Crystal form of an HIV nucleoside reverse transcriptase inhibitor

Abstract

This disclosure provides crystalline forms of a compound of Formula (A), and pharmaceutical compositions thereof. This disclosure further provides methods for their preparation and use in methods of treatment, prophylaxis, or delay in onset or progression of HIV infection or AIDS in a subject. This disclosure further provides dosage forms, such as oral tablets, of a compound of Formula (A) and its crystalline forms.

Description

CRYSTAL FORM OF AN HIV NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Applications Serial Nos. 63 / 889,995 filed September 29, 2025, and 63 / 734,309 filed December 16, 2024, the entire contents of which are incorporated by reference herein.FIELD

[0002] This disclosure relates generally to a solid form of an HIV nucleoside reverse transcriptase inhibitor compound. Nucleoside reverse transcriptase inhibitors may have therapeutic and research applications, in particular to the prevention of the transmission of HIV and for the prevention of AIDS.BACKGROUND

[0003] Human immunodeficiency virus (HIV-1) infection is a serious condition which if left untreated ultimately destroys the host’s immune system resulting in acquired immunodeficiency syndrome (AIDS) and premature death. Despite advances in antiretroviral therapies (ART), HIV continues to be a global epidemic and a global public health priority. Nucleotide reverse transcriptase inhibitors (NRTIs) are an ART that block HIV replication by inhibiting HIV reverse transcriptase activity. Upon entering cells, NRTIs such as tenofovir enter into obligate intracellular anabolic pathways for conversion to active phosphorylated forms, and it is their intracellular half-lives rather than their plasma concentrations that dictate their persistent effect.

[0004] Monumental advances have been made in the treatment of HIV over the past 40 years. The advent of combination antiretroviral (ARV) regimens has transformed HIV from an infection that rapidly leads to AIDS and death, to a manageable chronic disease. To date, significant research has focused on the development of more tolerable and convenient ARVs to decrease barriers associated with adherence and improve overall treatment outcomes (see Tseng, Seet & Phillips, Br J Clin Pharmacol. 2015; 79(2): 182-94). Moreover, in the absence of HIV vaccines, prophylactic agents are increasingly recognized as being key to decreasing the number of new infections. The most common prophylactic option is daily oral therapy (emtricitabine / tenofovir disoproxil fumarate or emtricitabine / tenofovir alafenamide), which has shown high effectiveness against HIV acquisition (Liegeon, Delaugerre & Molina, Infect Dis Clin North Am. 2024;38(3):453-74). But daily oral therapy regimens continue to meet challenges concerningadherence and are negatively influenced by factors such HIV-related stigma, concerns about adverse events, and a low perceived risk of acquiring HIV.

[0005] Currently, the only approved long-acting prophylactic option is cabotegravir, which is administered via intramuscular (IM) injection every 8 weeks. (See Gandhi RT, et al. JAMA 2023; 329(l):63-84; Landovitz RJ. et al. N Engl J Med. 2021; 385(7): 595-608.) Acceptance and accessibility of this regimen is limited by the healthcare service delivery system, the frequency of clinic visits, and potential side effects. As such, while over 6 million people globally had initiated HIV prophylaxis by the end of 2023, there were still an estimated 1.3 million new HIV infections that year (see UNAIDS.org, 2024 fact sheet, Global HIV Statistics). Thus, the need for more flexible and accessible long-acting options for HIV prophylaxis remains.

[0006] HIV drug therapy is life-long, and strict adherence to treatment regimens is critical to maintain viral suppression, reduce the risk of drug resistance, and minimize the risk of transmission. Efficacious and safe, well-tolerated drugs that are easy to take with low dosing frequency have the potential to improve a patient’s adherence and long-term treatment success, as well as increasing pre-exposure prophylaxis (PrEP) use among uninfected populations with a greater likelihood of acquiring HIV. The only oral PrEP drug products that have been approved by the U.S. Food and Drug Administration are TRUVADA® (emtricitabine / tenofovir DF) and DESCOVY® (emtricitabine / tenofovir AF), and both are approved for daily administration only.

[0007] Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) are an emerging class of potent antiretroviral agents that block HIV replication and have demonstrated the potential for long-acting administration. There is a need in the art for NRTTI drugs that are suitable for extended-duration dosing for prophylaxis, including once-monthly administration.SUMMARY

[0008] The present application provides novel cry stalline anhydrous forms of Compound A, i.e., crystalline Form 1. Compound A is ((27?,3S,5 )-5-(4-amino-2-chloro-777-pyrrolo[2,3- d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol) and has the following structure, i.e.. Formula A:

[0009] The disclosure further provides pharmaceutical compositions of crystalline Form 1 of the compound of Formula A, i.e., Compound A. The disclosure also provides methods for the inhibition of HIV reverse transcriptase, the treatment or prophylaxis of HIV infection, and / or the treatment, prophylaxis, and / or delay in the onset or progression of AIDS in a subject in need thereof by administering the crystalline Form 1 of Compound A. Further provided in this disclosure are methods for preparing crystalline Form 1.

[0010] Compound A is an NRTTI that exhibits antiviral potency and pharmacokinetics (PK) suitable for long-acting, oral dosing, and an attractive profile for HIV pre-exposure prophylaxis (PrEP). It is a 7-deaza-deoxy adenosine analog that features a 4'-ethynyl group on the ribose sugar moiety. Compound A is phosphorylated intracellularly to its pharmacologically active triphosphate (TP) form (Cmpd-A-TP), which inhibits reverse transcription and translocation. The PK properties of Compound A observed in preclinical and Phase 1 studies support once monthly (QM) dosing. See Raheem, el al. Discovery of COMPOUND A. a long-acting HIV nucleoside reverse transcriptase translocation inhibitor presented at CROI, March 3-6, 2024. which is herein incorporated by reference.

[0011] The inhibitory activity of Compound A has been shown to be specific against HIV virus. Iron footprinting and primer extension assays demonstrated that the active TP form of compound A inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. Compound A inhibited viral replication in human peripheral blood mononuclear cells (PBMCs). Following oral administration to monkeys, the TP form exhibited an intracellular half-life of approximately 48 hours in PBMCs. It exhibited a similar terminal half-life in plasma. The PK profile of compound A in rats and monkeys was characterized by low to moderate clearance and volume of distribution, with good oral absorption. See Raheem, et al., and U.S. Patent Publication No. 2015 / 0274767, published October 1, 2015 and herein incorporated by reference, describes Compound A, among other NRTTI compounds, and methods for its chemical synthesis. It states that Compound A was synthesized and isolated by preparative high performance liquid chromatography (prep-HPLC). The product-containing fractions from the HPLC column were collected and lyophilized to yield Compound A as a solid. Lyophilization is a common practice to generate amorphous solids. Amorphous solids tend to exhibit low thermodynamic stability.

[0012] In contrast, the crystalline Form 1 of this disclosure was generated using a crystallization process from a saturated solution. Form 1 is the most stable form of compound A, as shown by a polymorph screen.26089

[0013] Thus, in some aspects, the disclosure provides Compound A having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form. Form 1 may be characterized by a powder x-ray diffraction pattern (PXRD) obtained using Cu K alpha radiation. In other aspects, Form 1 may be characterized by a thermogravimetric analysis (TGA) curve, a differential scanning calorimeter (DSC) thermogram, and / or a solid state Fourier-transform infrared (FT-IR) spectrum. In some embodiments. Form 1 may be further characterized by particle size and / or morphology.

[0014] In some embodiments, Form 1 is characterized by a PXRD pattern comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70. and 25.18. In some embodiments, Form 1 is further characterized by a PXRD pattern containing peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 16.25, 18.17, 18.74, 20.70, 22.81, 25.18, 26.38, 26.88, and / or 29.94. In particular embodiments, Form 1 is characterized by peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17. 20.70, 22.81. 25.18, 26.38, and 26.88.

[0015] In some embodiments, Form 1 is characterized by a TGA curve showing about 0.05 weight (wt.) % loss at 200 °C, followed by thermal decomposition above about 240 °C. Form 1 may be characterized by a DSC thermogram showing a melting onset temperature of 220.8 °C.

[0016] In some embodiments, Form 1 is characterized by a solid state FT-IR spectrum exhibiting at least three of the following peaks: 613.52, 655.84. 702.36, 719.32, 917.24, 941.08, 1011.90, 1082.76, 1117.53, 1274.48, 1303.69, 1557.30, 1589.95, 1642.86, 2106.54, 2874.51, 3227.41, 3328.27, and 3437.67 cm'1. Form 1 may be characterized by at least six of these FT-IR peaks.

[0017] In some embodiments, Form 1 may be further characterized by a particle size D50 of 53.74 pm. In various embodiments, Form 1 exhibits a rod-like morphology.

[0018] Form 1 is a crystalline anhydrous free base form that may be characterized by a (a) PXRD pattern obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, and 25.18; (b) thermogravimetric analysis (TGA) curve showing about 0.05 wt. % loss at 200 °C, followed by thermal decomposition above 240 °C (c) differential scanning calorimeter (DSC) curve showing a melting onset temperature of about 220.8 °C; and (d) particle size (D50) of 53.74 pm.

[0019] The present disclosure further provides pharmaceutical compositions comprising Compound A in Form 1. and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is adapted for oral administration. The pharmaceutical composition may be present in an oral dosage form, such as an oral tablet. Form 1 is particularly suitable for formulation an oral dosage form, such as a tablet (e.g., a film-coated tablet).26089

[0020] The disclosed pharmaceutical compositions are useful for the treatment and prophylaxis of HIV infection. As such, in some aspects, the disclosure provides methods for the inhibition of HIV reverse transcriptase in a subject in need thereof which comprise administering to the subject an effective amount of Form 1 of the compound, or a pharmaceutical composition thereof. Further provided are methods for the treatment, prophylaxis, or delay in onset or progression of HIV infection or AIDS in a subject in need thereof that comprise administering to the subject an effective amount of Form 1 of the compound, or a pharmaceutical composition thereof. Further provided are methods for providing PrEP or post-exposure prophylaxis (PEP) of HIV infection in a subject that comprise administering to the subject an effective amount of Form 1 of the compound, or a pharmaceutical composition thereof. In various embodiments, the subject is human.

[0021] Form 1 of the compound is suitable for extended duration administration, such as once- monthly administration. In particular embodiments, the disclosed pharmaceutical compositions are useful for PrEP, e.g., once-monthly PrEP. In some embodiments, provided herein are methods for the prophylaxis (e.g., PrEP and PEP) of HIV infection by administering an effective amount of the disclosed crystalline Form 1, or any of the disclosed pharmaceutical compositions, to a subject. In particular embodiments, the disclosed pharmaceutical compositions are useful for oral once-monthly PrEP. Thus, in some embodiments, provided herein are methods for the prophylaxis (e.g., PrEP and PEP) of HIV infection by administering orally an effective amount of the disclosed crystalline Form 1, or any of the disclosed pharmaceutical compositions, to a subject once-monthly. In some embodiments, provided are methods of administering orally an effective amount of about 11 mg of the disclosed crystalline Form 1, or any of the disclosed pharmaceutical compositions, to a subject one-monthly. Methods of administering an oral tablet containing about 1 1 mg of Form 1 once-monthly are provided.

[0022] In some aspects, methods of administering an oral tablet comprising compound A are provided. In some embodiments, methods of administering an oral tablet comprising compound A in a form other than anhydrous crystalline Form 1 are provided, such as an amorphous form.

[0023] In some aspects, disclosed are methods of administering an oral tablet comprising compound A (e.g., wherein the compound has a form that is crystalline form 1) to a human subject. In various embodiments, the human subject is an adult. In some embodiments, the human subject is an adolescent. In some embodiments, the human subject is under eighteen years of age. In some embodiments, the human subject is between twelve and eighteen years of age. In some embodiments, the human subject is between sixteen and eighteen years of age. In some embodiments, the human subject weighs at least 35 kg. In other embodiments, the human subjectweighs less than 35 kg. In some embodiments, the human subject weighs between 25 kg and 35 kg. In other embodiments, the human subject weighs less than 25 kg. In sub-embodiments of these embodiments of administering to adult or pediatric (e.g. adolescent) human subjects, these methods are useful for oral once-monthly PrEP.

[0024] Methods of preparing compound A in Form 1 are also provided. In some embodiments, preparation methods are provided that involve precipitating the compound from a saturated methanol / water solution to provide crystals of Form 1, wherein Form 1 is a crystalline anhydrous free base form characterized by a PXRD obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, and 25.18.

[0025] Further provided are oral tablets comprising compound A. In some aspects, an oral tablet comprising compound A, wherein the compound is present in an amount of about 9 mg, 10 mg, 11 mg, or 12 mg, is provided. In some embodiments, the compound is present in an amount of about 11 mg. In particular embodiments, a tablet comprising compound A having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form charactenzed by a powder x-ray diffraction pattern (PXRD) obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18. 17, 20.70, and 25.18. The tablet may comprise about 11 mg of anhydrous Form 1.

[0026] Other embodiments, aspects and features of the present invention are further described herein or will be apparent from the following description, examples and appended claims.BRIEF DESCRIPTIONS OF THE DRAWINGS

[0027] FIGURE 1 is a graph of a powder X-Ray diffraction (“PXRD”) pattern of cry stal 1 i ne Form 1 of compound A, generated using copper (Cu) K alpha X-ray radiation. The graph plots the intensity of the peaks as defined by counts per second versus the diffraction angle 2 theta (20) in degrees.

[0028] FIGURE 2 depicts a differential scanning calorimetry (DSC) pattern of crystalline Form 1, generated using a calorimeter instrument.

[0029] FIGURE 3 is a scanning electron microscope (SEM) image of Form 1, showing in detail its rod-like morphology. A 100 pm scale is shown.

[0030] FIGURE 4 is a graph of a thermogravimetric analysis (“TGA”) of crystalline Form 1. The graph plots the weight (percentage) against temperature (°C).

[0031] FIGURE 5 is solid state Fourier-transform infrared (FT-IR) spectrum of crystalline Form 1. The spectrum was collected with 32 scans.

[0032] FIGURE 6 depicts a dynamic vapor sorption (DVS) pattern of crystalline Form 1. This pattern shows changes in weight of a sample of the compound as relative humidity is varied (y- axis).

[0033] FIGURE 7 depicts a particle size distribution (PSD) pattern for crystalline Form 1, generated using a Microtrac Flowsync analyzer.

[0034] FIGURE 8 is a plot of predicted concentration of the triphosphate metabolite of Compound A (Cmpd-A-TP) in human peripheral blood mononuclear cells over time (28 weeks) following once-monthly administration of 11 mg of Compound A, determined using a population PK model based on clinical data. The y-axis has a logarithmic scale. The horizontal dashed line represents the PK efficacy threshold, and the vertical dashed line represents a missed dose.

[0035] FIGURE 9 is a superimposed plot of individual concentrations of Compound A measured in human plasma over time (168 hours) following administration of an 11 mg tablet of Compound A to 16 healthy human subjects. The y-axis has a logarithmic scale.DETAILED DESCRIPTION

[0036] The present disclosure is directed to a novel polymorphic form of compound A, i.e., crystalline Form 1. Form 1 is an anhydrous crystalline solid that was generated by crystallization from a saturated solution. The present disclosure further encompasses pharmaceutical compositions (e.g., oral dosage forms) containing Form 1. The present disclosure also encompasses methods for the inhibition of HIV reverse transcriptase, the treatment of HIV or prophylaxis of infection by HIV, and / or the treatment, prophylaxis, and / or delay in the onset or progression of AIDS, which comprise administering to a subject an effective amount of crystalline anhydrous Form 1 of Compound A. The present disclosure also provides methods for pre-exposure prophylaxis (PrEP) of HIV infection by administering Form 1 to a subject. The present disclosure also provides methods for post-exposure prophylaxis (PEP) of HIV infection by administering Form 1 to a subject.

[0037] Form 1 may be provided as a free base. In other embodiments, Form 1 may be provided as a pharmaceutically acceptable salt.

[0038] The present disclosure further provides methods for the use of crystalline Form 1 in the manufacture of a medicament which may be useful (alone or together with additional active ingredients) for the inhibition of HIV reverse transcriptase, for the treatment of HIV or prophylaxis of infection by HIV, and / or the treatment, prophylaxis and / or delay in the onset or progression of AIDS.

[0039] Advantages of the disclosed crystalline compound includes high thermodynamic stability. Crys tai line Form 1 is an exceptionally stable polymorph of compound A — in particular, it is the most stable form of Compound A observ ed. Crystalline Form 1 is particularly suitable for formulation with pharmaceutically acceptable excipients in an oral dosage form, such as a tablet. As such, embodiments of the disclosed pharmaceutical compositions and medicaments encompass one or more tablets comprising crystalline Form 1.

[0040] Further aspects include processes for making crystalline Form 1. In some aspects, preparation procedures are disclosed that comprise precipitating the compound from a saturated solution of crude Compound A in methanol and water to provide crystals of Form 1. The compound may be precipitated from a supersaturated solution. In some embodiments of these preparation procedures, Form 1 is generated by dissolving crude Compound A in a saturated methanol / water solution, e.g., a 1 : 1 methanol / water solution (vol / vol). In some embodiments, Form 1 is generated by dissolution of crude Compound A in a methyl-tetrahydrofuran / water solution (MeTHF / water). Following the step of dissolving, a slow evaporation may be applied to the solution to obtain anhydrous crystals.

[0041] In some aspects, Form 1 may be characterized by a powder x-ray diffraction pattern (PXRD) obtained using copper X-ray tube (Cu K a) radiation. In some embodiments, Form 1 is characterized by a PXRD pattern comprising one or more peaks at diffraction angles degrees 2 theta (+ / - 0.2°) from among the following peaks: 16.25, 18.17, 18.74, 20.70, 22.81, 25.18, 26.38, 26.88, and / or 29.94. In some embodiments, Form l’s PXRD pattern exhibits peaks corresponding to at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 of these angles. In particular embodiments, Form 1 is characterized by a PXRD pattern that exhibits peaks at 18.17, 20.70, and 25.18 2 theta (+ / - 0.2°). In some embodiments. Form 1 is characterized by peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, 22.81, 25.18, 26.38, and 26.88.

[0042] In some embodiments, Form 1 has a PXRD pattern that comprises three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more of the diffraction angle values listed in Table 1, + / - 0.2° 2-theta. In some embodiments, Form l’s PXRD pattern comprises six or more, or nine or more, of those diffraction angle values. In some embodiments, Form l 's PXRD pattern exhibits all diffraction angle values listed in Table 1.

[0043] In other aspects, Form 1 may be characterized by a thermogravimetric analysis (TGA) curve, a differential scanning calorimetry (DSC) thermogram, and / or a solid state Fourier- transform infrared (FT-IR) spectrum.

[0044] Form 1 may be characterized by DSC. In some embodiments. Form 1 exhibits a melting peak, or onset temperature, of about 220.8 °C. In some embodiments, Form 1 exhibits a melting onset temperature of 220.78 °C. In some embodiments, Form 1 exhibits a melting peak of 222.07 °C. Form 1 is further characterized by a DSC thermogram substantially as shown in FIG. 2.

[0045] Form 1 may be characterized by TGA. In some embodiments. Form 1 exhibits an about 0.05 weight % loss at 200 °C. Form 1 may be characterized by a TGA curve substantially as shown in FIG. 4.

[0046] In particular embodiments, Form 1 exhibits (1) a TGA curve showing about 0.05 weight % loss at 200 °C, followed by thermal decomposition above about 240 °C; and / or (2) DSC thermogram showing a melting onset temperature of 220.8 °C.

[0047] Form 1 may be characterized by solid state FT-IR. In some embodiments, Form 1 is characterized by a solid state Fourier-transform infrared (FT-IR) spectrum exhibiting peaks corresponding to at least three, at least six, at least nine, or at least twelve of the following wavenumber values: 613.52. 655.84, 702.36, 719.32, 917.24. 941.08. 1011.90. 1082.76. 1117.53, 1274.48, 1303.69, 1557.30, 1589.95, 1642.86, 2106.54, 2874.51, 3227.41, 3328.27, and 3437.67 cm'1. In particular embodiments, Form l ’s FT-IR spectrum exhibits peaks at at least three of these wavenumber values. In some embodiments, Form l’s FT-IR spectrum exhibits peaks at all nineteen of these avenumbers. In some embodiments, Form l’s FT-IR spectrum exhibits peaks corresponding at least three, at least six, at least nine, or at least twelve of the wavenumber values listed in Table 2. In some embodiments, Form 1 is characterized by a solid state FT-IR spectrum substantially as shown in FIG. 5.

[0048] In some embodiments, Form 1 is characterized by a Dynamic Vapor Sorption pattern substantially as shown in FIG. 6.

[0049] In some embodiments, Form 1 is characterized by a particle size distribution substantially as shown in FIG. 6. Form 1 may exhibit a particle size D50 of 53.74 pm. Form 1 may exhibit a Dio of 14.65 pm and / or a D90 of 132.4 pm.

[0050] In Form 1 of Compound A. the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium or tritium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. As another example,different isotopic forms of carbon include radiocarbon, or carbon- 14 (14C). Isotopically-enriched Compound A can be prepared without undue experimentation by conventional techniques well known to those skilled in the art using appropriate isotopically-enriched reagents and / or intermediates. In one embodiment, Compound A has one or more of its hydrogen atoms replaced with tritium. In one embodiment, Compound A has one or more of its carbon atoms replaced with radiocarbon.

[0051] In the procedures provided in the Examples, compound A was prepared by organic synthesis and its conversion into the anhydrous cry stalline phase of Form 1 w as studied under various conditions.DEFINITIONS

[0052] Listed below7are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary7skill in the art. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry and formulation chemistry are those well-known and commonly employed in the art.

[0054] As used herein, the term ‘'composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients. As used herein, the term "pharmaceutical composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results from combining the specified ingredients. Ingredients suitable for inclusion in a pharmaceutical composition are pharmaceutically acceptable ingredients, which means the ingredients must be compatible with each other and not deleterious to the recipient thereof.

[0055] As used herein, the term “pharmaceutically acceptable carrier’ is meant to refer to any adjuvant, vehicle, excipient, glidant. sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, whetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0056] The compound of the invention exists in an '‘unsolvated” form, where a pharmaceutically acceptable solvent, such as water, has been removed. In particular, the compound exists in an anhydrous form. The terms “anhydrous” and “anhydrate” refer to a form in which water molecules have been removed from the cry stal lattice. That is, the disclosed26089 crystalline compound lacks any physical association (i.e., does not form a complex) with any water molecules.

[0057] As used herein, the term “co-crystal” refers to a crystalline material formed by combining the disclosed compound and one or more co-ciystal formers (i.e., a molecule, ion, or atom). In certain instances, co-crystals may have improved properties as compared to the free form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity , a cry stalline form of a normally amorphous compound, a crystalline form of a difficult-to-salt compound, decreased form diversity, more desired morphology, and the like. Methods for making and characterizing co-crystals are known to those of skill in the art.

[0058] As used herein, the term “subject” refers to an animal, preferably a mammal, that has been the object of treatment by or administration of a compound. In exemplary embodiments, the subject is a mammal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a domesticated animal. In some embodiments, the subject is a primate. The subject may a rodent, such as a rat. In some embodiments, the subject is human. In some embodiments, the subject is a dog (e.g., a beagle dog). In some embodiments, the subject is a non-human primate (NHP), such as a rhesus macaque.

[0059] The term “effective amount” indicates a sufficient amount to exert a therapeutic or prophylactic effect. For a patient not infected with HIV, e.g., for prophylactic uses, an effective amount is sufficient to achieve one or more of the following: a reduced susceptibility to HIV infection, and a reduced ability of the infecting virus to establish persistent infection for chronic disease.

[0060] The term “administration” and variants thereof (e.g., “administering” compound A) means providing the compound to the individual in need of treatment or prophylaxis. When a compound is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or prophylaxis of HIV infection or AIDS), "administration" and its variants are each understood to include provision of the compound and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.

[0061] As used herein, an “oral dosage form” refers to a pharmaceutical formulation, comprising the crystalline form of the compound A and at least one pharmaceutically acceptable excipient, that is suitable for administration through the mouth of the subject. As used herein, this term is intended to encompass both the combination of the specified ingredients in the specified26089 amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. An oral dosage form may include the entire amount of crystalline Form 1 of compound A.

[0062] An "anti -HIV agent” is any agent that is directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the or prophylaxis of HIV infection, and / or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and / or diseases or conditions arising therefrom or associated therewith.

[0063] “PXRD” refers to powder x-ray diffraction. Powder X-ray diffraction studies are widely used to characterize crystallinity and polymorphism. In exemplary embodiments, X-ray powder diffraction patterns are generated using a copper X-ray alpha radiation (Cu K a).

[0064] As used herein, the articles “a” and “an” refer to one or to more than one (i. e.. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0065] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules).

[0066] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 1 mg to 15 mg” is inclusive of the endpoints, 1 mg and 15 mg. and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0067] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of' and “consisting essentially of' the enumerated components, which allows the presence of only the named compound, along with any acceptable earners or fluids, and excludes other components or compounds.26089PHARMACEUTICAL COMPOSITIONS AND COMBINATIONS

[0068] In some aspect, compositions comprising compound A can, for example, be administered by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), transvaginally (such as in a vaginal ring delivery system), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and pharmaceutically-acceptable carrier (e.g., a carrier suitable for administration to a human patient), adjuvants and vehicles. Liquid preparations suitable for oral administration (e.g., 30 suspensions, syrups, elixirs and the like) can employ media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g.. capsules, tablets and mini-tablets) can employ solid excipients as such starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Parenteral compositions ty pically employ sterile water as a carrier and optionally other ingredients, such as solubility aids. Injectable solutions can be prepared, for example, using a carrier comprising a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further guidance for methods suitable for use in preparing pharmaceutical compositions is provided in Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2006).

[0069] The pharmaceutical compositions may be administered in either single or multiple doses. In exemplary embodiments, the pharmaceutical compositions may, for example, be administered orally, e.g., in an oral dosage form. The compositions may be administered orally in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and a pharmaceutically acceptable carrier.

[0070] Preferably, the pharmaceutical composition is in an oral unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0071] In some embodiments, the pharmaceutical compositions are adapted for oral administration. As such, oral dosage forms containing the disclosed pharmaceutical compositions are contemplated. In some embodiments, the compositions are provided as a solid oral dosage form, such as a tablet, capsule, or mini-tablet. In exemplary7embodiments, the compositions are provided as one or more tablets. In some embodiments, the compositions are provided as one or more capsules.

[0072] In some aspects, oral tablets comprising the disclosed compound and a pharmaceutically acceptable carrier are provided. In some aspects, capsules comprising the disclosed compound and a pharmaceutically acceptable carrier are provided.26089

[0073] In some aspects, oral tablets comprising about 11 mg of the compound of Formula A, and a pharmaceutically acceptable carrier, wherein the tablet is adapted for once-monthly administration, are provided.

[0074] In particular embodiments, the disclosed oral tablets comprise 11 mg of compound A. In some embodiments, the total tablet weight is about 280 mg. In particular embodiments, the total tablet weight is about 283 mg. In some embodiments, the total weight is 283.3 mg.

[0075] In some embodiments, the disclosed tablet comprises one or more pharmaceutically acceptable carriers selected from mannitol, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, carnauba wax, or any combination thereof. In some embodiments, the tablet comprises one or more diluents. These one or more diluents may comprise microcrystalline cellulose, lactose monohydrate, or both. In some embodiments, the tablet comprises a disintegrant or a superdisintegrant. In some embodiments, the tablet comprises a lubricant. As such, in some aspects, the tablet comprises one or more diluents, a disintegrant, and a lubricant.

[0076] In some embodiments, the disintegrant comprises croscarmellose sodium. In some embodiments, the disintegrant comprises crospovidone. The lubricant of the tablet may comprise magnesium stearate.

[0077] In some embodiments, the tablet comprises mannitol, microcrystalline cellulose, croscarmellose sodium, and / or magnesium stearate. In some embodiments, the tablet comprises each of lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the tablet comprises a polishing agent (or polisher), such as carnauba wax. In some embodiments, the tablet comprises a colorant. In particular embodiments, the tablet comprises a colorant and a polisher.

[0078] In some aspects, provided herein is a tablet the tablet comprises the following components, with weight of each component indicated in milligrams:

[0079] The tablets disclosed herein may be uncoated or coated (in which case they include an outer film coat). Although uncoated tablets may be used, it is more typical to provide a coated26089 tablet, in which case a conventional non-enteric coating may be used. Film coatings are known in the art and can be composed of hydrophilic polymer materials, but are not limited to, polysaccharide materials, such as hydroxypropylmethyl cellulose (HPMC), methylcellulose, hydroxyethyl cellulose (HEC). hydroxypropyl cellulose (HPC), poly(vinylalcohol-co-ethylene glycol) and other water-soluble polymers. As such, in particular embodiments, the disclosed tablets are film-coated tablets.

[0080] In some embodiments, any of the disclosed dosage forms (e.g., one or multiple tablets or capsules) comprises about 1 mg to 50 mg of compound A (e.g. form 1 of compound A), for example, about 1 to 5 mg, about 1 to 10 mg. about 5 to 15 mg, about 10 to 20 mg, about 20 to 30 mg, about 30 to 40 mg, about 25 to 50 mg, or about 40 to 50 mg. In particular embodiments, any of the disclosed dosage forms (e.g., a tablet) comprises about 9 mg to 12 mg of compound A.

[0081] In particular embodiments, the disclosed dosage form, e.g. a tablet, comprises about 11 mg of compound A. In some embodiments, the disclosed dosage form comprises between about 10.5 mg and 11.5 mg, about 10.7 and 11.5 mg, or about 10.75 mg to 11.25 mg of compound A. In some embodiments, the disclosed dosage form comprises between 10.69 mg and 11.49 mg of compound A.

[0082] In some embodiments, the disclosed dosage form, e.g. a tablet, comprises about 4% w / w of compound A, e.g. form 1 of compound A. The dosage form may comprise between 3.5% and 4.1% w / w of compound A. The dosage form may comprise about 3.9% w / w of compound A.

[0083] The amount and frequency of administration of the compound of the invention will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended monthly dosage regimen for oral administration can range from about 1 mg to 50 mg monthly.

[0084] NRTIs are one of 6 classes of HIV antiretrovirals (ARVs) used as components of potent and durable multi-drug regimens that typically combine two NRTIs with a non-nucleoside reverse transcriptase inhibitor, an integrase strand transfer inhibitor, or a protease inhibitor. Combination treatment maximizes treatment response and minimizes the emergence of drug resistance. Thus, in some aspects, any of the disclosed pharmaceutical compositions may further comprise one or more additional therapeutic agents that is not compound A, such a different antiHIV agent. In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent. In some embodiments, the additional therapeutic agent is an anti-HIV agent listed in Table A.26089

[0085] When administering a combination therapy of the invention to a subject, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, each of compound A and an additional therapeutic agent may be present in fixed dosage amounts in a single dosage unit (e.g., a capsule or a tablet).

[0086] In one embodiment, the compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

[0087] As noted above, the present invention is also directed to use of compound A with one or more anti -HIV agents. An “anti -HIV agent’' is any agent which is directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and / or the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS-related complexes (ARC). It is understood that an anti-HIV agent is effective in treating, or delaying the onset or progression of, HIV infection or AIDS and / or diseases or conditions arising therefrom or associated therewith. For example, the compound of this invention may be effectively administered, e.g., post-exposure, in combination with effective amounts of one or more anti-HIV agents selected from HIV antiviral agents, immunomodulators, anti-infectives, or vaccines useful for treating HIV infection or AIDS. Suitable HIV antivirals for use in combination with the compound of the invention include, for example, those listed in Table A as follows:Table A26089

[0088] Some of the drugs listed in the table are used in a salt form; e.g., abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.

[0089] In one embodiment, one or more anti-HIV drugs are selected from lenacapavir, GS- CA1, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine, doravirine, islatravir and lopinavir.

[0090] The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment of HIV infection may be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert;26089 the age, sex and general health of the subject; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the compound and the other agent(s) may be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g.. one component is administered once daily and another component is administered every six hours, or when the pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.

[0091] It is understood that the scope of combinations of compounds of this invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of HIV and / or AIDS. The HIV antiviral agents and other agents will ty pically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in editions of the Physicians' Desk Reference, such as the 63rd edition (2009) and earlier editions. The dosage ranges for a compound of the invention in these combinations can be the same as those set forth above.

[0092] For preparing pharmaceutical compositions of compound A, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 3 to about 97 percent active ingredient (e.g., from about 3 to about 5 percent). The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A Gennaro (ed.), 10 Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0093] Liquid form preparations include solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Liquid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.26089

[0094] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0095] Also included are solid form preparations, which are intended to be converted, shortly before use. to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.Administration

[0096] In the methods of the present invention (i.e., prophylaxis of HIV infection, or treating or delaying the onset or progression of AIDS), Compound A can be administered by any means that produces contact of the active agent with the agent’s site of action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0097] Administration of Compound A Form 1, or a pharmaceutically acceptable salt thereof, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. In some embodiments, the administration is oral administration.

[0098] The compound of the disclosure may be administered as a single dose at a frequency of once-daily or less. In various aspects, the compound may be administered as a single dose, once- monthly. The compound may be administered as multiple or divided doses, once-monthly.

[0099] In some embodiments, the disclosed methods comprise orally administering to the subject Form 1, or a pharmaceutically acceptable salt thereof, or any of the disclosed pharmaceutical compositions, once monthly. In some embodiments of these methods, any of the disclosed pharmaceutical compositions are provided in an oral dosage form. In particular embodiments, these compositions are provided in a tablet or capsule. In some embodiments, the compositions are provided in one or more tablets or capsules once monthly. In exemplary embodiments, the compositions are provided in one, two, or three tablets (or capsules) administered to the subject once monthly. In some embodiments, the compositions are provided in a single tablet (or capsule).

[0100] In exemplary aspects of the disclosed methods, the subject is a mammalian subject. In some aspects, the subject is human. In additional aspects, the subject is a non-human primate (NHP). In additional aspects, the subject is a dog. In additional aspects, the subject is a rodent, such as a rat.26089

[0101] The frequency of dosage of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, will be determined by the needs of the individual patient and can be, for example, once per day, once per week, or once per month. Administration of the compound, or a pharmaceutically acceptable salt thereof, continues for as long as necessary to treat the HIV infection, or any other indication described herein. For example, a compound, or a pharmaceutically acceptable salt thereof, can be administered to a human subject suffering from or at risk of contracting an HIV infection, e.g., for the duration of the subject’s life. In some embodiments, the disclosed compound is administered once-monthly for PrEP to a subject at risk of contracting an HIV infection, for the duration of the subject's life.

[0102] Administration can be intermittent, with a period of several or more days during which a patient receives a weekly or monthly dose of the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, followed by a period of one or more weeks or months during which a patient does not receive a dose of the compound or a pharmaceutically acceptable salt thereof. For example, a patient can receive a dose of the compound, or a pharmaceutically acceptable salt thereof, every other week.

[0103] Alternating periods of administration of the compound, or a pharmaceutically acceptable salt thereof, followed by non-administration of the compound, or a pharmaceutically acceptable salt thereof, can be repeated as clinically required to treat the patient.

[0104] The disclosed compound can be administered orally in a dosage range of 0.001 to 1000 mg / kg of mammal body weight in a single dose or in divided doses. One dosage range is 0.01 to 500 mg / kg body weight orally in a single dose or in divided doses. Another dosage range is 0. 1 to 100 mg / kg. or 0.5 to 50 mg / kg, body weight orally in single or divided doses. Exemplary dosages for larger mammals include 1, 5. 10, 15, 20, 25, 30, 50, and 100 mg / kg body weight.

[0105] Any of the disclosed dosages of Form 1 may be administered in a regimen that is less frequent than once daily. In some embodiments, Form 1 is administered once weekly. In some embodiments, Form 1 is administered semi -weekly. In particular embodiments, Form 1 is administered once monthly. In some embodiments, Form 1 is administered less often than once monthly.

[0106] For oral administration, the compositions may be provided in the form of tablets or capsules containing an effective amount of Form 1 of Compound A. In some embodiments, one or more tablets or capsules are administered that each comprise 1 to 50 milligrams of Compound A for the symptomatic adjustment of the dosage to the patient to be treated. This dosage may be administered less frequently than once daily, such as once monthly. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of26089 factors including the activity of the specific compound employed, the PK properties of that compound, the age, body weight, general health, sex, diet, mode and time of administration, drug combination, the severity of the particular condition, and the subject undergoing therapy.

[0107] In some aspects, any of the disclosed methods for treating HIV infection, treating AIDS, delaying the onset or progression of AIDS, and inhibiting HIV integrase may further comprise the administration to a subject of one or more additional therapeutic agents that is not compound A, or a pharmaceutically acceptable salt thereof. In various embodiments, the subject is human.

[0108] In various embodiments, the additional therapeutic agent is an anti-HIV agent. In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent. In some embodiments, the additional therapeutic agent is an anti-HIV agent listed in Table A.

[0109] The present invention also encompasses uses of the disclosed compound. In some aspects, crystalline Form 1 of compound A is provided for use in medicine; or for use in (i) a medicament, (ii) in the preparation of a medicament, for inhibiting HIV transmission. In these uses, the compound of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from anti-HIV agents.EXAMPLES

[0110] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.Example 1: Crystallization Process for Form 1[OHl] In one exemplary method of crystallization to generate Form 1, crude Compound A was dissolved in methanol to make a saturated solution. The excess solid was removed by filtration. Water was added to the filtrate until a 1: 1 water / methanol ratio (vol / vol) was reached. Methanol was slowly evaporated from the solution via a stream of nitrogen gas (N2) at ambient temperature for about 1 hour, and a crystalline solid roughly white in color was precipitated out as anhydrous free Form 1.Example 2: Form 1 StabilityPolymorph screens to identify Form 1 as the most stable crystalline phase

[0112] A slurry stress screen was performed with 18 different slurry conditions. No other new crystal forms were observed. A hydrate screen in aqueous-organic solvent mixtures (1326089 conditions) returned Form 1. The screen also identified a suspected dioxane / water solvate that only existed with the solvent mixture. A custom excipient screen to search for hydrate forms returned Form 1 only. No hydrates were encountered.Suitability of Compound A Form 1 for a tablet dosage form

[0113] Form 1 was the most stable form of Compound A identified by a significant margin. This form is chemically and physically stable in the solid state. An excipient compatibility study showed that Form 1 is compatible with commonly used excipients (including, but not limited to, microcrystalline cellulose (e g. Avicel®), Mannitol, Lactose, Crospovidone, Croscarmellose sodium, and Magnesium stearate) for an oral tablet dosage form. The morphology and particle attributes of Compound A Form 1 meet the requirement of a tablet dosage form with a low risk of segregation, i.e., non-uniformity in powder blend during tablet manufacturing that can lead to dosage non-uniformity.Example 3: Physical Characterizations of Form 1

[0114] Powder X-ray Diffraction (PXRD). A PXRD pattern of Form 1 was collected on a Bruker D8 Advance Powder X-ray Diffractometer (copper X-ray tube, Cu K a = 1.54 A, 40 kV, 40 mA, Madison, WI, USA). The powder was placed on the standard zero background silicon holder. The PXRD patterns were collected in the angular range of 2-40° 20 in a step scan mode in Bragg-Brentano geometry.

[0115] The PXRD data, including d-spacing and relative intensity7values, is described in Table 1. The pattern is depicted in Figure 1.Table 1. X-Ray Powder Diffraction of Form 1 : Characteristic 20, d-Spacings and Relative Intensity26089

[0116] Differential Scanning Calorimetry (DSC). The melting onset temperature of Compound A Form 1 was determined by DSC using a calorimeter instrument (DSC Q2000, TA Instruments, New Castle, DE). 4.84 mg of Form 1 powder was loaded on a Tzero pan and sealed with a Tzero hermetic lid with two pinholes on the lid. The powder was heated at a rate of 10 °C per minute. The melting onset temperature was determined by Universal Analysis software (Version 4.5 A).

[0117] As shown in Figure 2, the observed melting peak, or onset temperature, was 220.78 °C. The observed melting entropy was 173.9 J / g.

[0118] Scanning Electron Microscopy (SEM). Compound A Form 1 was mounted onto a SEM specimen holder with conductive carbon adhesive tab (Ted Pella, Inc. Redding, CA) and sputter coated with 5 nm of platinum in a sputter coater EMS 150T ES (Electron Microscopy Sciences, Hatfield, PA). SEM images were collected using a Hitachi SU5000 SEM (Hitachi High- Technologies Corporation, Tokyo, JP) with a voltage of 3 kV, a spot intensity' of 30%, a secondary electron (SE) mode, and a working distance of 5.0 mm under high vacuum mode.

[0119] An exemplary’ SEM image is shown as FIG. 3. A rod-like morphology- is observed.

[0120] Thermogravimetric Analysis (TGA). The decomposing temperature of Compound A Form 1 was determined by TGA using a Discovery TGA 1 instrument (TA Instruments).Roughly 12 mg of Form 1 powder was loaded on a platinum pan. The powder was heated at a rate of 30 °C per minute. Weight loss in the sample at 200 °C was determined by Universal Analysis software (Version 4.5A).

[0121] A plot of the TGA of Form 1 is shown as FIG. 4. Form 1 exhibited a 0.05% weight loss at 200 °C. Thermal decomposition of the sample above a temperature of about 240 °C was observed.

[0122] Solid State ET-IR Spectroscopy. A Nicolet FT-IR Attenuated Total Reflectance (ATR) from Thermo Fisher Scientific (model iZIO) was used to collect Fourier-transform infrared (FT- IR) spectra of Form 1. A small amount of sample powder was placed on top of the diamond ATR crystal and pressed gently by a pre-mounted sample clamp. The resolution for the IR spectra was 4 cm'1and each spectrum was collected with 32 scans. ATR effect and atmospheric contributions from carbon dioxide and water vapor were corrected by subtracting the background spectrum in the Omnic software.

[0123] The positions of the FT-IR wavenumbers that exhibited transmittance peaks are listed in Table 2. The FT-IR pattern is depicted in Figure 5.26089Table 2. FT-IR peaks of Form 1

[0124] Dynamic Vapor Sorption (DVS). The moisture adsorption behavior of Form 1 was carried out using a VTI-SA+ Vapor Sorption Analyzer at 25 °C. Approximately 15 mg of the sample was dried at 0% RH and 40 °C until a constant weight was reached. The relative humidity (RH) was increased to 5%. and then increase in 10% increments up to 95% RH and equilibrated for 30 min or until the weight increase was below 0.0010 wt.% per minute over 15 minutes. Following 95% RH, the RH was decreased in stepwise fashion back to 5%. At each step of the procedure, the change in weight was recorded as a function of time. Adsorption and desorption plots of weight change with varying relative humidity is shown as FIG. 6.

[0125] Particle Size Distribution (PSD). The distribution in particle size of Form 1 was measured using a Microtrac Flowsync analyzer. A sample of Form 1 was transferred to a 20 mL scintillation vial. Approximately 5 mL of IsoparG / 0.25% (w / v) lecithin fluid was added into the vial followed by gentle shaking to disperse the particles. After instrument initialization and background measurement (30 seconds), the suspension was poured into the flow cell unit. The vial was triple-rinsed with 1 mL of IsoparG / 0.25% lecithin (total 3 mL), and the entire rinse was poured into the FlowSync. The following conditions were used: 0.25% Lecithin in IsoparG as the fluid; 60% Flow; 30-second sonication at 50% (30 Watts); non-spherical particles; Refractive Indices: Particle = 1.51; Fluid = 1.42.

[0126] A plot of the PSD of Form 1 is shown as FIG. 7. The Dio value is 14.65 pm. The Dso value is 53.74 pm. The Ds>o value is 132.4 pm.Example 4: Selection of Dosing for Tablet Dosage Form

[0127] Compound A has been evaluated in seven Phase 1 studies and a Phase 2 study. In the Phase 1 studies, a total of 130 adults, including 12 participants with renal impairment and 37 participants living with HIV-1, were administered single or multiple QW oral doses of Compound A up to 200 mg. These participants were administered dry- filled gelatin capsules containing strengths of 0.25 mg, 0.5 mg, 1 mg, 3 mg, 5 mg. or 10 mg QM of Compound A.

[0128] In the Phase 2 study, a total of 301 participants at low likelihood of exposure to HIV received up to 6 once-monthly (QM) doses of Compound A of 3 mg [N=101], 6 mg [N=101], or 12 mg [N=99] during a 20-week study interv ention period. Each of these doses were generally well-tolerated. The administration frequency of QM is driven at least in part to Cmpd-A-TP's long demonstrated half-life in PBMCs of approximately 48 hours. See Raheem, et al.

[0129] The objective of this work was to use modeling and simulation to inform dose selection for phase 3 studies, in view of PK data from these Phase 1 and Phase 2 studies. In the Phase 2 study, sparse PK was collected for characterizing Compound A in and Cmpd-A-TP in human PBMCs. Plasma exposures in PBMCs (AUCo-iast and Cmax) increased linearly among the 3 mg. 6 mg and 12 mg doses. The PK of Compound A in and Cmpd-A-TP in this study was generally comparable to the PK observed in the Phase 1 studies.

[0130] Methods: A population pharmacokinetics (PK) modeling approach was used to evaluate the PK of Compound A and Compound A triphosphate (Cmpd-A-TP) by developing a preliminary model based on PK from five Phase 1 studies (two of which included 37 adults living with HIV-1) and the Phase 2 study. PK for both Compound A and Cmpd-A-TP was adequately described by a five-compartment model that was used to perform simulations to select the QM dose for Phase 3 studies. Cmpd-A-TP trough concentration at day 31 (C744Q was used as the most relevant timepoint for maintenance of efficacy. A dose selection of Compound A was targeted to achieve predicted Cmpd-A-TP concentrations above the PK preventive efficacy threshold (0.03 pmol / million PBMCs, or 0.15 pM) against wild-type HIV-1.

[0131] Results: Compound A oral QM doses ranging from 6 mg to 12 mg were considered for phase 3 based on predicted Cmpd-A-TP exposures. The considered doses were 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, and 12 mg. Sex and age were not identified as covariates while weight was included in the model. An 11-mg dose of Compound A QM was predicted to exceed the PK efficacy threshold in at least 95% of participants at 4 timepoints: 30 minutes after the 1st dose, 31days after the 1st dose, 31 days at steady state, and 38 days at steady state. The predicted steady state exposure parameters (AUCo-744h, Cmax and C?44h) for Cmpd-A-TP in units of pmol / million cells at a QM (31 days) dose is shown in Table 3, below:Table 3: Summary Steady-State PK Parameters at a dose of 11 mg Compound A administeredQM (31 Days)

[0132] A predicted concentration time profile of Cmpd-A-TP in PBMCs over a 28 week period following QM administration of 11 mg of Compound A is shown in Fig. 8. This plot shows the predicted concentrations of the metabolite following six doses of Compound A, until a simulated missed dose at week 27 (represented by the vertical dashed line). The shaded area that follows this dashed line, which represents the upper and lower 5th centiles of Cmpd-A-TP concentration, suggests the ability' of an 11 mg QM dose to have a forgiveness window of at least 1 week, in case of a missed or delayed dosing. The horizontal dashed line represents the PK efficacythreshold of 0.03 pmol / million PBMCs. The shaded area never dips below the efficacy threshold over the 28-week simulation.

[0133] Although Compound A is renally excreted, mild renal impairment (eGFR > 60 ml / min) is predicted to result in exposures similar to those in healthy individuals. Additionally, although weight is a covariate of exposure, the 11-mg dose is expected to be efficacious and well-tolerated in adults and adolescents weighing at least 35 kg, across various sub-populations. The 10-mg and 12-mg doses likewise met this criterion.

[0134] Although Compound A exposures are anticipated to be reduced by 10-30% during pregnancy, this reduction is not expected to be clinically meaningful, as adequate protective exposures of Compound A are predicted throughout pregnancy.

[0135] Conclusions: An oral dose of 11 mg was selected to provide efficacious exposures to prevent HIV-1 acquisition for at least 1 month in most subjects, including in sub-populations such as women who are pregnant, subjects with mild renal impairment, and adolescents weighing >35 kg, and to provide an additional 1-week of protective coverage for late doses.

[0136] Two phase 3 studies are being conducted to assess safety and efficacy of 11 mg QM Compound A for HIV-1 prevention (PrEP). In these studies, participants will be administered oral tablets containing about 11 mg of Compound A and pharmaceutically acceptable excipients microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate. The tablets are round white to off-white polished film-coated tablets (FCTs) having a dosage strength of 1 126089 mg of anhydrous Form 1. Tablets are packaged in high-density polyethylene (HDPE) bottles with child-resistant caps and induction seals, or in aluminum blister packs.Example 5: The Tablet Dosage Form

[0137] The dosage strengths, appearance, and excipients present in the clinical FCT dosage form are summarized in Tables 4 and 5, below.Table 4. Formulation Designation and Dosage Form Strengths

[0138] The drug product is made by mixing cry stalline anhydrous Form 1 of compound A with diluents microcrystalline cellulose and lactose monohydrate, disintegrant croscarmellose sodium and lubricant magnesium stearate. Dry granules are formed, and then additional magnesium stearate is mixed into the formulation. Tablets are compressed, and then an outer hydroxypropyl methylcellulose-based film coat and carnauba wax polisher are applied.

[0139] A detailed description of the process flow used to generate the 11 mg film-coated tablets containing Form 1 of Compound A follows:1. Microcrystalline cellulose, lactose monohydrate and croscarmellose sodium are deagglomerated (as necessary) through an appropriate screen prior to dispensing. Compound A is de-agglomerated through an appropriate screen prior to dispensing.2. Compound A, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium are charged to the diffusion (tumble) blender and blended.3. The lubricant, magnesium stearate (intra-granular), is de-agglomerated through an appropriate screen prior to dispensing. Magnesium stearate is charged to the blender and the blend is lubricated via diffusion (tumble) blending.4. The lubricated powder blend is dry’ granulated using a roller compactor with a mill fitted with a mesh screen.5. The lubricant, magnesium stearate (extra-granulator), is de-agglomerated through an appropriate screen prior to dispensing. The granules and extra-granular magnesium stearate are charged to the blender and the blend is lubricated via diffusion (tumble) blending.6. The lubricated granulation is compressed into tablets on a rotary tablet press.260897. The tablets are coated with an aqueous suspension of a hydroxypropyl methylcellulose-based film coat, dried, and polished with carnauba wax.Table 5. Compound A 11 mg FCT components

[0140] This tablet’s small image size (< 300 mg and < 9 mm in diameter) provides an ease of swallowability and supports pediatric administration. In particular, this tablet has a weight of 283.3 mg and diameter of 8.73 mm. The once-monthly dosing regimen combined with the small image size is intended to provide a suitable dosage form with high patient compliance to a wide range of patient populations, including patients with difficulty swallowing. This small, easy-to- swallow tablet is likewise expected to be efficacious and well-tolerated in adolescents of 12-18 years of age, such as ages 16-18, including adolescents weighing under 35 kg (e.g. 25-35 kg).

[0141] The metabolism of Compound A in adolescents is expected to be similar to that of adults (>18 years of age). In addition, the adolescent participants are expected to have generally comparable plasma Compound A and intracellular Cmpd-A-TP concentrations to those in adults. No dose adjustment is needed in adolescents weighing at least 35 kg, although a dose adjustment may be appropriate for adolescents weighing under 35 kg.

[0142] An open-label. Phase 1 study to evaluate pharmacokinetics and tolerability of compound A in healthy adult participants was conducted. On Day 1 , the disclosed tablets containing a single 11-mg dose of Compound A were administered to participants. PK samples were collected predose and up to 168 hours post-dose. A taste assessment questionnaire was administered immediately following dosing and 10 minutes post-dose on Day 1. Safety was monitored throughout the study by repeated clinical and laboratory evaluations. All participants who26089 received at least one dose of study drug (including participants who terminate the study early) returned to the clinical research unit (CRU) approximately 28 days after the last dose for followup procedures, and to determine if any adverse event had occurred since the last study visit. Sixteen (16), healthy adult male and female (of non-childbearing potential) participants were enrolled. Blood (plasma) samples were collected from subjects at 10 specified time points on Day 1, and daily thereafter until Day 8.

[0143] A plot of the individual concentration time profiles of Compound A in plasma to the 16 subjects is shown in FIG. 9. A burst in concentration is observed immediately after dosing, before reducing slowly between 12 hours and 168 hours post-dose.

[0144] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0145] All references (e g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

What is claimed is:

1. A compound of F ormula A,having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form characterized by a powder x-ray diffraction pattern (PXRD) obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.

17. 20.70, and 25.18.

2. The compound of claim 1, wherein the Form 1 is characterized by a powder x-ray diffraction pattern comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, 22.81, 25.18, 26.38, and 26.88.

3. The compound of claim 1 or 2, wherein the Form 1 is characterized by a powder x-ray diffraction pattern comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 16.25, 18.17, 18.74, 20.70, 22.81, 25.18, 26.38, 26.88, and 29.94.

4. The compound of claim 1 or 2, wherein the Form 1 is characterized by a powder x-ray diffraction pattern comprising six or more of the diffraction angle values listed in Table 1, + / - 0.2° 2-theta.

5. The compound of any one of claims 1-4, wherein the Form 1 is characterized by a powder x-ray diffraction pattern comprising nine or more of the diffraction angle values listed in Table 1, + / - 0.2° 2-theta.

6. A compound of Formula A having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form characterized by(1) a thermogravimetric analysis (TGA) curve showing about 0.05 weight % loss at 200 °C, followed by thermal decomposition above about 240 °C; or(2) a differential scanning calorimeter (DSC) thermogram showing a melting onset temperature of about 220.8 °C.

7. The compound of claim 6, wherein the Form 1 is further characterized by a TGA curve substantially as shown in FIG. 4.

8. The compound of claim 6 or 7, wherein the Form 1 is further characterized by a DSC thermogram substantially as shown in FIG. 2.

9. The compound of any one of claims 1-8, wherein the Form 1 is further characterized by a particle size (Dso) of 53.74 pm.

10. The compound of any one of claims 1-9, wherein the Form 1 is further characterized by a rod-like morphology.

11. The compound of any one of claims 1-10, wherein the Form 1 is further characterized by a solid state Fourier-transform infrared (FT-IR) spectrum exhibiting peaks corresponding to at least three of the following wavenumber values: 613.52, 655.84, 702.

36. 719.32, 917.24, 941.08, 1011.90, 1082.76, 1117.53, 1274.48, 1303.69, 1557.30, 1589.95, 1642.86, 2106.54, 2874.51, 3227.41, 3328.27, and 3437.67 cm’1.

12. The compound of any one of claims 1-11, wherein the Form 1 is further characterized by a solid state FT-IR spectrum exhibiting peaks corresponding to at least six of the following wavenumber values: 613.52, 655.84, 702.36, 719.32, 917.24, 941.08, 1011.90, 1082.76, 1117.53, 1274.48, 1303.69, 1557.30, 1589.95, 1642.86, 2106.54, 2874.51, 3227.41, 3328.27, and 3437.67 cm’1.

13. The compound of claim 11 or 12, wherein the Form 1 is further characterized by a solid state FT-IR spectrum substantially as shown in FIG. 5.

14. A compound of Formula A having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form characterized by: a) a PXRD pattern obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, and 25.18;b) a thermogravimetric analysis (TGA) curve showing about 0.05 wt. % loss at 200 °C, followed by thermal decomposition above 240 °C; c) a differential scanning calorimeter (DSC) curve showing a melting onset temperature of about 220.8 °C; and d) a particle size (Dso) of 53.74 pm.

15. A pharmaceutical composition comprising the compound of any one of claims 1- 14 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is adapted for oral administration.

17. The pharmaceutical composition of claim 15 or 16, wherein the pharmaceutical composition is present in a tablet.

18. A method for the inhibition of HIV reverse transcriptase in a subject that comprises administering to the subject an effective amount of the compound of any one of claims 1-14.

19. A method for the treatment, prophylaxis, or delay in onset or progression of HIV infection or AIDS in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-14.

20. A method for providing pre-exposure prophylaxis or post-exposure prophylaxis of HIV infection in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-14.

21. The method of any one of claims 18-20, wherein the subject is human.

22. The method of any one of claims 18-21, wherein the compound is administered once-monthly.

23. The method of any one of claims 18-22, wherein the effective amount of the compound is about 11 mg.2608924. The method of claim 21 or 22, wherein the human subject is under eighteen years of age.

25. The method of claim 24, wherein the human subject is between twelve and eighteen years of age, or between sixteen and eighteen years of age.

26. A method of preparing the compound of Formula A,comprising precipitating the compound from a saturated methanol / water solution to provide crystals of Form 1, wherein Form 1 is a cry stal 1 ine anhydrous free base form characterized by a PXRD obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.

17. 20.70, and 25. 18.

27. An oral tablet comprising the compound of Formula A,having a form that is Form 1, wherein Form 1 is a crystalline anhydrous free base form characterized by a powder x-ray diffraction pattern (PXRD) obtained using Cu K alpha radiation comprising peaks at diffraction angles degrees 2 theta (+ / - 0.2°) of 18.17, 20.70, and 25.18.

28. An oral tablet comprising the compound of Formula A, wherein the compound is present in an amount of about 9 mg, 10 mg, 11 mg, or 12 mg.

29. The tablet of claim 27 or 28, wherein the compound is present in an amount of about 11 mg.2608930. The tablet of any one of claims 27-29, wherein the total tablet weight is about 280 mg.

31. The tablet of any one of claims 27-30, wherein the tablet further comprises one or more diluents.

32. The tablet of claim 31, wherein the one or more diluents comprises microcrystalline cellulose and lactose monohydrate.

33. The tablet of any one of claims 27-32, wherein the tablet further comprises a disintegrant and a lubricant.

34. The tablet of claim 33, wherein the disintegrant comprises croscarmellose sodium.

35. The tablet of claim 33 or 34, wherein the lubricant comprises magnesium stearate.

36. The tablet of any one of claims 27-35, wherein the tablet further comprises a colorant and a polisher.

37. The tablet of any one of claims 27-36, wherein the tablet comprises the following components:

38. An oral tablet comprising about 11 mg of the compound of Formula A, and a pharmaceutically acceptable carrier, wherein the tablet is adapted for once-monthly administration.

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