, multiple doses once weekly over 29 days * Cohort B3: TBD mg Compound 1 or PBO, PO, multiple doses once weekly over 29 days * Cohort B4: TBD mg Compound 1 or PBO, PO, multiple doses once weekly over 29 days

[0294] Part B dosing regimens may or may not include loading dose(s) and may be administered under fasted or fed conditions depending on the results from the food effect cohort in Part A (Cohort A6 or A7), as it becomes available.Duration of Treatment

[0295] Part B (MAD, subjects with RGH): 29 daysDuration of Study

[0296] Part B (MAD, subjects with RGH): Up to 102 days, including up to 45 days of screening, 29 days of treatment, and 28 days of follow-up.Study Drug

[0297] The investigational medicinal products to be used in this study are Compound 1 and matching placebo.

[0298] The drug product is a tablet containing the mesylate salt of Compound 1 (equivalent to approximately 10 mg, 50 mg or 250 mg of Compound 1 free base) as described in Example 6. The active tablets were manufactured in accordance with Good Manufacturing Practices (GMP).

[0299] Matching placebo tablets contain standard compendial excipients and are manufactured in conformance with GMP. Matching PBO tablets have the same appearance as the Compound 1 active tablets.Dosages and Administration

[0300] All study drug doses for subjects in Part B are administered with 240 mL of water in the morning at the study site under supervision. In Part B, each subject’s dosing should occur at approximately the same time at each visit. Subjects will remain in an upright or sitting position forHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOat least 30 minutes after ingestion unless a supine position is required for ECGs or vital signs. Liquids, other than the 240 mL water for drug administration, will be restricted for 1 hour before and 1 hour after each PO dose. Following study drug administration, site personnel will perform a hand and mouth check to verify that the prescribed dose was swallowed.Fasting Requirements; Cohorts B1-B4

[0301] In Part B (subjects with RGH), all study drug doses will be 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.

[0302] Depending on availability of the food effect data from Cohort A6 or A7, if it is determined that subjects in Part B should take their study drug doses in a fed state, then all doses will be administered in the morning at the study site 30 minutes after the start of a standardized breakfast. All subjects will then fast 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 the duration of clinic stay). Subjects will have approximately 30 minutes to consume the meals.Dietary and Lifestyle Restrictions

[0303] Subjects will be required to comply with the following restrictions (in addition to restrictions noted in the inclusion / exclusion criteria) during study participation:• 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 35 (or 7 days from EOT), 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

[0304] 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.

[0305] Blood sampling for Compound 1 PK determination is carried out on day 1 and throughout the inpatient and outpatient follow-up periods.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0306] 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 the morphology of the lesions would be checked by the Investigator according to Table 26.Table 26: HSV Lesion Morphology Table during Phase 1b studyMorphology DescriptionProdrome Presence of prodrome, e.g., paresthesia Erythema Any redness, without evidence of other lesions of higher scorePapule Any swelling or solid superficial elevation with or without erythema but without any fluid Vesicle / pustule Presence of a blister containing clear or cloudy fluid, respectively with or without an erythematous base Ulcer / soft crust Collapse or rupture of a blister forming an ulcer with or without a moist floor. Big ulcer can appear with irregular shape and size due to confluence of evolving vesicles and pustulesHard crust Dry ulcer formed a noticeably hard, consolidated, firm mass or scab, an escharHard crust loss Loss of hard crustResidual abnormalities Residual abnormalities visual: erythema or flat residual scar tissue may be present, swelling / dry flakingHealed Normal skin / no signs or symptoms: re-epithelialization,no crust, swelling, or ulceration

[0307] Subjects will receive specific training on the procedure for the collection of anogenital swabs twice daily from Day 8 through Day 35 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 the supervision of trained site personnel, 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.

[0308] In addition to the twice daily swabbing of the anogenital region described above, a swab will also be collected by the subject from the site(s) of anogenital lesion(s) twice daily, should they occur. In addition, the subject will be instructed to visit the clinical site for an unscheduledHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOvisit 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.

[0309] HSV DNA extracted from genital swab samples will be analyzed in a quantitative realtime 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.

[0310] HSV DNA will be measured from anogenital swabs in Part B using a validated quantitative realtime PCR assay. The HSV DNA assay measures both HSV-1 and HSV-2. 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.

[0311] 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 greaterthan 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.

[0312] 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 if 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.

[0313] RGH episodes (i.e., a lesion with a morphology other than Healed - see Table 26) will not be documented as adverse events and will be captured as part of the RGH condition.Objectives and Endpoints

[0314] 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.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0315] A further primary objective is to characterize the PK of Compound 1 in plasma following single and multiple dose administration; the relevant endpoints are non-compartmental plasma PK parameters including AUG, Cmax, Tmax, Cmin, t½, CL / F, Vz / F, dose normalized AUCs and Cmax, and accumulation ratios, as applicable.

[0316] 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.

[0317] 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 logic 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.

[0318] An exploratory endpoint is to evaluate the potential for emergence of resistance to Compound 1; the relevant endpoint is the incidence of treatment-emergent HSV-2 variants with reduced susceptibility to Compound 1.

[0319] Another exploratory endpoint is to assess the PK / PD relationship between safety / efficacy endpoints and estimates of Compound 1 exposure; the relevant endpoints are PK / PD relationship between safety / HSV-2-related parameters and Compound 1 exposure estimates, including plasma AUC, Cmax, Cav, and Cmin.

[0320] Another exploratory endpoint is for subjects who provide an optional pharmacogenomic sample, to evaluate the potential contribution of host genomics to Compound 1 disposition and / or clinical / virologic outcomes; the relevant endpoints are valuation of known gene variants and any potential correlation with Compound 1 metabolism / PK and / or safety / efficacy endpoints.Summary of interim Resuits from Phase 1b Clinical Study of Helicase-Primase inhibitor, Compound 1

[0321] Interim results from the Phase 1 b clinical study of long-acting helicase-primase inhibitor, Compound 1, showed reductions in HSV type 2 (HSV-2) shedding rate, high viral load shedding rate, and virologically confirmed genital lesion rate, in participants seropositive for HSV-2 with recurrent genital herpes.

[0322] As described in more detail below, the study showed a 98% reduction in HSV-2 shedding rate compared to placebo (p<0.01) over the 29-day evaluation period in the 50 mg weekly dose cohort.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0323] The data also revealed a 91% reduction in virologically confirmed genital lesion rate compared to placebo (p<0.01) with the 50 mg weekly dose over the same period. Further, there was also a >99% reduction in the number of samples with high viral load, a potential surrogate for HSV-2 transmission and a secondary endpoint.

[0324] Compound 1 was observed to be well-tolerated at oral doses up to 50 mg weekly and the observed pharmacokinetic profile continues to support once-weekly oral dosing regimens.Brief Study Overview

[0325] As described above, the Phase 1b study was conducted in participants seropositive for HSV-2 with recurrent genital herpes. The study evaluated weekly oral dosing regimens over a 29-day period in up to four cohorts randomized 20:5 between Compound 1 and placebo with a pooled placebo analysis.

[0326] The Phase 1 b interim analysis includes data from cohort B1, evaluating a 50 mg weekly oral dose and cohort B2, evaluating a 20 mg weekly oral dose. A 10 mg weekly dosing regimen of Compound 1 is also being evaluated in cohort B3.

[0327] The Phase 1b study 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 observed half-life of Compound 1, the safety follow-up period for participants extends for 29 days after dosing (Day 57), with safety data available as of the data cutoff date through Day 57 for all participants from these cohorts that completed the evaluation period. The 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

[0328] The Phase 1 b interim analysis includes data from cohort B1, evaluating a 50 mg weekly oral dose and cohort B2, evaluating a 20 mg weekly oral dose.

[0329] Fifty participants were enrolled in the 50 mg and 20 mg cohorts; 40 assigned to Compound 1 (20 participants in each cohort) and 10 assigned to placebo (five in each cohort). Forty-six participants from these cohorts have completed the 29-day evaluation period while three discontinued treatment; one discontinued due to being lost to follow-up and two for other reasons not related to adverse events or study treatment. One participant was enrolled in the 20 mg cohort but did not receive treatment.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0330] Antiviral activity and clinical outcomes by treatment arm are summarized below in Table 27. The analysis additionally assessed whether participant-reported lesions were supported by any positive HSV-2 swab obtained during the duration of the reported lesion. Both virologically confirmed and overall lesion rates are provided in the study.Table 27: Antiviral activity and clinical outcomes50 mg Antiviral Activity and Clinical Outcomes PBO 20 mg QWQW HSV-2 Shedding Ratea16.9% 1.4% 0.4% High Viral Load Shedding Rateb11.8% 0.5% <0.1% Overall Genital Lesion Rate09.6% 1.8% 2.6% Virologically Confirmed HSV-2 Genital Lesion Rated8.4% <0.1% 0.7%PBO=placebo; QW=once weekly. 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.cOverall genital lesion rate calculated as the number of days with genital lesions of any kind present (including non HSV-2-associated lesions) divided by the total number of days assessed.dVirologically confirmed lesion rate calculated as the number of days with genital lesions associated with positive HSV-2 anogenital swabs present divided by the total number of days assessed.

[0331] Statistically significant reductions were observed in the viral shedding rate, high viral load shedding rate, and virologically confirmed genital lesion rate for both the 50 mg and 20 mg cohorts compared to placebo, as summarized below in Table 28.Table 28: Rate Reductions for Compound 1, 20 mg and 50 mg once weekly cohorts vs placebo% Rate Reductions vs PBO QW (p-valuea) 20 mg QW 50 mg QW % Reduction in HSV-2 Shedding Rate 92% (p<0.01) 98% (p<0.01) % Reduction in High Viral Load Shedding Rate 96% (p<0.01) >99%b% Reduction in Overall Genital Lesion Rate 82% (p=0.06) 73% (p=0.09) % Reduction in Virologically Confirmed HSV-2 Genital>99%b91% (p<0.01) Lesion RatePBO=placebo; QW=once weekly; High viral load = >10* HSV DNA copies / mLaStatistical analysis conducted using Poisson regression models and the corresponding p-values estimated accordingly.bP-value cannot be reliably calculated given the >99% reduction compared to placebo. The observed difference is consistent with a highly significant effect.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOPharmacokinetic (PK) Data

[0332] Across the 50 mg and 20 mg cohorts, Compound 1 demonstrated a PK profile that continues to support once-weekly dosing, see Figures 11 and 12. On days 1 and 29, multiple plasma samples were taken every couple of hours during the day. On days 8, 15 and 29, two plasma samples were taken; one pre-dose and one post-dose (ranging from a couple of minutes to a couple of hours after dosing).Safety Data

[0333] Compound 1 was observed to be well-tolerated at oral doses up to 50 mg weekly in participants seropositive for HSV-2 with recurrent genital herpes. The proportion of participants reporting treatment-emergent adverse events (TEAEs) was similar between Compound 1 (80%) and placebo (88.9%) recipients. Of the TEAEs reported, the majority were grade 1 or grade 2. The most common adverse events were upper respiratory tract infections and headaches. There have been no serious adverse events reported to date. One grade 3 adverse event of migraine was reported in a participant enrolled in the 20 mg / placebo cohort. The proportion of participants reporting treatment-emergent laboratory abnormalities was higher in placebo (44.4%) than in Compound 1 (32.5%) recipients, with all observed abnormalities grade 1 or grade 2.Summary

[0334] In summary, Compound 1, dosed using a weekly dosage regimen as described above, has been found to provide significant reductions in viral shedding rate, high viral load shedding rate, and virologically confirmed genital lesion rate, in participants seropositive for HSV-2 with recurrent genital herpes.

[0335] As described above, the study showed a 98% reduction in HSV-2 shedding rate compared to placebo (p<0.01) over the 29-day evaluation period in the 50 mg weekly dose cohort. The data also revealed a 91% reduction in virologically confirmed genital lesion rate compared to placebo (p<0.01) with the 50 mg weekly dose over the same period. There was also a >99% reduction in the number of samples with high viral load, a potential surrogate for HSV-2 transmission and a secondary endpoint. For the 20 mg weekly dose cohort, the study showed a 92% reduction in HSV-2 shedding rate compared to placebo (p<0.01) over the evaluation period. The data for this cohort also revealed a >99% reduction in virologically confirmed genital lesion rate compared to placebo over the same period. There was also a 96% reduction in the number of samples with high viral load, a potential surrogate for HSV-2 transmission and a secondary endpoint.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOExample 9: PK study of capsule formulationsCapsule Formulation Preparation

[0336] For the study described below, the two formulations were comprised of a 50:50 (w / w) mixture of Compound 1 Form I (or mesylate salt Form I) and pregelatinized starch. To prepare the powder blend, the individual components were weighed and triturated in a mortar and pestle for - 1 min. Once a uniform blend was obtained, the required amount of blend was weighed and manually filled into Capsugel coni-snap size 1 hard-gelatin capsules. Further details are provided in Table 29.Table 29: Compositional details of capsule FormulationsF6 F7 Componentmg / unit % mg / unit % Compound 1 Form I 50 50 — — Compound 1 Mesylate Salt,““ 61 50 Form IPregelatinized Starch (PGS)50 50 61 50 1500Size 1 Gelatin Capsule — — — — Total Powder 100 100 122 100Dosing

[0337] Adult male Beagle dogs with 8-10 kg body weight were used for the PK study (n=6). All dogs received an oral dose of Compound 1 capsule of 50 mg / dog via oral gavage, to ensure the complete oral dose was received; a small quantity of water (10 mL) was flushed down the gavage immediately after administration. Further details are provided in Table 30.Table 30: Dosing detailsStomach pH before Dose Formulation Pretreatment RoutePO dosing Level 50 F6Fasted, Pentagastrin- IM-6 mg / dog 2.00 - 3.00 POpg / kg (80 pL / kg) 50 F7mg / dogResults

[0338] The results of the PK study in dogs is presented in Table 31 and Figure 9.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO

[0339] As demonstrated by the pharmacokinetic results, plasma concentrations and AUC0-72hr for the mesylate salt capsule formulation are significantly higher than the free base capsule formulation.Table 31: PK study results for capsule formulationsF6 F7N 6 3Dose 50 mg / dog 50 mg / dog T1 / 2 1.2 hr 3.3 hr (CV%) (35.0%) (34.6%) Cmax 5.2 pM 13.1 pM (CV%) (52.4%) (29.2%) AUC0-72hr 15.7 hr*pM 63.9 hr*pM(CV%) (51.8%) (42.9%)

Claims

HGF Ref. P393744WOSMRH Ref: 37JD-434629-WOCLAIMS1. 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:OS" NH2or a pharmaceutically acceptable salt thereof, to the human subject in a dose of from about 1 mg to about 2000 mg, wherein the dose is administered no more than once every 5 days, 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 or once a month.

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

4. The method of claim 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 5 mg to about 50 mg, or from about 10 mg to about 40 mg, or from about 10 mg to about 35 mg once a week or from about 20 mg to about 50 mg once a week.

5. The method of claim 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 15 mg, once a week.

6. The method of claim 3, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg or about 50 mg, once a week, or about 30 mg once a week or about 50 mg once a week.

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

8. The method of claim 7, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 500 mg to about 2000 mg, or from about 1000 mg to about 2000 mg, or from about 1500 mg to about 2000 mg, once a month.

9. The method of claim 7, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is about 1750 mg, or about 1800 mg, or about 1900 mg, once a month.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO10. The method of any one of claims 1 to 9, wherein the dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, or at least 300 ng / mL for at least 80% of the dosing interval, or at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.

11. The method of any one of claims 1 to 9, wherein the dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 200 ng / mL for at least 80% of the dosing interval.

12. The method of any one of claims 1 to 9, wherein the dose achieves and maintains a plasma concentration in the human subject of Compound 1 of between 200 ng / mL and 600 ng / mL for at least 80% of the dosing interval.

13. The method of any one of claims 1 to 12, 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.

14. The method of claim 13, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 300 mg.

15. The method of claim 13 or 14, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily for one or two days, or for one day.

16. 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 two days, wherein the loading dose is from about 10 mg to about 300 mg, and the loading dose is administered once daily; andHGF Ref. P393744WOSMRH Ref: 37JD-434629-WOb. 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 1 mg to about 100 mg administered once a week or about 100 mg to about 2000 mg administered once a month.

17. The method of claim 16, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 50 mg to about 300 mg, and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 10 mg to about 50 mg once a week or from about 10 mg to about 40 mg once a week.

18. The method of claim 16, wherein the loading dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 50 mg to about 300 mg and the maintenance dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from about 1500 mg to about 2000 mg once a month.

19. The method of any one of claims 16 to 18, wherein the maintenance dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 250 ng / mL for at least 80% of the dosing interval, or at least 300 ng / mL for at least 80% of the dosing interval, or at least 500 ng / mL for at least 80% of the dosing interval, or at least 600 ng / mL for at least 80% of the dosing interval.

20. The method of any one of claims 16 to 18, wherein the dose achieves and maintains a plasma concentration in the human subject of Compound 1 of at least 200 ng / mL for at least 80% of the dosing interval.

21. The method of any one of claims 16 to 18, wherein the maintenance dose achieves and maintains a plasma concentration in the human subject of Compound 1 of between 200 ng / mL and 600 ng / mL for at least 80% of the dosing interval.

22. The method of any one of claims 1 to 21, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as an oral pharmaceutical composition, wherein the pharmaceutical composition is selected from the group consisting of a granule, a pellet, a tablet, a particle, a capsule, a suspension and a mini-tablet.

23. The method of claim 22, wherein the pharmaceutical composition is a tablet comprising about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

24. The method of claim 22, wherein the pharmaceutical composition is a tablet comprising about 1 mg to about 40 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

25. The method of claim 22, wherein the pharmaceutical composition is a tablet comprising about 20 mg to about 50 mg of Compound 1, or a pharmaceutically acceptable salt thereof.HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO26. The method of any one of claims 1 to 25, wherein the herpes virus infection being treated in the human subject is a HSV infection.

27. The method claim 26, wherein the HSV infection is HSV2.

28. The method claim 27, wherein the HSV infection is HSV2 with recurrent genital herpes.

29. The method of any one of claims 26 to 28, wherein the method suppresses recurrence of HSV symptoms or outbreaks in a human subject.

30. The method of any one of claims 26 to 29, wherein the method reduces viral shedding, or reduces the rate of viral shedding in a human subject with recurrent HSV, such as genital HSV2.

31. The method of any one of claims 26 to 30, wherein the method prevents or reduces the transmission of HSV, or an infectious disease caused by HSV.

32. The method of any one of claims 1 to 31, wherein Compound 1 is present as a mesylate salt.

33. The method of claim 32, wherein Compound 1 is present as crystalline Compound 1 mesylate salt Form I characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising five or more peaks selected from the peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 2θ (± 0.2° 2θ).

34. An oral pharmaceutical composition comprising Compound 1 represented by:or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the oral pharmaceutical composition comprises from about 1 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

35. An oral pharmaceutical composition according to claim 34, wherein the Compound 1 is present as a mesylate salt.

36. An oral pharmaceutical composition according to claim 35, wherein Compound 1 is present as crystalline Compound 1 mesylate salt Form I characterized by an XRPD pattern measured using Cu Kα radiation (1.5419 Å) comprising five or more peaks selected from the peaks at 7.2, 11.6, 14.3, 18.5, 19.1, 20.9, 24.0, 26.8, and 29.6° 2θ (± 0.2° 2θ).HGF Ref. P393744WOSMRH Ref: 37JD-434629-WO37. An oral pharmaceutical composition according to any one of claims 34 to 36, wherein the composition comprises a surfactant, or sodium lauryl sulfate.

38. An oral pharmaceutical composition according to any one of claims 34 to 37, for use in a method disclosed in any one of claims 1 to 33.

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