Oral pharmaceutical compositions

Description

1 / 135 ORAL PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION

[001] Compositions and methods are provided herein for treating and / or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection. In particular, highly bioavailable and long-acting oral pharmaceutical compositions are provided herein, comprising a potent helicase-primase inhibitor, i.e., 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazol-5-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 OF THE INVENTION

[002] Human herpesviruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing permanent infections in humans. This is due to their ability to exist in the host as an asymptomatic latent infection, where the virus remains dormant, or, after activation, as a lytic infection with associated symptoms. These viral infections have a wide global prevalence, and it is noteworthy that more than 90% of all humans are chronically infected with more than one human herpesvirus.

[003] Human herpes viruses are classified into three subfamilies (α, β, and γ) based on their biological characteristics, and the family consists of eight members: Herpes Simplex Virus subtypes 1 and 2 (HSV1, HSV2), Varicella Zoster Virus (VZV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and Human Herpes Virus 6-8 (HHV 6-8). Petition 870250094497, dated 10 / 16 / 2025, page 18 / 194 2 / 135

[004] HSV1 and 2 infections can cause disease in immunocompetent individuals. Both subtypes cause genital / anal and orolabial / nasal cavity (cold sores) skin lesions, although HSV2 is more commonly associated with the former and HSV1 with the latter. It is believed that more than 80% of genital infections are caused by HSV2. Globally, more than 500 million people have genital herpes infections, and approximately 50 to 80% of the world's population has orolabial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1, can also cause lesions on the fingers (whiteheads) and other areas of the skin.

[005] The vast majority of individuals infected with HSV will not exhibit noticeable symptoms. However, some will experience recurrent (and often severe) outbreaks of infection. In the US, 20 to 40% of the population will experience recurrent HSV-related cold sores. Significantly, cold sores and Whitlow's disease provide a very easy route of 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 leading cause of blindness, and HSV can also cause encephalitis in neonates, a potentially fatal condition. Other disorders believed to be caused by HSV include gladiatorial herpes, Mollaret's meningitis, and possibly Bell's palsy.

[006] Primary infection or reactivation of an existing herpes virus infection can be a major cause of disease in immunocompromised individuals. The main at-risk populations include patients undergoing solid organ or stem cell transplantation, patients undergoing cancer treatment, individuals with HIV / AIDS, and patients admitted to the ICU. Petition 870250094497, dated 10 / 16 / 2025, page 19 / 194 3 / 135

[007] Currently, there is no cure for HSV. Medications have been developed to reduce, to some extent, the occurrence and / or shorten the duration of outbreaks, but improved therapies are needed.

[008] Currently, nucleoside analogs, such as acyclovir and its prodrugs, such as valacyclovir and famciclovir, are used as agents against herpes viruses, such as HSV. To exert their effects, these nucleoside analogs must be phosphorylated by viral thymidine kinase (TK) and subsequently converted by cellular kinases into nucleoside triphosphate, which inhibits the activity of viral DNA polymerase. If the virus does not possess functionally active TK, as is the case, for example, with HHV1-resistant mutants or TK-negative viruses, the nucleoside analogs are unable to exert their effects.

[009] Nucleoside analogs are clinically administered in very high doses, for example, doses of several hundred milligrams to several grams are typically administered daily. Even at these high doses, which are often administered over long periods of treatment, these drugs are unable to completely prevent recurrent outbreaks of HSV infection symptoms. Nucleoside analogs also contribute little to the problem of viral shedding, which can asymptomatically facilitate the transmission of HSV to more individuals. Certain nucleoside analogs, especially when used in high doses, also raise safety concerns.For example, because these agents can incorporate host genome DNA via host DNA polymerase, their mutagenicity is a concern, as documented for the nucleoside analog ganciclovir (Aoki, Chapter 45 in Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition) 2015). Petition 870250094497, dated 10 / 16 / 2025, page 20 / 194 4 / 135

[0010] Given the inadequacy of existing treatments, there is an urgent medical need to develop improved and well-tolerated anti-herpes treatments.

[0011] One class of compounds currently under investigation are helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex, composed of helicase, primase, and cofactor subunits, which have essential functions for viral DNA replication. These agents are not nucleoside analogs and do not require TK phosphorylation to inhibit HSV replication, and are therefore potentially active against TK-deficient HSV, which, as described above, is an important mechanism of resistance to nucleoside analogs.

[0012] Two examples of helicase-primase inhibitors are BILS179 BS (Crute et al., (2002) Nature Medicine 8, p. 386-391) and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p. 201-206).

[0013] BILS-179 BS was administered orally to humans but was discontinued in early clinical trials due to adverse events (Ruebsamen et al., (2019) Med. Chem. Commun., DOI: 10,1039 / C9MD00233B). Similarly, amenamevir, which was also administered orally to humans, was discontinued from initial clinical trials with HSV due to adverse events. In a placebo-controlled, dose-finding study of 437 patients with recurrent genital herpes, amenamevir was administered orally in one of four doses: 100 mg, 200 mg, 400 mg, and 1200 mg. It was found that the wound healing time, that is, the primary outcome of the study, showed a significant difference only between the group with the highest single dose of 1200 mg and the group tested with placebo (Aoki, Chapter 45 in Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015). Petition 870250094497, dated 10 / 16 / 2025, page 21 / 194 5 / 135

[0014] 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 was described in document WO 2001 / 47904.

[0015] In a human clinical study, the effect of pritelivir on genital herpes suppression was studied in 156 subjects (Wald et al., (2014) New England Journal of Medicine 370, p. 201-210). Subjects received one of three daily oral doses or a weekly oral dose of pritelivir or placebo for 28 days. The four pritelivir dosing regimens were: a 20 mg loading dose followed by a 5 mg daily dose; a 100 mg loading dose followed by a 25 mg daily dose; a 300 mg loading dose followed by a 75 mg daily dose; and a 400 mg weekly dose. At high doses, pritelivir was found to reduce the genital shedding rate of HSV, the primary outcome of the study. Pritelivir also reduced the number of lesion days in healthy men and women with genital herpes. A daily oral dose of 75 mg showed the greatest antiviral effect, being superior to the weekly dose of 400 mg, administered less frequently.

[0016] As highlighted in the study report, although the HSV clearance rate was reduced at the highest daily dose of 75 mg compared to placebo, disruptive clearance remained. Discussing this finding, Wald et al. ((2014) New England Journal of Medicine 370, pp. 201-210) explain that persistent, low-level clearance was also observed with nucleoside therapy and that the pathogenesis of disruptive viral clearance during appropriate antiviral therapy with nucleoside analogs is poorly understood; it is not related to lack of adherence to the treatment regimen or viral resistance. The author also raises the question of whether further increases in the daily dose of pritelivir would reverse complete Petition 870250094497, dated 10 / 16 / 2025, page 22 / 194 6 / 135 directly affects viral elimination and should be addressed in subsequent clinical studies.

[0017] In accordance with this suggestion, a subsequent clinical study using an even higher daily oral dose was indeed conducted. In a 28-day Phase II clinical study involving 91 individuals with recurrent genital HSV-2, daily oral administration of 100 mg of pritelivir (following a 400 mg loading dose) resulted in HSV clearance in 2.4% of the genital swabs analyzed, compared to HSV clearance in 5.3% of the swabs after daily administration of 500 mg of valacyclovir. The study results were reported in Wald et al., (2016) (J. Am. Med. Assoc. 316(23), p. 2495-2503), and the publication mentions that the daily dose of 100 mg of pritelivir (after a loading dose of 400 mg) was chosen based on results from previous clinical trials that demonstrated high efficacy of the 75 mg daily dose in suppressing viral shedding.

[0018] In an ongoing phase III clinical trial, a 400 mg oral loading dose, followed by a daily oral dose of 100 mg of pritelivir for up to 28 days or until all HSV mucocutaneous lesions are healed, whichever occurs first, is being investigated (https: / / www.clinicaltrials.gov / ct2 / show / NCT03073967?term=pritelivir+f&draw=2&rank=2).

[0019] As is evident from the above, efforts to improve therapy with the small molecule-based antivirals described above, for example, to try to further reduce or prevent HSV shedding and viral reactivation, have largely focused on the use of higher oral doses of the drug (including high loading doses) and more frequent doses (e.g., multiple daily doses). Petition 870250094497, dated 10 / 16 / 2025, p. 23 / 194 7 / 135

[0020] There is still a continuing need for new and improved methods for treating HSV infections, and the present invention was designed with that in mind. SUMMARY OF THE INVENTION

[0021] In a first aspect, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises a compound (Compound 1) represented by: or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix.

[0022] It has been surprisingly discovered that when Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition comprising a solid dispersion according to the present invention, such composition provides beneficial properties, including high bioavailability and / or certain release profiles that allow elevated plasma levels to be rapidly achieved and maintained for prolonged periods. Notably, in some embodiments, the compositions of the present invention are capable, for example, after steady-state levels have been reached, of providing elevated, constant, and continuous plasma levels of Compound 1 for at least 14 days after administration. In some embodiments, the compositions of the present invention are capable of providing elevated, constant, and continuous plasma levels of Compound 1 for a prolonged period after only a single oral administration, i.e., without the need for Petition 870250094497, dated 10 / 16 / 2025, p. 24 / 194 8 / 135 a loading dose. It was also surprisingly discovered that certain compositions of the present invention are capable of providing even higher plasma levels of the helicaseprimase inhibitor for a prolonged period when administered in conjunction with food intake.

[0023] The benefits mentioned above offer the possibility of much less frequent dosing and / or the use of lower doses than other forms of administration. This is an unexpected finding. As described above, efforts to improve small molecule antiviral therapy have largely focused on increasing oral drug doses (including high loading doses) and using more frequent dosing regimens (e.g., multiple daily doses).

[0024] The present invention addresses the need for a novel treatment approach for HSV infections that can provide improvements in efficacy and / or safety and / or patient usability.

[0025] In a second aspect, the present invention provides a method for forming a pharmaceutical composition according to the first aspect. Various techniques can be used for forming the compositions of the present invention; however, certain processes have been found to offer specific advantages. For example, various techniques can be used for forming solid dispersions; however, spray drying has been found to offer specific advantages.

[0026] In a third aspect, the present invention provides a method for treating or preventing a herpes infection in an individual in need thereof, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition. Petition 870250094497, dated 10 / 16 / 2025, p. 25 / 194 9 / 135 according to the first aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The summary, as well as the detailed description below, are best understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the compositions and methods described, exemplary embodiments of the compositions and methods are shown in the drawings; however, the compositions and methods are not limited to the specific embodiments described. In the drawings:

[0028] FIG. 1 shows the mean plasma concentration-time profiles of Compound 1 after intravenous administration of the solution formulations described in Example 3 (open triangles) at 1 mg / kg in male Sprague-Dawley rats (n = 3).

[0029] FIG. 2 shows the mean plasma concentration-time profiles of Compound 1 after intravenous administration of the solution formulations described in Example 3 (open triangles) at 0.25 mg / kg in male cynomolgus monkeys (n=3).

[0030] FIG. 3 shows the mean plasma concentration-time profiles of Compound 1 after intravenous administration of the solution formulations described in Example 3 (open triangles) at 0.15 mg / kg in non-naive male Beagle dogs (n=3).

[0031] FIG. 4 shows the XRPD diffractogram of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0032] FIG. 5 shows the PLM image of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0033] FIG. 6 shows the results of the thermal analysis by DSC of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0034] FIG. 7 shows the TGA analysis of Lot 1 of the formulation. Petition 870250094497, dated 10 / 16 / 2025, page 26 / 194 10 / 135 of solid dispersion of Compound 1 described in Example 4 and Table 17.

[0035] FIG. 8 shows the XRPD diffractogram of Lot 2 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0036] FIG. 9 shows the PLM image of Lot 2 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0037] FIG. 10 shows the results of the thermal analysis by DSC of Lot 2 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0038] FIG. 11 shows the TGA analysis of Lot 2 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0039] FIG. 12 shows the XRPD diffractogram of Lot 3 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0040] FIG. 13 shows the PLM image for Lot 3 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0041] FIG. 14 shows the results of the thermal analysis by DSC of Lot 3 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0042] FIG. 15 shows the TGA analysis of Lot 3 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0043] FIG. 16 shows the XRPD diffractogram of Lot 4 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0044] FIG. 17 shows the PLM image for Lot 4 of the formula. Petition 870250094497, dated 10 / 16 / 2025, page 27 / 194 11 / 135 solid dispersion of Compound 1 described in Example 4 and Table 17.

[0045] FIG. 18 shows the results of the thermal analysis by DSC of Lot 4 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0046] FIG. 19 shows the TGA analysis of Lot 4 of the solid dispersion formulation of Compound 1 described in Example 4 and Table 17.

[0047] FIG. 20 shows the mean plasma concentration-time profile of the compositions described in Example 5 after oral administration of the 90% NMP / 10% TPGS solution formulations (closed squares), nanosuspension (open squares) and SDD suspension (crosses) described in Example 5 in male Sprague-Dawley rats (n=3).

[0048] FIG. 21 shows the mean plasma concentration-time profile of the compositions described in Example 6 after oral administration of the 85% PEG300 / 10% TPGS / 5% EtOH solution (triangles) and the SDD suspension formulation (diamonds) described in Example 6 in non-naive male Beagle dogs (n=3).

[0049] FIG. 22 and FIG. 23 show the mean plasma concentration-time profiles on Day 1 and Day 7 for the compositions described in Example 7 after oral administration at doses of 10 mg / kg (closed solid circles), 100 mg / kg (empty squares) and 300 mg / kg (closed solid triangles) in male Sprague-Dawley rats (n=3).

[0050] FIG. 24 and FIG. 23 show the mean plasma concentration-time profiles on Day 1 and Day 7 for the compositions described in Example 7 after oral administration at doses of 10 mg / kg (closed solid circles), 100 mg / kg (empty squares), and 300 mg / kg (closed solid triangles) in Sprague-Dawley rats. Petition 870250094497, dated 10 / 16 / 2025, page 28 / 194 12 / 135 males (n=3). FIG. 25 shows the mean plasma concentration-time profiles on Day 1 and Day 7 for the compositions described in Example 8 after oral administration at doses of 1 mg / kg (closed solid circles), 10 mg / kg (empty squares), and 100 mg / kg (closed solid triangles) in non-naive male Beagle dogs (n=3).

[0051] FIG. 26 and FIG. 27 show the mean plasma concentration-time profiles on Day 1 and Day 14 for the compositions described in Example 9 after oral administration at doses of 15 mg / kg in non-naive male (closed solid circles) and female (empty squares) Beagle dogs (n=2).

[0052] FIG. 28 shows the mean plasma concentration-time profiles after 14 consecutive days of oral administration of the compositions described in Example 9, at doses of 15 mg / kg in male (empty squares) and female (empty circles) non-naive Beagle dogs (n = 2 for each sex group).

[0053] FIG. 29 shows the mean plasma concentration-time profiles (n = 3) of Compound 1 after intravenous administration of the solution formulations described in Example 10 in non-naive male Beagle dogs, at a dose of 0.10 mg / kg of Compound 1 with (closed diamonds) and without (empty squares) oral administration of activated charcoal.

[0054] FIG. 30 shows the XRPD diffractogram of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 11 and Table 20.

[0055] FIG. 31 shows the results of the DSC thermal analysis of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 11 and Table 20.

[0056] FIG. 32 shows the SEM image of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 11 and Table 20. Petition 870250094497, dated 10 / 16 / 2025, page 29 / 194 13 / 135

[0057] FIG. 33 shows the XRPD diffractogram of Lot 1 of the solid dispersion formulation of Compound 1 described in Example 11 and Table 20, initial and after stress at 40 °C / 75% RH under open conditions for 5 days.

[0058] FIG. 34 shows the mean plasma concentration-time profile of the SDD suspension formulation composition described in Example 11 after oral administration to non-naive male Beagle dogs (n=3) on overnight fasting (open squares) and fed (closed squares).

[0059] FIG. 35 shows the mean plasma concentration-time profiles of Compound 1 after intravenous administration of the solution formulations described in Example 3A for (A) male Sprague Dawley rats (n=3) at 0.2 mg / kg; (B) male non-naive Beagle dogs (n=3) at 0.15 mg / kg; (C) male non-naive cynomolgus monkeys (n=3) at 0.2 mg / kg; and (D) non-naive Bama mini-pigs (n=3) at 0.25 mg / kg.

[0060] FIG. 36 shows the mean plasma concentration-time profile of the tablet composition described in Example 13 after oral administration of 100 mg (2 tablets of 50 mg) to non-naive male Beagle dogs pre-treated with pentagastrin in a fasted state (empty triangles), pre-treated with famotidine in a fasted state (empty circles) or fed state (empty squares) (n = 3 per arm).

[0061] FIG. 37 shows the mean plasma concentration-time profiles of the tablet composition described in Example 13 (closed squares) after oral administration of 100 mg (2 tablets of 50 mg) and of the SDD suspension formulation (closed circles) described in Example 12 after oral administration of 10 mg / kg to non-naive male Beagle dogs under fasting conditions (n ​​= 3 per arm).

[0062] FIG. 38 shows the mean plasma concentration-time profiles of the tablet composition described in Example 13. Petition 870250094497, dated 10 / 16 / 2025, page 30 / 194 14 / 135 (closed squares) after oral administration of 100 mg (2 tablets of 50 mg) and of the SDD suspension formulation (closed circles) described in Example 12 after oral administration of 10 mg / kg to non-naive male Beagle dogs under feeding conditions (n ​​= 3 per arm).

[0063] FIG. 39 shows the XRPD diffractograms of the solid dispersion formulations of Compound 1 described in Example 15.

[0064] FIG. 40 shows the XRPD diffractograms of the solid dispersion formulation of Compound 1:HPMCAS-HG described in Example 15 after stress stability at 40°C / 75% RH in open conditions for five days.

[0065] FIG. 41 shows the XRPD diffractograms of the solid dispersion formulation of Compound 1:Soluplus described in Example 15 after stress stability at open conditions of 40°C / 75% RH for five days.

[0066] FIG. 42 shows the XRPD diffractograms of the solid dispersion formulation of Compound 1:HPMCAS-LG described in Example 15 after stress stability at open conditions of 40°C / 75% RH for five days.

[0067] FIG. 43 shows the XRPD diffractograms of the solid dispersion formulations of Compound 1:HPMCAS-MG described in Example 15 after stress stability at open conditions of 40°C / 75% RH for five days.

[0068] FIG. 44 shows the concentrations of Compound 1 in the donor chamber of the Pion μflux device for the solid dispersion formulations of Compound 1 described in Example 15.

[0069] FIG. 45 shows the concentrations of Compound 1 in the acceptor chamber of the Pion μflux device for the solid dispersion formulations of Compound 1 described in Example 15.

[0070] FIG. 46 shows the average plasma concentration profiles Petition 870250094497, dated 10 / 16 / 2025, page 31 / 194 15 / 135 Time-dependent changes in the composition of the SDD suspension formulation described in Example 16 after oral administration to non-naive male Beagle dogs (n=3). DETAILED DESCRIPTION OF THE INVENTION

[0071] The compositions, their uses and methods described can be more easily understood by referring to the detailed description below, together with the accompanying figures, which form part of this description. It should be understood that the compositions and methods described are not limited to the specific compositions and methods described and / or shown herein, and that the terminology used herein is intended to describe particular embodiments only by way of example and is not intended to be limiting of the compositions and methods claimed. Definitions

[0072] Unless otherwise indicated, the following terms used in the descriptive report and claims have the meanings set forth below.

[0073] A reference to a specific numerical value includes at least that specific value, unless the context clearly indicates otherwise. When a range of values ​​is expressed, another modality includes from a specific value and / or up to another specific value. Furthermore, a reference to values ​​indicated in ranges includes all values ​​within that range. All ranges are inclusive and combinable.

[0074] It should be noted that certain features of the compositions and methods described, which are, for clarity, described here in the context of separate modalities, can also be provided in combination in a single modality. On the other hand, several features of the compositions and methods described, which are, for brevity, described in the context of a single modality, Petition 870250094497, dated 10 / 16 / 2025, page 32 / 194 16 / 135 can also be supplied separately or in any subcombination.

[0075] When used in this document, the singular forms um, uma and o(a) include the plural.

[0076] When used in this document, Cmax refers to the geometric mean maximum concentration of the active agent. This can be measured in vivo after administration of a composition of the invention to an individual and measurement of plasma drug levels at various times after dosing.

[0077] When used in this document, 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.

[0078] When used in this document, the term amorphous refers to a solid material lacking long-range order in the position of its molecules. Amorphous solids are substances in which the molecules are arranged randomly, so there is neither a well-defined arrangement, for example, molecular packing, nor long-range order. Amorphous solids are generally isotropic, that is, they exhibit similar properties in all directions and have no defined melting points. For example, an amorphous material is a solid material without characteristic sharp crystalline peak(s) in its X-ray power diffraction pattern (XRPD) (i.e., it is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.

[0079] When used in this document, the term substantially amorphous refers to a solid material with little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% Petition 870250094497, dated 10 / 16 / 2025, p. 33 / 194 17 / 135 of crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). Note also that the term substantially amorphous includes the descriptor amorphous, which refers to materials with no (0%) crystallinity. Conveniently, substantially amorphous material has less than about 5% crystallinity.

[0080] When used in this document, the term dispersion refers to a dispersed system in which one substance, the dispersed phase, is distributed, in discrete units, by a second substance (the continuous phase or vehicle or carrier). The size of the dispersed phase can vary considerably (e.g., single molecules or colloidal particles from nanometers to several microns in size). In general, dispersed phases can be solid, liquid, or gaseous. In the case of a solid dispersion, both the dispersed and continuous phases are solid. In pharmaceutical applications, a solid dispersion may include: an amorphous drug in an amorphous polymer; an amorphous drug in a crystalline polymer; a crystalline drug in an amorphous polymer; or a crystalline drug in a crystalline polymer. In this context, a solid dispersion may include an amorphous drug in an amorphous polymer, an amorphous drug in a crystalline polymer, or a crystalline drug in an amorphous polymer.In some embodiments, a solid dispersion includes the polymeric matrix that constitutes the dispersed phase, and the drug or compound constitutes the continuous phase. Alternatively, a solid dispersion includes the drug that constitutes the dispersed phase, and the polymeric matrix constitutes the continuous phase or carrier. Conveniently, the solid dispersion of the present invention comprises a dispersed phase, comprising Compound 1 or a pharmaceutically acceptable salt thereof, and a continuous phase, comprising at least one polymeric matrix. Most conveniently, the solid dispersion comprises Compound 1. Petition 870250094497, dated 10 / 16 / 2025, p. 34 / 194 18 / 135 amorphous or a pharmaceutically acceptable salt thereof in an amorphous polymeric matrix.

[0081] When used in this document, polymeric matrix refers to a polymer suitable for use in a solid dispersion according to the present invention and comprises inert and pharmaceutically acceptable polymers. Suitable matrix polymers include linear, branched or cyclic homopolymers, natural or synthetic (e.g., polysaccharides) and copolymers (e.g., block copolymers).

[0082] When used in this document, the term povidone polymer refers to polyvinylpyrrolidone or a derivative thereof, such as cross-linked polyvinylpyrrolidone or crospovidone.

[0083] When used in this document, the term copovidone polymer refers to a copolymer of vinylpyrrolidone and vinyl acetate, or a derivative thereof. An example of a copovidone polymer is PVP-VA64.

[0084] When used in this document, the term methacrylate polymer refers to a polymer of methacrylic acid and / or methyl methacrylate. This includes anionic copolymers, as shown below, which are a product of the polymerization of methacrylic acid and methyl methacrylate – p(MAA-co-MMA). The dissolution pH of p(MAA-co-MMA) is determined by the ratio of monomers used in the polymerization. For example, a 1:1 molar ratio of methyl methacrylate and methacrylic acid results in a dissolution above pH 6.0. The resulting polymer is designated as Type A. Type B, synthesized using a 2:1 molar ratio of methyl ester and carboxylic acid monomers, results in a dissolution pH >7.0. The chemical structure of p(MAA-co-MMA): n:m=1:1 (type A); n:m=2:1 (type B) is: Petition 870250094497, dated 10 / 16 / 2025, page 35 / 194 19 / 135 HjCO HU

[0085] Poly(methacrylic-co-methyl methacrylate) acid polymers are marketed, for example, by Evonik Industries under the trade name EUDRAGIT®. When used in this document, the term EUDRAGIT® L100 refers to a 1:1 anionic copolymer of methacrylic acid-methyl methacrylate (CAS number 25086-15-1), which dissolves in water above pH 6 and has an average molecular mass of approximately 125,000 g / mol.

[0086] When used in this document, the term HPMCAS refers to hydroxypropylmethylcellulose acetate succinate (CAS 7113897-1). HPMCAS is typically produced from HPMC by esterification with acetic anhydride and succinic anhydride in acetic acid, using a basic catalyst such as sodium acetate. The resulting product, as illustrated below, is precipitated by the addition of water and subsequently purified by washing with additional water. This reaction sequence leads to a plurality of hydrophobic sites and the ability to accept and donate hydrogen bonds. The chemical structure of HPMCAS is: R = -H -CH£HÍGHj)QCQCHj CHj -CHíWCHílCxrOCHiCHsCQOH -CHiCHÍtHjlQH -COCHs COCHjCHjCOOH

[0087] HPMCAS was introduced by Shin-Etsu Chemical Co., Ltd., Japan, as an enteric coating agent with three levels of substitution, designated according to the content of acetyl substituents. Petition 870250094497, dated 10 / 16 / 2025, p. 36 / 194 20 / 135 as L, M, or H (e.g., Shin-Etsu AQOAT® LF, MF, HF, LG, MG, and HG). The dissolution pH of HPMCAS ranges from approximately 5.5 (L) to approximately 6.5 (H), depending on the type of buffer used for dissolution. Dow Chemical also sells HPMCAS (e.g., Dow AFFINISOL® 716, 912, and 126), as does Ashland Chemical (e.g., AQUASOLVE® grades L, M, and H). Unlike HPMC, where replacement levels are specified in monographs, the range for HPMCAS is not limited to the three commercially available subranges. Manufacturer specifications for these products are shown below in Tables AC. Table A: Manufacturer specifications for AQOAT® HPMCAS Shin-Estu AS-LG AS-LF AS-MG AS-MF AS-HG AS-HF Viscosity (mm² / s) 2.4 - 3.6 2.4 - 3.6 2.4 - 3.6 Heavy metals <10 ppm <10 ppm <10 ppm Arsenic <2 ppm <2 ppm <2 ppm Free succinic acid <1.0% <1.0% <1.0% Loss on drying <5.0% <5.0% <5.0% Residue on ignition <0.20% <0.20% <0.20% Methoxy content 20.0 - 24.0% 21.0 - 25.0% 22.0 - 26.0% Hydroxypropoxy content 5.0 - 9.0% 5.0 - 9.0% 6.0 - 10.0% Acetyl content 5.0 - 9.0% 7.0 - 11.0% 10.0 - 14.0% Succinoyl content 14.0 - 18.0% 10.0 - 14.0% 4.0 - 8.0% Table B: Manufacturer specifications for AFFINISOL® products Dow HPMCAS 716 912 128 Hydroxypropyl 5.0 - 9.0% 5.0 - 9.0% 6.0 - 10.0% Methoxyl 20 - 24% 21 - 25% 22 - 26% Viscosity* (cP) 2.4 - 3.6 2.4 - 3.6 2.4 - 3.6 Residue on ignition <0.20% <0.20% <0.20% Loss on drying <5.0% <5.0% <5.0% Petition 870250094497, dated 10 / 16 / 2025, p. 37 / 194 21 / 135 Free acids <1.0% <1.0% <1.0% Acetate substitution 5.0 - 9.0% 7.0 - 11.0% 10.0 - 14.0% Succinate substitution 14.0 - 18.0% 10.0 - 14.0% 4.0 - 8.0% Acetic acid 0.5% 0.5% 0.5% *viscosity determined as a 2% solution in NaOH solution Table C: Manufacturer specifications for Ashland AQUASOLVE® HPMCAS products LF & LG MF & MG HF & HG Viscosity* (mPa*s) 2-4-3.6 2-4-3.6 2-4-3.6 Loss on drying <5% <5% <5% Residue on ignition <0.20% <0.20% <0.20% Heavy metals <10 ppm <10 ppm <10 ppm Arsenic <2 ppm <2 ppm <2 ppm Free succinic and acetic acid limit <1.0% <1.0% <1.0% Acetyl content 5-9% w / w 7-11% w / w 10-14% w / w Succinoyl content 14-18% w / w 10-14% w / w 4-8% w / w Methoxyl content 20-24% w / w 21-25% w / w w / w 22-26% w / w Hydroxypropoxy content 5-9% w / w 5-9% w / w 6-10% w / w *Measured for a 2% solution at 20°C.

[0088] The properties of HPMCAS can be affected, in particular, by the acetyl and succinoyl contents of the polymer. The determination of the w / w percentage of acetyl and succinoyl can be carried out by hydrolysis of the ester group of a weighted amount of polymer with 1 M NaOH, followed by determination of the acetyl and succinoyl contents in the hydrolyzed solutions by reversed-phase liquid chromatography against standard calibration solutions; this methodology is described in detail in Chen et al., Journal of AOAC International (2002), 85(4), 824-831, the contents of which are incorporated by reference. Petition 870250094497, dated 10 / 16 / 2025, page 38 / 194 22 / 135

[0089] When used in this document, the term HPMCP refers to hydroxypropyl methylcellulose phthalate (CAS 9050-31-1). The chemical structure of HPMCP, as illustrated below, is a phthalic ester medium of hydroxypropyl methylcellulose. The pH threshold for the rapid disintegration of HPMCP can be controlled by varying the phthalyl content. HPMCP is commercially available, for example, from Shin-Etsu (e.g., HP-55, HP-50, and HP-55S). The manufacturer's specifications for these products are shown below in Table D. The chemical structure of HPMCP is: Table D: Manufacturer specifications for HPMCP products Shin-Etsu HP-55 HP-55S HP-50 Labeled viscosity (cst) 40 170 55 Viscosity (cst) 32-48 136-204 44-66 Water <5.0% <5.0% <5.0% Residue on ignition <0.20% <0.20% <0.20% Chloride <0.07% <0.07% <0.07% Heavy metals <0.001% <0.001% <0.001% Free phthalic acid <1.0% <1.0% <1.0% Phthalyl content 27.0-35.0% 27.0-35.0% 21.0-27.0% Methoxy content 18.0-22.0% 18.0-22.0% 20.0-24.0% hydroxypropoxyl 5.0-9.0% 5.0-9.0% 6.0-10.0%

[0090] When used in this document, patient or individual refers to a mammal, including a domestic animal, an animal kept as livestock, and a zoo animal. Conveniently, the Petition 870250094497, dated 10 / 16 / 2025, page 39 / 194 23 / 135 patient or individual is a human being.

[0091] It should be understood that the references to be treated or treatment include prevention as well as relief of established symptoms of a condition. Treating or treatment of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition that develop in a human being who may be affected or predisposed to the state, disorder or condition, but does not yet present or presents clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., interrupting, reducing or delaying the development of the disease or a relapse thereof (in the 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.When used in this document, treatment and similar terms may specifically include reducing the severity and / or frequency of HSV-induced symptoms, eliminating HSV-induced symptoms and / or the underlying cause of those 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 remedying damage caused directly or indirectly by HSV infections. The term prevention, when used in this document in relation to an HSV infection or HSV-related disorder, refers to reducing the likelihood of HSV infection.In one modality, treating or treating a state, disorder or condition means inhibiting the state, disorder or condition, that is, interrupting, reducing or delaying the development of the disease or a relapse thereof (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) alleviating. Petition 870250094497, dated 10 / 16 / 2025, page 40 / 194 24 / 135 to alleviate or attenuate the disease, that is, to cause the regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. Conveniently, treat and similar terms mean to reduce the severity and / or frequency of HSV-induced symptoms, eliminate HSV-induced symptoms and / or the underlying cause of those symptoms, reduce the frequency or likelihood of HSV-induced symptoms and / or their underlying cause, delay, prevent and / or retard the progression of HSV-induced conditions and / or improve or remedy damage caused, directly or indirectly, by HSV infections.

[0092] A therapeutically effective amount or therapeutically effective dose means the amount of a compound that, when administered to a patient or individual to treat a disease, is sufficient to effect such treatment for the disease. When used in this document, the expression therapeutically effective dose or therapeutically effective amount may refer specifically to the amount of Compound 1 dosed to a patient or individual using a pharmaceutical composition, as described herein, that is effective in achieving a specific biological or therapeutic outcome, such as, but not limited to, biological or therapeutic outcomes disclosed, described, or exemplified herein. The therapeutically effective dose may vary depending on 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 an individual.Such results include, but are not limited to, 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 appropriate means in the art.

[0093] When values ​​are expressed as approximations, by using the antecedent approximately, it will be understood that the value Petition 870250094497, dated 10 / 16 / 2025, page 41 / 194 25 / 135 specifically constitutes another modality. Furthermore, the term approximately refers to a variation of ±10% from the nominal value, unless otherwise indicated or inferred.

[0094] The term "approximately," when used in reference to numerical ranges, cut-off points, or specific values, is used to indicate that the reported values ​​may vary by up to 10% from the listed value. Since many of the numerical values ​​used herein are determined experimentally, it should be understood by those skilled in the art that such determinations may, and often will, vary between different experiments. The values ​​used herein should not be considered unduly limiting because of this inherent variation. Thus, the term "approximately" is used to encompass variations of ±10% or less, variations of ±5% or less, variations of ±1% or less, variations of ±0.5% or less, or variations of ±0.1% or less from the specified value.

[0095] In several places in this descriptive report, values ​​are described in groups or ranges. Specifically, the description is intended to include all individual subcombinations of the members of such groups and ranges, as well as 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 describe individually 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 describe individually 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

[0096] When used in this document, when compositions are described as having, including or comprising specific components, or when processes are described as having, including or comprising specific process steps, it is considered Petition 870250094497, dated 10 / 16 / 2025, page 42 / 194 26 / 135 that the compositions of the present teachings also consist essentially of, or are composed of, the aforementioned components, and that the processes of the present teachings also consist essentially of, or are composed of, the aforementioned process steps.

[0097] The use of any examples or exemplary language in this document, such as, including, or for example, is intended only to better illustrate the present teachings and does not represent a limitation to the scope of the invention, unless claimed. No language in the descriptive report should be interpreted as indicating any unclaimed element as essential to the practice of the present teachings. Helicase-primase inhibitor, Compound 1

[0098] The term helicase-primase inhibitor, in the context of the present invention, denotes a compound or agent capable of reducing viral replication by inhibiting the viral complex consisting of DNA helicase, DNA primase, and cofactor subunits. The helicase-primase complex is used by herpes viruses; therefore, the helicase-primase inhibitor will have antiviral activity against one or more herpes viruses, such as one or more of subtypes 1 and 2 of Herpes Simplex Virus (HSV-1, HSV-2), Varicella-Zoster Virus (VZV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and Human Herpesvirus 6-8 (HHV 6-8).

[0099] The helicase-primase inhibitor has antiviral activity against HSV-1 and / or HSV-2.

[00100] The helicase-primase inhibitor is Compound 1, represented by: Petition 870250094497, dated 10 / 16 / 2025, page 43 / 194 27 / 135 F or a pharmaceutically acceptable salt thereof.

[00101] The compound shown above is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazol-5-sulfonamide (also referred to herein as Compound 1) and is a potent helicase-primase inhibitor. The compound is described as Examination 22 in document WO2024 / 049760A1 (PCT Application No. PCT / US2023 / 031285).

[00102] Compound 1 has an in vitro EC50 value of approximately 0.019 μM against HSV-1 and 0.011 μM against HSV-2. The in vitro EC50 value against HSV-1 and / or HSV-2 can be determined according to methods known to the skilled, such as those described in Field et al. (2013, Antiviral Res. 100, p. 297-299). The in vitro EC50 value can also be determined according to the assays described in the Examples section of this application.

[00103] Compound 1 was found to have a predicted human biological terminal half-life of more than 180 hours (see Examples 3 and 3A).

[00104] Compound 1 exhibits low or nonexistent levels of carbonic anhydrase inhibition, such as carbonic anhydrase I and / or carbonic anhydrase II inhibition. Carbonic anhydrase inhibition can be measured using a carbonic anhydrase I assay as described in Katritzky et al. (J. Med. Chem. 1987, 30:2058) and a carbonic anhydrase II assay as described in Iyer et al. (J. Biomol. Screen 2006, 11:782).

[00105] Compound 1 is sparingly soluble and has a solubility Petition 870250094497, dated 10 / 16 / 2025, page 44 / 194 28 / 135 in water at pH ~ 7.0 (measured at room temperature) less than 5 μg / ml.

[00106] Compound 1 of the present invention comprises both an original compound and any pharmaceutically acceptable salt of the original compound. It should be understood that Compound 1 may exhibit polymorphism and that the invention encompasses all such forms (including anhydrous / non-solvated forms, solvates and hydrates). Pharmaceutical Compositions of the Invention

[00107] In a first aspect, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises a compound (Compound 1) represented by: or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix.

[00108] The compositions of the invention provide high oral bioavailability and / or prolonged action. Although Compound 1 has low bioavailability, it has been found that, when formulated in pharmaceutical compositions of the present invention, which comprise a solid dispersion comprising Compound 1 or a pharmaceutically acceptable salt thereof and at least one polymeric matrix, it is possible to obtain immediate drug release with significantly improved solubility and dissolution rate. In addition, the drug can be maintained in solution for a significantly prolonged period after administration, providing a good level of prolonged exposure when administered. Petition 870250094497, dated 10 / 16 / 2025, page 45 / 194 29 / 135

[00109] In certain embodiments, the pharmaceutical compositions of the present invention comprise a solid dispersion comprising Compound 1 or a pharmaceutically acceptable salt thereof and at least one polymeric matrix, wherein Compound 1 or a pharmaceutically acceptable salt thereof is stabilized within the solid dispersion, for example, in a substantially amorphous (or totally amorphous) form. Such compositions have been found to provide rapid drug release with significant improvements in solubility and dissolution rate. In addition, the drug can be maintained in solution for a significantly prolonged period after administration, providing a good level of prolonged exposure when administered.When used in this document, the expression "stabilized within the solid dispersion in a substantially amorphous form" refers to Compound 1 or a pharmaceutically acceptable salt thereof being maintained in the solid dispersion in a substantially amorphous form, for example, with the aid of formulation approaches and excipients, such as at least one polymeric matrix, in order to provide beneficial solubility and dissolution rate properties after administration of the pharmaceutical composition. Conveniently, Compound 1 or a pharmaceutically acceptable salt thereof is stabilized within the pharmaceutical composition in amorphous form.

[00110] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises: a. Compound 1 or a pharmaceutically acceptable salt thereof, and b. at least one polymeric matrix; wherein the composition optionally contains one or more pharmaceutically acceptable excipients. Petition 870250094497, dated 10 / 16 / 2025, page 46 / 194 30 / 135

[00111] In one embodiment, the solid dispersion is a substantially amorphous solid dispersion. Conveniently, Compound 1 (or a pharmaceutically acceptable salt thereof) is present in less than about 15% (such as less than about 10%, less than about 5%, less than about 2%, or less than about 1%) of the crystalline form in the solid dispersion or composition. The skilled person will understand that there are several suitable methods for determining the crystallinity levels of a compound in solid dispersion compositions, including Raman mapping, hot-stage microscopy, atomic force microscopy, PLM, high-resolution PXRD, solid-state NMR, TAM (Thermal Activity Monitor), and FTRaman. When the crystalline drug is present, it may exist as crystalline domains or nanocrystalline domains within a dispersion, for example, within an amorphous dispersion.

[00112] In one embodiment, the solid dispersion is an amorphous solid dispersion. An amorphous dispersion may refer to a dispersion of amorphous compounds in a polymeric matrix, where the drug is in the molecularly dispersed state – also sometimes called a glassy solution. In such a glassy solution, the drug and the polymeric matrix are molecularly dispersed from each other in a single homogeneous phase, and differential scanning calorimetry (DSC) shows a single glass transition temperature peak (Tg).

[00113] Biphasic mixtures, also known as solid glass suspensions, contain a compound in a partially miscible state with the polymer and are more prone to phase separation during storage. A solid crystalline suspension may contain a polymer in an amorphous phase while the compound is in a crystalline phase. A DSC of this suspension shows a Tg peak for the polymer and a melting peak for the compound, indicating an absence of miscibility between the compound and the polymer. Petition 870250094497, dated 10 / 16 / 2025, page 47 / 194 31 / 135

[00114] In one embodiment, the solid dispersion has a single glass transition temperature (Tg).

[00115] In one embodiment, the solid dispersion comprises about 5% by weight to about 60% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In a convenient embodiment, the solid dispersion comprises about 30% by weight to about 60% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. In a convenient embodiment, the solid dispersion comprises about 10% by weight to about 50% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. Conveniently, the solid dispersion comprises about 10% by weight to about 30% by weight of Compound 1, or a pharmaceutically acceptable salt thereof. Conveniently, the solid dispersion comprises about 15% by weight or about 20% by weight of Compound 1, or a pharmaceutically acceptable salt thereof.

[00116] In one embodiment, the solid dispersion comprises about 30% by weight to about 95% by weight of at least one polymeric matrix. In a convenient embodiment, the solid dispersion comprises about 40% by weight to about 90% by weight, such as about 50% by weight to about 90% by weight, about 60% by weight to about 90% by weight, about 70% by weight to about 90% by weight, about 75% by weight to about 85% by weight of at least one polymeric matrix. In a convenient embodiment, the solid dispersion comprises about 60% by weight to about 90% by weight, about 70% by weight to about 90% by weight, about 80% by weight of at least one polymeric matrix.

[00117] In one embodiment, the solid dispersion comprises a weight / weight ratio of Compound 1, or a pharmaceutically acceptable salt thereof, to at least one polymeric matrix between 1:10 and 1:1. Conveniently, the solid dispersion comprises a ratio Petition 870250094497, dated 10 / 16 / 2025, p. 48 / 194 32 / 135 weight / weight of Compound 1, or a pharmaceutically acceptable salt thereof, to at least one polymeric matrix between 1:10 and 1:2 or between 1:10 and 1:3. Conveniently, the solid dispersion comprises a weight / weight ratio of Compound 1, or a pharmaceutically acceptable salt thereof, to at least one polymeric matrix of about 1:4.

[00118] In one embodiment, at least one polymer matrix is ​​a polymer matrix. In one embodiment, at least one polymer matrix is ​​composed of two matrix polymers. In a convenient embodiment, there is only one polymer matrix present in the solid dispersion.

[00119] In one embodiment, at least one polymer matrix is ​​an ionic or neutral polymer, insoluble in water or soluble in water. In one embodiment, at least one polymer matrix is ​​a neutral polymer insoluble in water. Conveniently, at least one polymer matrix is ​​a neutral polymer soluble in water. Conveniently, at least one polymer matrix is ​​an ionic polymer soluble in water. Conveniently, at least one polymer matrix is ​​a pH-sensitive polymer. A pH-sensitive polymer exhibits aqueous solubility dependent on the pH of the aqueous medium. For example, a pH-sensitive polymer may contain acidic groups that are ionized, or partially ionized, at physiological pH, so that the polymer dissolves at that pH. In one embodiment, the pH-sensitive polymer dissolves in aqueous medium at pH above 5.5, such as above 6.0, above 6.5, or above 7.0.In one embodiment, the pH-sensitive polymer does not dissolve in aqueous medium at a pH below 5.5, such as below 6.0 or below 6.5. In another embodiment, the polymer matrix does not dissolve in aqueous medium at a pH below 6.0.

[00120] In one embodiment, at least one polymeric matrix is Petition 870250094497, dated 10 / 16 / 2025, page 49 / 194 33 / 135 an ionic polymer or a pH-sensitive polymer, optionally wherein the pH-sensitive polymer dissolves in aqueous medium at a pH above 5.5;

[00121] In one embodiment, at least one polymeric matrix is ​​selected from among a povidone polymer, a copovidone polymer, a methacrylate polymer, a polymethacrylate-based copolymer, poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol), hydroxypropylmethylcellulose, hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate.

[00122] In one embodiment, the povidone polymer is Plasdone™, such as Plasdone™ K-12, Plasdone™ K-17, Plasdone™ K-25, Plasdone™ K-29 / 32, or Plasdone™ K-90. In one embodiment, the povidone polymer is Kollidon® 30. In one embodiment, the povidone polymer is crospovidone, such as Polyplasdone™.

[00123] In one embodiment, the copovidone polymer is PVPVA64, Kollidon® VA64, Plasdone™ S-630 or Plasdone™ S-630 Ultra.

[00124] In one embodiment, the methacrylate polymer is a methacrylic acid copolymer selected from the group consisting of: a methacrylic acid copolymer, methacrylic acid-methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, ammonium methacrylate copolymer and aminoalkyl methacrylate copolymer. In certain embodiments, the methacrylic acid copolymer is EUDRAGIT® L 100 or EUDRAGIT® L 12.5 (also referred to as or conforming to: Methacrylic acid copolymer, type A; Methacrylic acid-methyl methacrylate copolymer (1:1); Methacrylic acid copolymer L; DMF 1242 or PR-MF 6918); EUDRAGIT® S 100 and EUDRAGIT® S 12.5 (also known as or conforming to: Methacrylic acid copolymer, type B; Methacrylic acid-methyl methacrylate copolymer (1:2); Methacrylic acid copolymer S; DMF 1242 or PR-MF 6918); EUDRAGIT® L 100-55 (also known as Petition 870250094497, dated 10 / 16 / 2025, page 50 / 194 34 / 135 known as, or conforming to: Methacrylic acid copolymer, type C; Methacrylic acid-ethyl acrylate copolymer (1:1) type A; Dry methacrylic acid copolymer LD; or DMF 2584); EUDRAGIT® L 30 D-55 (also known as, or conforming to: Methacrylic acid copolymer dispersion; Methacrylic acid-ethyl acrylate copolymer dispersion (1:1) 30 percent; Methacrylic acid copolymer LD; JPE DMF 2584; PR-MF 8216); EUDRAGIT® FS 30 D (also known as DMF 13941 or DMF 2006-176); EUDRAGIT® RL 100 (also known as, or conforming to: Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); Aminoalkyl methacrylate copolymer RS; DMF 1242 or PR-MF 6918); EUDRAGIT® RL PO (also known as, or conforming to: Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); Aminoalkyl methacrylate copolymer RS; DMF 1242);EUDRAGIT® RL 12.5 (also known as, or conforming to: Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); DMF 1242 or PR-MF 6918); EUDRAGIT® L 100-55 (also known as, or conforming to: Methacrylic acid copolymer, type C; Methacrylic acid-ethyl acrylate copolymer (1:1) type A; Dry methacrylic acid copolymer LD; DMF 2584); EUDRAGIT® L 30 D-55 (also known as, or conforming to: Methacrylic acid copolymer NF; Methacrylic acid-ethyl acrylate copolymer dispersion (1:1) 30 percent; Methacrylic acid copolymer LD; DMF 2584 or PR-MF 8216); EUDRAGIT® FS 30 D (also known as, or conforming to: DMF 13941 or DMF 2006-176); EUDRAGIT® RL 100 (also known as, or conforming to: Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); Ammonium methacrylate copolymer; Petition 870250094497, dated 10 / 16 / 2025, page 51 / 194 35 / 135 non-alkyl methacrylate RS; DMF 1242; or PR-MF 6918); EUDRAGIT® RL PO (also known as, or conforming to: Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); Aminoalkyl methacrylate copolymer RS; or DMF 1242); EUDRAGIT® RL 12.5 (also known as, or conforming to: polymer conforming to Ammonium methacrylate copolymer, type A; Ammonium methacrylate copolymer (type A); DMF 1242 or PR-MF 6918); EUDRAGIT® RL 30 D (also known as, or conforming to: Ammonium methacrylate copolymer dispersion, type A; Ammonium methacrylate copolymer (type A); or DMF 1242); EUDRAGIT® RS 100 (also known as, or conforming to: Ammonium methacrylate copolymer, type B; NF Ammonium methacrylate copolymer (type B); RS aminoalkyl methacrylate copolymer; DMF 1242 or PR-MF 6918); EUDRAGIT® RS PO (also known as, or conforming to: Ammonium methacrylate copolymer, type B;Ammonium methacrylate copolymer (type B); Aminoalkyl methacrylate copolymer RS; or DMF 1242); EUDRAGIT® RS 12.5 (also known as, or conforming to: Ammonium methacrylate copolymer, type B; the NF polymer conforms to Ammonium methacrylate copolymer (type B); DMF 1242 or PR-MF 6918); EUDRAGIT® RS 30 D (also known as, or conforming to: Ammonium methacrylate copolymer dispersion, type B; the NF polymer conforms to Ammonium methacrylate copolymer (type B); or DMF 1242); EUDRAGIT® E 100 (also known as, or conforming to: Amino methacrylate copolymer; NF Basic butylated methacrylate copolymer; Aminoalkyl methacrylate copolymer E; DMF 1242 or PR-MF 6918); EUDRAGIT® E PO (also known as, or conforming to: Amino methacrylate copolymer; Petition 870250094497, dated 10 / 16 / 2025, page 52 / 194 36 / 135 Aminoalkyl methacrylate copolymer E; Amino methacrylate copolymer; DMF 1242); EUDRAGIT® E 12.5 (also known as, or conforming to: Amino methacrylate copolymer; Basic butyl methacrylate copolymer; DMF 1242 or PR-MF 6918); EUDRAGIT® NE 30 D (also known as, or conforming to: Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion; Polyacrylate Dispersion 30%; (Poly(ethyl acrylate-methyl methacrylate) Dispersion 30%); 2822 or PR-MF 6918); EUDRAGIT® NE 40 D (also known as, or conforming to: DMF 2822); EUDRAGIT® NM 30 D (also referred to as Polyacrylate Dispersion 30%; (Poly(ethylacrylatemethylmethacrylate) 30% Dispersion); or DMF 2822; PLASTOID® B (also referred to as, or in accordance with: DMF 12102), or similar.

[00125] In certain embodiments, the methacrylate polymer is a poly(methacrylic-co-methyl methacrylate) acid.

[00126] In certain embodiments, the methacrylate polymer is EUDRAGIT® L100, EUDRAGIT® L100-55 or an equivalent.

[00127] In certain embodiments, the methacrylate polymer is a 1:1 anionic copolymer of methacrylic acid-methyl methacrylate with CAS number 25086-15-1.

[00128] In certain embodiments, the methacrylate polymer is an anionic copolymer of methacrylic acid-methyl methacrylate 1:1 that dissolves in water above pH 6, having an average molecular mass of approximately 125,000 g / mol.

[00129] In certain embodiments, the methacrylate polymer is an anionic copolymer of methacrylic acid-methyl methacrylate 1:1, with CAS number 25086-15-1, which dissolves in water with a pH above 6, with an average molecular mass of approximately 125,000 g / mol.

[00130] In one embodiment, poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol) is Soluplus®. Petition 870250094497, dated 10 / 16 / 2025, page 53 / 194 37 / 135

[00131] In one embodiment, hydroxypropyl methylcellulose (HPMC) has about 29% methoxyl groups and about 8.5% hydroxypropyl groups. In one embodiment, hydroxypropyl methylcellulose is HPMC E5LV, such as METHOCEL™ E5LV.

[00132] In a convenient embodiment, at least one polymeric matrix is ​​selected from copovidone polymer, poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol), hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate.

[00133] In a convenient embodiment, at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate, EUDRAGIT® L 100, EUDRAGIT® E 100, PVP-VA64, HPMC E3 and Soluplus®. In a convenient embodiment, at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate, EUDRAGIT® L 100, PVP-VA64, HPMC E3 and Soluplus®. Conveniently, at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate and Soluplus®.

[00134] In a convenient embodiment, at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate.

[00135] Certain polymeric matrices (e.g., HPMCAS) have been shown to be particularly advantageous in terms of providing solid dispersions. In one convenient embodiment, at least one polymeric matrix is ​​hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[00136] In one convenient embodiment, hydroxypropylmethylcellulose succinate acetate dissolves in aqueous medium at pH above 5.5, pH above 6.0, or pH above 6.5. In another embodiment, hydroxypropylmethylcellulose succinate acetate does not dissolve in aqueous medium at pH below 6.0 or pH below 6.5. In one embodiment Petition 870250094497, dated 10 / 16 / 2025, page 54 / 194 38 / 135 In a convenient embodiment, hydroxypropylmethylcellulose succinate acetate does not dissolve in aqueous medium at a pH below 5.5. In a convenient embodiment, hydroxypropylmethylcellulose succinate acetate does not dissolve in aqueous medium at a pH below 6.0.

[00137] In a convenient embodiment, hydroxypropylmethylcellulose succinate acetate exhibits: i. an acetyl content of 5 to 9% by weight / weight and a succinoyl content of 14 to 18% by weight / weight; ii. an acetyl content of 7 to 11% w / w and a succinoyl content of 10 to 14% w / w; or iii. an acetyl content of 10 to 14% w / w and a succinoyl content of 4 to 8% w / w.

[00138] In a more convenient embodiment, hydroxypropylmethylcellulose succinate acetate has an acetyl content of 7 to 11% w / w and a succinoyl content of 10 to 14% w / w.

[00139] In a more convenient embodiment, hydroxypropylmethylcellulose succinate acetate has an acetyl content of 10 to 14% w / w and a succinoyl content of 4 to 8% w / w.

[00140] In one embodiment, at least one polymer matrix is ​​HPMCAS-L, HPMCAS-M, or HPMCAS-H. Conveniently, at least one polymer matrix is ​​HPMCAS-M. Conveniently, at least one polymer matrix is ​​HPMCAS-L. Most conveniently, at least one polymer matrix is ​​HPMCAS-H.

[00141] In one embodiment, hydroxypropylmethylcellulose succinate acetate has an average molecular weight of about 15,000 to 25,000, as well as about 17,000 to 20,000.

[00142] The solid dispersions of the present invention exhibit good stability. Therefore, in one embodiment, the solid dispersion is stable for at least four weeks, as well as for at least eight or twelve weeks. In this context, 'stable' refers to stability. Petition 870250094497, dated 10 / 16 / 2025, p. 55 / 194 39 / 135 physical and / or chemical performance of Compound 1 or of a pharmaceutically acceptable salt thereof within the solid dispersion. Evidence of maintenance of the dissolution profile or pharmacokinetics of the solid dispersion during the mentioned storage period may serve as an indicator of stability.

[00143] Physical stability refers to the maintenance of Compound 1 or a pharmaceutically acceptable salt thereof in the same physical form; when the solid dispersion is a substantially amorphous solid dispersion, the amount of crystalline Compound 1 or a pharmaceutically acceptable salt thereof does not increase significantly during the mentioned storage period; when the solid dispersion is an amorphous solid dispersion, no crystallization (or a very low level of) of Compound 1 or a pharmaceutically acceptable salt thereof is observed during the mentioned storage period. Therefore, in one embodiment, the solid dispersion does not exhibit crystalline peaks of Compound 1 or a pharmaceutically acceptable salt thereof by XRPD when stored for at least four weeks, as well as for at least eight or twelve weeks, as well as for at least twenty-four or thirty-six weeks.In one embodiment, the solid dispersion does not exhibit crystalline peaks by XRPD when stored for at least four weeks, as well as for at least eight or twelve weeks at 25°C and 60% relative humidity (RH). In one embodiment, the solid dispersion does not exhibit crystalline peaks by XRPD when stored for at least twenty-four or thirty-six weeks at 25°C and 60% RH. In one embodiment, the solid dispersion does not exhibit crystalline peaks by XRPD when stored for at least four weeks, as well as for at least eight or twelve weeks at 40°C and 75% RH. In one embodiment, the solid dispersion does not exhibit crystalline peaks by XRPD when stored for at least twenty-four or thirty weeks. Petition 870250094497, dated 10 / 16 / 2025, p. 56 / 194 40 / 135 and six weeks at 40°C and 75% relative humidity.

[00144] Chemical stability is related to the low levels of impurities formed during the mentioned storage period. Typically, these are impurities related to Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the solid dispersion exhibits total impurities by HPLC of less than 2.5%, such as less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5%, when stored for at least four weeks, as well as for at least eight or twelve weeks at 25°C and 60% relative humidity (RH).

[00145] The moisture content of the solid dispersion can influence the dissolution profile or pharmacokinetics of the solid dispersion. The water content of the solid dispersion can be determined by several methods evident to a person skilled in the art, such as Karl Fischer titration. In one embodiment, the solid dispersion has a water content of less than 5% by weight, such as less than 4% by weight, less than 3% by weight, less than 2% by weight, or less than 1.5% by weight.

[00146] Solid dispersions according to the present invention can be produced by techniques such as spray drying, hot melt extrusion or solvent granulation. In a convenient embodiment, the solid dispersion is a spray-dried solid dispersion.

[00147] To facilitate the formation of the solid dispersion or to improve the stability of the solid dispersion, additional excipients may also be present in the solid dispersion. In one embodiment, the solid dispersion further comprises one or more excipients selected from the group consisting of a surfactant (such as sodium lauryl sulfate, polysorbates and sorbitan esters), a diluent, a binder, an adsorbent (such as colloidal silica), a lubricant, a disintegrant, a drying agent, a pH modifier, a former of Petition 870250094497, dated 10 / 16 / 2025, page 57 / 194 41 / 135 salt, a complexing agent and a glidant.

[00148] In one embodiment, the solid dispersion does not contain a plasticizer. In another embodiment, the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix, but does not contain any additional excipients.

[00149] In one embodiment, the solid dispersion has a particle size distribution comprising 90% (Dv(90)) of the dispersion with a size of 250 μm or less, such as 150 μm, 75 μm, 50 μm, 35 μm, or 20 μm, or less. The skilled person will be aware of suitable techniques, such as laser diffraction, as described in the Examples section, which can be used to determine the particle size and particle size distribution of the solid dispersion material.

[00150] The present description provides pharmaceutical compositions comprising a solid dispersion of Compound 1 or a pharmaceutically acceptable salt thereof with at least one polymeric matrix, as discussed herein. In general, pharmaceutical compositions can be formed by combining a solid dispersion of the description with at least one excipient. The resulting pharmaceutical composition can then be formed into a unit dosage form. Therefore, a pharmaceutical composition comprising a solid dispersion, as described in this document, and further comprising one or more pharmaceutically acceptable excipients is provided.

[00151] In one embodiment, the pharmaceutical composition comprises a surfactant. In one embodiment, the surfactant is a non-ionic surfactant. In one embodiment, the surfactant is an ionic surfactant. In one embodiment, the surfactant is selected from benzylkonium chloride, benzethonium chloride, cetylpyridinium chloride, poloxa Petition 870250094497, dated 10 / 16 / 2025, page 58 / 194 42 / 135 mero 188, poloxamer 407, polyoxyl stearate, polysorbates, sodium lauryl sulfate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate and Vitamin E TPGS. Conveniently, the surfactant is sodium lauryl sulfate. Conveniently, the surfactant is present at 0.25-2.0% by weight, as approximately 1% by weight, of the pharmaceutical composition.

[00152] In one embodiment, the pharmaceutical composition further comprises a crystallization inhibitor. The crystallization inhibitor may retard or prevent the nucleation of crystalline Compound 1 or a pharmaceutically acceptable salt thereof and may function to stabilize the amorphous state of the solid dispersion and help maintain Compound 1 in solution.

[00153] The crystallization inhibitor may be (i) a surfactant, as described above; (ii) a cellulose ether, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose, hydroxyethylcellulose and hydroxyethylethylcellulose; or (iii) a copovidone polymer, such as PVP-VA64. In one embodiment, the crystallization inhibitor is hydroxypropylmethylcellulose.

[00154] In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from a filler, a diluent, a binder, a disintegrant, a lubricant and a glide agent.

[00155] Examples of pharmaceutically acceptable fillers or diluents include lactose, sugar, corn starch, microcrystalline cellulose, mannitol, calcium phosphate, sorbitol, and glycine. In one embodiment, the filler or diluent is selected from lactose, microcrystalline cellulose, and mannitol; conveniently, microcrystalline cellulose and mannitol. Conveniently, each filler or diluent is present at 5-30% by weight of the pharmaceutical composition, conveniently at 5-15% by weight of the pharmaceutical composition. Petition 870250094497, dated 10 / 16 / 2025, page 59 / 194 43 / 135

[00156] Examples of pharmaceutically acceptable binders include hydroxypropylcellulose, hypromellose, povidone, starch, methylcellulose, gelatin, pregelatinized starch, and xanthan gum.

[00157] Examples of pharmaceutically acceptable disintegrants include crospovidone, croscarmellose, sodium starch glycolate, and slightly substituted hydroxypropylcellulose; conveniently, the disintegrant is croscarmellose sodium. Conveniently, the disintegrant is present at 1.0-5.0% by weight, such as 2.0-4.0% by weight, of the pharmaceutical composition.

[00158] 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. Conveniently, the lubricant is present at 0.5-2.0% by weight, such as 1.0-2.0% by weight, of the pharmaceutical composition.

[00159] Examples of pharmaceutically acceptable glide agents include colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch, and talc; conveniently, the glide agent is colloidal silicon dioxide. Conveniently, the glide agent is present at 0.5-2.0% by weight, such as 1.0-2.0% by weight, of the pharmaceutical composition.

[00160] In one embodiment, the pharmaceutical composition is in a unit dosage form comprising from about 1 mg to about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[00161] In one embodiment, the pharmaceutical composition is in a unit dosage form suitable for oral administration. In another embodiment, the pharmaceutical composition is in a unit dosage form selected from the group consisting of a granule. Petition 870250094497, dated 10 / 16 / 2025, page 60 / 194 44 / 135 lo, a pellet, a tablet, a particle, a capsule, a suspension and a mini-tablet. Tablets

[00162] Conveniently, the pharmaceutical compositions of the present invention can be formulated as tablets for oral administration.

[00163] Tablets may include pills, tablets, mini-tablets, micro-tablets and / or orally disintegrating tablets. The tablets of the present invention may have any shape or size. In one 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 another embodiment, the pharmaceutical composition is a tablet with a total weight of 250-500 mg, conveniently 300-500 mg, such as about 400 mg.

[00164] In one embodiment, the tablet comprises 50-70% by weight of the solid dispersion according to the present invention. Conveniently, the tablet comprises 55-65% by weight of the solid dispersion according to the present invention.

[00165] It should be understood that, in the present context, the % by weight or % by weight values ​​specified herein for tablet pharmaceutical forms refer to the percentage by weight of an ingredient in the tablet core, therefore excluding any outer coatings or films.

[00166] In one embodiment, the tablet disintegrates in less than 15 minutes when tested in water at 37°C, according to the USP disintegration test protocol. In another embodiment, the tablet disintegrates in less than 10 minutes, such as less than 7 minutes or less than 5 minutes, when tested in 0.01 N hydrochloric acid (SGF) at 37°C, according to the disintegration test protocol. Petition 870250094497, dated 10 / 16 / 2025, page 61 / 194 45 / 135 USP recording.

[00167] The tablet compositions according to the present invention comprise a solid dispersion and, optionally, one or more pharmaceutically acceptable excipients.

[00168] In one embodiment, one or more pharmaceutically acceptable excipients are selected from among a filler, a diluent, a binder, a surfactant, a disintegrant, a lubricant, a glide agent, and a crystallization inhibitor. Conveniently, one or more pharmaceutically acceptable excipients are selected from among a filler, a diluent, a disintegrant, a lubricant, and a glide agent.

[00169] In one embodiment, the pharmaceutical composition of the tablet comprises a surfactant. In one embodiment, the surfactant is a non-ionic surfactant. In one embodiment, the surfactant is an ionic surfactant. In one embodiment, the surfactant is selected from benzylkonium chloride, benzethonium chloride, cetylpyridinium chloride, poloxamer 188, poloxamer 407, polyoxyl stearate, polysorbates, sodium lauryl sulfate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, and Vitamin E TPGS. Conveniently, the surfactant is sodium lauryl sulfate. Conveniently, the surfactant is present at 0.25-2.0% by weight, as about 1% by weight, of the tablet.

[00170] In one embodiment, the pharmaceutical composition of the tablet further comprises at least one pharmaceutically acceptable filler or diluent. In one embodiment, the filler or diluent is selected from lactose, sugar, corn starch, microcrystalline cellulose, mannitol, calcium phosphate, sorbitol, and glycine. In another embodiment, the filler or diluent is selected from lactose, microcrystalline cellulose, and mannitol, conveniently microcrystalline cellulose and mannitol. Conveniently, each filler or diluent Petition 870250094497, dated 10 / 16 / 2025, page 62 / 194 46 / 135 is present in 5-30% by weight of the tablet, conveniently in 5-15% by weight of the tablet.

[00171] In one embodiment, the pharmaceutical composition of the tablet further comprises a pharmaceutically acceptable disintegrant. Examples of pharmaceutically acceptable disintegrants include crospovidone, croscarmellose, sodium starch glycolate, and slightly substituted hydroxypropylcellulose; conveniently, the disintegrant is croscarmellose sodium. Conveniently, the disintegrant is present at 1.0-5.0% by weight, such as 2.0-4.0% by weight, of the tablet.

[00172] In one embodiment, the pharmaceutical composition of the tablet further comprises a pharmaceutically acceptable lubricant. 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. Conveniently, the lubricant is present at 0.5-2.0% by weight, such as 1.0-2.0% by weight, of the tablet.

[00173] In one embodiment, the pharmaceutical composition of the tablet further comprises a pharmaceutically acceptable glide agent. Examples of pharmaceutically acceptable glide agents include colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch, and talc; conveniently, the glide agent is colloidal silicon dioxide. Conveniently, the glide agent is present at 0.5-2.0% by weight, such as 1.0-2.0% by weight, of the tablet.

[00174] When formed by compression, the tablet conveniently has a resistance of at least 5 kiloponds (kp) / cm2 and, more preferably, at least 7 kp / cm2. In this case, resistance is the fracture strength, also known as the hardness of the tablet. Petition 870250094497, dated 10 / 16 / 2025, page 63 / 194 47 / 135 tablet, required to fracture a tablet formed from the materials, divided by the maximum cross-sectional area of ​​the tablet normal to that force. The compressive strength required to achieve this strength will depend on several factors, such as the size of the tablet, but generally the strength will be greater than about 5 kp / cm2. In a convenient embodiment, the tablets have a strength of about 10-25 kp / cm2.

[00175] Optionally, the tablet may be coated by methods well known in the art. The coating may be pH-independent (such as sealant coatings or film coatings) or pH-dependent (such as enteric coatings or modified-release coatings). In Vitro Dissolution

[00176] To simulate oral administration, the solid dispersions and pharmaceutical compositions of the present invention can be tested in a two-stage biorelevant dissolution method. The method comprises an initial acidic phase (0-30 minutes) conducted at pH 2 using simulated gastric fluid, followed by a subsequent neutral phase (30-210 minutes) conducted at pH 6.8 using 0.1 M pH 6.8 buffered FaSSIF medium containing 2.24 mg / mL of FaSSIF powder. Pharmacokinetics

[00177] As mentioned previously, the compositions of the present invention have been found to be particularly advantageous for improving the bioavailability of Compound 1 or a pharmaceutically acceptable salt thereof. The compositions of the invention offer the benefit of immediate drug release to achieve effective antiviral levels, followed by prolonged drug release to provide high plasma levels for extended periods.

[00178] Advantageously, certain compositions of the present invention may exhibit high and / or equivalent, or superior, bioavailability. Petition 870250094497, dated 10 / 16 / 2025, p. 64 / 194 48 / 135 or, oral solutions. Therefore, in one embodiment, a pharmaceutical composition is provided as described herein, wherein the composition exhibits a bioavailability relative to an oral solution greater than 50%, such as greater than 70%, greater than 80%, greater than 90%, or greater than 100%.

[00179] Advantageously, certain compositions of the present invention may exhibit low pharmacokinetic variability in plasma concentrations after administration. Advantageously, certain compositions of the present invention may exhibit reduced pharmacokinetic variability when compared to oral solutions, even at high doses.

[00180] In certain embodiments, the compositions of the present invention may exhibit low pharmacokinetic variability in plasma concentrations of Compound 1 after oral administration to an individual, despite variations in the individual's gastric pH, such as variations from pH 1 to pH 7.

[00181] It has also been surprisingly discovered that certain compositions of the present invention are capable of providing higher plasma levels of Compound 1 for a prolonged period when administered in conjunction with food intake. Thus, in some embodiments, the compositions of the present invention are administered in conjunction with food intake. Particular Compositions of the Invention

[00182] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix, and wherein the solid dispersion comprises amorphous Compound 1 or a pharmaceutically acceptable salt thereof in an amorphous polymeric matrix. Conveniently, Compound 1 is present in Petition 870250094497, dated 10 / 16 / 2025, p. 65 / 194 49 / 135 solid dispersion in its neutral free form. More conveniently, the solid dispersion is a spray-dried solid dispersion.

[00183] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1 and at least one polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the solid dispersion comprises: a) approximately 10% by weight to approximately 30% by weight of Compound 1; and b) about 60% by weight to about 90% by weight or about 70% by weight to about 90% by weight of at least one polymeric matrix.

[00184] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1 and at least one polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the solid dispersion comprises: a) approximately 30% by weight to approximately 60% by weight of Compound 1; and b) approximately 40% by weight to approximately 70% by weight of at least one polymeric matrix.

[00185] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein a) the solid dispersion comprises Compound 1 and at least one polymeric matrix; b) the solid dispersion is an amorphous solid dispersion; and (c) The solid dispersion comprises a weight / weight ratio of Compound 1 to at least one polymeric matrix between 1:10 and 1:2. Petition 870250094497, dated 10 / 16 / 2025, page 66 / 194 50 / 135

[00186] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the at least one polymeric matrix is ​​a water-soluble ionic or neutral polymer.

[00187] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the at least one polymeric matrix is: i. an ionic polymer or a pH-sensitive polymer, optionally wherein the pH-sensitive polymer dissolves in aqueous medium at a pH above 5.5; ii. selected from a povidone polymer, a copovidone polymer, a methacrylate polymer, a polymethacrylate-based copolymer, poly(vinyl caprolactam-co-vinyl acetate-coethylene glycol), hydroxypropylmethylcellulose, hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate; iii. selected from a copovidone polymer, poly(vinyl caprolactam-co-vinyl acetate-co-ethylene glycol), hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate; or iv. selected from hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate.

[00188] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polyethylene matrix. Petition 870250094497, dated 10 / 16 / 2025, page 67 / 194 51 / 135 meric, wherein the solid dispersion is an amorphous solid dispersion, and wherein at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose acetate succinate, EUDRAGIT® L 100, PVPVA64, HPMC E3 and Soluplus®. Conveniently, Compound 1 is present in the solid dispersion in its neutral free form. More conveniently, the solid dispersion is a spray-dried solid dispersion.

[00189] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, and a polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate, EUDRAGIT® L 100, PVP-VA64, HPMC E3 and Soluplus®. Conveniently, the polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate and Soluplus®.

[00190] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises Compound 1, and a polymeric matrix, wherein the solid dispersion is an amorphous solid dispersion, and wherein the polymeric matrix is ​​selected from HPMCAS-H and Soluplus®. Conveniently, the solid dispersion is a spray-dried solid dispersion.

[00191] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion (such as a spray-dried solid dispersion), wherein a) the solid dispersion comprises Compound 1 and at least one polymeric matrix; b) the solid dispersion is an amorphous solid dispersion; c) the solid dispersion comprises a weight / weight ratio of Compound 1 to at least one polymeric matrix between 1:10 and Petition 870250094497, dated 10 / 16 / 2025, page 68 / 194 52 / 135 1:2; and d) at least one polymeric matrix is ​​hydroxypropylmethylcellulose acetate succinate.

[00192] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion (such as a spray-dried solid dispersion), wherein a) the solid dispersion comprises Compound 1 and at least one polymeric matrix; b) the solid dispersion is an amorphous solid dispersion; c) the solid dispersion comprises a weight / weight ratio of Compound 1 to at least one polymeric matrix between 1:10 and 1:2; and d) at least one polymer matrix is ​​Soluplus®.

[00193] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a solid dispersion (such as a spray-dried solid dispersion), wherein: a) the solid dispersion comprises Compound 1 and a polymeric matrix; b) the solid dispersion is an amorphous solid dispersion; c) the polymeric matrix is ​​an ionic or neutral polymer that is either insoluble in water or soluble in water (conveniently, the polymeric matrix is ​​selected from hydroxypropylmethylcellulose acetate succinate, EUDRAGIT® L 100, PVP-VA64, HPMC E3, and Soluplus®); and (d) The solid dispersion further comprises one or more excipients selected from the group comprising a surfactant (such as sodium lauryl sulfate), a diluent (such as lactose, microcrystalline cellulose and / or mannitol), a binder, a lubricant (such as magnesium stearate), a disintegrant (such as croscarmellose sodium), a drying agent, a pH modifier, a salt former, a complexing agent and a glidant (such as colloidal silicon dioxide). Petition 870250094497, dated 10 / 16 / 2025, page 69 / 194 53 / 135

[00194] In one embodiment, the present invention provides a pharmaceutical composition for oral tablets comprising a solid dispersion (such as a spray-dried solid dispersion), wherein: a) the solid dispersion comprises Compound 1 and at least one polymeric matrix; b) the solid dispersion is an amorphous solid dispersion; c) the solid dispersion comprises a weight / weight ratio of Compound 1 to at least one polymeric matrix between 1:10 and 1:2; and (d) The pharmaceutical composition for oral tablets further comprises at least one or more pharmaceutically acceptable excipients selected from a bulking agent, a diluent, a surfactant, a disintegrant, a lubricant and a glidant.

[00195] Conveniently, at least one or more pharmaceutically acceptable excipients selected in the pharmaceutical composition for oral tablets comprise: a) a surfactant selected from benzylkonium chloride, benzethonium chloride, cetylpyridinium chloride, poloxamer 188, poloxamer 407, polyoxyl stearate, polysorbates, sodium lauryl sulfate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate and Vitamin E TPGS; b) at least one pharmaceutically acceptable filler or diluent selected from lactose, sugar, corn starch, microcrystalline cellulose, mannitol, calcium phosphate, sorbitol and glycine; c) a pharmaceutically acceptable disintegrant selected from crospovidone, croscarmellose, sodium starch glycolate and slightly substituted hydroxypropylcellulose; Petition 870250094497, dated 10 / 16 / 2025, page 70 / 194 54 / 135 (d) a pharmaceutically acceptable lubricant selected from magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, sodium stearyl fumarate, mineral oil, hydrogenated vegetable oil, and polyethylene glycol; and (e) a pharmaceutically acceptable glide selected from colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, starch and talc. Preparation of Compositions

[00196] In a second aspect, the present invention provides a method for forming a pharmaceutical composition according to the first aspect.

[00197] The compositions according to the present invention comprise a solid dispersion and, optionally, one or more pharmaceutically acceptable excipients. The solid dispersion can be formed by any known technique. It should be noted that the solid dispersions of the present invention can be prepared by methods such as spray drying, melt extrusion, coprecipitation, solvent-controlled coprecipitation, lyophilization, kneading technique, co-molding, gel trapping, electrospinning and / or centrifugal coating. In certain embodiments (such as spray drying), the compounds and at least one polymeric matrix are dissolved in a solvent to form a mixture, and the solvent is evaporated to form a solid dispersion. In certain embodiments (such as hot melt extrusion), the solid dispersion is formed without the use of solvents.

[00198] In one aspect of the second modality, the method comprises the following steps: i) combine Compound 1, or a pharmaceutically acceptable salt thereof, and at least one polymeric matrix in a solvent to form a mixture; Petition 870250094497, dated 10 / 16 / 2025, page 71 / 194 55 / 135 ii) dry the mixture to form a solid dispersion; and iii) optionally, combine the solid dispersion with one or more pharmaceutically acceptable excipients selected from a filler, a diluent, a binder, a surfactant, a disintegrant, a lubricant, a glide agent and a crystallization inhibitor.

[00199] In one embodiment, the solvent in step i) is an organic solvent. In another embodiment, the solvent in step i) is a combination of water and an organic solvent.

[00200] Organic solvents may include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. Supercritical carbon dioxide may also be used as a solvent, or supercritical carbon dioxide may be used with an organic co-solvent such as acetone, methanol, ethanol, and / or acetonitrile. Preferred organic solvents are methanol, acetone, tetrahydrofuran, ethyl acetate, methylene chloride, and mixtures thereof. In one embodiment, the organic solvent is a water-miscible organic solvent, such as methanol, ethanol, n-propanol, isopropanol, acetone, or acetonitrile. In another embodiment, the organic solvent is acetone. In another embodiment, the solvent in step i) is a combination of water and a water-miscible organic solvent.In one embodiment, the solvent in step i) is a combination of water and acetone. In another embodiment, the solvent in step i) is a combination of water and acetone in a v / v ratio between 1:99 and 30:70, such as between 1:99 and 10:90, or approximately 5:95.

[00201] At least one polymeric matrix in step i) is selected from one or more of the polymers described herein for the compositions according to the first aspect of the invention. In a fashion Petition 870250094497, dated 10 / 16 / 2025, page 72 / 194 56 / 135 In this embodiment, at least one polymeric matrix is ​​selected from hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate. In one embodiment, at least one polymeric matrix is ​​hydroxypropylmethylcellulose succinate acetate.

[00202] In one embodiment, in step (i), about 1 to 60% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, is combined with about 30 to 95% by weight of at least one polymeric matrix.

[00203] In one embodiment, the solids content of the atomizing solution is between 2 and 20% by weight.

[00204] In certain embodiments, a surfactant is added to the mixture in step i). For example, a surfactant such as sodium lauryl sulfate (SLS), polysorbates or sorbitan esters may be added.

[00205] In certain embodiments, one or more additional excipients are added to the mixture in step i). Suitable excipients may include crystallization inhibitors, glidants, disintegrants, pH modifiers, salt formers, or complexing agents. In one embodiment, the glidant is colloidal silicon dioxide.

[00206] After at least a portion of Compound 1 and at least one polymeric matrix have been dissolved, the solvent can be removed in step ii) by evaporation or by mixing with a non-solvent. Exemplary processes are spray drying, spray coating (e.g., pan coating and fluidized bed coating), and precipitation by rapid mixing of the compound and the polymer mixture with carbon dioxide (CO2), hexane, heptane, water with appropriate pH, or some other non-solvent.

[00207] Preferably, solvent removal in step ii) results in a substantially homogeneous solid dispersion. To achieve this objective, it is generally desirable to rapidly remove the solvent from the solution, such as in a process where the solution is atomized, and the Petition 870250094497, dated 10 / 16 / 2025, page 73 / 194 57 / 135 compound and the polymer dispersion solidify rapidly.

[00208] In certain embodiments, the solvent can be removed by spray drying, for example, a process involving breaking liquid mixtures into small droplets (atomization) and rapidly removing the solvent from the mixture in a spray drying apparatus, where there is a strong driving force for the evaporation of the solvent from the droplets. Spray drying processes and equipment are described in general in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition, 1984). Further details on spray drying processes and equipment are reviewed by Marshall, Atomization and Spray-Drying, 50 Chem. Eng. Prog. Monogr. Series 2 (1954) and Masters, Spray Drying Handbook (Fourth Edition, 1985). The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the drying droplet temperature.This can be accomplished by (1) maintaining the pressure in the spray drying apparatus at a partial pressure; or (2) mixing the liquid droplets with a hot drying gas; or (3) both (1) and (2). In addition, at least some of the heat required for solvent evaporation can be provided by heating the spray solution.

[00209] In a convenient embodiment, in step (ii), drying comprises spray drying.

[00210] Solvent-containing feed can be spray-dried under a wide variety of conditions and still produce solid dispersions with acceptable properties. For example, various types of nozzles can be used to atomize the spraying solution, introducing it into the spray-drying chamber as a collection of small droplets. Essentially, any type of nozzle will work. Petition 870250094497, dated 10 / 16 / 2025, page 74 / 194 58 / 135 can be used to atomize the solution, provided that the droplets formed are small enough to dry sufficiently (due to solvent evaporation) so that they do not stick to or coat the wall of the spray drying chamber.

[00211] The outlet air temperature is a parameter that can affect the morphology of the product, such as particle size, surface roughness, density, particle stickiness, residual solvent or moisture levels, product yield, etc. In one embodiment, the outlet air temperature is 30 to 50°C, such as 40 to 50°C, or about 45°C.

[00212] The atomizing solution can be supplied to the atomizing nozzle(s) over a wide range of temperatures and flow rates. Generally, the temperature of the atomizing solution can vary from slightly above the freezing point of the solvent to about 20°C above its boiling point at ambient pressure (by pressurizing the solution) and, in some cases, even higher. The flow rates of the atomizing solution to the atomizing nozzle can vary over a wide range, depending on the nozzle type, the size of the spray dryer, and the spray drying conditions, such as the inlet temperature and the drying gas flow rate. Generally, the energy for the evaporation of the solvent from the atomizing solution in a spray drying process comes mainly from the drying gas.

[00213] The drying gas can, in principle, be essentially any gas and can be an inert gas, such as nitrogen, nitrogen-enriched air, or argon. The drying gas is typically introduced into the drying chamber at a temperature between about 60°C and about 300°C and preferably between about 80°C and about 240°C. Other drying gas temperatures can also be used in the formation of solid dispersions of the present invention. Petition 870250094497, dated 10 / 16 / 2025, p. 75 / 194 59 / 135

[00214] Generally, the solvent content of the solid dispersion when exiting the spray drying chamber should be less than about 10% by weight or less than about 2% by weight.

[00215] After spray drying, a secondary drying step can be used to remove excess residual solvent, as the presence of solvents can plasticize the solid dispersion, increasing molecular mobility, and may result in the development of crystal growth. After its formation, the solid dispersion can be dried to remove residual solvent using suitable drying processes such as tray drying, vacuum drying, fluidized bed drying, microwave drying, belt drying, rotary drying, and other drying processes known in the art. Preferred secondary drying methods include vacuum drying or tray drying. To minimize chemical degradation during drying, drying can occur under an inert gas, such as nitrogen, or under vacuum.

[00216] In one embodiment, the resulting formulation is a granulate or a particulate and is combined with one or more pharmaceutically acceptable extragranular excipients, selected from a filler, a diluent, a binder, a surfactant, a disintegrant, a lubricant, a glide agent, and a crystallization inhibitor. Conveniently, the extragranular excipients are selected from a filler, a diluent, a disintegrant, a lubricant, and a glide agent.

[00217] In a convenient embodiment, the method further comprises compressing the composition into a tablet. In one embodiment, the compression force used to form the tablet is less than or equal to 100 MPa, such as less than or equal to 75 MPa.

[00218] Optionally, the tablet can be coated by method Petition 870250094497, dated 10 / 16 / 2025, page 76 / 194 60 / 135 of the well-known techniques. The coating can be pH-independent (such as sealant coatings or film coatings) or pH-dependent (such as enteric coatings or modified-release coatings).

[00219] In one embodiment, a pharmaceutical composition is provided that is obtained by, or obtainable by, a method in accordance with the second aspect of the invention.

[00220] It should be understood that the release rate of Compound 1 may vary; for example, a short initial burst of the active agent may be observed shortly after administration, followed by a period of lower release. However, prolonged release means that plasma levels of Compound 1 can be maintained at therapeutically effective plasma concentrations for most, if not all, of the prolonged release period.

[00221] In some embodiments, the compositions of the present invention are capable of providing a low initial burst and elevated, steady, and continuous plasma levels of Compound 1 for an extended period after a single oral administration, i.e., without the need for a loading dose.

[00222] Advantageously, applicants have found that the prolonged release afforded by certain compositions of the invention and the resulting continuous plasma levels at therapeutically effective concentrations over a prolonged period allow the possibility of using lower doses than those expected of Compound 1.

[00223] Advantageously, the compositions of the invention are able to maintain a therapeutically effective plasma concentration of the drug for a prolonged period.

[00224] Helicase-primase inhibitors are typically subject to binding to plasma proteins. Depending on the extent of binding to plasma proteins, the free fraction (active agent does not bind) Petition 870250094497, dated 10 / 16 / 2025, p. 77 / 194 61 / 135 of the) may be low relative to the protein-bound fraction. For example, pritelivir is typically subject to 97-98% protein binding, so the free fraction may represent only 2-3% of the total plasma concentration. In one embodiment, the plasma concentrations mentioned here refer to unbound plasma concentrations.

[00225] In one embodiment, the pharmaceutical composition according to the present invention, after oral administration to an individual requiring treatment, achieves and maintains in the individual a total geometric mean plasma concentration (bound and unbound to proteins) of Compound 1 of at least 1000 ng / mL, such as at least 1100 ng / mL, for most, if not all, of a period of at least 5 days, conveniently a period of 7 days, or even more conveniently a period of 14 days or a period of 28 days. Oral administration may initially involve regular administration, for example, by means of daily dosing for a period of 1 to 7 days, to achieve steady-state plasma concentrations.Conveniently, the pharmaceutical composition according to the present invention, after oral administration, and after eleven steady-state levels have been achieved in an individual requiring treatment, maintains in the individual a total geometric mean plasma concentration (bound and unbound to protein) of Compound 1 of at least 1100 ng / mL, for most, if not all, of a period of at least 5 days, such as a period of 7 days, conveniently a period of 14 days, and even more conveniently a period of 28 days.

[00226] In some convenient embodiments, the compositions of the present invention are capable of providing elevated, stable, and continuous plasma levels of Compound 1 for an extended period after only a single oral administration, i.e., without the need for... Petition 870250094497, dated 10 / 16 / 2025, p. 78 / 194 62 / 135 sufficiency of a loading dose. Conveniently, such a pharmaceutical composition according to the present invention, after oral administration, maintains, in an individual requiring treatment, a total geometric mean plasma concentration (unbound and protein-bound) of Compound 1 of at least 1100 ng / mL, during most, if not all, of a period of at least 5 days, such as a period of 7 days, conveniently a period of 14 days and, even more conveniently, a period of 28 days.

[00227] Conveniently, the pharmaceutical composition according to the present invention is administered every eleven weeks. Conveniently, the pharmaceutical composition according to the present invention is administered every two weeks. Conveniently, the pharmaceutical composition according to the present invention is administered every eleven months.

[00228] It has been surprisingly found that certain compositions of the present invention are capable of providing higher plasma levels of Compound 1 for a prolonged period when administered together with food intake. This allows the possibility of using lower doses of Compound 1 than expected. Thus, in some embodiments, the compositions of the present invention are administered together with food intake. Conveniently, these compositions are oral suspensions or oral tablets comprising a solid dispersion. Conveniently, these compositions are oral suspensions comprising a solid dispersion. Conveniently, these compositions are oral tablets comprising a solid dispersion. Uses and Therapeutic Applications

[00229] The present invention provides a method for treating a herpes virus infection (conveniently an HSV) in an individual in need thereof, the method comprising the administration of Petition 870250094497, dated 10 / 16 / 2025, page 79 / 194 63 / 135 Administration of a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to an individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00230] The present invention also provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof, for use as a medicament.

[00231] The present invention also provides a pharmaceutical composition according to the first aspect of the invention comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a herpes virus infection (conveniently an HSV) in an individual in need thereof.

[00232] The present invention also provides the use of a pharmaceutical composition according to the first aspect of the invention, comprising Compound 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a herpes virus infection (conveniently an HSV) in an individual in need thereof.

[00233] In a specific embodiment, the present invention provides a method for inhibiting HSV replication in an individual in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00234] In one embodiment, the present invention also provides Petition 870250094497, dated 10 / 16 / 2025, pp. 80 / 194 64 / 135 a method for reducing the likelihood or severity of symptoms of an HSV infection in an individual in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00235] In one embodiment, the present invention provides a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection in an individual in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00236] In one embodiment, the present invention provides a method for suppressing the recurrence of HSV symptoms or outbreaks in an individual in need thereof, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00237] In one embodiment, the present invention provides a pharmaceutical composition according to the first aspect of the invention, comprising Compound 1 or a pharmaceutically acceptable salt thereof for use in suppressing the recurrence of symptoms or outbreaks of HSV in an individual in need thereof.

[00238] In one embodiment, the present invention provides the Petition 870250094497, dated 10 / 16 / 2025, page 81 / 194 65 / 135 use of a pharmaceutical composition, according to the first aspect of the invention, comprising Compound 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the suppression of recurrence of symptoms or outbreaks of HSV in an individual in need thereof.

[00239] In one embodiment, the present invention provides a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection in an individual in need thereof, comprising the method administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, according to the first aspect of the invention. In a specific embodiment, the disease or disorder caused by, or associated with HSV infection, is selected from among herpes labialis (e.g., orolabial herpes labialis or Whitlow's disease), genital herpes, HSV-related keratitis, HSV-related encephalitis, pneumonia, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis, and Bell's palsy.

[00240] In a specific embodiment, the disease or disorder caused by, or associated with, HSV infection is selected from either herpes labialis (orolabial herpes labialis or Whitlow's disease) or genital herpes. In one embodiment, the disease or disorder is either recurrent herpes labialis or recurrent genital herpes. Individuals with a history of multiple recurrences of herpes labialis or recurrent genital herpes, for example, HSV that recurs six or more times a year, may be considered to have recurrent HSV.

[00241] In one modality, the herpes virus treated is HSV2. In another modality, the herpes virus to be treated is HSV2 and the individual requiring treatment has recurrent genital herpes. Petition 870250094497, dated 10 / 16 / 2025, p. 82 / 194 66 / 135 due to HSV2.

[00242] In one modality, the herpes virus being treated is HSV1. In another modality, both HSV1 and HSV2 herpes viruses are being treated.

[00243] In one embodiment, the herpes virus to be treated is resistant to nucleoside antiviral therapy. In another embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

[00244] In one embodiment, the herpes virus infection to be treated is resistant to nucleoside antiviral therapy, for example, acyclovir-resistant mucocutaneous HSV infection. In another embodiment, the HSV infection to be treated is a mucocutaneous HSV infection resistant to treatment with nucleoside analog antiviral therapy, such as acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir.

[00245] In one specific modality, the individual who needs the methods described here is immunocompromised. The individual may be immunocompromised due to conditions such as HIV infection, cancer, hematopoietic cell or solid organ transplantation, chronic use of glucocorticoids, or genetic immunodeficiency.

[00246] In one specific modality, the individual who needs the methods described here is a newborn or a child.

[00247] In one specific modality, the individual is a herpes-positive patient.

[00248] In one specific embodiment, the individual requiring the methods described herein has acyclovir-resistant mucocutaneous HSV infection. This individual may have been diagnosed with this condition based on clinical failure, for example, no improvement after oral or intravenous doses for at least 7 days with approved doses of acyclovir. Petition 870250094497, dated 10 / 16 / 2025, pp. 83 / 194 67 / 135

[00249] In one specific embodiment, the individual who needs the methods described herein has a primary genital herpes infection related to HSV. In another embodiment, the individual who needs the methods described herein has a severe or progressive genital herpes infection related to HSV.

[00250] In a specific embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce the recurrence of HSV infections (i.e., provide suppressive therapy) that cause diseases or disorders such as cold sores or genital herpes. In one embodiment, the reduction in the number of lesion recurrences over a year can be reduced by 20, 30, 40, 50, 75, 90, or 95% or more. Conveniently, the lesion rate over a year can be reduced by 90% or more.

[00251] In a specific embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce the duration of recurrent episodes of HSV infection, for example, by one or more days, for example, at least 2, 3, 4, 5, 14, 21 or 28 days.

[00252] In a specific embodiment, pharmaceutical compositions according to the first aspect of the invention can reduce the healing time of lesions (e.g., the total recovery time of lesions) and the duration of symptoms resulting from HSV infections in diseases or disorders such as cold sores or genital herpes. The lesion healing time can be defined as the complete epithelialization of the HSV mucocutaneous lesion(s) within the treatment period and the absence of the appearance of new lesions, for example, as assessed by a physician.

[00253] In a specific embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce pain or the intensity of pain (for example, at the site of the injury) caused Petition 870250094497, dated 10 / 16 / 2025, p. 84 / 194 68 / 135 as a consequence of HSV infections in diseases or disorders, such as cold sores or genital herpes.

[00254] In a specific embodiment, the pharmaceutical compositions according to the first aspect of the invention can reduce viral shedding or reduce the viral shedding rate in individuals with frequent recurrent HSV, for example, genital HSV type 2. For example, the mucocutaneous shedding rate of genital HSV in an individual can be measured by collecting skin and mucosal swabs and, for HSV detection, for example, by analyzing HSV DNA samples with a quantitative real-time fluorescent polymerase chain reaction (PCR) assay. The frequency of HSV2 detection (viral shedding rate) can be defined as the number of days with a genital swab positive for HSV divided by the total number of days on which genital swabs were obtained. The reduction in the HSV shedding rate among individuals who received the compositions of the invention relative to the shedding rate among individuals who received placebo or other treatments can be compared.The amount of HSV in positive swabs and the frequency of genital lesions and elimination episodes can also be monitored.

[00255] In a specific embodiment, the present invention provides a method for reducing (or suppressing or substantially eliminating) the shedding of HSV by rupture in an individual who needs it, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00256] In one embodiment, the present invention provides a pharmaceutical composition according to the first aspect of the invention. Petition 870250094497, dated 10 / 16 / 2025, p. 85 / 194 69 / 135 tion, comprising Compound 1 or a pharmaceutically acceptable salt thereof, for use in reducing (or substantially suppressing or eliminating) the shedding of HSV by rupture in an individual requiring it.

[00257] In one embodiment, the present invention provides the use of a pharmaceutical composition according to the first aspect of the invention, comprising Compound 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the reduction (or suppression or substantial elimination) of HSV shedding by rupture in an individual in need thereof.

[00258] In a specific embodiment, the present invention provides a method for preventing the transmission of an infectious disease caused by HSV, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00259] In a specific embodiment, the present invention provides a method for reducing the side effects observed when Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally to an individual with an infectious disease caused by HSV, the method comprising administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00260] For use in accordance with the present invention, the appropriate dosage is expected to vary depending, for example, on the nature Petition 870250094497, dated 10 / 16 / 2025, page 86 / 194 70 / 135 za and severity of the infection to be treated and is within the competence of the physician responsible for the treatment. Normally, the indicated administration dose may be in the range of about 0.1 to about 1000 μg / kg of body weight. In some cases, the administration dose of the compound may be less than 400 μg / kg of body weight. In other cases, the administration dose may be less than 200 μg / kg of body weight. In other cases, the administration dose may be in the range of about 0.1 to about 100 μg / kg of body weight. In one embodiment, the therapeutically effective amount of Compound 1, or of a pharmaceutically acceptable salt thereof, is about 5 mg to about 900 mg, as well as about 40 mg to 600 mg, conveniently as 100 mg to about 600 mg. In one embodiment, the therapeutically effective amount of Compound 1, or of a pharmaceutically acceptable salt thereof, is from about 40 mg to about 100 mg, as well as about 50 mg.

[00261] Advantageously, applicants have found that the prolonged release provided by the compositions of the invention and the resulting stable plasma levels remained at a therapeutically effective plasma concentration for an extended period after administration, allowing the possibility of using lower doses than expected.

[00262] The dose, for example, after reaching steady-state levels, can conveniently be administered only once every 5 days or less, once a week or less, every two weeks or less, once a month or less, once every two or three months or less. Conveniently, the dose can be conveniently administered once a week, once every two weeks, once a month, or once every two months.

[00263] In a convenient embodiment, the unit dosage form of the pharmaceutical composition is a tablet. In a modal Petition 870250094497, dated 10 / 16 / 2025, p. 87 / 194 71 / 135 In a convenient embodiment, the unit dosage form of the pharmaceutical composition comprises from about 1 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In a convenient embodiment, the unit dosage form of the pharmaceutical composition comprises from about 25 mg to about 100 mg of Compound 1, or a pharmaceutically acceptable salt thereof, such as about 50 mg.

[00264] Advantageously, applicants have found that stable plasma levels, maintained at a therapeutically effective plasma concentration for a prolonged period after administration, can be enhanced by administering certain compositions of the invention in conjunction with food intake.

[00265] Oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, with food intake, improves the pharmacokinetics of the helicase-primase inhibitor compared to oral pharmacokinetics when the compound is administered on an empty stomach. This treatment approach offers a number of potential benefits. For example, the treatment approach allows for the administration of lower doses of the helicase-primase inhibitor, thereby reducing the incidence and / or extent of drug-related adverse effects, decreasing the costs of drug therapy, and reducing the number of tablets and / or the frequency of dosing, which in turn aids patient use and adherence.

[00266] In a convenient embodiment, the composition of the present invention is administered in conjunction with the ingestion of food.

[00267] In one embodiment, the present invention provides a method for treating a herpes virus infection (conveniently an HSV) in an individual in need thereof, the method comprising administering orally to the individual, in connection with Petition 870250094497, dated 10 / 16 / 2025, pp. 88 / 194 72 / 135 the ingestion of food, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention.

[00268] The term food should be understood to encompass any edible food with nutritional value as a supplier of energy. Thus, food may be a solid, semi-solid, or liquid substance comprising one or more of the basic ingredients, namely, carbohydrates, fats, and proteins. Compound 1, or a pharmaceutically acceptable salt thereof, is considered administered in connection with food intake if Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a time shortly before the commencement of food intake, during food intake, or within a relatively short period of time after food intake. In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a time that is within the interval defined as 30 minutes before the commencement of food intake and 2 hours after the commencement of food intake.Conveniently, Compound 1, or a pharmaceutically acceptable salt thereof, is administered during food intake or within 1 hour of the start of food intake. More conveniently, Compound 1, or a pharmaceutically acceptable salt thereof, is administered within 30 minutes of the start of food intake.

[00269] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is administered substantially at the same time as food intake. Conveniently, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with food or within 30 minutes after ingestion of Petition 870250094497, dated 10 / 16 / 2025, pp. 89 / 194 73 / 135 foods.

[00270] Food can be any suitable food, for example, a meal. In one embodiment, a meal refers to one of three substantial intakes of food typical for an individual during a typical day. In one aspect, a meal involves the intake of at least 400, 600, 800, or 1000 calories, although the amount of food ingested may vary according to the size, weight, and general health of the individual. In one embodiment, the term meal refers to a meal as defined by the FDA's food effect test guidelines and may include a high-fat meal or a low-fat meal. In one embodiment, the food is a high-fat meal. When used in this document, the term high-fat meal generally refers to a meal in which at least about 50% of the calories provided are from fat and the meal has a total caloric content of at least about 700 kcal.In one definition, the food is a low-fat meal. In this definition, a low-fat meal can be defined as a meal in which approximately 25% of the calories provided come from fat and the meal has a total caloric content of 400 to 600 kcal.

[00271] It should be understood that the quantity and caloric value of a meal (e.g., a low-fat meal or a high-fat meal) required to achieve a desirable level of improvement in the oral pharmacokinetics of the helicase-primase inhibitor may vary based on the age and / or weight of an individual, e.g., a human patient.

[00272] In one embodiment, oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, in conjunction with food intake, provides an increase in any one, two, three, or four of the following parameters: Cmax, Tmax, and Petition 870250094497, dated 10 / 16 / 2025, pp. 90 / 194 74 / 135 AUC, compared to administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a fasting individual. Combinations

[00273] The pharmaceutical compositions of the present invention can be administered alone as monotherapy or can be administered in addition to one or more other substances and / or treatments. Such combined treatment can be achieved through simultaneous, sequential or separate administration of the individual components of the treatment.

[00274] Methods involving the administration of a second active agent are also considered here. For example, in addition to being infected with HSV, an individual or patient may also have comorbidities related to HSV infection, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by HSV infection. Pharmaceutical compositions in combination with at least one other agent that has previously been shown to treat these HSV-related conditions are also considered here. Such combined treatment may be carried out independently (through simultaneous, sequential, or separate administration of the individual components of the treatment) and / or through pharmaceutical compositions of the present invention that include a second active agent.

[00275] Therefore, a method is provided here for treating or preventing HSV infection in an individual in need thereof, comprising the method administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition according to the first aspect of the invention, and co-administering to the individual a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. Petition 870250094497, dated 10 / 16 / 2025, pp. 91 / 194 75 / 135 effective of an additional therapeutic agent.

[00276] In one 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; and vi. other helicase-primase inhibitors, such as amenamevir.

[00277] In some cases, a pharmaceutical composition described according to the first aspect of the invention may be administered as part of a combination therapy in conjunction with one or more antivirals, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir, or the respective drugs valacyclovir or famciclovir.

[00278] In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both, may be equal to, greater than, or less than the effective amounts of each compound administered as monotherapy. Therapeutically effective amounts of a compound and antiviral described may be co-administered to the individual, that is, administered to the individual simultaneously or separately, in any order and by the same or different routes of administration. In some cases, it may be advantageous to initiate administration of Compound 1 first, for example, one or more days or weeks before the start of antiviral administration. In addition, additional drugs may be administered concurrently with the above combination therapy. Petition 870250094497, dated 10 / 16 / 2025, pp. 92 / 194 76 / 135 Kits

[00279] In one embodiment, the pharmaceutical compositions and methods described herein provide kits for the treatment of disorders such as those described herein. These kits comprise a pharmaceutical composition described herein in a container and, optionally, instructions that teach the use of the kit according to the various methods and approaches described herein. Such kits may also include information such as scientific literature references, package insert materials, clinical trial results and / or summaries thereof and the like, which indicate or establish the activities and / or benefits of the composition and / or which describe the dosage, administration, side effects, drug interactions or other information useful to the healthcare professional. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on clinical trials in humans.The kits described herein may be supplied, marketed, and / or promoted to healthcare professionals, including physicians, nurses, pharmacists, formulation staff, and similar professionals. In some forms, the kits may also be marketed directly to consumers.

[00280] In one embodiment, the present invention provides a kit comprising a pharmaceutical composition of the invention for oral administration to an individual and instructions, for example, printed instructions, for administering the composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in connection with food intake (conveniently with or shortly after food). In one embodiment of this aspect, the instructions also inform the individual that oral administration of Compound 1, or a pharmaceutically acceptable salt thereof, with food results in an improvement in oral pharmacokinetics and / or exposure. Petition 870250094497, dated 10 / 16 / 2025, pp. 93 / 194 77 / 135 systemic and / or oral bioavailability of Compound 1, compared to administration without food.

[00281] The pharmaceutical compositions of the invention can be used for diagnosis and as research tools.

[00282] In addition to being useful for human treatment, the pharmaceutical compositions of the invention may be useful for the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and the like. Conveniently, such animals include horses, dogs and cats.

[00283] The invention is illustrated below by the following non-limiting examples. EXAMPLES Materials and methods Table 1: Materials and Equipment Material and Equipment Trade Name or Model Abbreviation or Equipment ID Manufacturer Aceto na N / A Acetone EMD Water N / A H2O MQ-1 Methanol N / A MeOH EMD Tetrahydrofuran N / A THF Fisher Methylene Chloride N / A DCM Fisher N-methylpyrrolidone N / A NMP Fisher Ethanol N / A EtOH Fisher Ethyl Acetate N / A EtOAc Fisher Hypromellose Succinate Acetate Grade MG AQOAT®-MG HPMCAS-MG Shin-Etsu Hypromellose Succinate Acetate Grade LG AQOAT®-LG HPMCAS-LG Shin-Etsu Hypromellose Succinate Acetate Grade HG AQOAT®-HG HPMCAS-HG Shin-Etsu Petition 870250094497, dated 10 / 16 / 2025, pp. 94 / 194 78 / 135 Material and Equipment Trade Name or Model Abbreviation or Equipment ID Manufacturer Poly(butyl methacrylate-co-(2-desmethylaminoethyl) methacrylate-comethyl methacrylate) 1:2:1 Eudragit® E PO N / A Evonik Hypromellose E5LV Hypromellose HPMC E5LV DOW PEG 6000 / vinyl caprolactam / vinyl acetate copolymer Soluplus® N / A BASF Polyvinylpyrrolidone / vinyl acetate copolymer Kollidon®VA 64 PVP-VA64 BASF Polyethylene glycol 300 N / A PEG 300 Sigma Da-tocopherol succinate polyethylene glycol N / A TPGS Sigma Poloxamer 188 Kolliphor® P 188 N / A BASF Polyvinylpyrrolidone grade K30 Povidone K30 PVP-K30 Sigma Spray Dryer Yamato DL410 DL410 Yamato Spray Dryer B-290 Buchi Buchi Spray Dryer PSD-3 PSD-3 Gea

[00284] Solid dispersions were characterized using one or more of the following analytical methods: differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), residual solvents by top-free sampling by gas chromatography (GC-HS), polarized light microscopy (PLM), assay and impurities by high-performance liquid chromatography (HPLC) and water content by Karl Fischer titration (KF). I. Differential Scanning Calorimetry (DSC)

[00285] DSC was performed using a TA Instruments Discovery DSC2500 differential scanning calorimeter equipped with a Petition 870250094497, dated 10 / 16 / 2025, pp. 95 / 194 79 / 135 TA Instruments 90 Refrigerated Cooling System operating in modulated or ramp mode. DSC was used to measure thermodynamic events and characteristics of compounds and subsequent solid dispersions. The events to be observed include the glass transition temperature (Tg), defined as the temperature at which amorphous materials transition from a low-mobility glassy state to a high-mobility rubbery state, cold crystallization (Tc), defined as a crystallization event at a temperature below the melting temperature, and the melting temperature (Tm). Samples were placed in non-hermetic aluminum containers and heated at a heating rate of 10°C / min from room temperature, gradually increasing to 300°C. The system was purged with a nitrogen flow of 50 mL / min to ensure an inert atmosphere during measurement. Samples were also analyzed by MDSC.A summary of the analysis parameters for DSC and MDSC can be found in Tables 2 and 3. Table 2: Analysis Parameters by DSC Parameters Value Instrument TA Discovery DSC2500 Sample Containers Tzero Al, Non-hermetic Temperature Range RT -300°C Heating Rate 10°C / min Scan Mode Ramp Purge Gas Nitrogen Table 3: MDSC Analysis Parameters Parameters Value Instrument TA Discovery DSC2500, Sample Containers Tzero Al, Non-hermetic Temperature Range -50 - 300°C Heating Rate 2°C / min Petition 870250094497, dated 10 / 16 / 2025, pp. 96 / 194 80 / 135 Parameters Value Sweep Mode Modulated Modulation Frequency 60s Modulation Amplitude 1°C IL Thermographic Analysis (TGA)

[00286] The variation in sample weight during compound heating was monitored by TGA. The sample was exposed to a temperature gradient, starting at room temperature and increasing at 10°C / min to a final temperature of 300°C. A precision balance recorded the variation in sample weight as a function of temperature. The parameters of the TGA analysis are presented in Table 4. Table 4. TGA Analysis Parameters Parameters / Values ​​Instrument: TA Discovery TGA500 Temperature Range: RT-300°C Method: Ramp Heating Rate: 10.0°C / min Container: Aluminum, Open Purge Gas: Nitrogen III. X-ray Powder Diffraction (XRPD)

[00287] XRPD was performed using a Rigaku Smartlab SE X-ray diffractometer to evaluate the crystallinity of the bulk API and subsequent solid dispersion materials. Amorphous materials exhibit an amorphous halo diffraction pattern, without discrete peaks that would be found in a crystalline material. Samples were irradiated with monochromatic CuKa radiation and analyzed between 3° and 40° in continuous scanning mode. Samples were rotated during analysis to minimize preferred orientation effects. A summary of the XRPD analysis parameters can be found Petition 870250094497, dated 10 / 16 / 2025, pp. 97 / 194 81 / 135 found in Table 5. Table 5 · XRPD Analysis Parameters Parameters Value Instrument Rigaku Smartlab SE X-ray Wavelength Intensity Ratio Cu, Ka, Ka1 (A): 1.540598, Ka2(A):1.544426 Ka2:Ka1:0.50 X-ray Tube Configuration 40 kV, 15 mA, Scan Mode 1D Scan Range (20") 3-40° Step Size (20") 0.02° Scan Speed ​​(20") 107 min Scan Type Scan Mode 1D D / tex Ultra 250 Rotation / / Support Accessory for automatic sample exchange ASC-48 Receiving Slit Width 20 mm (Soller slit: 2.5 degrees; length limiting slit: 10 mm) Diverging Slit Width 1 / 2 degree (incident slit; incident Soller slit 2.5 degrees) Blade Wire Width / / IV. Amorphous Content by Polarized Light Microscopy (PLM)

[00288] Compounds, dry solid dispersions, and solid dispersion suspensions were analyzed by PLM. Samples were dispersed with methyl silicone oil on a glass slide and observed by PLM. Samples were inspected using an Olympus BX53 microscope. V· Water Content by Karl Fischer Colorimetric Titration (KF)

[00289] The samples were analyzed for water content using a Metrohm 915 Ti-Touch Karl Fischer Colorimetric Titrator. Petition 870250094497, dated 10 / 16 / 2025, pp. 98 / 194 82 / 135 Samples of approximately 100 mg were sealed in 6 mL resealable vials, followed by measurement of water content using the following parameters: Hydranal Coulomat AG-Oven reagent, oven temperature of 130°C, and sample extraction time of 300 seconds. VL Analysis of Assays and Impurities by HPLC

[00290] The assay and impurities of the solid dispersion samples were evaluated using an experimental HPLC method (Table 6). Table 6 · HPLC Parameters for Assay and Impurities Parameters Value Waters X-Bridge C18 Column (4.6x150 mm 5 µm) PN 186003116 Mobile Phase A 10 mM ammonium acetate buffer solution Mobile Phase B Acetonitrile Diluent DMSO: ACN = 5:95 (v / v) Gradient Program Type Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 70 30 4.0 55 45 10.0 45 55 12.0 40 60 18.0 20 80 20.0 20 80 20.1 70 30 25.0 70 30 Flow Rate 1.0 mL / min Column Temperature 40°C Sample Temperature Room Temperature Injection Volume 5 µL Detection Method UV Petition 870250094497, dated 10 / 16 / 2025, pp. 99 / 194 83 / 135 Parameters Value Detection Wavelength 286 VIL Residual Solvent by Sampling of the Free Top by Gas Chromatography

[00291] The residual solvent content of the solid dispersions was measured by GC-HS after secondary drying. Measurements were performed using an Agilent 8890B with a GC series FID detector, equipped with an Agilent 7697A free-top sampler. A 30 m x 0.32 mm x 1.8 μm capillary column with a GC column of 6% cyanopropylphenyl and 94% dimethylpolysiloxane was used for the test. GC samples were prepared by dissolving approximately 100 mg of sample in 5 mL of N-methylpyrrolidone (NMP). The GC method parameters are summarized in Table 7. Table 7 Analysis Parameters by GC-HS Parameter Value Injector Temperature 230°C Split Ratio 10:1 Carrier Gas Nitrogen Detector FID Detector Temperature 250°C Flow Composition (N2) 25 mL / min H2 Flow 30 mL / min Air Flow 300 mL / min Run Time 17.7 min Column Temperature Program Rate (°C / min) Value (°C) Holding Time (min) Initial / 45 0.2 Ramp 1 2 50 0.0 Petition 870250094497, dated 10 / 16 / 2025, pp. 100 / 194 84 / 135 Parameter Value Ramp 2 10 100 0.0 Ramp 3 30 250 5.0 LC-MS analysis of plasma samples

[00292] The methodology and LC-MS conditions used to analyze the helicase-primase inhibitor, Compound 1, in plasma samples from oral pharmacokinetic studies (Examples 5 to 9) are described in Tables 8 to 11. Table 8. LC-MS parameters for quantification of Compound 1 in rat plasma samples from the Single Oral Dose Pharmacokinetic Study. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Internal Standard: diclofenac Parent Compound ID (m / z) / Daughter Compound ID (m / z) Compound 1 Masses Q1 / Q3: 465.10 / 232.20 Da Diclofenac Masses Q1 / Q3: 296.20 / 214.20 Da Column Xbridge BEH C18 (2.1x50 mm, 2.5 pm) Flow Rate 0.60 mL / min Column Temperature 50°C Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1mM Mobile Phase B Methanol / Ammonium Acetate 5mM Program Type Gradient Program Gradient Time (min) Percentage of Mobile Phase A Percentage of Mobile Phase B 0.20 90 10 0.40 40 60 Petition 870250094497, dated 10 / 16 / 2025, pp. 101 / 194 85 / 135 Parameter Value 1.40 10 90 1.80 10 90 1.81 90 10 2.20 Interruption Interruption Sample Temperature Room Temperature Injection Volume 1.0 pL MS Detection Mode Multiple Reaction Monitoring (MRM) Retention Time 1.49 min (Compound 1) 1.56 min (Diclofenac) Table 9 · LC-MS parameters for quantification of Compound 1 in canine plasma samples from the Single Oral Dose Pharmacokinetic Study Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Internal Standard: diclofenac Parent Compound ID (m / z) / Daughter Compound ID (m / z) Compound 1 Masses Q1 / Q3: 465.10 / 232.20 Da Diclofenac Masses Q1 / Q3: 296.20 / 214.20 Da Column Xbridge BEH C18 (2.1x50 mm, 2.5 pm) Flow Rate 0.60 mL / min Column Temperature 50°C Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1mM Mobile Phase B Methanol / Ammonium Acetate 5mM Program Type Gradient Petition 870250094497, dated 10 / 16 / 2025, pp. 102 / 194 86 / 135 Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.20 90 10 0.40 40 60 1.40 10 90 1.80 10 90 1.81 90 10 2.20 Interruption Interruption Sample Temperature Room Temperature Injection Volume 1.0 pL MS Detection Mode Multiple Reaction Monitoring (MRM) Retention Time 1.44 min (Compound 1) 1.49 min (Diclofenac) Table 10 · LC-MS parameters for quantification of compound 1 in plasma samples from rats or dogs from Seven-Day Oral Dose Pharmacokinetic Studies Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Internal Standard: diclofenac Parent Compound ID (m / z) / Daughter Compound ID (m / z) Compound 1 Masses Q1 / Q3: 465.10 / 232.20 Da Diclofenac Masses Q1 / Q3: 296.20 / 214.20 Da Column Xbridge BEH C18 (2.1x50 mm, 2.5 µm) Flow Rate 0.60 mL / min Column Temperature 60°C Sample Diluent MeOH:H2O 50:50 (v:v) Petition 870250094497, dated 10 / 16 / 2025, pp. 103 / 194 87 / 135 Mobile Phase A Water / Formic acid 0.025% / Ammonium acetate 1mM Mobile Phase B Methanol / Ammonium acetate 5mM Program Type Gradient Gradient Program Time (min) % of Mobile Phase A % of Mobile Phase B 0.20 90 10 0.40 40 60 1.40 10 90 1.80 10 90 1.81 90 10 2.20 Stop Stop Sample Temperature Room Temperature Injection Volume 1.0 pL MS Detection Mode Multiple Reaction Monitoring (MRM) Retention Time 1.34 min (Compound 1) 1.40 min (Diclofenac) Table 11. LC-MS parameters for quantification of Compound 1 in plasma samples from dogs in the Fourteen-Day Oral Dose Pharmacokinetic Study. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Internal Standard: glipizide Parent Compound ID (m / z) / Daughter Compound ID (m / z) Compound 1 Masses Q1 / Q3: 465.10 / 232.20 Da Glipizide Masses Q1 / Q3: 446.20 / 321.10 Da Column Xbridge BEH C18 (2.1x50 mm, 2.5 µm) Flow Rate 0.60 mL / min Petition 870250094497, dated 10 / 16 / 2025, pp. 104 / 194 88 / 135 Column Temperature 50°C Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1mM Mobile Phase B Methanol / Ammonium Acetate 5mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.20 90 10 0.60 30 70 1.50 10 90 2.00 10 90 2.01 90 10 2.50 Stop Stop Sample Temperature Room Temperature Injection Volume 1.0 pL MS Detection Mode Multiple Reaction Monitoring (MRM) Retention Time 1.32 min (Compound 1) 1.24 min (Glipizide)

[00293] The methodology and LC-MS conditions used to analyze Compound 1 in plasma samples from intravenous injection pharmacokinetic studies (Example 3) are described in Tables 12 to 14. Table 12 · LC-MS parameters for quantification of Compound 1 in rat plasma samples after intravenous administration in the study described in Example 3 · Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) Petition 870250094497, dated 10 / 16 / 2025, pp. 105 / 194 89 / 135 MS Conditions Positive, ESI Column ACQUITY UPLC-BEH C18 (2.1x50 mm, 1.7 pm) Flow Rate 0.60 mL / min Column Temperature 60°C Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1mM Mobile Phase B Methanol / Ammonium Acetate 5mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 90 10 0.20 90 10 1.20 10 90 1.80 10 90 1.81 90 10 2.20 Interrupt Interrupt Sample Temperature Room Temperature Injection Volume 2.0 pL Mode MS Detection Multiple Reaction Monitoring (MRM) Retention Time 1.43 min Table 13. LC-MS parameters for quantification of Compound 1 in canine plasma samples after intravenous administration in the study described in Example 3. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Petition 870250094497, dated 10 / 16 / 2025, pp. 106 / 194 90 / 135 ACQUITY UPLC-BEH C18 column (2.1x50 mm, 1.7 pm) Flow rate 0.60 mL / min Column temperature 60°C Sample diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic acid 0.025% / Ammonium acetate 1mM Mobile Phase B Methanol / Ammonium acetate 5mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 90 10 0.20 98 2 1.20 98 2 1.80 10 90 1.81 90 10 2.20 Stop Stop Sample Temperature Room Temperature Injection Volume 1.0 pL MS Detection Mode Monitoring of multiple reactions (MRM) Retention Time 1.48 min Table 14. LC-MS parameters for quantification of Compound 1 in monkey plasma samples after intravenous administration in the study described in Example 3. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Column ACQUITY UPLC-BEH C18 (2.1x50 mm, 1.7 pm) Petition 870250094497, dated 10 / 16 / 2025, pp. 107 / 194 91 / 135 Flow rate 0.60 mL / min Column temperature 60°C Sample diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic acid 0.025% / Ammonium acetate 1mM Mobile Phase B Methanol / Ammonium acetate 5mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 95 5 0.30 95 5 1.50 10 90 2.00 10 90 2.01 95 5 2.60 Interruption Interruption Sample Temperature Room Temperature Injection Volume 1.0 μL MS Detection Mode Multiple reaction monitoring (MRM) Retention Time 1.69 min EXAMPLE 1: Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazol-5-sulfonamide (Compound 1) Petition 870250094497, dated 10 / 16 / 2025, pp. 108 / 194 92 / 135 Caption: Step / 1-chloro-3-isocyanatopropane Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (1-2)

[00294] A mixture of 2-amino-4-methylthiazole (compound 1-1; 6 g, 52.632 mmol) and 1-chloro-3-isocyanatopropane (6.26 g, 52.632 mmol) in THF (60 mL) was heated to 70°C for 6 h. To the resulting solution, TBAB (1.7 g, 5.263 mmol) and K2CO3 (18.15 g, 131.58 mmol) were added in portions, maintaining the same temperature and under continuous stirring at 70°C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 6070% EtOAc in heptane) to give compound titer 1-2 (5.1 g, 49.22%) as a whitish solid. TLC: EtOAc 70% / heptane (Rf: 0.5). Calculated MS for Chemical Formula: C8H11N3OS: 197.06; Found: 198.17 [M + 1]+.RMN de1H (400 MHz, DMSO-de) δ 7.30 (s, 1H), 6.60 (s, 1H), 3.99 (t, J = 5.4 Hz, 2H), 3.20 - 3.19 (m, 2H), 2.28 (s, 3H), 1.99 - 1.89 (m, 2H). Síntese of 1-(2',5'-difluoro-[1,1'-bifenil]-4-il)-3-(4-metiltiazol-2-il)tetrahydropirimidin-2(1H)-ona (1-3) Petition: 870250094497, on 10 / 16 / 2025, p. 109 / 194 93 / 135

[00295] To a stirred solution of compound 1-2 (5 g, 25.380 mmol) in 1,4-dioxane (100 mL) was added Int. 1A (8.16 g, 30.456 mmol), K2CO3 (8.75 g, 63.45 mmol) followed by CuI (0.96 g, 5.076 mmol) and the resulting reaction mixture was purged under nitrogen for 20 min. To this resulting reaction mixture, 1,2-dimethylethylenediamine (0.9 g, 10.152 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated at 120°C for 24 h in a sealed tube. After completion of the reaction, the reaction mixture was filtered through a Celite® bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash® chromatography (eluting with 30-40% EtOAc in heptane) to give compound titer 1-3 (4.1 g, 41.96%) as a whitish solid. TLC: 50% EtOAc / Heptane (Rf: 0.5).MS calculada para a Fórmula Química: C20H17F2N3OS: 385,11; Encontrado: 385,90 [M + 1]+. NMR de1H (400 MHz, DMSO-d6) δ 7,61 (d, J = 7,8 Hz, 2H), 7,54 - 7,35 (m, 4H), 7,35 - 7,21 (m, 1H), 6,70 (s, 1H), 4,17 (t, J = 5,6 Hz, 2H), 3,81 (t, J = 4,9 Hz, 2H), 2,26 (s, 3H), 2,24 - 2,21 (m, 2H). Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahidropyrimidin-1 (2 H )-yl)-4-methylthiazol-5-sulfonic acid (1-4).

[00296] To a stirred solution of compound 1-3 (4 g, 10.389 mmol) in dry DCM (40 mL) at 0°C in an inert atmosphere, chlorosulfuric acid (2.07 mL, 31.168 mmol) was added and the resulting reaction mixture was slowly heated to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether. The solid obtained was filtered and dried under vacuum to give the title compound 1-4 (3.35 g, crude) as a whitish solid. TLC: EtOAc 100% (Rf: 0.2). MS calculated for Petition 870250094497, dated 10 / 16 / 2025, pp. 110 / 194 94 / 135 the chemical formula: C20H17F2N3O4S2: 465.06; Found: 466 [M + 1]+. Synthesis of 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazol-5-sulfonamide (Compound 1)

[00297] A stirred solution of compound 1-4 (3.3 g, 7.096 mmol) in POCl3 (33 mL) was stirred at 90°C for 5 h. The reaction mixture was concentrated under reduced pressure to dryness. The resulting residue was dissolved in THF (66 mL) and aqueous ammonia (33 mL) was added at -5°C, continuing stirring at room temperature for a further 12 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 100% EtOAc) to provide the desired product, Compound 1 (1.1 g, 44.64%), as a white solid.RMN de1H (400 MHz, DMSO-d6) δ 7.65-7.59 (m, 2H), 7.55 (br s, 2H), 7.53-7.48 (m, 2H), 7.48-7.36 (m, 2H), 7.31-7.25 (m, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.29-2.18 (m, 2H). Síntese de 4'-bromo-2,5-difluoro-1,1'-bifenila (Int. 1A)

[00298] To a stirred solution of 4-bromo-iodobenzene (5 g, 17.674 mmol) in 1,4-dioxane: H2O (50:5 mL), (2,5-difluorophenyl)boronic acid (3.07 g, 19.441 mmol) and K3PO4 (7.5 g, 35.348 mmol) were added, and the reaction mixture was purged under nitrogen for 10 min. To this resulting solution, PdCb(dppf) (1.29 g, 1.767 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated to 80°C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a Celite® pad, and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered Petition 870250094497, dated 10 / 16 / 2025, pp. 111 / 194 95 / 135 of the and concentrated under reduced pressure. The crude compound was purified by CombiFlash® chromatography (eluting with 100% heptane) to give the title compound Int. 1A (2.3 g, 48.62%) as a whitish solid. TLC: 100% heptane (Rf: 0.5). 1H NMR (400 MHz, CDC1a) δ 7.58 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.15-7.06 (m, 2H), 7.05-6.97 (m, 1H). EXAMPLE 2: Biological assay data for 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin21(2H)-yl)-4-methylthiazol-5-sulfonamide (Compound 1) Cell culture

[00299] Vero cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 100 units / mL of penicillin and streptomycin. Cells were passed 2 to 3 times per week to maintain subconfluent densities. Antiviral assay for HSV-1

[00300] Vero cells were seeded in 96-well plates at a density of 2.5 x 10³ cells per well and left to fix overnight. After fixation, the medium was replaced with 50 μL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL of penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add the compounds to the culture, using an 8-point triple-serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. After compound addition, 50 μL of infection medium containing 80 TCID50 HSV-1 cells were added to the cells and incubated at 37 °C for 4 days. After incubation, the plates were equilibrated at room temperature, the medium was removed, and 60% of a 1:1 dilution of Cell titer glow and phosphate-buffered saline solution was added to the cells. After 5 minutes of incubation, cell viability was assessed. Petition 870250094497, dated 10 / 16 / 2025, pp. 112 / 194 96 / 135 was quantified by measuring luminance using a Tecan Infinite M1000 Pro plate reader. Antiviral assay for HSV-2

[00301] Vero cells were seeded in 96-well plates at a density of 1.0 χ 104 cells per well and left to fix overnight. After fixation, the medium was replaced with 50 μL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL of penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add the compounds to the culture using an 8-point triple-serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. After compound addition, 50 μL of infection medium containing 160 TCID50 of the HSV-2 G strain were added to the cells and incubated at 37 °C for 5 days. After incubation, 10 μL / well of the WST-8 chromogenic reagent were added and the plates were incubated at 37 °C for 3 hours. After incubation, cell viability was quantified by measuring absorbance at 460 nm and 620 nm using a Tecan Infinite M1000 Pro plate reader.

[00302] In the antiviral assay for HSV-1, Compound 1 showed an EC50 of 0.019 μM (n=22). In the antiviral assay for HSV-2, Compound 1 showed an EC50 of 0.011 μM (n=35). EXAMPLE 3: Pharmacokinetic Studies in Rats, Monkeys, and Dogs after Intravenous Administration of Compound 1 - Formulation Preparation - Rat

[00303] A solution of 0.2 mg / mL of Compound 1 in 10% MPN, 10% Solutol® HS15 and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 at NMP was prepared. 2) An equal volume of the stock solution of Compound 1 and Petition 870250094497, dated 10 / 16 / 2025, pp. 113 / 194 97 / 135 of Solutol® HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation was a clear solution. Dosage in Animals - Rat

[00304] Male Sprague-Dawley (SD) rats weighing 230-250 g and aged 6-8 weeks were used for the pharmacokinetic study in rats. The animals had free access to food and water. The Compound 1 solution described above was administered by intravenous injection to animals (n = 3) to achieve a dose of 1.0 mg / kg.

[00305] At each time point, approximately 200 μL of whole blood were collected in K2EDTA tubes. The blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain a plasma sample in 15 minutes. The plasma samples were stored at approximately -70°C until analyzed by LC-MS, according to the method described above. Results

[00306] The mean plasma concentration profiles (n = 3) after intravenous (IV) administration in rats of 1.0 mg / kg of Compound 1 solution can be found in Figure 1. Formulation Preparation - Monkey

[00307] A 0.25 mg / mL solution of Compound 1 in 10% DMSO, 10% Solutol® HS15, and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 in DMSO was prepared. 2) An equal volume of the stock solution of Compound 1 and Solutol® HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution. Petition 870250094497, dated 10 / 16 / 2025, pp. 114 / 194 98 / 135 to achieve the target concentration. The final formulation was a clear solution. Dosage in Animals - Monkey

[00308] Non-naive male cyno monkeys were used for the pharmacokinetic study in monkeys. The animals had free access to food and water. The prepared solution was administered by intravenous injection to each group of animals (n = 3) to achieve a dose of 0.25 mg / kg.

[00309] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00310] The mean plasma concentration profiles (n = 3) after intravenous (IV) administration of 0.25 mg / kg of the Compound 1 solution can be found in Figure 2. Formulation Preparation - Dog

[00311] A solution of 0.15 mg / mL of Compound 1 in 10% DMSO, 10% Solutol® HS15 and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 in DMSO was prepared. 2) An equal volume of the stock solution of Compound 1 and Solutol® HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation resulted in a clear solution. Dosage for Animals - Dogs Petition 870250094497, dated 10 / 16 / 2025, pp. 115 / 194 99 / 135

[00312] Non-naive male Beagles were used for the pharmacokinetic study in dogs. The animals had free access to food and water. The prepared solution was administered by intravenous injection to each group of animals (n=3) to achieve a dose of 0.15 mg / kg.

[00313] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. The blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. The plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00314] The mean plasma concentration profiles (n=3) after intravenous (IV) administration of 0.15 mg / kg of the Compound 1 solution can be found in Figure 3. Summary

[00315] Intravenous administration of Compound 1 in rats, monkeys, and dogs at doses of 1 mg / kg, 0.25 mg / kg, and 0.15 mg / kg, respectively, resulted in long terminal half-lives, as shown in Table 15. Based on these data, Compound 1 is expected to also exhibit a long terminal half-life in humans. Table 15. Half-life data from intravenous studies Compound 1 Rat t1 / 2 (hour) 22 Mouse t1 / 2 (hour) 49.6 Dog t1 / 2 (hour) 34.9 EXAMPLE 3A: Additional Pharmacokinetic Studies of Compound 1 Petition 870250094497, dated 10 / 16 / 2025, pp. 116 / 194 100 / 135 in Rats, Monkeys, Dogs and Miniature Pigs after intravenous administration Formulation Preparation - Rat

[00316] A 0.2 mg / mL solution of Compound 1 in 10% MPN, 10% Solutol HS15, and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 at NMP was prepared. 2) An equal volume of the stock solution of Compound 1 and Solutol HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation was a clear solution. Dosage in Animals - Rat

[00317] Male Sprague Dawley (SD) rats weighing 180-184 g and aged 6-8 weeks were used for the pharmacokinetic study in rats. The animals had free access to food and water. The Compound 1 solution described above was administered by intravenous injection (1 mL / kg) to each animal (n=3) to achieve a dose of 0.2 mg / kg.

[00318] At each time point, approximately 200 μL of whole blood were collected in K2EDTA tubes. The blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain a plasma sample in 15 minutes. The plasma samples were stored at approximately -70°C until analyzed by LC-MS according to the method described above. Formulation Preparation - Monkey

[00319] A 0.2 mg / mL solution of Compound 1 in 10% DMSO, 10% Solutol HS15, and 80% saline solution was prepared as follows: Petition 870250094497, dated 10 / 16 / 2025, pp. 117 / 194 101 / 135 1) A stock solution of Compound 1 in DMSO was prepared. 2) An equal volume of the stock solution of Compound 1 and Solutol HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation was a clear solution. Dosage in Animals - Monkey

[00320] Non-naive male cyno monkeys were used for the pharmacokinetic study in monkeys. The animals had free access to food and water. The Compound 1 solution described above was administered by intravenous injection (1 mL / kg) to each animal (n=3) to achieve a dose of 0.2 mg / kg.

[00321] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain a plasma sample in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Formulation Preparation - Dog

[00322] A 0.15 mg / mL solution of Compound 1 in 10% DMSO, 10% Solutol HS15, and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 in DMSO was prepared. 2) Equal volumes of the stock solution of Compound 1 and Solutol HS15 were combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation was a clear solution. Petition 870250094497, dated 10 / 16 / 2025, pp. 118 / 194 102 / 135 Dosage for Animals - Dogs

[00323] Non-naive male Beagles were used for the pharmacokinetic study in dogs. The animals had free access to food and water. The Compound 1 solution described above was administered by intravenous injection (1 mL / kg) to each animal (n=3) to achieve a dose of 0.15 mg / kg.

[00324] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Formulation Preparation - Miniature Pig

[00325] A 0.25 mg / mL solution of Compound 1 in 10% DMSO, 10% Solutol HS15, and 80% saline solution was prepared as follows: 1) A stock solution of Compound 1 in DMSO was prepared. 2) An equal volume of the stock solution of Compound 1 and Solutol HS15 was combined and mixed. 3) The above solution was diluted with normal saline solution to reach the target concentration. The final formulation was a clear solution. Dosage in Animals - Miniature Pig

[00326] Bama Naϊve pigs (15-16 kg) were used for the pharmacokinetic study in minipigs. The animals had free access to food and water. The Compound 1 solution described above was administered by intravenous injection (1 mL / kg) to each animal (n = 3) to achieve a dose of 0.25 mg / kg.

[00327] At each time point, approximately 0.5 mL of Petition 870250094497, dated 10 / 16 / 2025, pp. 119 / 194 103 / 135 Whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00328] Mean plasma concentration profiles (n = 3) after intravenous (IV) injection of Compound 1 solution in rats, dogs, monkeys and mini-pigs can be found in Figure 35 (A)-(D). Summary

[00329] Intravenous administration of Compound 1 to rats, dogs, monkeys, and mini-pigs at doses of 0.2 mg / kg, 0.15 mg / kg, 0.2 mg / kg, and 0.25 mg / kg, respectively, resulted in the terminal half-lives and clearances shown in the following table: Species Half-life (days) Clearance (L / hr / kg) Rat 0.8 0.02 Dog 2.3 0.002 Monkey 3.0 0.004 Miniature pig 5.6 0.0018

[00330] Based on the pharmacokinetic data above in multiple species and using allometric scaling, the predicted human terminal biological half-life for Compound 1 is 7.6 days (182 hours), with a clearance of 0.06 L / h. EXAMPLE 4: Preparation of Solid Dispersions of Compound 1

[00331] A preliminary screening for solid dispersions prepared by rotary evaporation was performed. Compound 1 (30 mg), the polymer, and the surfactant were dissolved in THF / Acetone / H2O (5 / 4 / 1, v / v / v) to obtain a clear solution. These solutions were placed at 60 °C in a rotary evaporator for complete drying. After drying, the solid dispersions were analyzed to determine crystallinity. From this preliminary screening, a solid dispersion Petition 870250094497, dated 10 / 16 / 2025, pp. 120 / 194 104 / 135 using HPMCAS LG was selected for fabrication by means of a spray drying method. Four batches of solid dispersion were prepared using the conditions described in Table 16. Table 16. Spray drying conditions Composition SD 15:85 of Compound 1:HPMCAS LG Atomizing Solvent 5:4:1 of THF:Acetone:Water Atomizing Solution (% by weight of total solids) 2.2-2.7 Yamato DL410 Spray Dryer Nozzle Type Binary Nozzle 1A Solution Flow Rate (kg / h) 45-50ml / min Atomizing Pressure (bar) 0.1 Inlet Temperature (°C) 100 Outlet Temperature (°C) 50 Secondary Drying Temperature / Time 24-48 hours at 40°C

[00332] The four batches of solid dispersion were characterized in terms of drug load, purity, residual solvents, water content and DSC, and the results of this characterization work are presented in Table 17. Table 17. Characterization of the solid dispersion Example: Formulations Assay Purity Residual Solvents DSC Batch 1 15:85 of Compound 1: HPMCAS LG 13.6% 97.9% Water content: 3.2% of Solvent residue: THF 93 ppm Tg~105.51 Batch 2 15:85 of Compound 1: HPMCAS LG 14.2% 98.3% Water content: 0.61% of Solvent residue: Acetone 1028 ppm; THF 5765 ppm Tg~94.63 Petition 870250094497, dated 10 / 16 / 2025, pp. 121 / 194 105 / 135 Example: Formulations Assay Purity Residual Solvents DSC Batch 3 15:85 of Compound 1: HPMCAS LG 13.7% 98.5% Water content: 1.50% of Solvent residue: Acetone 322 ppm; THF 7537 ppm Tg~107.76 Batch 4 15:85 of Compound 1: HPMCAS LG 14.1% 99.1% Water content: 1.47% of Solvent residue: Acetone 853 ppm; THF 10824 ppm Tg~105.90

[00333] Initial XRPD characterization indicated that all SDs were amorphous dispersions and no crystalline peaks were observed in the SD diffractograms (Figures 4, 8, 12 and 16). Thermal analysis showed that all dispersions exhibited a single Tg, indicating a closely mixed amorphous solid dispersion with good homogeneity (see Figures 6, 10, 14 and 18). PLM images are shown in Figures 5, 9, 13 and 17, and TGA profiles are shown in Figures 7, 11, 15 and 19. EXAMPLE 5: Pharmacokinetic Study of Compound 1 in a Single Oral Dose in Rats Formulation Preparation: solution in NMP 90% / TPGS 10%

[00334] A solution of Compound 1 in NMP 90% / Vitamin E TPGS 10% at a concentration of 100 mg / mL was prepared as follows: 1) Weigh the appropriate amount of Compound 1 2) Compound 1 dissolved in NMP 90% solvent / Vitamin E TPGS 10%.

[00335] The final dosage formulation was a clear solution. Formulation Preparation: nanosuspension

[00336] A suspension of PVP K30 0.5% plus Poloxamer 188 Petition 870250094497, dated 10 / 16 / 2025, pp. 122 / 194 106 / 135 A 0.5% solution at a concentration of 50 mg / ml was prepared as follows: 1) Weigh the appropriate amount of Compound 1 2) PVP K30 and Poloxamer 188 dissolved in water to prepare the vehicle. 3) Drug added to vehicle and nanomills

[00337] The final dosage formulation was a white homogeneous suspension. The particle size distribution (PSD) of the suspension was determined as Dvw = 0.144 μm, DV50 = 0.200 μm and Dv90 = 0.303 μm. Formulation Preparation: Spray Dry Dispersion Suspension (SDD)

[00338] An SDD (Lot 1 of Example 4, Table 17) in HPMC 0.5% in Water at a concentration of 100 mg / mL (drug concentration of 13.6 mg / mL) was prepared as follows: 1) 3521.31 mg of SDD were weighed in a mortar of appropriate size. 2) 5 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 30.213 mL of 0.5% HPMC in water were added slowly, and a pestle was used to break up the powder clumps to obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00339] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Dosage in Animals

[00340] Male Sprague-Dawley (SD) rats weighing 230-250 g and aged between 6 and 8 weeks were used for the pharmacokinetic study in rats. The animals had free access to food. Petition 870250094497, dated 10 / 16 / 2025, pp. 123 / 194 107 / 135 and water. The prepared compositions were administered orally to each group of animals (n = 3), with dosage volumes appropriate to achieve the respective doses.

[00341] At each time point, approximately 110 μL of whole blood / time point was collected in a K2EDTA tube via the jugular vein. The blood sample was placed on ice and centrifuged at 2000 g for 5 min to obtain a plasma sample in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00342] The dosages and pharmacokinetic parameters resulting after oral administration of the Compound 1 solution in 90% NMP / 10% TPGS, the Compound 1 nanosuspension, and the Compound 1 SDD suspension are presented in Table 18, and the mean plasma concentration profiles (n=3) are presented in Figure 20. The Compound 1 SDD suspension achieved a much higher exposure than the solution and nanosuspension formulations. Furthermore, elevated levels and prolonged exposure of at least 48 hours (study duration) were achieved. Table 18. Dosage in rats and pharmacokinetic data. Drug Formulation Concentration (mg / mL) Vol. (mL / kg) Dose (mg / kg) Cmax (ng / mL) AUCfinal (hr*ng / mL) NMP 90% / TPGS 10% Solution 100 1 100 536 11362 PVP K30 0.5% plus Poloxamer 188 nanosuspension 0.5% 50 2 100 211 7067 SDD in HPMC 0.5% in aqueous suspension 13.6 7.35 100 49667 588287 Petition 870250094497, dated 10 / 16 / 2025, pp. 124 / 194 108 / 135 EXAMPLE 6: Single-Dose Oral Pharmacokinetic Study of Compound 1 in a Dog Preparation of the Formulation: solution in PEG300 85% / TPGS 10% / EtOH 5%

[00343] A solution of Compound 1 in PEG300 85% / TPGS 10% / EtOH 5% at a concentration of 2 mg / mL was prepared as follows: 1) 77.92 mg of Compound 1 weighed into a clear tube. 2) 87.759 mL of PEG300 85% / TPGS 10% / EtOH 5% were added to the tube containing the compound. 3) Vortex the tube for 5 minutes. Sonicate it for 10 minutes.

[00344] The final dosage formulation resulted in a clear, colored solution. Formulation Preparation: SDD Suspension

[00345] An SDD (Lot 1 of Example 4, Table 17) in HPMC 0.5% in Water at 100 mg / mL (drug concentration of 13.6 mg / mL) was prepared as follows: 1) 3521.31 mg of SDD were weighed in a mortar of appropriate size. 2) 5 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 30.213 mL of 0.5% HPMC in water were added slowly, and a pestle was used to break up the powder clumps to obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00346] The final dosage formulation was a homogeneous suspension Petition 870250094497, dated 10 / 16 / 2025, pp. 125 / 194 109 / 135 white genera. The suspension was shaken before dosing. Dosage in Animals

[00347] Non-naive male Beagles were used for the pharmacokinetic study in dogs. The animals had free access to food and water. The prepared solution and suspension formulations were administered orally to each group of animals (n = 3) with appropriate dosage volumes to achieve the respective doses.

[00348] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. The blood samples were placed on ice and centrifuged at 2000 g for 5 min to obtain plasma samples in 15 minutes. The plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00349] Dosage amounts and resulting pharmacokinetic parameters following oral administration of Compound 1 solution in PEG300 85% / TPGS 10% / EtOH 5% and Compound 1 SDD suspension are shown in Table 19, and mean plasma concentration profiles (n = 3) are shown in Figure 21. The Compound 1 SDD suspension achieved superior exposure to the solution formulation. High plasma levels were achieved, and prolonged exposure for at least 48 hours (study duration) was evident. Furthermore, the pharmacokinetic variability in plasma levels of the SDD suspension was significantly lower than that observed with Compound 1 in the PEG300 85% / TPGS 10% / EtOH 5% solution composition. Table 19. Dosage and Pharmacokinetic Data for Dogs Formulation Dose (mg / kg) Cmax (ng / mL) AUCfinal (hr*ng / mL) Cmax / Dose AUCfinal / Dose SDD in HPMC 0.5% aqueous suspension 10 11607 294851 1161 29485 Petition 870250094497, dated 10 / 16 / 2025, pp. 126 / 194 110 / 135 Formulation Dose (mg / kg) Cmax (ng / mL) AUCfinal (hr*ng / mL) Cmax / Dose AUCfinal / Dose Solution in PEG300 85% / TPGS 10% / EtOH 5% 4 3673 86767 918 21692 EXAMPLE 7: Seven-Day Oral Dosing Pharmacokinetic Study in Rats Formulation 1: SDD suspension at a concentration of Compound 1 of 1 mg / mL, dosed at 10 mL / kg to achieve 10 mg / kg.

[00350] An SDD (Lot 4 of Example 4, Table 17) in HPMC 0.5% in Water at 1 mg / mL was prepared as follows: 1) 485.06 mg of SDD were weighed into a new tube. 2) 68.393 mL of 0.5% HPMC in water were added to the tube containing the SDD. 3) The mixture was stirred for 40 minutes. 4) The mixture was homogenized with ULTRA-TURRAX T10 at medium speed for about 1 minute and then the mixing was paused for half a minute. This procedure was repeated 4 times.

[00351] The final dosage formulation was a white homogeneous suspension. The suspension was stirred before dosing. Formulation 2: SDD suspension at a concentration of Compound 1 of 10 mg / mL, dosage of 10 mL / kg to reach 100 mg / kg.

[00352] An SDD (Lot 4 of Example 4, Table 17) in HPMC 0.5% in Water at 10 mg / mL was prepared as follows: 1) 4822.98 mg of SDD were weighed into a new tube. 2) 68.004 mL of 0.5% HPMC in water were added to the tube containing the SDD. 3) The mixture was stirred for 40 minutes. 4) The mixture was homogenized with ULTRA-TURRAX T10 at medium speed for about 1 minute, and then the mixture Petition 870250094497, dated 10 / 16 / 2025, pp. 127 / 194 111 / 135 was paused for half a minute. This procedure was repeated 4 times.

[00353] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Formulation 3: SDD suspension at a concentration of Compound 1 of 30 mg / mL, dosage of 10 mL / kg to reach 300 mg / kg.

[00354] An SDD (Lot 4 of Example 4, Table 17) in HPMC 0.5% in Water at 30 mg / mL was prepared as follows: 1) 14,251.25 mg of SDD were weighed into a new tube. 2) 66.981 mL of 0.5% HPMC in water were added to the tube containing the SDD. 3) The mixture was stirred for 40 minutes. 4) The mixture was homogenized with ULTRA-TURRAX T10 at medium speed for about 1 minute, and then the mixing was paused for half a minute. This procedure was repeated 4 times.

[00355] The final dosage formulation was a white homogeneous suspension. The suspension was stirred before dosing. Dosage in Animals

[00356] Male Sprague-Dawley (SD) rats weighing 230-250 g and aged between 6 and 8 weeks were used for the pharmacokinetic study in rats. The animals had free access to food and water. The prepared compositions were administered orally daily for seven days to each group of animals (n=3), with dosage volumes appropriate to achieve the respective doses.

[00357] At each time point, approximately 110 μL of whole blood / time point was collected in a K2EDTA tube via the jugular vein. The blood sample was placed on ice and centrifuged at 2000 g for 5 min to obtain a plasma sample in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results Petition 870250094497, dated 10 / 16 / 2025, pp. 128 / 194 112 / 135

[00358] The mean plasma concentration profiles (n=3) of the compositions at the three dosage levels on Day 1 and Day 7 are shown in Figures 22 and 23. The SDD suspension of Compound 1 was able to rapidly achieve high exposure. Evidence of accumulation was present on Day 7 and plasma levels at the 100 mg / kg and 300 mg / kg doses were similar. EXAMPLE 8: Seven-Day Oral Dosage Pharmacokinetic Study in Dogs Formulation 1: SDD suspension at a concentration of Compound 1 of 0.2 mg / mL, dosed at 5 mL / kg to achieve 1 mg / kg.

[00359] An SDD (Lot 2 of Example 4, Table 17) in HPMC 0.5% in Water at 0.2 mg / mL was prepared as follows: 1) 338.14 mg of SDD were weighed in a mortar of appropriate size. 2) 5 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 229.435 mL of 0.5% HPMC in water were added slowly, and the powder was used to break up the clumping and obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00360] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Formulation 2: SDD suspension at a concentration of Compound 1 of 2 mg / mL, dosage at 5 mL / kg to achieve 10 mg / kg.

[00361] An SDD (Lot 2 of Example 4, Table 17) in HPMC 0.5% in Water at 2 mg / mL was prepared as follows: 1) 3,378.05 mg of SDD were weighed in a mortar of appropriate size. Petition 870250094497, dated 10 / 16 / 2025, pp. 129 / 194 113 / 135 2) 5 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 227.707 mL of 0.5% HPMC in water were added slowly, and the powder was used to break up the clumping to obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00362] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Formulation 3: SDD suspension at a concentration of Compound 1 of 20 mg / mL, dosed at 5 mL / kg to achieve 100 mg / kg.

[00363] An SDD (Lot 2 of Example 4, Table 17) in HPMC 0.5% in Water at 20 mg / mL was prepared as follows: 1) 33.858 g of SDD were weighed in a mortar of appropriate size. 2) 45 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 185.234 mL of 0.5% HPMC in water were added slowly, and the powder was used to break up the clumping to obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00364] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Dosage in Animals

[00365] Non-naive male Beagles were used for the pharmacokinetic study in dogs. The animals had free access to food and water. The prepared compositions were administered orally. Petition 870250094497, dated 10 / 16 / 2025, pp. 130 / 194 114 / 135 daily, for seven days, to each group of animals (n=3), with dosage volume appropriate to achieve the respective doses.

[00366] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00367] The mean plasma concentration profiles (n=3) of the compositions at the three dosage levels on Day 1 and Day 7 are shown in Figures 24 and 25. The SDD suspension of Compound 1 was able to rapidly achieve high exposure. Evidence of accumulation was present on Day 7 and plasma levels at the 10 mg / kg and 100 mg / kg doses were similar. EXAMPLE 9: Fourteen-Day Oral Dosage Pharmacokinetic Study in Dogs Formulation 1: SDD suspension at a Compound 1 concentration of 3 mg / mL, dosage of 5 mL / kg to achieve 15 mg / kg.

[00368] An SDD (Lot 3 of Example 4, Table 17) in HPMC 0.5% in Water at 0.2 mg / mL was prepared as follows: 1) 4851.0 mg of SDD were weighed in a mortar of appropriate size. 2) 5 mL of HPMC solution were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 3) 214.912 mL of 0.5% HPMC in water were added slowly, and the powder was used to break up the clumping and obtain a suspension. 4) The suspension was transferred to an appropriate container. Petition 870250094497, dated 10 / 16 / 2025, pp. 131 / 194 115 / 135 of.

[00369] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Dosage in Animals

[00370] Male or female non-naive Beagles were used for the pharmacokinetic study in dogs. The animals had free access to food and water. The prepared compositions were administered orally daily for fourteen days to each group of animals (n=2), with a dosage volume of 5 mL / kg to achieve a dose of 15 mg / kg.

[00371] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00372] The mean plasma concentration profiles (n=2) of the compositions in male and female dogs on Day 1 and Day 14 are shown in Figures 26 and 27. The SDD suspension of Compound 1 was able to rapidly achieve high exposure. Evidence of accumulation was present on Day 14. Plasma levels for female and male dogs were similar.

[00373] The mean plasma concentration-time profile after 14 days of consecutive oral administration of 15 mg / kg / day, once daily (n = 2 for each sex group) is shown in Figure 28. The SDD suspension of Compound 1 rapidly achieved high exposure. Notably, plasma concentrations remained very high even after dosing was stopped at 14 days. Plasma levels remained significantly higher than Petition 870250094497, dated 10 / 16 / 2025, pp. 132 / 194 116 / 135 the target level of 1100 ng / mL for an extended period. EXAMPLE 10: Study IV in dogs with and without oral administration of charcoal. Formulation Preparation - IV

[00374] A 0.1 mg / mL solution of Compound 1 in 10% DMSO / 10% Solutol HS15 / 80% Saline Solution was prepared as follows: 1) 4.63 mg of Compound 1 were weighed into a suitably sized tube. 2) 4.57 mL of DMSO were added to the tube. It was vortexed for 2 minutes. 3) 4.57 mL of Solutol HS15 were added to the tube above. It was vortexed for 2 minutes. 4) 36.54 mL of saline solution were added. It was vortexed for 1 minute.

[00375] The final formulation was a clear solution. Preparation of the Formulation - Oral Activated Charcoal

[00376] A suspension of 100 mg / mL of activated charcoal in saline solution was prepared as follows: 1) 300 g of activated charcoal were weighed into a suitably sized tube. 2) 3000 mL of saline solution were added to the tube. 3) The mixture was stirred for 10 minutes and then sonicated for 10 minutes. 4) The final formulation was a suspension. Dosage for Animals - Dogs

[00377] Two groups of non-naive male beagles were used for the pharmacokinetic study in dogs (n=2 per group). The prepared oral formulation was administered orally with a dose of 25 grams of activated charcoal to the animals in Group 2. Immediately after the Petition 870250094497, dated 10 / 16 / 2025, pp. 133 / 194 117 / 135 Oral administration, the prepared intravenous formulation was administered by intravenous infusion over 10 minutes to animals in Group 1 and Group 2, with dosage volumes appropriate to achieve the respective doses. Animals in Group 1 were fed before administration. Animals in Group 2 were fasted overnight before administration and fed 4 hours after oral administration.

[00378] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -80°C until analyzed by LC-MS. Results

[00379] The mean plasma concentration profiles (n=3) after intravenous (IV) administration of 0.10 mg / kg of Compound 1, with and without oral administration of charcoal, can be found in Figure 29. It is observed that clearance was slower and overall exposure was higher when Compound 1 was administered without oral administration of charcoal. While with co-administration of oral charcoal, Compound 1 could be adsorbed by charcoal in the intestine and reabsorption was reduced, indicating that intestinal reabsorption may play a role in clearance and exposure after administration of Compound 1. Summary of pharmacokinetic studies

[00380] In two different species, long-acting oral formulations containing the helicase primase inhibitor, Compound 1, were found to provide rapid exposure and sustained, stable plasma levels of the drug for significantly longer periods after oral administration. Furthermore, release was achieved Petition 870250094497, dated 10 / 16 / 2025, pp. 134 / 194 118 / 135 at different dosage levels and the variability in pharmacokinetics was low. Intestinal reabsorption may play a role in the high exposure achieved and clearance after oral administration of Compound 1. EXAMPLE 11: Preparation of Additional Solid Dispersion of Compound 1

[00381] A solid dispersion of Compound 1 using HPMCAS HG was fabricated using a spray drying method. The preparation conditions are described in Table 20. Table 20. Spray drying conditions Composition of SD 20:80 of Compound 1:HPMCAS HG Atomizing Solvent 95:5 of THF:Water Atomizing Solution (% by weight of total solids) 2 Büchi B-290 Spray Dryer Nozzle Type Two Fluids - 1.5 mm Air Capsule, 0.7 mm Liquid Tip Solution Flow Rate (mL / min) 12.2 Inlet Temperature (°C) 120-121 Outlet Temperature (°C) 62-67 Secondary Drying Temperature / Time 89 hours at 40°C

[00382] The solid dispersion was characterized in terms of drug charge and purity, and the results of this characterization work are presented in Table 21. Table 21. Characterization of the solid dispersion Example: Formulations Purity Test Lot 1 20:80 of Compound 1:HPMCAS HG 20.1% 99.7% Petition 870250094497, dated 10 / 16 / 2025, pp. 135 / 194 119 / 135

[00383] Initial XRPD characterization indicated that the SDD was amorphous and no crystalline peaks were observed in the SD diffractogram (Figure 30). Thermal analysis showed that the dispersion had a single Tg, indicating a closely mixed amorphous solid dispersion with good homogeneity (see Figure 31). A SEM image is shown in Figure 32.

[00384] A stability study was also conducted. The HPMCAS HG SDD was subjected to stress at 40 °C / 75% RH under open conditions for 5 days, and the SDD proved to be physically stable. No crystalline peaks were observed. Furthermore, the SDD was chemically stable and no additional impurities or increased impurities were observed (see Table 22 and Figure 33). Table 22. Characterization of the stability of the solid dispersion. Conditions Appearance XRPD Purity (%) % Area in RRT 0.56 0.80 1.36 1.72 Initial White powder Amorphous 99.61 0.11 0.10 0.07 0.11 40C / 75% / open, 5d White powder Amorphous 99.61 0.11 0.10 0.07 0.11 EXAMPLE 12: Single-Dose Oral Pharmacokinetic Study of Compound 1 in Dogs under fed and fasted conditions Formulation Preparation: SDD Suspension:

[00385] An SDD (Lot 1 of Example 11, Tables 20 and 21) in HPMC 0.5% in Water at 25 mg / mL (drug concentration of 5 mg / mL) was prepared as follows: 5) 3012 mg of SDD were weighed in a mortar of appropriate size. 6) 5 mL of 0.5% HPMC in water were added slowly. During the addition, a pestle was used to thoroughly mix and moisten the powder to obtain a moist paste. 7) 115.5 mL of 0.5% HPMC in water were added slowly and a pestle was used to break up the powder clumps. Petition 870250094497, dated 10 / 16 / 2025, pp. 136 / 194 120 / 135 to obtain a homogeneous suspension. 8) The suspension was transferred to an appropriate container.

[00386] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Dosage in Animals

[00387] Non-naive male Beagles were used for the pharmacokinetic study in dogs and divided into two groups. In Group 1, the animals were fed overnight before administration and then had free access to food and water 4 hours after administration. In Group 2, all animals were fed before administration. The prepared suspension formulation was administered orally to the animals (n = 3) at 2 mL / kg to achieve a dose of 10 mg / kg.

[00388] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS. Results

[00389] The pharmacokinetic parameters resulting from oral administration of the Compound 1 SDD suspension are shown in Table 23 and the mean plasma concentration profiles (n = 3) are shown in Figure 34. The Compound 1 SDD suspension achieved high plasma concentrations immediately within 4 hours, under both fed and fasting conditions. Notably, plasma concentrations remained very high after only a single 10 mg / kg dose. Plasma levels remained significantly above the target level of 1100 ng / mL for at least 4 hours. Petition 870250094497, dated 10 / 16 / 2025, pp. 137 / 194 121 / 135 less than 5 days and equal to or greater than target levels for approximately 14 days. The target plasma concentration was derived from pritelivir, adjusted for protein drift and the potency of Compound 1. Table 23. Pharmacokinetic Data for Dogs Dose Group (mg / kg) Tmax (hr) Cmax (ng / mL) C24hr (ng / mL) C14days (ng / mL) AUC0-14days (hr*ng / mL) 1 10 4 20133 4300 1103 871128 2 10 10 9660 8110 1397 1311690 EXAMPLE 13: Preparation of Tablet Compositions of Compound 1 Preparation of solid dispersion for use in tablet formulation.

[00390] A solid dispersion of Compound 1 using HPMCAS HG was fabricated using a commercial-scale spray dryer. The preparation conditions are described in Table 24. Table 24: Spray drying conditions Composition of SD 20:80 of Compound 1:HPMCAS HG Batch Size 12.5 kg Atomizing Solvent 95:5 of THF:Water Atomizing Solution (% by weight of total solids) 1.8 Spray Dryer GEA PSD-3 Nozzle Type High Pressure Nozzle Solution Flow Rate (kg / h) 45 Inlet Temperature (°C) 90 Outlet Temperature (°C) 50 Secondary Drying Temperature / Time 24 hours at 40°C

[00391] The solid dispersion was characterized with respect to the charge of the Petition 870250094497, dated 10 / 16 / 2025, page 138 / 194 122 / 135 maco and purity, and the results of this characterization work are presented in Table 25. Table 25 · Characterization of the solid dispersion Test Item Results Appearance Whitish powder Assay 19.3% Total Impurity 0.22% Residual Solvent - THF (GC) 297 ppm XRPD Amorphous Form Tg 103.9°C Preparation of the tablet composition

[00392] A tablet composition using the solid dispersion was manufactured by the dry granulation method. The composition of the tablet formulation is presented in Table 26. Table 26 · Tablet composition Component 50mg mg / Tablet % Intragranulation SDD 250.00 62.50 MCC, Avicel PH 105 47.00 11.75 Mannitol, Parteck M100 46.00 11.50 Croscarmellose Sodium 12.00 3.00 Sodium Lauryl Sulfate 4.00 1.00 Colloidal Silicon Dioxide 3.00 0.75 Magnesium Stearate 2.00 0.50 Final Mixture MCC, Avicel PH 200 20.00 5.00 Croscarmellose Sodium 12.00 3.00 Colloidal Silicon Dioxide 1.00 0.25 Magnesium Stearate 3.00 0.75 Total 400.00 100.00

[00393] The tablet formulation was prepared as follows: Petition 870250094497, dated 10 / 16 / 2025, page 139 / 194 123 / 135 ma.

[00394] SDD was mixed with the intragranular excipients described in Table 26. Roller compaction was used to granulate the mixture. The extragranular components were then added and mixed. The final mixture was pressed into tablets. The tablet formulation was characterized and the results of this characterization are presented in Table 27. Table 27. Tablet characterization Item Results Average tablet weight 401.53 mg RSD of Tablet Weight 0.48% Thickness 5.5 mm Hardness 15.7-18.7 kp Disintegration Time 96-109 sec. Friability 0.2% EXAMPLE 14: Pharmacokinetic Study of a Single-Dose Solid Dispersion Tablet in Fed / Fasting Dogs Dosage in Animals

[00395] Non-naive male Beagles were used for the pharmacokinetic study in dogs and divided into the following three groups: N Dose Food Pretreatment Stomach pH before oral administration Group 1 3 100 mg Fasting Pentagastrin 1.5-2 Group 2 3 100 mg Fasting Famotidine 6-7 Group 3 3 100 mg Fed None Not measured

[00396] Dogs in Group 1 were pre-treated with pentagastrin to reduce gastric pH. 30 minutes before each dose administration for Group 1, 6 μg / kg (80 μL / kg) of pentagastrin was administered intramuscularly to the animals. Stomach pH was measured Petition 870250094497, dated 10 / 16 / 2025, pp. 140 / 194 124 / 135 days prior to oral administration of the Compound 1 tablet. A tube was inserted into the stomach via a catheter and a small volume of gastric fluid was aspirated through the tube. The pH of the gastric fluid was determined using a pH meter.

[00397] Dogs in Group 2 were pre-treated with famotidine to increase gastric pH. Sixty minutes before each dose administration for Group 2, 40 mg / dog of the famotidine tablet was administered orally to the animals. Stomach pH was measured before oral administration of the Compound 1 tablet. A tube was inserted into the stomach via a catheter and a small volume of gastric fluid was aspirated through the tube. The pH of the gastric fluid was determined using a pH meter.

[00398] The tablets manufactured as described in Example 13 were administered orally by gavage to achieve a dose of 100 mg per dog (2 tablets of 50 mg). Water (10 mL) was injected into the gavage after tablet administration.

[00399] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS, using the following conditions: LC-MS parameters for quantification of Compound 1 in canine plasma samples after oral administration. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Column ACQUITY UPLC-BEH C18 (2.1x50 mm, 2.5 µm) Flow Rate 0.60 mL / min Column Temperature 60°C Petition 870250094497, dated 10 / 16 / 2025, pp. 141 / 194 125 / 135 Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1 mM Mobile Phase B Methanol / Formic Acid 0.025% / Ammonium Acetate 1 mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 90 10 0.20 90 10 0.40 40 60 1.80 10 90 1.81 90 10 2.20 Stop Stop Sample Temperature Room temperature Injection Volume 1.0 μL MS Detection Mode Multiple Reaction Monitoring (MRM) Retention Time 1.21 min Results

[00400] The pharmacokinetic parameters resulting from oral administration of the tablet formulations are presented in Table 28, and the mean plasma concentration profiles (n=3) are presented in Figure 36. Tablet formulations administered on an empty stomach, with pretreatment with pentagastrin or famotidine, achieved rapid plasma concentrations. Notably, plasma concentrations remained elevated after only one dose. Plasma levels remained significantly above the target level of 1100 ng / mL for at least 5 days. The target plasma concentration was derived from pritelivir, adjusted for Compound 1 protein drift and potency. The results indicate that the Petition 870250094497, dated 10 / 16 / 2025, pp. 142 / 194 126 / 135 The pharmacokinetic behavior of tablet formulations after oral administration in dogs is resistant to differences in gastric pH.

[00401] Data from Group 3 indicate that exposure is increased in the presence of food. Plasma concentrations remained elevated after only one dose. Plasma levels remained significantly above the target level of 1100 ng / mL for at least 14 days. Table 28. Pharmacokinetic Data for Dogs Dose (mg / dog) Tmax (hr) Cmax (ng / mL) C24hr (ng / mL) C14 days (ng / mL) AUC0-14 days (hr*ng / mL) Group 1 100 4 8303 5010 376 607492 Group 2 100 3.33 11300 4987 364 627829 Group 3 100 32 28467 26167 3187 3821060 Comparison of the tablet with the fasting SDD suspension

[00402] The mean plasma concentration profile (n=3) of the fasting tablet formulation, compared with the SDD suspension formulation dosed at 10 mg / kg fasting, as described in Example 12, is shown in Figure 37. The data show that the tablets were able to provide comparable exposure to the fasting SDD suspension. Comparison of the tablet with the SDD suspension in the fed state.

[00403] The SDD suspension formulation described in Example 12 was dosed to fed, non-naive male beagles. The animals received a meal 0.5 to 1 hour before administration. The prepared suspension formulation was administered orally to the animals (n=3) at 2 mL / kg to achieve a dose of 10 mg / kg.

[00404] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples Petition 870250094497, dated 10 / 16 / 2025, pp. 143 / 194 127 / 135 were placed on ice and centrifuged at 2000 g for 5 min to obtain plasma samples in 15 minutes. The plasma samples were stored at approximately -70°C until analyzed by LC-MS.

[00405] The mean plasma concentration profile (n = 3) of the tablet formulation after food administration (Group 3), compared with the SDD suspension formulation dosed at 10 mg / kg after food administration, is shown in Figure 38. The data indicate that exposure is increased in the presence of food for both formulations. Plasma concentrations remained elevated after only one dose. Plasma levels remained significantly above the target level of 1100 ng / mL for at least 14 days. EXAMPLE 15: Preparation and testing of other Solid Dispersions of Compound 1

[00406] The following solid dispersions containing Compound 1 were prepared using a spray drying method: Example 15O - Spray-dried Compound 1 without polymer (No polymer) Example 15A - 20:80 of Comp. 1: Eudragit® L100 SD Example 15B - 20:80 of Comp. 1: Eudragit® E100 SD Example 15C - 20:80 of Comp. 1: Soluplus® SD Example 15D - 20:80 of Comp. 1: PVP VA64 SD Example 15E - 20:80 of Comp. 1: HPMC E3 SD Example 15F - 20:80 of Comp. 1: HPMCAS-LG SD Example 15G - 20:80 of Comp. 1: HPMCAS-MG SD Example 15H - 20:80 of Comp. 1: HPMCAS-HG SD

[00407] All formulations were spray-dried from a 95:5 THF:water solution. A secondary tray drying process was used to remove residual solvent after the initial process. Petition 870250094497, dated 10 / 16 / 2025, pp. 144 / 194 128 / 135 spray drying. In this operation, the wet SDI was heated to 40°C and stored in a convection tray oven for approximately 66 hours. A summary of the spray drying parameters and recovered yields is shown in Table 29. Table 29: Summary of Spray Drying Parameters for SDs from Comp. 1 Formulation 15O 15A 15B 15C 15D 15E 15F 15G 15H Atomizing Solvent 95:5 THF: Water Atomizing Solution Solids Content (% by weight) 2% Nozzle Type Dual Fluid - 1.5 mm Air Cap, 0.7 mm Liquid Tip Pump Rate 30% Flow Q 28% 25% 28% 25% 28% 28% 28% 25% 25% Inlet Temp. (°C) 118-121 122-123 119-121 119-121 118-121 117-120 120-121 119-121 119-120 Temp. Outlet Temperature (°C) 69-71 74-77 74-77 75-78 75-78 76-79 73-75 77-78 78-79 Dry Solids Yield (% by weight) 54.2 54.7 40.6 66.2 34.9 65.1 45.2 44.0 62.9

[00408] All SD formulations were obtained as whitish powders. Thermal analysis by MDSC showed that all dispersions presented a single Tg, indicative of an intimately mixed amorphous solid dispersion with good homogeneity.

[00409] Preliminary performance of sample dissolution Petition 870250094497, dated 10 / 16 / 2025, pp. 145 / 194 129 / 135 SD and Compound 1 by mass were tested in a biorelevant dissolution experiment without sinking. Approximately 0.5 mg of SD samples were dispersed in 6 mL of SGF medium and magnetically stirred at 250 rpm at 37°C. After 30 min, 5 mL of cFaSSIFV2 (2X) medium were added to the above medium and the pH was adjusted to 6.5 with 100 μL of NaHCO3 (80 g / L). At each time point of 15 and 30 min in SGF and 15, 30, 60, and 120 min in FaSSIF, 0.5 mL of the suspension was withdrawn and centrifuged. The supernatants were analyzed by HPLC.

[00410] All SD formulations provided an increase in drug dissolution and maintenance in the intestinal environment, with 20% Comp 1 in Soluplus (Ex. 15C) and HPMCAS-H (Ex. 15H) showing the best dissolution performance. Dissolution results are presented in Table 30. Table 30: Summary of MDSC data and dissolution tests for the Examples Example. Formulations Tg (°C) Concentration (μg / mL) In SGF (pH 1.7) In FaSSIF (pH 6.5) 15 min 30 min 45 min 60 min 90 min 150 min Pure API — 0.10 0.07 0.14 0.12 0.14 0.12 15O API SD 95.5 0.64 0.42 0.26 0.27 0.28 0.46 15A 20:80 of Comp. 1:Eudragit® L100 SD 111.0 0.74 0.44 0.33 0.30 0.28 0.28 15B 20:80 of Comp. 1:Eudragit® E100 SD 58.4 0.49 0.16 0.09 0.08 0.06 0.06 15C 20:80 Comp. 1:Soluplus® SD 79.3 1.35 1.16 3.03 3.42 3.74 3.94 Petition 870250094497, dated 10 / 16 / 2025, pp. 146 / 194 130 / 135 15D 20:80 Comp. 1:PVP VA64 SD 98.0 2.77 1.63 0.57 0.72 0.85 1.45 15E 20:80 de Comp. 1:HPMC E3 SD 109.9 0.36 0.23 0.50 0.38 0.40 0.48 15F 20:80 Comp. 1:HPMCAS-LG SD 100.5 0.66 0.27 0.59 0.65 0.53 0.54 15G 20:80 Comp. 1:HPMCAS-MG SD 98.1 0.49 0.34 1.31 0.98 0.85 1.27 15H 20:80 Comp. 1:HPMCAS-HG SD 97.6 0.39 0.37 1.99 2.67 2.42 1.64

[00411] The SDs in Soluplus (Ex. 15C), HPMCAS-LG (Ex. 15F), HPMCAS-MG (Ex. 15G) and HPMCAS-HG (Ex. 15H) were characterized by GC, XPRD and HPLC. The XPRD diffractograms are shown in Figure 39 and show that all SDs were amorphous. The GC, assay and purity results are summarized in Table 31. Table 31: Characterization of SDs Ex. 15C 15F 15G 15H Formulation 20:80 of Comp. 1:Soluplus® SD 20:60 of Comp. 1:HPMCASLG SD 20:80 of Comp. 1:HPMCASMG SD 20:80 of Comp. 1:HPMCASHG SD GC (THF, ppm) 716 81 114 64 Assay (%) 20.4 19.3 20.2 20.1 Purity (%) 99.73 99.73 99.72 99.61 Stress Stability of Solid Dispersions of Compound 1

[00412] To evaluate the physical and chemical stability of the SDD formulations of Compound 1, four dispersions - Example 15C (20:80 of Comp. 1: Soluplus), Example 15F (20:80 of Comp. 1: HPMCAS-LG), Example 15G (20:80 of Comp. 1: HPMCAS-MG) and Example 15H (20:80 of Comp. 1: HPMCAS-HG) were aged for 5 days at 40°C / 75% RH in open packages. Approximately 0.5 g of Petition 870250094497, dated 10 / 16 / 2025, pp. 147 / 194 131 / 135 each sample was placed in an open HDPE bottle, without a lid, and a cotton swab was placed over the neck of the bottle.

[00413] The SDs were evaluated for physical and chemical stability by appearance, amorphous character by XRPD assay and impurities by HPLC, after aging.

[00414] Appearance tests showed that all stability samples, except for the SD sample in soluplus, exhibited freely flowing whitish powder after aging. The 20:80 Comp. 1:Soluplus® SD sample was observed to form a clump and adhered to the bottom of the vial.

[00415] The assay and purity data are presented in Table 32. Table 32: Characterization of SDs Example Formulation Condition Assay (%) Purity (%) Impurities (%) RRT0.56 RRT0.80 RRT1.36 RRT1.72 15°C 20:80 of Comp. 1 :Soluplus® SD Initial 20.4 99.73 / 0.09 0.07 0.10 40°C / 75% open, 5 days 19.1 99.73 / 0.10 0.07 0.10 15°F 20:80 of Comp. 1:HPMCA S-LG SD Initial 19.3 99.73 / 0.10 0.07 0.11 40°C / 75% open, 5 days 19.5 99.73 / 0.09 0.07 0.11 15G 20:80 of Comp. 1:HPMCA S-MG SD Initial 20.2 99.72 / 0.09 0.08 0.10 40°C / 75% open, 5 days 19.9 99.72 / 0.10 0.07 0.11 15H 20:80 of Comp. 1:HPMCA S-HG SD Initial 20.1 99.61 0.11 0.10 0.07 0.11 40°C / 75% open, 5 days 19.7 99.61 0.11 0.10 0.07 0.11 Petition 870250094497, dated 10 / 16 / 2025, pp. 148 / 194 132 / 135

[00416] After stabilization under stress in open conditions of 40°C / 75% RH for five days, XRPD pore analysis of the aged SDD samples showed that the 20:80 Comp. 1:HPMCAS-HG sample remained amorphous, with no detectable crystalline material (Figure 40). The 20:80 Comp. 1:Soluplus® SD sample showed evident signs of crystalline material after aging in open conditions of 40°C / 75% RH for five days (Figure 41). The 20:80 Comp. 1:HPMCAS-LG (Figure 42) and 20:80 Comp. 1:HPMCAS-MG (Figure 43) samples showed some small crystalline peaks after aging in open conditions of 40°C / 75% RH for five days. In Vitro Test of Solid Dispersions of Compound 1 using Pion's pflux device

[00417] The dissolution and permeation of SDs in Soluplus (Ex. 15C), HPMCAS-LG (Ex. 15F), HPMCAS-MG (Ex. 15G), and HPMCAS-HG (Ex. 15H) were subsequently evaluated using a PION pflux device. Approximately 20 mL of ASB (Acceptor Sink Buffer, pH 7.4, Pion Inc.) were initially added to the acceptors. Then, approximately 5 mg of solid dispersions were dispersed in 16 mL of SGF medium in the donor chamber and magnetically stirred at 250 rpm at 37°C. The donor and acceptor chambers were connected via a semipermeable membrane. After 30 min, 4 mL of concentrated FaSSIF medium were added to the donor chamber to achieve the target API concentration of 50 pg / mL for 3 h. Data were collected at 1 point / min. The results from the donor and recipient chambers are shown in Figures 44 and 45. EXAMPLE 16: Pharmacokinetic Study of Compound 1 in a Single Oral Dose in Dogs

[00418] Four Dispersions - Example 15C (20:80 of Comp. 1: Soluplus), Example 15F (20:80 of Comp. 1: Soluplus), Example 15G Petition 870250094497, dated 10 / 16 / 2025, pp. 149 / 194 133 / 135 (20:80 of Comp. 1: HPMCAS-MG) and Example 15H (20:80 of Comp. 1: HPMCAS-HG) were administered orally to dogs to evaluate pharmacokinetics. Formulation Preparation: SDD Suspension

[00419] SDD in HPMC 0.5% in Water at 125 mg / mL (drug concentration of 25 mg / mL) was prepared as follows: 1) 1800 mg of SDD were weighed in a mortar of appropriate size. 2) 2 mL of HPMC solution were added slowly. During the addition, a pestle was used to mix and moisten the powder carefully, obtaining a moist paste. 3) 70 mL of 0.5% HPMC in water were added slowly, and a pestle was used to break up the powder clumps and obtain a suspension. 4) The suspension was transferred to an appropriate container.

[00420] The final dosage formulation was a homogeneous white suspension. The suspension was shaken before dosing. Dosage in Animals

[00421] Non-naive male Beagles were used for the pharmacokinetic study in dogs. The animals were fasted overnight before dosing. The prepared suspension formulations were administered orally to each group of animals (n = 3) with appropriate dosage volumes to achieve the respective doses.

[00422] At each time point, approximately 0.5 mL of whole blood was collected in K2EDTA tubes. Blood samples were placed on ice and centrifuged at 2000 g for 5 minutes to obtain plasma samples in 15 minutes. Plasma samples were stored at approximately -70°C until analyzed by LC-MS, using the following conditions: Petition 870250094497, dated 10 / 16 / 2025, pp. 150 / 194 134 / 135 LC-MS parameters for quantification of Compound 1 in canine plasma samples after oral administration. Parameter Value Instrument LC-MS / MS-47 (Triple Quad 6500+) MS Conditions Positive, ESI Column ACQUITY UPLC-BEH C18 (2.1x50 mm, 2.5 pm) Flow Rate 0.60 mL / min Column Temperature 60°C Sample Diluent MeOH:H2O 50:50 (v:v) Mobile Phase A Water / Formic Acid 0.025% / Ammonium Acetate 1 mM Mobile Phase B Methanol / Formic Acid 0.025% / Ammonium Acetate 1 mM Program Type Gradient Gradient Program Time (min) % Mobile Phase A % Mobile Phase B 0.0 90 10 0.20 90 10 0.40 40 60 1.80 10 90 1.81 90 10 2.20 Interruption Interruption Sample Temperature Room temperature Injection Volume 1.0 pL MS Detection Mode Multiple reaction monitoring (MRM) Retention Time 1.21 min Results

[00423] Dosages and pharmacokinetic parameters resulting after oral administration of suspensions prepared with the four Petition 870250094497, dated 10 / 16 / 2025, pp. 151 / 194 135 / 135 different SDDs are presented in Table 33 and the mean plasma concentration profiles (n=3) are presented in Figure 46. Table 33. Dosage and Pharmacokinetic Data in Dogs Example: Formulation Dose (mg / kg) Cmax (ng / mL) AUC(0-24hr) (hr*ng / mL) 15C 20:80 of Comp. 1:Soluplus® SD 10 28367 340832 15F 20:80 of Comp. 1:HPMCAS-LG SD 10 5697 62206 15G 20:80 of Comp. 1:HPMCAS-MG SD 10 14300 170070 15H 20:80 of Comp. 1:HPMCAS-HG SD 10 30067 326889 Petition 870250094497, dated 10 / 16 / 2025, pp. 152 / 194

Claims

1 / 4 CLAIMS 1. Oral pharmaceutical composition, characterized in that it comprises a solid dispersion, wherein the solid dispersion comprises a compound (Compound 1) represented by: or a pharmaceutically acceptable salt thereof, and at least one matrix polymer.

2. Composition according to claim 1, characterized in that the solid dispersion is a substantially amorphous solid dispersion.

3. Composition according to claim 1, characterized in that the solid dispersion is an amorphous solid dispersion.

4. Composition according to claim 1, characterized in that the solid dispersion has a single glass transition temperature (Tg).

5. Composition, according to any one of claims 1 to 4, characterized in that Compound 1 is in its neutral free form.

6. Composition, according to any one of claims 1 to 5, characterized in that the solid dispersion comprises from about 5% by weight to about 60% by weight of Compound 1 or a pharmaceutically acceptable salt thereof.

7. Composition, according to any one of claims 1 to 6, characterized in that the solid dispersion comprises from about 30% by weight to about 95% by weight of at least a matrix polymer.

8. Composition, according to any one of claims 1 to 7, characterized in that the solid dispersion comprises about 5% by weight to about 20% by weight of Compound 1 or of a pharmaceutically acceptable salt thereof and about 60% by weight to about 95% by weight of at least one matrix polymer.

9. Composition according to any one of claims 1 to 8, characterized in that at least one matrix polymer is an ionic or neutral polymer, insoluble in water or soluble in water.

10. Composition according to claim 9, characterized in that at least one matrix polymer is: i. an ionic polymer or a pH-sensitive polymer, optionally wherein the pH-sensitive polymer dissolves in aqueous medium at a pH above 5.5; ii. selected from a povidone polymer, a copovidone polymer, a methacrylate polymer, a polymethacrylate-based copolymer, poly(vinyl caprolactam-vinyl acetate-co-ethylene glycol), hydroxypropylmethylcellulose, hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate; iii. selected from a copovidone polymer, poly(vinyl caprolactam-vinyl acetate-co-ethylene glycol), hydroxypropylmethylcellulose succinate acetate and hydroxypropylmethylcellulose phthalate; or iv. selected from hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate.

11. Composition, according to any one of claims 1 to 10, characterized in that there is only one parent polymer present in the solid dispersion.

12. Composition, according to any of claims 1 to 11, characterized in that the solid dispersion is a spray-dried solid dispersion.

13. Composition, according to any one of claims 1 to 12, characterized in that it is in a pharmaceutical form suitable for oral administration, selected from the group consisting of a granule, a pellet, a tablet, a particle, a capsule, a suspension and a mini-tablet.

14. Composition according to claim 13, characterized in that it is a tablet with a total weight of less than 1000 mg, such as less than 900 mg or less than 600 mg.

15. Composition, according to claim 13 or 14, the pharmaceutical composition characterized in that it comprises from about 1 mg to about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

16. Composition, according to any one of claims 1 to 15, characterized in that it is chemically and / or physically stable for at least four weeks.

17. Composition, according to any one of claims 1 to 16, characterized in that, after oral administration to a fasting human subject, it produces a plasma concentration in the subject after administration of Compound 1 of at least 1100 ng / mL for at least 80% of the dosing interval, the dosing interval being at least 2 days.

18. Composition, according to any one of claims 1 to 17, characterized in that it is for use as a medicament.

19. Method for treating a herpes virus infection (such as HSV) in an individual in need thereof, characterized in that it comprises administering a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to the individual, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition as defined in any one of claims 1 to 17.

20. Method according to claim 19, characterized in that the pharmaceutical composition is administered no more than once every 5 days, no more than once every 7 days, no more than once every 10 days, twice a month, once a month, once every two months, once every three months, once every six months or once a year.

21. Method for increasing the bioavailability of Compound 1, or a pharmaceutically acceptable salt thereof, compared to oral administration of an equivalent dose of Compound 1, or a pharmaceutically acceptable salt thereof, in a crystalline form, characterized in that it comprises oral administration to an individual of a pharmaceutical composition as defined in any one of claims 1 to 17.

22. Solid dispersion, characterized in that it comprises: a. compound 1 or a pharmaceutically acceptable salt thereof; b. at least one matrix polymer; and c. optionally one or more pharmaceutically acceptable excipients. Petition 870250094497, dated 10 / 16 / 2025, pp. 156 / 194

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