Crystalline forms, pharmaceutical compositions and methods of use thereof

Abstract

Pharmaceutical compositions and dosage forms of crystalline form A of a PRMT5 inhibitor of formula (I), methods of making and methods of use thereof.

Description

CRYSTALLINE FORMS, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and prionty to U.S. Provisional Patent Application Nos. 63 / 627,451, filed on January 31, 2024, and 63 / 644,376, filed on May 8, 2024, the entire contents of which are incorporated by reference herein.BACKGROUND

[0002] Development of pharmaceutical compositions comprising one or more novel active ingredients requires a variety of considerations, such as route of administration (e.g, enteral, parenteral, topical, etc.), dosage form (e.g., solid - tablet, capsule, etc.; liquid - solution, suspension, syrup, etc.), strength of active ingredient(s) (e.g., 1 mg - 1,000 mg), non-therapeutic component(s) (e.g, excipients) and their respective amounts, and each of these considerations may involve additional considerations such as stability, degradation, sensitivity to light, solubility, taste if administered enterally, palatability, pH, skin irritability, microbial growth, etc. Advancing a novel active ingredient (e.g, a PRMT5 inhibitor) through rigorous regulatory entities requires discovering and developing a pharmaceutical composition that addresses these, or other, considerations.

[0003] WO2023114507 describes a crystalline form of a PRMT5 inhibitor of formula (I) and certain pharmaceutical compositions thereof. The exemplary pharmaceutical compositions described in WO2023114507 comprise 12.5% w / w API (tablet strength 12.5 mg and 50 mg), 29.4% API (tablet strength of 100 mg) and 40 % w / w API (tablet strength of 300 mg). The lower tablet strengths were used in a Phase I clinical study of the Compound of formula (I). During clinical development, the inventors discovered that the higher strength tablets containing higher API loads (29.4% w / w and 40% w / w) could not be reproducibly manufactured on the larger scale required for late-stage clinical testing and commercialization. Additionally, the 40% w / w API formulation could not be reproducibly manufactured even in small-scale laboratory settings.

[0004] It is believed that clinical efficacy would require relatively high daily doses of the compound of formula (I). Preparation of higher strength tablets using the lower API load compositions of WO2023114507 e.g., compositions comprising 12.5% API) would result in large tablet sizes, and the need to administer a high number of tablets daily, which wouldnegatively impact ease of administration, patient compliance and ultimately clinical efficacy. Accordingly, to facilitate patient compliance and therapeutic efficacy, there is a need for pharmaceutical compositions containing high loads of the compound of formula (I) that could be used for the reproducible, large scale manufacturing of dosage forms for late-stage clinical development and commercialization.SUMMARY

[0005] In some embodiments, provided is a pharmaceutical composition comprising crystallineForm A of a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein crystalline Form A has an X- Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees and wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0006] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the cry stalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

[0007] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the cry stalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

[0008] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0009] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

[0010] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0011] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8,9±0,2, 12.7±0.2, 14.0±0.2, 19.H0.2, 19,9±0,2 and 22.6±0.2 degrees;(b) microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) colloidal silicon dioxide;(d) croscarmellose sodium; and(e) magnesium stearate.

[0012] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0013] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0014] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in termsof 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g, colloidal silicon dioxide);(d) an intragranular disintegrant (e.g, croscarmellose sodium);(e) an extragranular lubricant (e.g, magnesium stearate);(f) an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g, colloidal silicon dioxide);(h) an extragranular disintegrant (e.g, croscarmellose sodium); and(i) an extragranular lubricant (e.g., magnesium stearate).

[0015] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) intragranular microcrystalline cellulose PH 101;(c) intragranular colloidal silicon dioxide;(d) intragranular croscarmellose sodium;(e) extragranular magnesium stearate;(f) extragranular microcrystalline cellulose PH 102;(g) extragranular colloidal silicon dioxide;(h) extragranular croscarmellose sodium; and(i) extragranular magnesium stearate.

[0016] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.H0.2, 19,9±0.2 and 22.6±0.2 degrees;(b) about 42% (w / w) of an intragranular filler comprising microcry stalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate).

[0017] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0018] In some embodiments, provided is a dosage form comprising a pharmaceutical composition as described herein.

[0019] In some embodiments, provided is a dosage form intended for oral administration comprising a pharmaceutical composition as described herein.

[0020] In some embodiments, provided is a process for preparing a pharmaceutical composition as described herein, comprising:(a) Charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a prelubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;

[0021] In some embodiments, provided is a process for preparing a dosage form of as described herein, comprising:(a) Charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre- lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally,(h) Coating the dosage form.

[0022] In some embodiments, provided is a process for preparing a pharmaceutical composition as described herein, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;

[0023] In some embodiments, provided is a process for preparing a dosage form of as described herein, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally,(h) Coating the dosage form.

[0024] In some embodiments, provided is a processes for preparing a pharmaceutical composition as described herein, comprising:(a) Charging in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant;v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubncation extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0025] In some embodiments, provided is a process for preparing a dosage form as described herein, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.(m) Compressing the pharmaceutical composition into a dosage form; and, optionally,(n) Coating the dosage form.

[0026] In some embodiments, provided is a pharmaceutical composition or a dosage form prepared by any of the processes described herein.

[0027] In some embodiments, provided is a method for treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0028] In some embodiments, provided is a method of treating a cancer in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject, wherein the MTA level can be assessed directly (e.g, by ELISA or LC- MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing);b) comparing the test sample with a reference, wherein MTAP deficiency and / or MTA accumulation in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering an effective amount (e.g., a therapeutically effective amount) of a pharmaceutical composition or dosage form as described herein to the subject identified in step b).

[0029] In some embodiments, provided is a use of a pharmaceutical composition or dosage form described herein in a method for treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0030] In some embodiments, provided is a use of a pharmaceutical composition or dosage form described herein in the manufacture of a medicament for treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof.

[0031] In some embodiments, provided is a pharmaceutical composition or dosage form described herein for use in a method for treating an MTAP-deficient and / or an MTA- accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0032] In some embodiments, a pharmaceutical composition or dosage form described herein for use in the manufacture of a medicament for treating an MTAP-deficient and / or an MTA- accumulating disease in a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 A is an exemplary X-ray powder diffraction pattern of crystalline Form A of the compound of formula (I).

[0034] FIG. 2A shows an exemplary thermogravimetric analysis (TGA) thermogram of the compound of formula (I).

[0035] FIG. 2B shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A the compound of formula (I), under a heat-cool -heat protocol, showing a melt peak at about 169 °C.

[0036] FIG. 2C shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A the compound of formula (I) under a heat-cool-heat protocol, showing a glass transition temperature (Tg) of 94.6 °C.

[0037] FIG. 3A shows the change of water content (thick curve) and relative humidity (thin curve) as a function of time in an exemplary DVS experiment for the compound of formula (I) (Crystalline form A).

[0038] FIG. 3B shows the change of water content as a function of relative humidity in an exemplary DVS experiment for the compound of formula (I) (Crystalline form A).

[0039] FIG. 4 shows a 20X enlarged microscope image of the Crystalline form A of the compound of formula (I) after wet milling.

[0040] FIG. 5 shows a schematic representation of the process for manufacturing the pharmaceutical compositions and dosage forms of the present disclosure.

[0041] FIG. 6 shows a schematic representation of the process for manufacturing the pharmaceutical compositions and dosage forms used in Phase I clinical trials (WO2023114507).

[0042] FIG. 7 shows the particle size distribution (PSD) of the milled granules of an exemplary pharmaceutical composition (intragranular blend).

[0043] FIG. 8A shows a comparison of tablet hardness as a function of compression force for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets. Compression speed 20 rpm, 10 minute run.

[0044] FIG. 8B shows a comparison of tablet weight as a function of compression force for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets. Compression speed 20 rpm, 10 minute run.

[0045] FIG. 9A shows a comparison of tablet hardness as a function of compression speed for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets. The highlighted band represents the target hardness.

[0046] FIG. 9B shows a comparison of tablet weight as a function of compression speed for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets.

[0047] FIG. 10A shows a comparison of tablet hardness over the course of a steady -state run at 20 rpm speed for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets. The run duration is 50 minutes for the 250 mg tablets and 90 minutes for the 200 mg tablets.

[0048] FIG. 10B shows a comparison of tablet weight over the course of a steady-state run at 20 rpm speed for 250 mg (50% w / w API) and 200 mg (40% w / w API) tablets. The run duration is 50 minutes for the 250 mg tablets and 90 minutes for the 200 mg tablets.

[0049] FIG. 11 A compares the dissolution profile for one 200 mg tablet of the new formulation comprising 40% API with the dissolution profile for two 100 mg tablets of the Phase I formulation at pH 1.2.

[0050] FIG. 1 IB compares the dissolution profile for one 200 mg tablet of the new formulation comprising 40% API with the dissolution profile for two 100 mg tablets of the Phase I formulation at pH 4.5.

[0051] FIG. 11C compares the dissolution profile for one 200 mg tablet of the new formulation comprising 40% API with the dissolution profile for two 100 mg tablets of the Phase I formulation at pH 6.8.DETAILED DESCRIPTION

[0052] As generally described herein, the present disclosure provides pharmaceutical compositions and dosage forms containing crystalline form A of a compound of formula (I):methods of making the pharmaceutical compositions and dosage forms, and methods of using the pharmaceutical compositions to treat medical conditions, diseases, and disorders e.g, proliferation diseases such as cancers.Definitions

[0053] As used in the present disclosure, the following words and phrases are generally intended to have the meanings as set forth below unless expressly indicated otherwise or the context in which they are used indicates otherwise.

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical andbiological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0055] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0056] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0057] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0058] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, in certain contexts, “an element” means one element and / or in certain contexts more than one element. By way of another example, in certain contexts “a filler” means one filler and / or in certain contexts more than one filler (e.g., a mixture of two or more fillers).

[0059] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0060] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0061] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0062] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0063] At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0064] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0065] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0066] As used herein, “XRPD” refers to X-ray powder diffraction. An XRPD pattern is an x-y graph with 20 (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. Theseare the diffraction peaks which may be used to characterize a cry stalline material. The diffraction peaks are usually represented and referred to by their position on the x-axis rather than the intensity of the diffraction peaks on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)). Thus, intensity is not typically used by those of skill in the art to characterize a crystalline material. As with any data measurement, there may be variability in XRPD data. In addition to the variability in diffraction peak intensity, there may also be variability in the position of the diffraction peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of diffraction peaks for purposes of characterization. Such variability in the position of diffraction peaks along the x-axis may be derived from several sources. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature, and orientation may all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate using different parameters and may lead to slightly different diffraction patterns from the same crystalline material. Likewise, different software packages process XRPD data differently and this may also lead to variability. These and other sources of variability are known to those of ordinary skill in the art. Due to such sources of variability, the values of each X-ray diffraction peak may be preceded with the term “about” or proceeded with an appropriate range defining the experimental variability (e.g, ± 0.1°, ± 0.2°, ± 0.3°, ± 0.4°, ± 0.5°, etc.).

[0067] Crystalline forms, such as crystalline forms of a compound of formula (I), are readily analyzed by XRPD. The data from x-ray powder diffraction may be used in multiple ways to characterize crystalline forms. For example, the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline form (e.g, of a compound of formula (I). A smaller subset of such data, however, may also be suitable and used for characterizing such crystalline forms. Indeed, often even a single x-ray powder diffraction peak may be used to characterize such a crystalline form. With respect to crystalline forms of a compound of formula (I), any one or more of the peaks in the x-ray powder diffraction pattern of FIG. 1 A may be used to characterize the crystalline form of a compound of formula (I) disclosed herein.

[0068] The term “characteristic peaks” when referring to the peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g, a crystalline form of a compound of formula (I)) refers to a collection of specific diffraction peaks whose values span a range of 20 values (e.g., 0°-40°) that are, as a whole, unique to that specific crystalline form.

[0069] As used herein, “crystalline” refers to a solid phase of a given chemical entity having well-defined 3-dimensional structural order. The atoms, ions, and / or molecules are arranged in a regular, periodic manner within a repeating 3-dimensional lattice. In various embodiments, a crystalline material may comprise one or more discreet crystalline forms.

[0070] As used herein, the terms “cry stalline form,” “cry stalline solid form,” “crystal form,” “solid form,” and related terms herein refer to crystalline modifications comprising a given substance (e.g, the compound of formula (I)), including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0071] The term “substantially crystalline” refers to solid forms that may be at least a particular weight percent cry stalline. Particular weight percentages may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In some embodiments, the particular weight percent of crystallinity is at least 90%. In certain other embodiments, the particular weight percent of crystallinity is at least 95%. In some embodiments, the compound of formula (I) can be a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., a crystalline form with the XRPD pattern shown in FIG. 1 A).

[0072] The term “substantially pure” relates to the composition of a specific crystalline solid form (e.g. , a crystalline form of the compound of formula (I)) that may be at least a particular weight percent free of impurities and / or other solid forms. Particular weight percentages may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, the compound of formula (I) can be a substantially pure sample of any of the cry stalline solid forms described herein, (e.g., a crystalline form with the XRPD pattern shown in FIG. 1A (Form A)). In some embodiments, the compound of formula (I) can be a substantially pure crystalline form with the XRPD pattern shown in FIG. 1 A (Form A).

[0073] As used herein, the term “anhydrous” or “anhydrate” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) means that no water molecules form a portion of the unit cell of the crystalline form. An anhydrous crystalline form may nonethelesscontain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., , as residual solvent molecule left behind from the production of the crystalline form). In a preferred embodiment, water can make up about 0.5% by weight of the total composition of a sample of an anhydrous form. In a more preferred embodiment, water can make up about 0.2% by weight of the total composition of a sample of an anhydrous form. In some embodiments, a sample of an anhydrous crystalline form of the compound of formula (I) contains no water molecules, e.g, no detectable amount of water.

[0074] As used herein, the term “desolvated” or “unsolvated” when referring to a crystalline form (e.g, a crystalline form of the compound of formula (I)) means that no solvent molecules form a portion of the unit cell of the cry s tall me form. An unsolvated crystalline form may nonetheless contain solvent molecules that do not form part of the unit cell of the unsolvated crystalline form (e.g, as residual solvent molecule left behind from the production of the crystalline form). In a preferred embodiment, the solvent can make up 0.5% by weight of the total composition of a sample of an unsolvated form. In a more preferred embodiment, solvent can make up 0.2% by weight of the total composition of a sample of an unsolvated form. In some embodiments, a sample of an unsolvated crystalline form of the compound of formula (I) contains no solvent molecules, e.g, no detectable amount of solvent.

[0075] As used herein, the terms “polymorph,” “polymorphic form,” “polymorphs,” “polymorphic forms” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules, or ions (e.g, the compound of formula (I)). Different polymorphs may exhibit different physicochemical properties including, but not limited to, melting temperatures, solubilities, dissolution rates, and physical stabilities as a result of differences in the arrangement or conformation of the molecules or ions in the crystal lattice.

[0076] The term “solvate” when referring to a crystalline form of the compound of formula (I) means that solvent molecules (e.g, organic solvents and water), form a portion of the unit cell of the cry s tall me form. Solvates that contain water as the solvent are also referred to herein as “hydrates.”

[0077] As used herein, “dissolution profile” refers to dissolution testing of a drug substance or drug product at multiple time points. Dissolution profiles for drug substances (e.g., the compound of formula (I)) or drug products (e.g., the pharmaceutical compositions described herein) may be performed for characterization and quality control to ensure the drug is released at a defined range of rates in a well-defined dissolution aqueous media that is at least sinkconditions for that drug, or in biorelevant media such as simulated gastric or intestinal fluids representing either the fasted or fed states. In certain cases, but not others, dissolution testing may be predictive of or give insight into in vivo bioavailability of the drug substance. Dissolution testing may be performed using USP testing protocols and dissolution apparatus.

[0078] As used herein, “granulation” refers to a process of forming granules from a powdered or particulate material. As used herein, “Dry granulation” refers to a process in which granules are formed without the presence of a liquid solution and may be useful in the preparation of granules of materials sensitive to heat, moisture, or solvents. For example, roller compaction is a dry granulation process. As used herein, “Wet granulation” refers to the formation of granules wherein the particles are bound together using a binder or a liquid solution. Examples of wet granulation are high shear granulation and fluid bed granulation.

[0079] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refer to the combination of a therapeutically active agent with a pharmaceutically acceptable excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0080] “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or human, as appropriate; or means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0081] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration.

[0082] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0083] Examples of bases include, but are not limited to, alkali metal (e.g, sodium and potassium) hydroxides, alkaline earth metal (e.g, magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is Ci-4 alkyl, and the like.

[0084] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a Ci-4 alkyl group), and the like.

[0085] For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0086] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g, brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavors, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropylmethylcellulose, polyvinyl pyrrolidine, and colors, and the like. For examples of excipients, see Gennaro, Remington’s Pharmaceutical Sciences, 18thEd., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9thEd. Pharmaceutical Press, London, UK (2020).

[0087] Examples of diluents or fillers include, but are not limited to, a sugar (e.g, mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, polydextrose, and combinations thereof), an inorganic material (e.g, dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, a starch (e.g, apregelatinized starch), a microcrystalline cellulose, a silicified microcrystalline cellulose, a polysaccharide, a cellulose (e.g., a hydroxypropylcellulose, a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropylmethylcellulose, a hydroxyethylcellulose), a dextrin, a maltodextrin, an alginate, a collagen, a polyvinylpyrrolidone, a polyvinylacrylate, polyethylene oxide, and polyethylene glycol. Sugar is defined herein to include sugar alcohols.

[0088] Examples of disintegrants include, but are not limited to, alginic acid, an alginate, primogel, a cellulose (e.g., hydroxypropylcellulose), polacrillin potassium, sodium starch glycolate, sodium croscarmellose, a polyplasdone (e.g., a crospovidone), and a starch (e.g, com starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0089] Examples of binders include, but are not limited to, a hydroxypropylcellulose, hydroxyethylcellulose, a hydroxypropylmethy cellulose (e.g, a low viscosity hydroxypropylmethy cellulose), a sugar, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl acetate, a polydextrose, a chitosan, a carrageenan, carbophil, a microcrystalline cellulose, gum tragacanth, guar gum, gellan gum, gelatin, and a starch (e.g., com starch).

[0090] Examples of wetting agents include, but are not limited to, a pol oxamer (e.g., pol oxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), a poly dimethylsiloxane, a polysorbate (e.g., polyoxyethylene 20 sorbitan mono-oleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholate, polyethoxylated castor oil, cetyl trimethylammonium bromide, nonoxynol, d-tocopherol polyethylene glycol 1000 succinate, and docusate sodium.

[0091] Examples of lubricants and glidants include, but are not limited to, a wax, a glyceride, a light mineral oil, a polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oil (e.g, hydrogenated vegetable oil), an alkyl sulfate, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0092] Examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0093] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.

[0094] Examples of coatings include but are not limited to, a film forming polymer (e.g, a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropylmethylcellulose, a hydroxypropyl cellulose, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvinyl alcohol, a Eudragit / acrylate) and a plasticizer (e.g, triacetin, polyethylene glycol, propylene glycol).

[0095] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of the compound of formula (I) described herein) can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.

[0096] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g, young adult, middle-aged adult or senior adult)) and / or a nonhuman animal, e.g, a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0097] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g, tablets, capsules, granules, powders, minitabs, sachets, stickpacks, reconstitutable powders, dry powder inhalers, lozenges, and chewables.

[0098] As used herein, “administering” means oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g, a mini-osmotic pump, to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or). Parenteral administration includes, e.g, intramuscular and subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g, anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of formula (I) can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (morethan one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g, to reduce metabolic degradation).

[0099] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0100] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”). In one embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0101] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g, to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (z.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).

[0102] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0103] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0104] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0105] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g, enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, ofNotre Dame Press, Notre Dame, IN 1972). Additionally encompassed are compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0106] The “enantiomeric excess” (“e.e ”) or “% enantiomeric excess” (“%e.e.”) of a composition as used herein refers to an excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition can contain 90% of one enantiomer, e.g, the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. e.e. = (90-10)7100 = 80%.

[0107] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0108] The “diastereomeric excess” (“d.e.”) or “% diastereomeric excess” (“%d.e.”) of a composition as used herein refers to an excess of one diastereomer relative to one or more different diastereomers present in the composition. For example, a composition can contain 90% of one diastereomer, and 10% of one or more different diastereomers. d.e. = (90-10) / 100 = 80%.

[0109] Thus, a composition containing 90% of one diastereomers and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.Compound

[0110] In some embodiments, provided herein is N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)- 2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)-2-oxoacetamide, a PRMT5 inhibitor (e.g, an MTA-uncompetitive PRMT5 inhibitor) compound of formula (I).

[0111] The compound of formula (I) is also known as TNG908.

[0112] In some embodiments, the compound of formula (I) is a crystalline form of the compound of formula (I). The compound of formula (I) can also be referred to as “Compound I.”

[0113] In some embodiments, the crystalline form of the compound of formula (I) is crystalline Form A. In some embodiments, Form A has an XRPD pattern with one or more (e.g., one, two,three, four or five) characteristic peaks between and including the following values of 20 in degrees: 6.2 to 6.6 (e.g, 6.4±0.2), 8.7 to 9.1 (e.g., 8.9±0.2), 12.5 to 12.9 (e.g, 12.7±0.2), 13.8 to 14.2 (e.g, 14.0±0.2), 18.9 to 19.3 (e.g, 19.1±0.2), 19.7 to 20.1 (e.g, 19.9±0.2) and 22.4 to 22.8 (e.g., 22.6±0.2). In some embodiments, Form A has an XRPD pattern with one or more (e.g., one, two, three, four, five, six, seven, eight, nine or ten) characteristic peaks between and including the following values of 20 in degrees: 6.2 to 6.6 (e.g., 6.4±0.2), 8.7 to 9.1 (e.g., 8.9±0.2), 12.5 to 12.9 (e.g, 12.7±0.2), 13.6 to 14.0 (e.g, 13.8±0.2), 13.8 to 14.2 (e.g, 14.0±0.2), 18.1 to 18.5 (e.g, 18.3±0.2), 18.9 to 19.3 (e.g., 19. H0.2), 19.7 to 20.1 (e.g., 19.9±0.2), 22.4 to 22.8 (e.g., 22.6±0.2), 24.1 to 24.5 (e.g, 24.3±0.2), 26.0 to 26.4 (e.g, 26.2±0.2), 26.5 to 26.9 (e.g, 26.7±0.2) and 28.0 to 28.4 (e.g, 28.2±0.2).

[0114] In some embodiments, the X-ray powder diffraction pattern for Form A may comprise one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

[0115] In some embodiments, the X-ray powder diffraction pattern for Form A may comprise one or more (e.g, one, two, three, four, five, six, seven, eight, nine, or ten) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2.

[0116] In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19. U0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least four characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24,3±0,2, 26,2±0,2 and 26.7±0.2, 28.2±0,2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least five characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2,24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least six characteristic peaks, in terms of 26, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least seven characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least eight characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least nine characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, I9.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2 and 26.7±0.2, 28.2±0.2. In some embodiments, the X-ray powder diffraction pattern for Form A comprises at least ten characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.9±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2.

[0117] In some embodiments, Form A has an XRPD pattern with characteristic peaks at the following values of 29 in degrees: 6.4±9.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2.

[0118] In some embodiments, Form A has an XRPD pattern with characteristic peaks at the following values of 20 in degrees: 6.4±9.2, 8.9±0.2, 12.7±0.2, 13.8±9.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, 26.7±0.2 and 28.2±0.2.

[0119] In some embodiments, Form A has an XRPD pattern (obtained using CuKa radiation) with characteristic peaks comprising one, two, three, four, five, six, seven, eight, nine, or ten characteristic peaks, in terms of 20 values in degrees shown in Table 1 (±0.2 degrees).Table. 1. XRPD peaks for Form A of a compound of formula (I)

[0120] In some embodiments, Form A is substantially characterized by the thermal gravimetric analysis (TGA) as shown in FIG 2A. In some embodiments, Form A can be characterized by the thermal gravimetric analysis (TGA) shown in FIG 2A, which shows two small loses in mass below 250 °C, totaling to about 0.5% loss of water, and showing decomposition at temperatures above 250 °C.

[0121] In some embodiments, Form A is substantially characterized by the differential scanning calorimetry profile (DSC) shown in FIG 2B. In some embodiments, Form A can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG 2B, showing a melt peak at about 168.7 °C.

[0122] In some embodiments, Form A is substantially characterized by the DVS profile as shown in FIG 3A and FIG. 3B.

[0123] In some embodiments, Form A has a unit cell as determined by cry stal X-ray crystallography of the following dimensions: a = 5.0705(2) A; b = 13.9249(7) A; c = 13.9877(7) a= 87.522(2)°; 0= 85.730(2)° and y = 81.474(2)°. In some embodiments, Form A has a triclinic crystal system. In some embodiments, Form A has a Pl space group. In some embodiments, form A has a volume of 973.47(8) A3. In some embodiments, form A has a Z value of 2. In some embodiments, Form A has a density of 1.397 Mg / m3.'

[0124] In some embodiments, crystalline form A appears as needles (see, e.g., FIG. 4).

[0125] In some embodiments, the crystalline form of the compound of formula (I) comprises a mixture of two or more crystalline forms. In some embodiments, the crystalline form of the compound of formula (I) is substantially pure ciy stal 1 ine Form A.

[0126] The compound of formula (I) and crystalline Form A described herein can be prepared, for example, as described in WO2023114507.

[0127] In some embodiments, the crystalline form A of the compound of formula (I) has a DIO of between 2-4 pm. In some embodiments, the API comprising cry stalline form A of the compound of formula (I) has a D50 of between 6-10 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) has a D90 of between 18-35 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) D90 of between 25-30 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) has a D90 of less than 30 pm.

[0128] In some embodiments, API comprising crystalline form A of the compound of formula (I) is subjected to wet milling prior to incorporation in the pharmaceutical compositions and dosage forms described herein to optimize particle size.Pharmaceutical Compositions

[0129] In some embodiments, provided are pharmaceutical compositions comprising crystallineForm A of a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein crystalline Form A is as described herein.

[0130] In some embodiments, provided are pharmaceutical compositions comprising as the pharmaceutically active ingredient a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as crystalline Form A as described herein.

[0131] In some embodiments, provided are pharmaceutical compositions comprising crystalline Form A of a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein crystalline Form A is as described herein and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0132] In some embodiments, provided are pharmaceutical compositions comprising as the pharmaceutically active ingredient a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as crystalline Form A as described herein and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0133] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the cry stalline form A of compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101.

[0134] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the cry stalline form A of compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102.

[0135] In some embodiments the composition comprises one or more additional pharmaceutically acceptable excipients.

[0136] The amounts and ranges described below as pertaining to “a compound of formula (I)” can refer to the compound of formula (I) generally, to a crystalline form of a compound of formula (I), or to the crystalline form A of the compound of formula (I) described herein.

[0137] The pharmaceutical compositions and dosage forms described herein are characterized by relatively high API loads, which are beneficial for minimizing dosage form (e.g., tablet) size, thus improving patient dosing convenience. High API loads, particularly in the case of crystalline APIs such as the instant case can result blends with sub-optimal manufacturability properties (e.g., uniformity, flow, compressibility, API release profiles) requiring careful optimization of the pharmaceutical excipients. The intragranular blend properties, including blend uniformity and blend density are similar between formulations containing 40% API and formulations containing 50% w / w API. Ribbon solid fraction, ribbon thickness, particle size distribution, granule bulk density and granule flow are also similar between an exemplary formulation containing 40% w / w API and a formulation containing 50% w / w API (Example 10). Tablets containing a 40% w / w API load require lower force to achieve equivalent tablet tensile strength, have lower intra-tablet hardness variation, and lower % RSD. Additionally, tablets containing 40% w / w API have lower tablet weight variability at various compression forces and compression speeds, and improved tablet hardness variability compared to compositions comprising 50% w / w API.

[0138] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 45% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of a compound of formula (I). In someembodiments, the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 42% (w / w) of crystalline form A of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) to about 41% (w / w) of a compound of formula (I).

[0139] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w) or about 50% (w / w) of the compound of formula (I).

[0140] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w) or about 45% (w / w) of the compound of formula (I).

[0141] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 36% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of the compound of formula (I). In some embodiments, the pharmaceuticalcomposition comprises about 49% (w / w). In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of the compound of formula (I).

[0142] In some embodiments, the filler comprises a sugar, an inorganic material, a microcrystalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate or combinations thereof.

[0143] In some embodiments, the filler comprises a sugar, an inorganic material, and combinations thereof. In some embodiments, the sugar is selected from the group consisting of mannitol, lactose, sucrose, fructose, glucose, maltose, and combinations thereof. In some embodiments, the inorganic material is selected from the group consisting of dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0144] In some embodiments, the filler comprises a microcrystalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate, and combinations thereof. In some embodiments, the cellulose is selected from the group consisting of a hydroxypropylcellulose, a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropylmethylcellulose, or combinations thereof.

[0145] In some embodiments, the filler comprises microcrystalline cellulose (e.g, Avicel®). The microcrystalline cellulose filler can be of different grades. In some embodiments, the filler comprises microcrystalline cellulose PH 101, PH 102 or a mixture thereof. In some embodiments, the filler comprises microcrystalline cellulose PH 101 (e.g., Avicel® PH 101). In some embodiments, a portion of the filler comprises microcrystalline cellulose PH 101 (e.g., Avicel® PH 101) and another portion of the filler comprises microcrystalline cellulose PH 102 (e.g., Avicel® PH 102). In some embodiments, the filler used in the intragranular blend comprises microcrystalline cellulose PH 101 and the filler used in the extragranular blend comprises microcrystalline cellulose PH 102. In some embodiments, the filler used in the intragranular blend consists substantially of microcry stalline cellulose PH 101 and the filler used in the extragranular blend consists substantially of microcrystalline cellulose PH 102.

[0146] In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) filler.

[0147] In some embodiments, the pharmaceutical composition comprises about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) filler or about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) filler or about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 51% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 54% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 56% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 57% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 58% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 59% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) filler.

[0148] In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) microcrystalline cellulose. In someembodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) microcrystalline cellulose.

[0149] In some embodiments, the pharmaceutical composition comprises about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) or about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) microcrystalline cellulose or about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 51% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 54% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 56% (w / w) microcrystalline cellulose. In someembodiments, the pharmaceutical composition comprises about 57% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 58% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 59% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) microcrystalline cellulose.

[0150] In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the glidant comprises colloidal silicon dioxide, talc, kaolin, bentonite, or combinations thereof.

[0151] In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the glidant consists substantially of colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is prepared through a process involving flame hydrolysis of silicon tetrachloride in an oxy-hydrogen flame and is referred to as “fumed silica” or “untreated fumed silica” (e.g, Aerosil® 200, CAB-O-SIL® M-5P).

[0152] The amount of glidant in the composition influences blend flow and compressibility, and the increase in glidant in the pharmaceutical compositions described herein in comparison to the compositions described in WO2023114507 results in improved blend flow, contributing to adequate granulation for the intragranular blend and improved compressibility for the extragranular blend. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) glidant.

[0153] In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w), about 1.75% (w / w), about 1.9% (w / w), about 2% (w / w), about 2.1% (w / w), about 2.25% (w / w), about 2.5% (w / w) or about 3% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) glidant. In some embodiments, the pharmaceuticalcomposition comprises about 2.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) glidant.

[0154] In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) colloidal silicon dioxide.

[0155] In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w), about 1.75% (w / w), about 1.9% (w / w), about 2.0% (w / w), about 2.1% (w / w), about 2.25% (w / w), about 2.5% (w / w) or about 3% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) colloidal silicon dioxide.

[0156] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the disintegrant comprises sodium starch glycolate, a crospovidone, croscarmellose sodium, or combinations thereof. In some embodiments, the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol®). In some embodiments, the disintegrant consists substantially of croscarmellose sodium (e.g., Ac-Di-Sol®).

[0157] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0%(w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 2.9% (w / w), about 3% (w / w), about 3.1% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w) or about 4.0% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.75% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) disintegrant.

[0158] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 2.9% (w / w), about 3% (w / w), about 3.1% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w) or about 4.0% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w)croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.75% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) croscarmellose sodium.

[0159] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the lubricant comprises sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, or combinations thereof.

[0160] In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant consists substantially of magnesium stearate.

[0161] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) lubricant.

[0162] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.25% (w / w) or about 1.5% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) lubricant.

[0163] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) magnesium stearate. In some embodiments,the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) magnesium stearate.

[0164] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.25% (w / w) or about 1.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) magnesium stearate.

[0165] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate); wherein the compound of formula (I), the filler, the glidant, the disintegrant and the lubricant are present in the amounts described herein.

[0166] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate); wherein the compound of formula (I), the filler, the glidant, the disintegrant and the lubricant are present in the amounts described herein.

[0167] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I) as described herein(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0168] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0169] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0170] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the cry stall i ne form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of a filler comprising microcry stalline PH 101 or a combination of microcry stalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0171] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the cry stall i ne form A of compound of formula (I) ;(b) about 52% (w / w) to about 56% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcry stalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 2.5% (w / w) to about 3.5% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.75% (w / w) to about 1.25% (w / w) of a lubricant e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0172] In some embodiments, the composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 54 % (w / w) of a filler e.g, microcry stalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0173] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I) as described herein(b) microcry stall ine cellulose PH 101 or a combination of rmcrocrystalline cellulose PH 101 and PH 102;(c) colloidal silicon dioxide;(d) croscarmellose sodium; and(e) magnesium stearate.

[0174] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystallme cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0175] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystallme cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0176] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I);(b) about 52% (w / w) to about 56% (w / w) of microcrystallme cellulose PH 101 or a combination of microcrystallme cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of colloidal silicon dioxide;(d) about 2.5% (w / w) to about 3.5% (w / w) of croscarmellose sodium;(e) about 0.75% (w / w) to about 1.25% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0177] In some embodiments, the composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I);(b) about 54 % (w / w) of microcr stalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the composition.

[0178] The pharmaceutically acceptable excipients can be present in either the intragranular or the extragranular components of the pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the intragranular and the extragranular components.

[0179] In some embodiments, the pharmaceutical composition contains an intragranular filler is selected from the fillers described herein. In some embodiments, the intragranular filler comprises microcrystalline cellulose (e.g., Avicel®). In some embodiments, the intragranular filler consists substantially of a microcrystalline cellulose e.g., Avicel®). The average particle size of the microcrystalline cellulose affects binding to the active ingredient and additional excipients and a closer match between the particle size of the API and the particle size of the microcrystalline cellulose is believed to contribute to better binding and better manufacturability. The median particle size of microcrystalline cellulose PH 101 and PH 102 is ~50 pm and -100 pm, respectively. The average particle size of the API is -25 pm. Thus, in some embodiments, the intragranular filler comprises a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101). In some embodiments, the intragranular filler consists substantially of a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101).

[0180] The ratio of API to intragranular filler can influence the uniformity of API in the blend and lower ratios of API to intragranular filler can make it more difficult to achieve acceptable API uniformity.. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.6. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and1.4. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.2. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1. 1. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.05. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.0. In some embodiments, the w / w ratio of API to intragranular filler is between 0.95 and 1.05. In some embodiments, the w / w ratio of API to intragranular filler is between 0.95 and 1.0. In some embodiments, the w / w ratio of API to intragranular filler is about 0.95.

[0181] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular filler.

[0182] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w) or about 47% (w / w) intragranular filler.

[0183] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 26%(w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 32% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 36% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) intragranular filler.

[0184] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical compositioncomprises about 35% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular microcrystalline cellulose PH 101.

[0185] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w) or about 47% (w / w) intragranular microcrystalline cellulose PH 101.

[0186] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 26% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical compositioncomprises about 32% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 36% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) intragranular microcry stalline cellulose PH 101.

[0187] In some embodiments, the pharmaceutical composition contains an extragranular filler selected from the fillers described herein. Addition of an extragranular filler results in better compression compared to high API compositions lacking an extragranular filler. In some embodiments, the extragranular filler comprises a microcrystalline cellulose (e.g, Avicel®). Insome embodiments, the extragranular filler consists substantially of a microcrystalline cellulose (e.g., Avicel®). Because the intragranular phase represents a large proportion of the final composition, the properties of the extragranular filler (e.g, filler particle size distribution, flow, etc.) should be selected to match the behavior of the granules and to avoid a negative impact on the flow and compressibility of the final mixture. In some embodiments, the extragranular filler comprises microcrystalline cellulose PH 102 (e.g, Avicel® PH 102). In some embodiments, the extragranular filler consists substantially of microcrystalline cellulose PH 102 (e.g, Avicel® PH 102).

[0188] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) extragranular filler.

[0189] In some embodiments, the pharmaceutical composition comprises about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w) , about 17% (w / w) , about 18% (w / w) , about 19% (w / w) or about 20% (w / w) extragranular filler.

[0190] In some embodiments, the pharmaceutical composition comprises about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w) or about 16% (w / w) extragranular filler.

[0191] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about13% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 14% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 19% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) extragranular filler.

[0192] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) extragranular microcrystalline cellulose PH 102.

[0193] In some embodiments, the pharmaceutical composition comprises about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w) , about 17% (w / w) , about 18% (w / w) , about 19% (w / w) or about 20% (w / w) extragranular microcrystalline cellulose PH 102.

[0194] In some embodiments, the pharmaceutical composition comprises about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w) or about 16% (w / w) extragranular microcrystalline cellulose PH 102.

[0195] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical compositioncomprises about 10% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 13% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 14% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 19% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) extragranular microcrystalline cellulose PH 102.

[0196] In some embodiments, the pharmaceutical composition comprises an intragranular glidant selected from the glidants described herein. In some embodiments, the intragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M- 5P). The amount of intragranular glidant influences blend flow and the selected amounts of intragranular glidant contribute to rendering the intragranular blend amenable to dry granulation.

[0197] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) intragranular glidant.

[0198] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w) or about 1.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w),about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) intragranular glidant.

[0199] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular glidant.

[0200] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) intragranular colloidal silicon dioxide.

[0201] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w),about 1.4% (w / w) or about 1.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) intragranular colloidal silicon dioxide.

[0202] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular colloidal silicon dioxide.

[0203] In some embodiments, the pharmaceutical composition comprises an extragranular glidant selected from the glidants described herein. In some embodiments, the extragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M- 5P). The amount of extragranular glidant in the composition influences blend flow andcompressibility, and the selected amounts of glidant in the pharmaceutical compositions described herein contribute to improved blend flow for the extragranular blend and improved compressibility.

[0204] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular glidant.

[0205] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w) or about 1.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) extragranular glidant.

[0206] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about1.25% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular glidant.

[0207] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular colloidal silicon dioxide.

[0208] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w) or about 1.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) extragranular colloidal silicon dioxide.

[0209] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w)extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular colloidal silicon dioxide.

[0210] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein. In some embodiments, the intragranular disintegrant consists substantially of croscarmellose sodium.

[0211] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) intragranular disintegrant.

[0212] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) intragranular disintegrant.

[0213] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprisesabout 0.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) intragranular disintegrant.

[0214] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) intragranular croscarmellose sodium.

[0215] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w),about 2.25% (w / w) or about 2.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) intragranular croscarmellose sodium.

[0216] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) intragranular croscarmellose sodium.

[0217] In some embodiments, the pharmaceutical composition comprises an extragranular disintegrant selected from the disintegrants described herein. In some embodiments, the extragranular disintegrant consists substantially of croscarmellose sodium.

[0218] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) extragranular disintegrant.

[0219] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) extragranular disintegrant.

[0220] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) extragranular disintegrant. In someembodiments, the pharmaceutical composition comprises about 1.7% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) extragranular disintegrant.

[0221] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) extragranular croscarmellose sodium.

[0222] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) extragranular croscarmellose sodium.

[0223] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) extragranular croscarmellose sodium. In someembodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) extragranular croscarmellose sodium.

[0224] In some embodiments, the pharmaceutical composition comprises an intragranular lubricant selected from the lubricants described herein. In some embodiments, the intragranular lubricant consists substantially of magnesium stearate.

[0225] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) intragranular lubricant.

[0226] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) intragranular lubricant.

[0227] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) intragranular lubricant.

[0228] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about0.46% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) intragranular lubricant.

[0229] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) intragranular magnesium stearate.

[0230] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) intragranular magnesium stearate.

[0231] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) intragranular magnesium stearate.

[0232] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceuticalcomposition comprises about 0.5% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) intragranular magnesium stearate.

[0233] In some embodiments, the pharmaceutical composition comprises an extragranular lubricant selected from the lubricants described herein. In some embodiments, the extragranular lubricant consists substantially of magnesium stearate.

[0234] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) extragranular lubricant.

[0235] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) extragranular lubricant.

[0236] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) extragranular lubricant.

[0237] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about0.52% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) extragranular lubricant.

[0238] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) extragranular magnesium stearate.

[0239] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) extragranular magnesium stearate.

[0240] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) extragranular magnesium stearate.

[0241] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) extragranularmagnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) extragranular magnesium stearate.

[0242] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients. In some embodiments, the compound of formula (I), the intragranular filler and the additional excipients are present in the w / w percentages recited in any of the embodiments described herein.

[0243] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0244] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g, colloidal silicon dioxide);(d) an intragranular disintegrant (e.g., croscarmellose sodium);(e) an extragranular lubricant (e.g, magnesium stearate);(f) an extragranular filler (e. , microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g, colloidal silicon dioxide);(h) an extragranular disintegrant (e.g., croscarmellose sodium); and(i) an extragranular lubricant (e.g., magnesium stearate).

[0245] In some embodiments, the compound of formula (I), the intragranular filler, the extragranular filler, the intragranular glidant, the extragranular glidant, the intragranular disintegrant, the extragranular disintegrant, the intragranular lubricant and the extragranular lubricant are present in the w / w percentages recited in any of the embodiments described herein.

[0246] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)(b) intragranular microcrystalline cellulose PH 101;(c) intragranular colloidal silicon dioxide;(d) intragranular croscarmellose sodium;(e) extragranular magnesium stearate;(f) extragranular microcrystalline cellulose PH 102;(g) extragranular colloidal silicon dioxide;(h) extragranular croscarmellose sodium; and(i) extragranular magnesium stearate.

[0247] In some embodiments, the compound of formula (I), the intragranular microcrystalline cellulose, the extragranular microcrystalline cellulose, the intragranular silicon dioxide, the extragranular silicon dioxide, the intragranular croscarmellose sodium, the extragranular croscarmellose sodium, the intragranular magnesium stearate and the extragranular magnesium stearate are present in the w / w percentages recited in any of the embodiments described herein.

[0248] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e. , colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0249] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 35% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(1) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0250] In some embodiments, the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.25% (w / w) to about 1.75% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.3% (w / w) to about 0.7% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 8% (w / w) to about 16% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.8% (w / w) to about 1.2% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.25% (w / w) to about 1.75% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.3% (w / w) to about 0.7% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0251] In some embodiments, the pharmaceutical composition comprises:(a) about 38% (w / w) to about 42% (w / w) of crystalline form A of the compound of formula (I);(b) about 40% (w / w) to about 44% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.9% (w / w) to about 1.1% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.4% (w / w) to about 1.6% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.4% (w / w) to about 0.6% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 10% (w / w) to about 14% (w / w) of an extragranular filler e.g., microcrystalline cellulose PH 102);(g) about 0.9% (w / w) to about 1.1% (w / w) of an extragranular glidant (e.g. , colloidal silicon dioxide);(h) about 1.4% (w / w) to about 1.6% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.4% (w / w) to about 0.6% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0252] In some embodiments, the pharmaceutical composition comprises:(a) about 39% (w / w) to about 41% (w / w) of crystalline form A of the compound of formula (I);(b) about 41% (w / w) to about 43% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.45% (w / w) to about 1.55% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.45% (w / w) to about 0.55% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 11% (w / w) to about 13% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.95% (w / w) to about 1.05% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.45% (w / w) to about 1.55% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0253] In some embodiments, the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g, magnesium stearate).

[0254] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of intragranular colloidal silicon dioxide;(d) about 0.5% (w / w) to about 2.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate;(f) about 5% (w / w) to about 20% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.5% (w / w) to about 1.5% (w / w) of extragranular colloidal silicon dioxide;(h) about 0.5% (w / w) to about 2.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0255] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 35% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of intragranular colloidal silicon dioxide;(d) about 0.5% (w / w) to about 2.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate;(f) about 5% (w / w) to about 20% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.5% (w / w) to about 1.5% (w / w) of extragranular colloidal silicon dioxide;(h) about 0.5% (w / w) to about 2.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0256] In some embodiments, the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.25% (w / w) to about 1.75% (w / w) of intragranular croscarmellose sodium;(e) about 0.3% (w / w) to about 0.7% (w / w) of intragranular magnesium stearate;(f) about 8% (w / w) to about 16% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.8% (w / w) to about 1.2% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.25% (w / w) to about 1.75% (w / w) of extragranular croscarmellose sodium; and(i) about 0.3% (w / w) to about 0.7% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0257] In some embodiments, the pharmaceutical composition comprises:(a) about 38% (w / w) to about 42% (w / w) of crystalline form A of the compound of formula (I);(b) about 40% (w / w) to about 44% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.9% (w / w) to about 1.1% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.4% (w / w) to about 1.6% (w / w) of intragranular croscarmellose sodium;(e) about 0.4% (w / w) to about 0.6% (w / w) of intragranular magnesium stearate;(f) about 10% (w / w) to about 14% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.9% (w / w) to about 1.1% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.4% (w / w) to about 1.6% (w / w) of extragranular croscarmellose sodium; and(i) about 0.4% (w / w) to about 0.6% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0258] In some embodiments, the pharmaceutical composition comprises:(a) about 39% (w / w) to about 41% (w / w) of crystalline form A of the compound of formula (I);(b) about 41% (w / w) to about 43% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.95% (w / w) to about 1.05% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.45% (w / w) to about 1.55% (w / w) of intragranular croscarmellose sodium;(e) about 0.45% (w / w) to about 0.55% (w / w) of intragranular magnesium stearate;(I) about 11% (w / w) to about 13% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.95% (w / w) to about 1.05% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.45% (w / w) to about 1.55% (w / w) of extragranular croscarmellose sodium; and(i) about 0.45% (w / w) to about 0.55% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0259] In some embodiments, the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).Dosage Forms

[0260] In some embodiments, provided are dosage forms comprising a pharmaceutical composition described herein.

[0261] In some embodiments, provided are dosage forms intended for oral administration comprising a pharmaceutical composition described herein.

[0262] In some embodiments, the dosage form is selected from the group consisting of a powder, a sachet, a stickpack, a capsule, a minitab, and a tablet.

[0263] In some embodiments, the dosage form is a tablet.

[0264] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.

[0265] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 750 mg.

[0266] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 225 mg to 650 mg.

[0267] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 240 mg to about 260 mg, about 300 mg to about 325 mg, about 360 mg to about 390 mg, about 480 mg to about 520 mg or about 600 mg to about 650 mg,.

[0268] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 250 mg, about 312.5 mg, about 375 mg, about 500 mg, or about 625 mg.

[0269] In some embodiments, the dosage form comprises about 50 mg to about 350 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 300 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 250 mg of the crystalline form A of the compound of formula (I).

[0270] In some embodiments, the dosage form comprises about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg or about 350 mg of crystalline form A of the compound of formula (I).

[0271] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg or about 300 mg of crystalline form A of the compound of formula (I).

[0272] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of crystalline form A of the compound of formula (I).

[0273] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg, about 200 mg, or about 300 mg of crystalline form A of the compound of formula (I).In some embodiments, the dosage form comprises about 100 mg or about 200 mg of crystalline form A of the compound of formula (I).

[0274] In some embodiments, the dosage form comprises about 50 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 75 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 100 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 125 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 150 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 175 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 200 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 225 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 275 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 300 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 325 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 350 mg of crystalline form A of the compound of formula (I).

[0275] In some embodiments, the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.25 mg intragranular magnesium stearate, 30 mg extragranular microcrystalline cellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O- SIL® M-5P), 3.75 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.25 mg extragranular magnesium stearate.

[0276] In some embodiments, the dosage form comprises 125 mg Compound of formula (I), 131.25 mg intragranular microcry stalline cellulose PH 101, 3.13 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.56 mg intragranular magnesium stearate, 37.50 mg extragranular microcrystalline cellulose PH 102, 3.13 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.56 mg extragranular magnesium stearate.

[0277] In some embodiments, the dosage form comprises 150 mg Compound of formula (I), 157 mg intragranular microcrystalline cellulose PH 101, 3.75 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.88 mg intragranular magnesium stearate, 45 mg extragranular microcrystalline cellulose PH 102, 3.75 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O- SIL® M-5P), 5.63 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.88 mg extragranular magnesium stearate.

[0278] In some embodiments, the dosage form comprises 200 mg Compound of formula (I), 210 mg intragranular microcrystalline cellulose PH 101, 5.0 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 60 mg extragranular microcrystalline cellulose PH 102, 5.0 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O- SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.

[0279] In some embodiments, the dosage form comprises 250 mg Compound of formula (I), 262.5 mg intragranular microcrystalline cellulose PH 101, 6.25 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 9.38 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 3.13 mg intragranular magnesium stearate, 75 mg extragranular microcrystallinecellulose PH 102, 6.25 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 9.38 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.13 mg extragranular magnesium stearate.

[0280] In some embodiments, the dosage form is a tablet.

[0281] In some embodiments, the tablet further comprises a coating. In some embodiments, the coating is selected from the group consisting of a film forming polymer, a plasticizer, and combinations thereof. In some embodiments, the film forming polymer is selected from the group consisting of a hypromellose, an ethylcellulose, cellulose acetate, a poly vinylpyrrolidone, a polyvinyl alcohol, a polyacrylate, and combinations thereof. In some embodiments, the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propylene glycol, and combinations thereof. In some embodiments, the coating comprises polyvinyl alcohol.

[0282] In some embodiments, the coating comprises a colorant selected from the group consisting of titanium dioxide, an aluminum lake, an iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.Methods of Making

[0283] In some embodiments, provided are processes for preparing a pharmaceutical composition as described herein.

[0284] In some embodiments, provided is a process for preparing a pharmaceutical composition comprising crystalline form A of a compound of formula (I) as described in any of the embodiments herein, comprising:(a) Charging and blending crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition.

[0285] In another aspect, provided are processes for preparing the dosage forms comprising crystalline form A of a compound of formula (I) described in any of the embodiments herein, for example, comprising:(a) Charging and blending crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into dosage forms; and, optionally,(h) Coating the dosage forms.

[0286] A schematic process for preparing the dosage forms described herein is depicted in FIG. 5.

[0287] The pharmaceutical compositions described herein are amenable to a streamlined and scalable manufacturing process, with a reduced number of steps when compared to the process described in WO2023114507 (FIG. 6).

[0288] The order of addition of components for the blending steps influences the uniformity of API in the blend and impacts the distribution of low-level components in the blend. Uniform distribution of low-level components in the intragranular blend is important to successfully achieve dry granulation of the intragranular blend. For example, lack of uniform distribution of glidant in the intragranular blend can result in sub-optimal granulation with a wide particle size distribution, which would negatively impact extragranular blending and eventually compressibility of the final blend. In some embodiments, the order of addition is as shown in Table. 2.T able. 2. Order of addition of ingredientsMCC - microcrystalline celluloseCCS - croscarmellose sodiumAPI - compound of formula (I)

[0289] In some embodiments, provided are processes for preparing a pharmaceutical composition as described herein, for example, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I) as described herein; iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0290] In another aspect, provided are processes for preparing the dosage forms described herein, for example, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I) as described herein; iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend;ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(1) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubncation extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.(m) Compressing the pharmaceutical composition into dosage forms; and, optionally,(n) Coating the dosage forms.

[0291] The selection of granule milling screen size in the milling step influences the particle size distribution of the resulting granules. In some embodiments, the milling step employs 3.15 mm wired screen size followed by 1 mm wired screen size, resulting in a profile of milled granules with acceptable particle size distribution, including low levels of fines, amenable for processing during tablet compression, which is typically difficult to achieve for a crystalline drug substance formulation with a high drug.

[0292] An exemplary particle size distribution profile obtained with the wired screen size selections described herein is shown in FIG. 7.

[0293] In some embodiments, the intragranular filler consists substantially of microcrystalline cellulose PH 101.

[0294] In some embodiments, the intragranular disintegrant consists substantially of croscarmellose sodium.

[0295] In some embodiments, the intragranular glidant consists substantially of colloidal silicon dioxide.

[0296] In some embodiments, the intragranular lubricant consists substantially of magnesium stearate.

[0297] In some embodiments, the extragranular filler consists substantially of microcrystalline cellulose PH 102.

[0298] In some embodiments, the extragranular disintegrant consists substantially of croscarmellose sodium.

[0299] In some embodiments, the extragranular glidant consists substantially of colloidal silicon dioxide.

[0300] In some embodiments, the extragranular lubricant consists substantially of magnesium stearate.

[0301] In some embodiments, the desired amounts of crystalline form A of a compound of Formula (I), intragranular filler, intragranular disintegrant, intragranular glidant, intragranular lubricant, extragranular filler, extragranular disintegrant, extragranular glidant and extragranular lubricant are selected to result in pharmaceutical compositions having the w / w percentages of ingredients described in the “Pharmaceutical composition” section.

[0302] In some embodiments, granulating the intragranular blend to obtain granules comprises a dry granulation process step. In some embodiments, granulating the intragranular blend to obtain granules comprises a wet granulation process step.

[0303] In some embodiments, the tablet comprises a coating. In some embodiments, the coating comprises one or more film-forming polymers selected from the group consisting of a hypromellose, an ethylcellulose, a polyvinylpyrrolidone, a polyacrylate, a plasticizer, and combinations thereof. In some embodiments, the coating comprises a polyvinyl alcohol.

[0304] In some embodiments, the coating comprises a colorant selected from the group consisting of titanium dioxide, an aluminum lake, an iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0305] In some embodiments, provided is a pharmaceutical composition or a dosage form as described herein prepared by the processes described herein.Methods of Use and TreatmentTreatment of MTAP-deficient and / or MTA-accumulating proliferation disorders

[0306] 5-Methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-l -phosphate. MTAP- deletion is a common genetic event in human cancer. MTAP deletion frequency in a subset of human cancers is described in Cerami et al., Cancer Discov. (2012);2(5):40I-4; Gao et al., Sci Signal. (2013);6(269):pl 1 ; and Lee et al., Nat. Gen. (2014) 46(11): 1227-32. For example, more than 50% of malignant peripheral nerve sheath tumor (MPNST) have deletions in MTAP (Lee et al., Nat. Gen. (2014)). Other cancers with high MTAP deletion frequencies are glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous lung cancer, melanoma, diffuse large B cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, stomach cancer, glioma, adrenal carcinoma, thymoma, breast cancer, liver cancer, ovarian cancer, renal papillary cancer, uterine cancer, prostate cancer, and renal clear cell cancer. MTAP deletion in cells is one of the mechanisms that leads to MTAP-deficiency, increased intracellular MTA accumulation, and confers enhanced dependency on the protein arginine methyltransferase 5 (PRMT5) in cancer cells. Other mechanisms leading to MTAP deficiency include, inter alia, MTAP translocations and MTAP epigenetic silencing which could also lead to MTAP -null and / or MTAP deficient tumors. PRMT5 mediates the formation of symmetric dimethylarginine (SDMA); thus, the PRMT5 activity can be assessed by measuring the SDMA levels using the antibody against an SDMA or SDMA modified polypeptide.

[0307] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g, cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g, a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), apharmaceutical composition comprising a compound of formula (I) as described herein, or a dosage form as described herein. In some cases, the MT AP -deficiency is an MTAP-deletion.

[0308] In some embodiments, provided is a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or a pharmaceutical composition comprising a compound of formula (I) of the present disclosure for use in a method of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0309] In some embodiments, provided is a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or a pharmaceutical composition comprising a compound of formula (I) of the present disclosure for use in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0310] In some embodiments, provided is a use of a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or of a pharmaceutical composition comprising a compound of formula (I) of the present disclosure in a method of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0311] In some embodiments, provided is use of a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or of a pharmaceutical composition comprising a compound of formula (I) of the present disclosure in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0312] In some embodiments, provided are methods for treating an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer) in a subject in need thereofcomprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g, a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), a pharmaceutical composition comprising a compound of formula (I) as described herein, or a dosage form as described herein.

[0313] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g, cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the method comprises administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0314] In some embodiments, provided are methods of treating an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g, cancer) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiment, the method comprises administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0315] In some embodiments, the subject is human.

[0316] In some embodiments, the disease is an MTAP-deficient and / or MTA-accumulating cancer. In some embodiments, the cancer is an MTAP-deleted cancer.

[0317] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g. pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0318] In some embodiments, the cancer is an MTAP-deficient and / or MTA-accumulating glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g, esophageal squamous cell carcinoma or esophagealadenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0319] In some embodiments, the cancer is a cancer selected from the group of pancreatic cancer, NSCLC, glioblastoma, mesothelioma and sarcoma.

[0320] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is histology agnostic (z.e., is any MTAP-deficient and / or MTA-accumulating cancer) regardless of histology. In some embodiments, the cancers recited herein are MTAP-deleted cancers.

[0321] In some embodiments, the cancer is a central nervous system (CNS) malignancy . In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy r is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0322] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous).In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0323] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0324] In some embodiments, the compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) and dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTAP- deficient cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTAP- deficient cells. In one embodiment, the subject in need thereof suffers from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g., intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, chol angiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0325] In some embodiments, the cancer is a central nervous system (CNS) malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, theCNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0326] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0327] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0328] In some embodiments, the compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTA- accumulating cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTA- accumulating cells. In one embodiment, the subject in need thereof suffers from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, chol angiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0329] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0330] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0331] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0332] In some embodiments, the compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTAP deficient and / or MTA-accumulating cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), crys tailine forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTAP deficient and / or MTA-accumulating cells. In one embodiment, the subject in needthereof suffers from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g., intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0333] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0334] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0335] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous),mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.Combination therapies

[0336] In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g, cancers) with a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, compnsing a compound of formula (I)) or dosage forms thereof, as described herein in combination with one or more therapeutic agents.

[0337] In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g, cancers) with a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, compnsing a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent. In some embodiments, provided are methods of treatment of MTAP- deficient and / or MTA accumulating proliferative disorders (e.g, cancers) with a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g., cancers) with a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0338] The term “Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agenf ’) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g, synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g, powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g, the administration of three or more therapeutic agent.

[0339] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.

[0340] In some embodiments, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e g., comprising a compound of formula (I)) or dosage forms thereof, as described herein are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0341] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a general chemotherapeutic agent selected from anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5 -fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopunne (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), nab- paclitaxel (Abraxane®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hy camptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0342] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an EGFR-inhibitor (e.g., cetuximab, panitumimab, erlotinib, gefitinib and EGFRi NOS). In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a MAPK-pathway inhibitor (e.g, BRAFi, panRAFi, MEKi, ERKi; PI3K-mTORpathway inhibitors, such as alpha-specific PI3Ki, pan-class I PI3Ki and mT0R / PI3Ki, particularly everolimus and analogues thereof).

[0343] MTAP-deletion can co-occur with mutations in the KRAS gene (e.g, KRASG12C). In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a KRAS inhibitor (e.g, a pan-KRAS or a specific G12C, G12D, G13C inhibitor, e.g, adagrasib, sotorasib, LY3537982, RMC-6236, RMC-6291, RMC-9805, RMC-8839).

[0344] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a Spliceosome inhibitor (e.g, SF3bl inhibitors; e.g, E7107).

[0345] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an HD AC inhibitor or DNA methyltransferase inhibitor. In some embodiments, the HD AC inhibitor is Tnchostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5 -azacytidine.

[0346] In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a MAT2A inhibitor (e.g, AG-270, IDE397, S95035).

[0347] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an inhibitor of a protein which interacts with or is required for PRMT5 function, including, but not limited to, pICIN, WDR77 or RIOK1.

[0348] In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an HDM2 inhibitor and / or 5-FU or other purine analogues (e.g., 6-thioguanine, 6- mercaptopurine).

[0349] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a CDK4 inhibitor, including, but not limited to, LEE011 or a CDK 4 / 6 inhibitor (e.g, palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzemo").

[0350] In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and targeted treatments contingent on the dependency of individual target tumors on relevant pathways as determined by suitable predictive markers, including but not limited to: inhibitors of HDM2i, PI3K / mT0R-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi.

[0351] In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) and immunotherapy.

[0352] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a cancer immunotherapy (e.g., a checkpoint blocking antibody) to treat a subject (e.g., a human subject), e.g., having a disease or disorder described herein (e.g., a cancer described herein)).

[0353] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab).

[0354] In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody (e.g., anti- PD-1 or anti-PD-Ll). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538); CT- 011; AMP-224; pembrolizumab (MK-3475); pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-Ll agent (e.g., an anti-PD-Ll antibody, e.g., BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); envafolimab; cosibelimab; sugemalimab, AUNP-12 or atezolizumab (MPDL-3280A) or an anti- PD-Ll small molecule (e.g., CA-170)).

[0355] In some embodiments, the immunotherapeutic agent is a checkpoint blocking antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT including IMP321 and MGA271).

[0356] In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0357] In some embodiments, the immunotherapeutic agent is a co-stimulatory antibody (e.g., anti-4-lBB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0358] In some embodiments, the immunotherapeutic agent is a cancer vaccine such as a neoantigen. These vaccines can be developed using peptides or RNA.

[0359] In some embodiments, the immunotherapeutic agent is an oncolytic virus.

[0360] In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0361] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a disease-specific huMAB (e.g., an anti-HER3 huMAB).

[0362] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an ADC / ADCC contingent on the expression of relevant surface targets on target tumors of interest.

[0363] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and one or more DNA damage pathway inhibitor. In some embodiments, a DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chkl inhibitor (e.g., AZD7762). In some embodiments, a DNA damage pathway inhibitor is a DNA alkylating agent.

[0364] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a PARP inhibitor. In some embodiments, a PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, E7016, iniparib, and 3-aminobenzamide.

[0365] Some patients may experience allergic reactions to the PRMT5 inhibitors described herein and / or other anti-cancer agent(s) during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of an allergic reaction. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an anti-allergic agent (e.g., corticosteroids, including, but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu- Medrol®); antihistamines, such as diphenhydramine (e.g., Benadryl®), hydroxyzine, andcyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (Brethine®)).

[0366] Some patients may experience nausea during and after administration of the PRMT5 inhibitors described herein and / or other anti-cancer agent(s); therefore, anti-emetics are used in preventing nausea (upper stomach) and vomiting. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an anti-emetic (e.g., aprepitant (Emend®), ondansetron (Zofran®), granisetron HC1 (Kytril®), lorazepam (Ativan®, dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof).

[0367] Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an analgesic (e.g., an over-the-counter analgesic (e.g., Tylenol®), an opioid analgesic (e.g., hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®)).

[0368] In an effort to protect normal cells from treatment toxicity and to limit organ toxicities, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a cytoprotective agent (e.g, Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid)).

[0369] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International (e.g., IMS World Publications).

[0370] The above-mentioned compounds, which can be used in combination with a PRMT5 inhibitor as described herein, can be prepared and administered as described in the art, including, but not limited to, in the documents cited above.

[0371] In one embodiment, provided are pharmaceutical compositions comprising at least one compound of the present disclosure (e.g, a crystalline form of a compound of formula (I), e.g, crystalline form A) together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents.

[0372] In particular, compositions will either be formulated together as a combination therapeutic or administered separately.

[0373] In combination therapy, a PRMT5 inhibitor as described herein and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.

[0374] In a preferred embodiment, the compound of the present disclosure (a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) and the other anti-cancer agent(s) is generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The PRMT5 inhibitor as described herein and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.

[0375] In another aspect, provided are kits that include one or more PRMT5 inhibitor(s) as described herein (a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage formsthereof, as described herein) and a second therapeutic agent as disclosed herein are provided. Representative kits include (a) a PRMT5 inhibitor as described herein (a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), (b) at least one other therapeutic agent, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration.

[0376] A compound of formula (I), crystalline forms e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein may also be used in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the present disclosure may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and radiation.Patient Selection and Monitoring

[0377] In some embodiments, provided is a method of determining if a subject having or having been diagnosed with a cancer (e.g., a cancer patient) will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) contacting a test sample obtained from said subject with a reagent capable of detecting human cancer cells that have MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g. , a reference sample taken from a non- cancerous or normal control subject), wherein the presence of MTAP deficiency and / or MTA accumulation in said test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms (e.g.,crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein).

[0378] In some embodiments, provided is a method of determining if a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) contacting a test sample obtained from a subject having or having been diagnosed with said cancer with a reagent capable of detecting human cancer cells that have MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g, a reference sample taken from a non- cancerous or normal control subject), wherein the presence of MTAP deficiency and / or MTA accumulation in said test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein). In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0379] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g, low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, theCNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0380] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0381] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0382] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells. The level of expression of PRMT5 can be considered when determining the therapeutically effective dosage of a PRMT5 inhibitor.

[0383] In one aspect, provided is a method of determining the sensitivity of a cancer cell to PRMT5 inhibition (e.g., inhibition with an MTA-uncompetitive PRMT5 inhibitor, e.g, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) assaying the production, level, activity, expression or presence of MTAP), in said cancer cell;b) comparing the production, level, activity, expression or presence of MTAP in the cancer cell with the production, level, activity, expression or presence of MTAP, respectively, in a non-cancerous or normal control cell, wherein a decreased level, activity or expression in the cancer cell indicates MTAP deficiency and wherein MTAP deficiency indicates that said cancer cell is sensitive to the PRMT5 inhibitor.

[0384] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g., intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0385] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0386] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, thecancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0387] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0388] In one embodiment, provided is a method of determining the sensitivity of a cancer cell to a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) assaying for level, activity or expression of the MTAP gene or its gene product in both the cancer cell and a normal control cell, wherein a decreased level, activity or expression in the cancer cell indicates MTAP deficiency; b) assaying for PRMT5 expression in said cancer cell; c) comparing the PRMT5 expression with PRMT5 expression in the cancer cell and a normal control cell; wherein the similarity in PRMT5 expression, and the presence of said MTAP deficiency in said cancer cell, indicates said cell is sensitive to a PRMT5 inhibitor.

[0389] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0390] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, theCNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0391] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer isDLBCL

[0392] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0393] In one aspect the provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer (e.g., a cancer associated with MTAP deficiency and / or MTA accumulation) comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells in a test sample obtained from said subject), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g. , a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said subject will respond to therapeutic treatment with a PRMT5 inhibitor; andc) administering a therapeutically effective amount of PRMT5 inhibitor (e.g., an MTA- uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA- cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g, cry stalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0394] In one aspect provided is a therapeutic method of treating a cancer (e.g. , a cancer associated with MTAP deficiency and / or MTA accumulation) in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g. , a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent); and c) administering a therapeutically effective amount of PRMT5 inhibitor (e.g, an MTA- uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA- cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0395] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma),astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0396] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0397] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0398] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0399] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

[0400] In one aspect provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer associated with MTAP deficiency and / or MTA accumulation comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g., by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent); and c) administering a therapeutically effective amount of a composition comprising a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), cry stalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0401] In one aspect provided is a therapeutic method of treating cancer associated with MTAP deficiency and / or MTA accumulation in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutictreatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent); and c) administering a therapeutically effective amount of a composition comprising a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor e.g, a compound of formula (I), crystalline forms e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0402] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0403] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0404] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous),mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer isDLBCL

[0405] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0406] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

[0407] In some embodiments provided is a method of determining if a subject having or having been diagnosed with a cancer associated with MTAP deficiency and / or MTA accumulation will respond to treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g. , a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent).

[0408] In some embodiments provided is a method of determining if a cancer associated with MTAP deficiency and / or MTA accumulation will respond to treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive PRMT5 inhibitor, e.g, a compound of formula (I), crystallineforms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from a subject having or having been diagnosed with said cancer (e.g., by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g., by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g. , a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent).

[0409] In some embodiments, the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g, bladder urothelial carcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

[0410] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from glioma (e.g, low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors. In some embodiments, the CNS malignancy is glioma. In some embodiments, the CNS malignancy is low grade glioma. In some embodiments, the CNS malignancy is intermediate grade glioma. In some embodiments, the CNS malignancy is glioblastoma or glioblastoma multiforme. In some embodiments, the CNS malignancy is glioblastoma. In some embodiments, the CNS malignancy is glioblastoma multiforme. In some embodiments, the CNS malignancy is a MTAP-deleted glioblastoma. In some embodiments, the CNS malignancy is anintracranial MPNST tumor. In some embodiments, the CNS malignancy is CNS metastases from solid tumors.

[0411] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL

[0412] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0413] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.Sample preparation

[0414] Further provided are assays for the detection of MTAP deficiency and / or MTA accumulation. They can include detecting a mutation related to MTAP deficiency and / or MTA accumulation, e.g., in a body fluid such as blood (e.g, serum or plasma) bone marrow, cerebral spinal fluid, peritoneal / pleural fluid, lymph fluid, ascites, serous fluid, sputum, lacrimal fluid, stool, and urine, or in a tissue such as a tumor tissue. The tumor tissue can be fresh tissue or preserved tissue (e.g, formalin fixed tissue, e.g, paraffin-embedded tissue).

[0415] Body fluid samples can be obtained from a subject using any of the methods known in the art. Methods for extracting cellular DNA from body fluid samples are well known in the art. Typically, cells are lysed with detergents. After cell lysis, proteins are removed from DNA using various proteases. DNA is then extracted with phenol, precipitated in alcohol, and dissolved in an aqueous solution. Methods for extracting acellular DNA from body fluid samples are also known in the art. Commonly, a cellular DNA in a body fluid sample is separated from cells, precipitated in alcohol, and dissolved in an aqueous solution.Detection ofPRMT5 selectivity

[0416] Samples, once prepared, can be tested for MTAP deficiency and / or MTA accumulation, either or both of which indicates that the sample is sensitive to treatment with a PRMT5 inhibitor. Cells can be determined to be MTA accumulating by techniques known in the art; methods for detecting MTA include, as a non-limiting example, liquid chromatographyelectrospray ionization-tandem mass spectrometry (LC-ESI-MS / MS), as described in Stevens et al. 2010. J. Chromatogr. A. 1217: 3282-3288; and Kirovski et al. 2011 Am. J. Pathol. 178: 1145- 1152; and references cited therein. The detection of MTAP deficiency can be done by any number of ways, for example: DNA sequencing, PCR based methods, including RT-PCR, microarray analysis, Southern blotting, Northern blotting, Next Generation Sequencing, and dip stick analysis. In some embodiments, MTAP deficiency is evaluated by any technique known in the art, for example, immunohistochemistry utilizing an anti-MTAP antibody or derivative thereof, and / or genomic sequencing, or nucleic acid hybridization, or amplification utilizing at least one probe or primer comprising a sequence of at least 12 contiguous nucleotides (nt) of the sequence of MTAP wherein the primer is no longer than about 30 nt.

[0417] The polymerase chain reaction (PCR) can be used to amplify and identify MTAP deficiency from either genomic DNA or RNA extracted from tumor tissue. PCR is well known in the art and is described in detail in Saiki et al., Science 1988, 239:487.

[0418] Methods of detecting MTAP deficiency by hybridization are provided. The method comprises identifying MTAP deficiency in a sample by its inability to hybridize to MTAP nucleic acid. The nucleic acid probe is detectably labeled with a label such as a radioisotope, a fluorescent agent or a chromogenic agent. Radioisotopes can include without limitation; 3H, 32P, 33P and 35S etc. Fluorescent agents can include without limitation: FITC, texas red, rhodamine, etc.

[0419] The probe used in detection that is capable of hybridizing to MTAP nucleic acid can be from about 8 nucleotides to about 100 nucleotides, from about 10 nucleotides to about 75 nucleotides, from about 15 nucleotides to about 50 nucleotides, or about 20 to about 30 nucleotides. The kit can also provide instructions for analysis of patient cancer samples, wherein the presence or absence of MTAP deficiency indicates if the subject is sensitive or insensitive to treatment with a PRMT5 inhibitor.

[0420] Single stranded conformational polymorphism (SSCP) can also be used to detect MTAP deficiency. This technique is well described in Orita et al., PNAS 1989, 86:2766-2770.Measurement of Gene Expression

[0421] Evaluation of MTAP deficiency and measurement of MTAP gene expression, and measurement of PRMT5 gene expression can be performed using any method or reagent known in the art.

[0422] Detection of gene expression can be by any appropriate method, including for example, detecting the quantity of mRNA transcribed from the gene or the quantity of cDNA produced from the reverse transcription of the mRNA transcribed from the gene or the quantity of the polypeptide or protein encoded by the gene. These methods can be performed on a sample by sample basis or modified for high throughput analy sis. For example, using Affymetrix™ U133 microarray chips.

[0423] In one aspect, gene expression is detected and quantitated by hybridization to a probe that specifically hybridizes to the appropriate probe for that biomarker. The probes also can be attached to a solid support for use in high throughput screening assays using methods known in the art.

[0424] In one aspect, the expression level of a gene is determined through exposure of a nucleic acid sample to the probe-modified chip. Extracted nucleic acid is labeled, for example, with a fluorescent tag, preferably during an amplification step.

[0425] Hybridization of the labeled sample is performed at an appropriate stringency level. The degree of probe-nucleic acid hybridization is quantitatively measured using a detection device.

[0426] Alternatively, any one of gene copy number, transcription, or translation can be determined using known techniques. For example, an amplification method such as PCR may be useful. General procedures for PCR are taught in MacPherson et al., PCR: A Practical Approach, (IRL Press at Oxford University Press (1991)). However, PCR conditions used for each application reaction are empirically determined. A number of parameters influence the success of a reaction. Among them are annealing temperature and time, extension time, Mg 2+ and / or ATP concentration, pH, and the relative concentration of primers, templates, and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis followed by visualization with ethidium bromide staining and ultraviolet illumination. In one embodiment, the hybridized nucleic acids are detected by detecting one or more labels attached to the sample nucleic acids. The labels can be incorporated by any of a number of means well known to those of skill in the art. However, in one aspect, the label is simultaneously incorporated during the amplification step in the preparation of thesample nucleic acid. Thus, for example, polymerase chain reaction (PCR) with labeled primers or labeled nucleotides will provide a labeled amplification product. In a separate embodiment, transcription amplification, as described above, using a labeled nucleotide (e.g., fluorescein- labeled UTP and / or CTP) incorporates a label in to the transcribed nucleic acids.

[0427] Alternatively, a label may be added directly to the original nucleic acid sample (e.g., mRNA, poly A, mRNA, cDNA, etc.) or to the amplification product after the amplification is completed. Means of attaching labels to nucleic acids are well known to those of skill in the art and include, for example nick translation or end-labeling (e.g., with a labeled RNA) by kinasing of the nucleic acid and subsequent attachment (ligation) of a nucleic acid linker joining the sample nucleic acid to a label (e.g., a fluorophore).

[0428] In one example, the gene expression can be measured through an in-situ hybridization protocol that can detect RNA molecules on a slide containing tissue sections or cells (e.g., through RNAscope®).

[0429] Detectable labels suitable for use in the methods disclosed herein include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Useful labels include biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g., Dynabeads™), fluorescent dyes (e.g., fluorescein, texas red, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., 3H, 1251, 35 S, 14C, or 32P) enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and calorimetric labels such as colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads.

[0430] Detection of labels is well known to those of skill in the art. Thus, for example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted light. Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and calorimetric labels are detected by simply visualizing the colored label. The detectable label may be added to the target (sample) nucleic acid(s) prior to, or after the hybridization, such as described in WO 97 / 10365. These detectable labels are directly attached to or incorporated into the target (sample) nucleic acid prior to hybridization. In contrast, “indirect labels” are joined to the hybrid duplex after hybridization. Generally, the indirect label is attached to a binding moiety that has been attached to the target nucleic acid prior to the hybridization. For example, the target nucleic acid may bebiotinylated before the hybridization. After hybridization, an avidin-conjugated fluorophore will bind the biotin bearing hybrid duplexes providing a label that is easily detected. For a detailed review of methods of labeling nucleic acids and detecting labeled hybridized nucleic acids see Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24: Hybridization with Nucleic Acid Probes, P. Tijssen, ed. Elsevier, N.Y. (1993).Detection of polypeptides

[0431] Protein levels of MTAP can be determined by examining protein expression or the protein product. Determining the protein level involves measuring the amount of any immunospecific binding that occurs between an antibody that selectively recognizes and binds to the polypeptide of the biomarker in a sample obtained from a subject and comparing this to the amount of immunospecific binding of at least one biomarker in a control sample.

[0432] A variety of techniques are available in the art for protein analysis. They include but are not limited to radioimmunoassays, ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g, colloidal gold, enzyme or radioisotope labels), Western blot analysis, immunoprecipitation assays, immunofluorescent assays, flow cytometry, immunohistochemistry, HPLC, mass spectrometry, confocal microscopy, enzymatic assays, surface plasmon resonance and PAGE-SDS.Adjacent biomarkers

[0433] Near or adjacent to MTAP on chromosome 9 are several other biomarkers. CDKN2A is often, if not usually, deleted along with MTAP. Additional genes or pseudogenes in this region include: C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0434] In some embodiments of the methods, the cell that is MTAP-deficient is also deficient in CDKN2A. In some embodiments, the cell that is MTAP-deficient is also deficient in one or more of: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0435] Thus, in various methods involving a step of evaluating a cell for MTAP deficiency or determining if a cell is MTAP-deficient, this step can comprise the step of determining if the cell is deficient for one or more of these markers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0436] Thus, in some embodiments, the disclosure encompasses: A method of determining if a subject having or having been diagnosed with a cancer will respond to therapeutic treatment witha PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent), comprising the steps of: a) evaluating a test sample obtained from said subject for MTAP deficiency, and evaluating a reference sample from a non-cancerous or normal control subject for MTAP deficiency, wherein MTAP deficiency in the test sample relative to the reference sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive PRMT5 inhibitor, e.g, a crystalline form of a compound of formula (I)); wherein MTAP deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, and wherein the method can further comprise the following steps: b) determining the level of MTAP in the subject, wherein steps a) and b) can be performed in any order; c) administering a therapeutically effective amount of a PRMT5 inhibitor (e.g, an MTA- uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA- cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject; and d) determining the level of PRMT5 activity in the subject following step c), wherein a decrease in the level of PRMT5 activity is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d) are performed after steps a) and b).

[0437] In some embodiments, the disclosure encompasses: A method of determining if a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent), comprising the steps of: a) evaluating a test sample obtained from a subject having or having been diagnosed with said cancer for MTAP deficiency, and evaluating a reference sample from a non- cancerous or normal control subject for MTAP deficiency, wherein MTAP deficiency in the test sample relative to the reference sample indicates that the cancer will respond totherapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, noncompetitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein); wherein MTAP deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, and wherein the method can further comprise the following steps: b) determining the level of MTAP in the subject, wherein steps a) and b) can be performed in any order; c) administering a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA- uncompetitive PRMT5 inhibitor, e.g., a compound of formula (I), crystalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject; and d) determining the level of PRMT5 activity in the subject following step c), wherein a decrease in the level of PRMT5 activity is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d) are performed after steps a) and b).Assaying for biomarkers andPRMT5 inhibitor treatment

[0438] A number of patient stratification strategies could be employed to find patients likely to be sensitive to PRMT5 inhibition with an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent (e g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), including but not limited to, testing for MTAP deficiency and / or MTA accumulation.

[0439] Once a patient has been assayed for MTAP deficiency and / or MTA accumulation and predicted to be sensitive to treatment with a PRMT5 inhibitor, administration of any PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g, a crystalline form of a compound of formula (I)) to a patient can be effected in one dose, continuously or intermittently throughout the course oftreatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents may be empirically adjusted.Dosage

[0440] The dose ranges and recitations below refer to the dose of the compound of formula (I) contained in the dosage forms and pharmaceutical compositions described herein that are administered to the subject in need thereof as part of the methods described herein.

[0441] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 100 mg to about 2000 mg of the compound of formula (I) once or twice daily.

[0442] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 200 mg to about 2000 mg of the compound of formula (I) once or twice daily.

[0443] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 100 mg to about 1000 mg of the compound of formula (I) once or twice daily.

[0444] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 200 mg to about 1000 mg of the compound of formula (I) once or twice daily.

[0445] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 600 mg of the compound of formula (I) once or twice daily.

[0446] In some embodiments, the method comprises administering the dose of the compound of formula (I) once daily (e.g., every' 24 hours).

[0447] In some embodiments, the method comprises administering the dose of the compound of formula (I) twice daily (e.g., every 12 hours).

[0448] In some embodiments, the method comprises administering to the subject a pharmaceutical composition or dosage form as described herein at a dose of about 600 mg of the compound of formula (I) twice daily (e.g, every 12 hours).Kits

[0449] In some embodiments provided are kits related to methods of use described herein.

[0450] In one embodiment, provided is a kit for predicting the sensitivity of a subject having or having been diagnosed with an MTAP-deficiency-related cancer for treatment with a PRMT5 inhibitor is provided. The kit comprises: i) reagents capable of detecting human MT AP-defi cient and / or MTA-accumulating cancer cells; and ii) instructions for how to use said kit.Selected Embodiments

[0451] Embodiment 1. A pharmaceutical composition comprising crystalline Form A of a compound of formula (I)and at least one pharmaceutically acceptable excipient; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees; and wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0452] Embodiment 2. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101;wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

[0453] Embodiment 3. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the cry stalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

[0454] Embodiment 4. The pharmaceutical composition of any one of embodiments 1-3, wherein the pharmaceutical composition comprises one or more additional pharmaceutically acceptable excipients.

[0455] Embodiment 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of a compound of formula (I).

[0456] Embodiment 6. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of a compound of formula (I).

[0457] Embodiment 7. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 40% (w / w) to about 45% (w / w) of a compound of formula (I).

[0458] Embodiment 8. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of a compound of formula (I).

[0459] Embodiment 9. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of a compound of formula (I).

[0460] Embodiment 10. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 38% (w / w) to about 42% (w / w) of crystalline form A of a compound of formula (I).

[0461] Embodiment 11. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 39% (w / w) to about 41% (w / w) of a compound of formula (I).

[0462] Embodiment 12. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w) or about 50% (w / w) of the compound of formula (I).

[0463] Embodiment 13. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w) or about 45% (w / w) of the compound of formula (I).

[0464] Embodiment 14. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises about 40% (w / w) of the compound of formula (I).

[0465] Embodiment 15. The pharmaceutical composition of any one of embodiments 1-14, wherein a portion of the filler comprises microcrystalline cellulose PH 101 (e.g., Avicel® PH 101) and another portion of the filler comprises microcrystalline cellulose PH 102 (e.g., Avicel® PH 102).

[0466] Embodiment 16. The pharmaceutical composition of any one of embodiments 1-14, wherein the filler used in an intragranular blend comprises microcrystalline cellulose PH 101 and the filler used in an extragranular blend comprises microcrystalline cellulose PH 102.

[0467] Embodiment 17. The pharmaceutical composition of any one of embodiments 1-14, wherein the filler used in an intragranular blend consists substantially of microcrystalline cellulose PH 101 and the filler used in an extragranular blend consists substantially of microcrystalline cellulose PH 102.

[0468] Embodiment 18. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) filler.

[0469] Embodiment 19. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) filler.

[0470] Embodiment 20. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) filler.

[0471] Embodiment 21. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) filler.

[0472] Embodiment 22. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about57% (w / w), about 58% (w / w) filler or about 60% (w / w) filler.

[0473] Embodiment 23. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) filler or about 60% (w / w) filler.

[0474] Embodiment 24. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 54% (w / w) filler.

[0475] Embodiment 25. The pharmaceutical composition of any one of embodiments 1-17, wherein the pharmaceutical composition comprises about 54% (w / w) of a combination of intragranular microcrystalline cellulose PH 101 and extragranular microcrystalline cellulose PH 102.

[0476] Embodiment 26. The pharmaceutical composition of any one of embodiments 1-25, wherein the pharmaceutical composition comprises a glidant.

[0477] Embodiment 27. The pharmaceutical composition of embodiment 26, wherein the glidant comprises colloidal silicon dioxide.

[0478] Embodiment 28. The pharmaceutical composition of embodiment 26, wherein the glidant consists substantially of colloidal silicon dioxide.

[0479] Embodiment 29. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) glidant.[04S0] Embodiment 30. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) glidant.

[0481] Embodiment 31. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) glidant.

[0482] Embodiment 32. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) glidant.

[0483] Embodiment 33. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 1.5% (w / w), about 1.75% (w / w), about 1.9% (w / w), about 2.0% (w / w), about 2.1% (w / w), about 2.25% (w / w), about 2.5% (w / w) or about 3% (w / w) glidant.

[0484] Embodiment 34. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 2.0% (w / w) glidant.

[0485] Embodiment 35. The pharmaceutical composition of any one of embodiments 1-28, wherein the pharmaceutical composition comprises about 2.0% (w / w) silicon dioxide.

[0486] Embodiment 36. The pharmaceutical composition of any one of embodiments 1-35, wherein the pharmaceutical composition comprises a disintegrant.

[0487] Embodiment 37. The pharmaceutical composition of embodiment 36, wherein the disintegrant comprises croscarmellose sodium (e.g, Ac-Di-Sol®).

[0488] Embodiment 38. The pharmaceutical composition of embodiment 36, wherein the disintegrant consists substantially of croscarmellose sodium (e.g., Ac-Di-Sol®).

[0489] Embodiment 39. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) disintegrant.

[0490] Embodiment 40. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) disintegrant.

[0491] Embodiment 41. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) disintegrant.

[0492] Embodiment 42. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) disintegrant.

[0493] Embodiment 43. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 2.9% (w / w), about 3% (w / w), about 3.1% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w) or about 4.0% (w / w) disintegrant.

[0494] Embodiment 44. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 3% (w / w) disintegrant.

[0495] Embodiment 45. The pharmaceutical composition of any one of embodiments 1-38, wherein the pharmaceutical composition comprises about 3% (w / w) croscarmellose sodium.

[0496] Embodiment 46. The pharmaceutical composition of any one of embodiments 1-45, wherein the pharmaceutical composition comprises a lubricant.

[0497] Embodiment 47. The pharmaceutical composition of embodiment 46, wherein the lubricant comprises magnesium stearate.

[0498] Embodiment 48. The pharmaceutical composition of embodiment 46, wherein the lubricant consists substantially of magnesium stearate.

[0499] Embodiment 49. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) lubricant.

[0500] Embodiment 50. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) lubricant.

[0501] Embodiment 51. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) lubricant.

[0502] Embodiment 52. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) lubricant.

[0503] Embodiment 53. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.25% (w / w) or about 1.5% (w / w) lubricant.

[0504] Embodiment 54. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 1.0% (w / w) lubricant.

[0505] Embodiment 55. The pharmaceutical composition of any one of embodiments 1-48, wherein the pharmaceutical composition comprises about 1.0% (w / w) magnesium stearate.

[0506] Embodiment 56. A pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (wherein crystallineForm A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) charactenstic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0507] Embodiment 57. A pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrate (e.g, croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0508] Embodiment 58. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g, colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

[0509] Embodiment 59. The pharmaceutical composition of embodiment 56, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

[0510] Embodiment 60. The pharmaceutical composition of embodiment 56, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microciystalline PH 101 or a combination of microciystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrate (e.g, croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

[0511] Embodiment 61. The pharmaceutical composition of embodiment 56, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the cry stall ine form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) t...

Claims

CLAIMS1. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

2. A pharmaceutical composition comprising: (a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees.

3. The pharmaceutical composition of claims 1 or 2, wherein the pharmaceutical composition comprises one or more additional pharmaceutically acceptable excipients.

4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 39% (w / w) to about 41% (w / w) of a compound of formula (I).182 i]5. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 40% (w / w) of the compound of formula (I).

6. The pharmaceutical composition of any one of claims 1-5, wherein a portion of the filler comprises microcrystalline cellulose PH 101 (e.g., Avicel® PH 101) and another portion of the filler comprises microcrystalline cellulose PH 102 (e.g., Avicel® PH 102).

7. The pharmaceutical composition of any one of claims 1-5, wherein the filler used in an intragranular blend consists substantially of microcrystalline cellulose PH 101 and the filler used in an extragranular blend consists substantially of microcrystalline cellulose PH 102.

8. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) filler.

9. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) filler.

10. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 54% (w / w) filler.

11. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 54% (w / w) of a combination of intragranular microcrystalline cellulose PH 101 and extragranular microcrystalline cellulose PH 102.

12. A pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (wherein crystallineForm A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, nthree, four or five) characteristic peaks, in terms of 20, selected from the peaks at 6.4±0.2, 8.9±0.2,12.7±0.2, 14.0±0.2, 19.H0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g, colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

13. A pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e. , colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

14. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.184 i]15. The pharmaceutical composition claim 12, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 54 % (w / w) of a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1 % (w / w) of a lubricant e.g., magnesium stearate); thereby totaling 100% (w / w) of the pharmaceutical composition.

16. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

17. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I);(b) about 52% (w / w) to about 56% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of colloidal silicon dioxide;(d) about 2.5% (w / w) to about 3.5% (w / w) of croscarmellose sodium;(e) about 0.75% (w / w) to about 1.25% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.185 n18. The pharmaceutical composition claim 12, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I);(b) about 54 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the pharmaceutical composition.

19. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises an intragranular filler.

20. The pharmaceutical composition of claim 19, wherein the intragranular filler consists substantially of a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101).

21. The pharmaceutical composition of claim 19 or 20, wherein the w / w ratio of API to intragranular filler is between 0.9 and 1.6.

22. The pharmaceutical composition of claim 19 or 20, wherein the w / w ratio of API to intragranular filler is between 0.95 and 1.05.

23. The pharmaceutical composition of claim 19 or 20, wherein the w / w ratio of API to intragranular filler is about 0.95.

24. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) intragranular filler.

25. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular filler.

26. The pharmaceutical composition of claim 19 or 20, wherein the pharmaceutical composition comprises about 42% (w / w) intragranular filler.186II27. The pharmaceutical composition of any one of claims 1-26, wherein the pharmaceutical composition comprises an extragranular filler.

28. The pharmaceutical composition of claim 27, wherein the extragranular filler consists substantially of microcrystalline cellulose PH 102 (e.g, Avicel® PH 102).

29. The pharmaceutical composition of claim 27 or 28, wherein the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular filler.

30. The pharmaceutical composition of claim 27 or 28, wherein the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) extragranular filler.

31. The pharmaceutical composition of claim 27 or 28, wherein the pharmaceutical composition comprises about 12% (w / w) extragranular filler.

32. The pharmaceutical composition of any one of claims 1-31, wherein the pharmaceutical composition comprises an intragranular glidant.

33. The pharmaceutical composition of claim 32, wherein the intragranular glidant consists substantially of colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P).

34. The pharmaceutical composition of claim 32 or 33, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular glidant.

35. The pharmaceutical composition of claim 32 or 33, wherein the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular glidant.

36. The pharmaceutical composition of claim 32 or 33, wherein the pharmaceutical composition comprises about 1.0% (w / w) intragranular glidant.

37. The pharmaceutical composition of any one of claims 1-36, wherein the pharmaceutical composition comprises an extragranular glidant.187 n38. The pharmaceutical composition of claim 37, wherein the extragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

39. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular glidant.

40. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular glidant.

41. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition comprises about 1.0% (w / w) extragranular glidant.

42. The pharmaceutical composition of any one of claims 1-41, wherein the pharmaceutical composition comprises an intragranular disintegrant.

43. The pharmaceutical composition of claim 42, wherein the intragranular disintegrant consists substantially of croscarmellose sodium.

44. The pharmaceutical composition of claim 42 or 43, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular disintegrant.

45. The pharmaceutical composition of claim 42 or 43, wherein the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular disintegrant.

46. The pharmaceutical composition of claim 42 or 43, wherein the pharmaceutical composition comprises about 1.5% (w / w) intragranular disintegrant.

47. The pharmaceutical composition of any one of claims 1-46, wherein the pharmaceutical composition comprises an extragranular disintegrant.

48. The pharmaceutical composition of claim 47, wherein the extragranular disintegrant consists substantially of croscarmellose sodium.188 n49. The pharmaceutical composition of claim 47 or 48, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular disintegrant.

50. The pharmaceutical composition of claim 47 or 48, wherein the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular disintegrant.

51. The pharmaceutical composition of claim 47 or 48, wherein the pharmaceutical composition comprises about 1.5% (w / w) extragranular disintegrant.

52. The pharmaceutical composition of any one of claims 1-51, wherein the pharmaceutical composition comprises an intragranular lubricant.

53. The pharmaceutical composition of claim 52, wherein the intragranular lubricant consists substantially of magnesium stearate.

54. The pharmaceutical composition of claim 52 or 53, wherein the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular lubricant.

55. The pharmaceutical composition of claim 52 or 53, wherein the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular lubricant.

56. The pharmaceutical composition of claim 52 or 53, wherein the pharmaceutical composition comprises about 0.5% (w / w) intragranular lubricant.

57. The pharmaceutical composition of any one of claims 1-56, wherein the pharmaceutical composition comprises an extragranular lubricant.

58. The pharmaceutical composition of claim 57, wherein the extragranular lubricant consists substantially of magnesium stearate.

59. The pharmaceutical composition of claim 57 or 58, wherein the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular lubricant.189 n60. The pharmaceutical composition of claim 57 or 58, wherein the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular lubricant.

61. The pharmaceutical composition of claim 57 or 58, wherein the pharmaceutical composition comprises about 0.5% (w / w) extragranular lubricant.

62. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

63. A pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2 and 22.6±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g., colloidal silicon dioxide);(d) an intragranular disintegrant (e.g., croscarmellose sodium);(e) an extragranular lubricant (e.g, magnesium stearate);(f) an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g, colloidal silicon dioxide);(h) an extragranular disintegrant (e.g., croscarmellose sodium); and(i) an extragranular lubricant (e.g., magnesium stearate).

64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

65. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of intragranular colloidal silicon dioxide;(d) about 0.5% (w / w) to about 2.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate;(f) about 5% (w / w) to about 20% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.5% (w / w) to about 1.5% (w / w) of extragranular colloidal silicon dioxide;(h) about 0.5% (w / w) to about 2.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

66. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition comprises:(a) about 39% (w / w) to about 41% (w / w) of crystalline form A of the compound of formula (I);(b) about 41% (w / w) to about 43% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.95% (w / w) to about 1.05% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.45% (w / w) to about 1.55% (w / w) of intragranular croscarmellose sodium;(e) about 0.45% (w / w) to about 0.55% (w / w) of intragranular magnesium stearate;(f) about 11% (w / w) to about 13% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.95% (w / w) to about 1.05% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.45% (w / w) to about 1.55% (w / w) of extragranular croscarmellose sodium; and(i) about 0.45% (w / w) to about 0.55% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

67. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

68. A dosage form comprising a pharmaceutical composition of any one of claims 1-67.

69. A dosage form intended for oral administration comprising a pharmaceutical composition of any one of claims 1-67.

70. The dosage form of claim 68 or 69, wherein the dosage form is a tablet.

71. The dosage form of any one of claims 68-70, wherein the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.

72. The dosage form of any one of claims 68-71, wherein the dosage form comprises about 100 mg to about 300 mg of the crystalline form A of the compound of formula (I).

73. The dosage form of any one of claims 68-71, wherein the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of crystalline form A of the compound of formula (I).

74. The dosage form of any one of claims 68-71, wherein the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.25 mg intragranular magnesium stearate, 30 mg extragranular microcrystalline cellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg extragranular croscarmellose sodium (Ac-Di- Sol®) and 1.25 mg extragranular magnesium stearate.

75. The dosage form of any one of claims 68-71, wherein the dosage form comprises 125 mg Compound of formula (I), 131.25 mg intragranular microcrystalline cellulose PH 101, 3.13 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mgintragranular croscarmellose sodium (Ac-Di-Sol®), 1.56 mg intragranular magnesium stearate, 37.50 mg extragranular microcrystalline cellulose PH 102, 3.13 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg extragranular croscarmellose sodium (Ac-Di- Sol®) and 1.56 mg extragranular magnesium stearate.

76. The dosage form of any one of claims 68-71, wherein the dosage form comprises 150 mg Compound of formula (I), 157 mg intragranular microcrystalline cellulose PH 101, 3.75 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.88 mg intragranular magnesium stearate, 45 mg extragranular microcrystalline cellulose PH 102, 3.75 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg extragranular croscarmellose sodium (Ac-Di- Sol®) and 1.88 mg extragranular magnesium stearate.

77. The dosage form of any one of claims 68-71, wherein the dosage form comprises 200 mg Compound of formula (I), 210 mg intragranular microcrystalline cellulose PH 101, 5.0 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 60 mg extragranular microcrystalline cellulose PH 102, 5.0 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.

78. The dosage form of any one of claims 68-71, wherein the dosage form comprises 250 mg Compound of formula (I), 262.5 mg intragranular microcrystalline cellulose PH 101, 6.25 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 9.38 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 3.13 mg intragranular magnesium stearate, 75 mg extragranular microcrystalline cellulose PH 102, 6.25 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 9.38 mg extragranular croscarmellose sodium (Ac-Di- Sol®) and 3.13 mg extragranular magnesium stearate.

79. The dosage form of any one of claims 68-78, wherein the dosage form is a tablet.194 a80. A process for preparing a pharmaceutical composition of any one of claims 1-67, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition.

81. A process for preparing a dosage form of any one of claims 68-79, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre- lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally,195II(h) Coating the dosage form.

82. A pharmaceutical composition or a dosage form prepared by the process of claim 80 or 81.

83. A pharmaceutical composition of any one of claims 1-67 or dosage form of any one of claims 68-79 containing a therapeutically effective amount of the compound of formula (I) for use in a method of treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof, wherein the method comprises administering to the subject the pharmaceutical composition of any one of claims 1 to 67 or dosage form of any one of claims 68-79.

84. The pharmaceutical composition for use or dosage form for use of claim 83 wherein the disease is a proliferating disease.

85. The pharmaceutical composition for use or dosage form for use of claim 83 wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

86. The pharmaceutical composition for use or dosage form for use of claim 85 wherein the cancer is histology agnostic.

87. The pharmaceutical composition for use or dosage form for use of claim 85 wherein the cancer is glioma, glioblastoma, malignant peripheral nerve sheath tumors (MPNST, e.g, intracranial MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, sarcoma or a CNS metastasis from a solid tumor.

88. The pharmaceutical composition for use or dosage form for use of claim 85 wherein the cancer is a CNS malignancy.196 a89. The pharmaceutical composition for use or dosage form for use of claim 88, wherein the CNS malignancy is glioma (e.g., low grade glioma, intermediate grade glioma), intracranial MPNST tumors, glioblastoma, glioblastoma multiforme, or CNS metastases from solid tumors.

90. The pharmaceutical composition for use or dosage form for use of claim 88, wherein the CNS malignancy is a MTAP-deleted glioblastoma.

91. The pharmaceutical composition for use or dosage form for use of any one of claims 83-90, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 200 mg to about 1000 mg of the compound of formula (I) once or twice daily.

92. The pharmaceutical composition for use or dosage form for use of any one of claims 83-90, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 600 mg of the compound of formula (I) once or twice daily.

93. The pharmaceutical composition for use or dosage form for use of claim 91 or 92 wherein the pharmaceutical composition for use or dosage form for use comprises administering the dose of the compound of formula (I) once daily.

94. The pharmaceutical composition for use or dosage form for use of any one of claims 83-93 wherein the pharmaceutical composition for use or dosage form for use further comprises administration of a second therapeutic agent.

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