Drug product formulations of fidrisertib

Abstract

The present disclosure relates to pharmaceutical compositions and oral dosage forms comprising of Compound (I) or a pharmaceutically acceptable salt thereof, intragranular excipient and extragranular excipient. The present disclosure also relates to methods of using said compositions and oral dosage forms in the treatment of Fibrodysplasia Ossificans Progressiva (FOP).

Description

DRUG PRODUCT FORMULATIONSCROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 747,728 filed on January 21, 2025, the entire contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] Activin receptor-like kinase-2 (ALK2) is encoded by the Activin A receptor, type I gene (ACVR1). ALK2 is a serine / threonine kinase in the bone morphogenetic protein (BMP) pathway (Shore et al., Nature Genetics 2006, 38: 525-27). Inhibitors of ALK2 and mutant forms of ALK2 have the potential to treat a number of diseases, including fibrodysplasia ossificans progressiva (FOP); heterotopic ossification (HO) induced by, for example, major surgical interventions, trauma (such as head or blast injuries), protracted immobilization, or severe bums; diffuse intrinsic pontine glioma (DIPG), a rare form of brain cancer; and anemia associated with chronic inflammatory, infectious or neoplastic disease.

[0003] The structure of Compound (I) as a sesqui- succinate salt is shown below. The synthesis of Compound (I), as well as, the corresponding sesqui- succinate salt are disclosed in International Application Nos. PCT / US2017 / 027775 and PCT / US2020 / 045847, the entire contents of which are incorporated herein by reference. Compound (I), also known as BLU-782, IPN60130 or Fidrisertib, is a potent and selective ALK2 inhibitor that selectively target a / K2 mutations in patients suffering from FOP.

[0004] Compound (I) Sesqui-succinate can also be referred to as: (R)-tetrahydrofuran-3-yl 4-(6-(5-(4-ethoxy-l-isopropylpiperidin-4-yl)pyridin-2-yl)pyrrolo[l,2-b]pyridazin-4-yljpiperazine- 1 -carboxylate sesqui-succinate and has the following chemical structure.Compound (I) Sesqui-succinate1MEl\59654703.vl

[0005] There is a need to develop pharmaceutical compositions that are suitable for medical use.SUMMARY

[0006] The present disclosure features pharmaceutical compositions comprising Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of a filler, a disintegrant, and a lubricant; and extragranular excipient, wherein the extragranular excipient comprises of a disintegrant and a lubricant.Compound (I)

[0007] The present disclosure also features oral dosage forms, such as, but not limited to a capsule comprising Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of a filler, a disintegrant, and a lubricant; and extragranular excipient, wherein the extragranular excipient comprises of a disintegrant and a lubricant.

[0008] The present disclosure provides a method of treating or ameliorating FOP in a subject comprising administering to the subject in need thereof a pharmaceutical composition disclosed herein.

[0009] The present disclosure provides a method of treating or ameliorating diffuse intrinsic pontine glioma in a subject, comprising administering to the subject in need thereof a pharmaceutical composition disclosed herein.

[0010] The present disclosure also provides a method of inhibiting aberrant ALK2 activity in a subject, comprising administering to the subject in need thereof a pharmaceutical composition disclosed herein.

[0011] The present disclosure also provides a use of the pharmaceutical composition of the disclosure in any of the methods of the disclosure described above. In one embodiment,2MEl\59654703.vlprovided is the pharmaceutical composition of the disclosure for use in any of the method of the disclosure described herein. In another embodiment, provided is use of the pharmaceutical composition of the disclosure for the manufacture of a medicament for any of the method of the disclosure described.BRIEF DESCRIPTIONS OF DRAWINGS

[0012] FIG. 1 is a manufacturing flow diagram for Compound (I) Sesqui-succinate Capsules, 10 mg, 50 mg and 100 mg.

[0013] FIG. 2 is a plot showing Compound (I) Sesqui-succinate content trend for batch W07065 after 12 months of storage at 25 °C / 60 %RH, at 30 °C / 75 %RH and at 40 °C / 75 %RH respectively.

[0014] FIG. 3 is a plot showing Compound (I) Sesqui-succinate water content trend for batch W07065 after 12 months of storage at 25 °C / 60 %RH and at 30 °C / 75 %RH and after 6 months of storage at 40 °C / 75 %RH respectively.

[0015] FIG. 4 is a plot showing the dissolution profile from the ICH stability study.

[0016] FIG. 5 is a plot showing the dissolution trend for batch W07065 after 12 months of storage at 25 °C / 60 %RH, at 30 °C / 75 %RH and at 40 °C / 75 %RH.

[0017] FIG. 6 shows the UV online dissolution profiles of batch W07065. FIG. 6A is a UV online dissolution profile of batch W07065 at 25 °C / 60 %RH. FIG. 6B is the UV online dissolution profile of batch W07065 at 30 °C / 75 %RH. FIG. 6C is the UV online dissolution profile of batch W07065 at 40 °C / 75 %RH.

[0018] FIG. 7 shows the influence of speed stirring of batch W07065 on dissolution profiles at 75 rpm and 50 rpm after 12 months of storage. FIG. 7A is a dissolution profile of batch W07065 at 75 rpm and 50 rpm after 12 months of storage at 25 °C / 60 %RH. FIG. 7B is a dissolution profile of batch W07065 at 75 rpm and 50 rpm after 12 months of storage at 30 °C / 75 %RH.

[0019] FIG. 8 is a plot showing the dissolution profile for 10 mg capsule.

[0020] FIG. 9 is a schema of the bioequivalence study design.3MEl\59654703.vlDETAILED DESCRIPTION

[0021] It was discovered that Compound (I) is a highly potent and selective ALK2 inhibitor. Pharmaceutical compositions comprising of Compound (I) Sesqui-succinate salt at 10% w / w and 40% w / w were developed with suitable density, flow properties and fill volume to allow for filling into size 4 and size 1 capsules respectively at 10 mg and 50 mg dose strengths.

[0022] The desired target product profile for a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof is an immediate release capsule.

[0023] The properties of the intragranular and extragranular excipients, such as bulk density and flow properties contribute to a free-flowing blend for capsule filling.Pharmaceutical Compositions

[0024] “Extragranular” is of or pertaining to additional excipients that are incorporated in a formulation after granulation, i.e., ingredients that are located externally to a granule structure.

[0025] “Intragranular” is of or pertaining to additional excipients that are incorporated in a formulation prior to granulation, i.e., ingredients that are located internally in a granule structure.

[0026] In one aspect, the present disclosure features a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof, intragranular excipient and extragranular excipient. Granulation is used in the present invention to improve the flowability of the powder to be filled into capsules, which can be poor especially when API (Active Pharmaceutical Ingredient) content is high. It also increases the powder density, allowing to reduce the capsule size for a specific dose, and can also improve the homogeneity of the blend. Once the granules are obtained, the flow properties of the intragranular phase is improved by adding extragranular excipients.

[0027] In one aspect, the pharmaceutical composition disclosed herein is prepared in an oral dosage form.

[0028] In one aspect, the Compound (I) is a free base, or a pharmaceutically acceptable salt thereof. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,4MEl\59654703.vlphosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts and the like. (See, for example, Berge etal. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0029] In one embodiment, the Compound (I) is a sesqui-succinate salt, wherein the molar ratio between Compound (I) and succinic acid is 1:1.5. It has been found that a 1:1.5 succinic salt has good solubility in water and in simulated gastric fluids (PCT / US2020 / 045847). The succinic salt also has the additional advantage that it exists as a single polymorph and undergoes no thermal transitions below its melting point, indicating a high degree of form stability that is suitable towards formulation development.

[0030] In one aspect, the pharmaceutical composition or an oral dosage form comprises Compound (I) or a pharmaceutically acceptable salt thereof from 4% to 50% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 5% to 45% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 4% to 6% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 8% to 12% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 9% to 11% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 13% to 17% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 18% to 22% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 23% to 27% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 25% to 35% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 28% to 32% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition5MEl\59654703.vlcomprises Compound (I) or a pharmaceutically acceptable salt thereof from 29% to 31% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 33% to 37% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 34% to 36% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 38% to 42% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 39% to 41% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 43% to 47% w / w of the pharmaceutical composition or an oral dosage form. In one embodiment, the pharmaceutical composition comprises Compound (I) or a pharmaceutically acceptable salt thereof from 44% to 46% w / w of the pharmaceutical composition or an oral dosage form.

[0031] In one aspect, the pharmaceutical composition or an oral dosage form comprises an amount of 5 mg to 200 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg to 200 mg of Compound (I). In one aspect, the pharmaceutical composition or an oral dosage form comprises an amount of 5 mg to 100 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg to 100 mg of Compound (I). In one embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 5 mg to 50 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg to 50 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 5 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 10 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 10 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 15 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 15 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 20 mg of6MEl\59654703.vlCompound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 20 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 25 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 25 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 30 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 30 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 35 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 35 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 40 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 40 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 45 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 45 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 50 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 100 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of Compound (I).

[0032] In one embodiment, the pharmaceutical composition or an oral dosage form comprises a sesqui- succinate salt of Compound (I) in an amount equivalent to 5 mg to 100 mg of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 13.10 mg of a sesqui-succinate salt of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 26.2 mg of a sesqui-succinate salt of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 39.3 mg of a sesqui-succinate salt of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 52.4 mg of a sesqui-succinate salt of Compound (I). In one specific embodiment, the pharmaceutical composition or an oral dosage form comprises an amount of 65.5 mg of a sesqui-succinate salt of Compound (I). In one specific embodiment, the pharmaceutical7MEl\59654703.vlcomposition or an oral dosage form comprises an amount of 131.0 mg of a sesqui-succinate salt of Compound (I).

[0033] In a particular embodiment, the Compound (I) is 5% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 10% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 15% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 20% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 25% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 30% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 35% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In another particular embodiment, the Compound (I) is 40% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 45% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular embodiment, the Compound (I) is 50% w / w of the total weight of the pharmaceutical composition or an oral dosage form.Intragranular Excipient

[0034] In one aspect, the pharmaceutical composition or an oral dosage form comprises intragranular excipient. The intragranular excipient comprises of a filler, a disintegrant, and / or a lubricant. In one embodiment, the pharmaceutical composition or an oral dosage form comprises intragranular excipient, and the intragranular excipient comprises of a filler, a disintegrant, and a lubricant.

[0035] Filler: The pharmaceutical compositions disclosed herein are suitable for an immediate release solid dosage form, such as a capsule. Filler excipients (also referred to as a diluent herein) with high bulk density and good flow properties are crucial in developing a pharmaceutical formulation in order to generate a free-flowing blend for capsule filing. The flow properties are characterized by known methods in the art, such as, Bulk / Tapped Density, Carr’s Index and Hausner Ratio.8MEl\59654703.vl

[0036] In one aspect, the filler in the intragranular excipient is from 45% to 90% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 80% to 90% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 81% to 87% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 82% to 86% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 44% to 64% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 49% to 59% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 50% to 58% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 52% to 56% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 85% to 90% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 80% to 85% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 75% to 80% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 70% to 75% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 65% to 70% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 60% to 65% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 55% to 60% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 50% to 55% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the filler in the intragranular excipient is from 45% to 50% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one specific embodiment, the filler in the intragranular excipient is 84% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one specific embodiment, the filler in9MEl\59654703.vlthe intragranular excipient is 54% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0037] Non-limiting examples of a filler that can be used in the intragranular excipient, alone or in combination, may be selected from lactose, including anhydrous lactose or lactose monohydrate; starches, including directly compressible and hydrolyzed starches; mannitol, including directly compressible, spray dried and crystalline mannitols; sorbitol; xylitol; dextrose and dextrose monohydrate; sucrose-based diluents including confectioner’s sugar; calcium-based diluents including monobasic calcium sulfate monohydrate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate; calcium sulfate dihydrate, or granular calcium lactate trihydrate; dextrans; inositol; hydrolyzed cereal solids; amylose; celluloses including food grade sources of amorphous cellulose and powdered cellulose: microcrystalline cellulose, modified or co-processed microcrystalline cellulose, extragranular microcrystalline cellulose (Avicel® PH 102, Avicel® HFE 102, Avicel® PH-302), or silicified microcrystalline cellulose (Prosolv® SMCC HD 90, Prosolv® SMCC 90); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Other examples of suitable fillers are starch (e.g., cellulose, potato or com starch), salts (e.g., calcium hydrogenphosphate, magnesium oxide,), sugars like lactose (e.g., lactose monohydrate), silicates (e.g., silicium dioxide), talc, isomalt, or polyvinyl alcohol.

[0038] The filler(s) selected preferably exhibit suitable flow properties and where capsules and tablets are desired, improve compressibility. Mixtures of fillers can also be used to optimize the desired properties. For example, materials usually compress by either plastic deformation or brittle fracture. Mannitol is a brittle fracturing filler, which in combination with a plastic deforming filler such as microcrystalline cellulose can result in an optimal compacting formulation that holds its shape after compaction and have little relaxation / friability.

[0039] Co-processed fillers such as Prosolv® SMCC HD 90 were identified as a good candidate with higher bulk density and flow properties. Prosolv® is a silicified microcrystalline cellulose (SMCC).

[0040] In one embodiment, the filler is microcrystalline cellulose, for example, silicified microcrystalline cellulose (SMCC). In a particular embodiment, SMCC is 84% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In a particular aspect,10MEl\59654703.vlSMCC is 54% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0041] Disintegrant: A disintegrant with excellent water uptake (wicking properties) and rapid swelling properties improves porosity and promotes faster integration and drug dissolution at lower levels such as from 1.5% to 3% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0042] In one aspect, the disintegrant in the intragranular excipient is from 1% to 4% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one aspect, the disintegrant in the intragranular excipient is from 1.5% to 3% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one aspect, the disintegrant in the intragranular excipient is from 2% to 3% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one aspect, the disintegrant in the intragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0043] Non-limiting examples of a disintegrant that can be used in the intragranular excipient, either individually or in combination, include starches, including sodium starch glycolate and pregelatinized com starches, clays, celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (AC-DI-SOL® SD-711), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums. In one aspect, the disintegrant may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression.

[0044] In one embodiment, the disintegrant in the intragranular excipient is croscarmellose sodium. In a particular embodiment, croscarmellose sodium in the intragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0045] Lubricant: Further, a lubricant is incorporated into a pharmaceutical composition or an oral dosage form to generate a robust immediate release formulation.

[0046] In one aspect, the lubricant in the intragranular excipient is from 0.1% to 1% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one aspect, the lubricant in the intragranular excipient is from 0.2% to 0.7% w / w of the total weight of11MEl\59654703.vlthe pharmaceutical composition or an oral dosage form. In one embodiment, the lubricant in the intragranular excipient is from 0.4% to 0.6% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the lubricant in the intragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0047] Non-limiting examples of a lubricant that can be used either individually or in combination in the intragranular excipient include glyceryl behaptate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates, hydrogenated vegetable oils, colloidal silica, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycol, sodium oleate, sodium lauryl sulfate, glyceryl dibehenate (Compritol 888 ATO), and magnesium lauryl sulfate. Other non-limiting examples of suitable lubricants include talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.

[0048] In a particular embodiment, the lubricant in the intragranular excipient is magnesium stearate. Magnesium stearate reduces friction between the equipment and granulated mixture during compression of capsule and tablet formulations. In one embodiment, magnesium stearate in the intragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.Extragranular Excipient

[0049] In one aspect, the pharmaceutical composition or an oral dosage form comprises extragranular excipient. The extragranular excipient comprises of a disintegrant, and / or a lubricant. In one embodiment, the pharmaceutical composition or an oral dosage form comprises extragranular excipient, and the extragranular excipient comprises of a disintegrant, and a lubricant.

[0050] Disintegrant: In the pharmaceutical composition or an oral dosage form of the disclosure, the disintegrant in the intragranular excipient and the disintegrant in the extragranular excipient is the same.

[0051] In one aspect, the disintegrant in the extragranular excipient is from 1% to 4% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the disintegrant in the extragranular excipient is from 1.5% to 3% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment,12MEl\59654703.vlthe disintegrant in the extragranular excipient is from 2% to 3% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the disintegrant in the extragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0052] Non-limiting examples of a disintegrant that can be used in the extragranular excipient, either individually or in combination include sodium starch glycolate and pregelatinized corn starches, clays, celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (AC-DI-SOL® SD-711), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums. In one aspect, the disintegrant may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression.

[0053] In a particular embodiment, the disintegrant in the extragranular excipient is croscarmellose sodium. In a particular embodiment, croscarmellose sodium in the extragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0054] Lubricant: In the pharmaceutical composition or an oral dosage form of the disclosure, the disintegrant in the intragranular excipient and in the extragranular excipient is the same.

[0055] In one aspect, the lubricant in the extragranular excipient is from 0.1% to 1% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the lubricant in the extragranular excipient is from 0.2% to 0.7% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the lubricant in the extragranular excipient is from 0.4% to 0.6% w / w of the total weight of the pharmaceutical composition or an oral dosage form. In one embodiment, the lubricant in the extragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0056] Non-limiting examples of a lubricant that can be used either individually or in combination in the extragranular excipient include glyceryl behaptate, stearic acid and salts thereof, including magnesium, calcium and sodium stearates, hydrogenated vegetable oils, colloidal silica, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, DL-leucine, polyethylene glycol, sodium oleate, sodium lauryl sulfate,13MEl\59654703.vlglyceryl dibehenate (Compritol 888 ATO), and magnesium lauryl sulfate. Other non-limiting examples of suitable lubricants include talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.

[0057] In a particular embodiment, the lubricant in the extragranular excipient is magnesium stearate. In a particular embodiment, magnesium stearate in the extragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition or an oral dosage form.

[0058] In one aspect, the present disclosure features a pharmaceutical composition or an oral dosage form comprising 8-12% w / w (e.g., 9-11% w / w) of Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of 82-86% w / w (e.g., 83-85% w / w) of a filler, 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant; and extragranular excipient, wherein the extragranular excipient comprises of 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant.

[0059] In a particular embodiment, the present disclosure features a pharmaceutical composition or an oral dosage form comprising 10% w / w of Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of 84% w / w of a filler, 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant; and extragranular excipient, wherein the extragranular excipient comprises of 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant.

[0060] In one aspect, the present disclosure features a pharmaceutical composition or an oral dosage form comprising 38-42% w / w (e.g., 39-41% w / w) of Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of 52-56% w / w (e.g., 53-55% w / w) of a filler, 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant; and extragranular excipient, wherein the extragranular excipient comprises of 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant.

[0061] In a specific embodiment, the present disclosure features a pharmaceutical composition or an oral dosage form comprising 40% w / w of Compound (I) or a pharmaceutically acceptable salt thereof; intragranular excipient, wherein the intragranular excipient comprises of 54% w / w of a filler, 2.5% w / w of a disintegrant, and 0.5% w / w of a14MEl\59654703.vllubricant; and extragranular excipient, wherein the extragranular excipient comprises of 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant.

[0062] In one embodiment, the present disclosure features a pharmaceutical composition or an oral dosage form wherein the filler is microcrystalline cellulose, for example, silicified microcrystalline cellulose (SMCC); the disintegrant in the intragranular excipient and the disintegrant in the extragranular excipient is croscarmellose sodium; and the lubricant in the intragranular excipient and the lubricant in the extragranular excipient is magnesium stearate.

[0063] In one aspect, the oral dosage form described herein is a capsule or tablet.

[0064] In one aspect, the capsule comprises a capsule shell and a capsule formulation. The capsule formation comprises the pharmaceutical composition disclosed herein.

[0065] In one aspect, the capsule shell comprises of titanium dioxide and hypromellose, also known as hydroxypropyl methylcellulose (HPMC).

[0066] The capsule can be a hydroxypropyl methylcellulose (HPMC) capsule or a gelatin capsule.

[0067] In a particular aspect, the capsule is a hydroxypropyl methylcellulose (HPMC) capsule.

[0068] A “nonfunctional film coating” is used to change capsule or tablet appearance, swallowability, mask the taste of the active pharmaceutical ingredient (API), and to protect tablets from the negative environmental effects such as humidity, oxidation, and light effects and potentially improve drug product stability. It will not however alter (extend or delay) the release rate of the drug molecule from the capsules or tablets.

[0069] Suitable non-functional polymer coatings, alone or in combination, may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcoholpolyethylene glycol copolymers, acrylic polymers, and polyethylene glycols.

[0070] As used herein, “the total weight of the pharmaceutical composition” or “the total weight of an oral dosage form” means the material within the oral dosage form (e.g., within a capsule) or the oral dosage form without any coating (e.g., without the capsule coating).

[0071] As used herein, the term “about”, when used in connection with amounts, weight percent, or a ratio of ingredients in a composition or a dosage form, includes the value of a 15MEl\59654703.vlspecified amount, weight percent or ratio (or a range of the amount, weight percent or ratio) that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified amount, or weight percent, or ratio.

[0072] An oral dosage form can be prepared into any suitable dosage forms, such as capsule, dragee, granule, powder, or tablet. In one embodiment, the oral dosage form is a capsule.

[0073] In one aspect, the size of the capsule is from size 4 to size OEL. In one embodiment, the size of the capsule is from size 4 to size 00. In another embodiment, the size of the capsule is from size 4 to size 0. In another embodiment, the size of the capsule is from size 3 to size 0.

[0074] In a particular embodiment, the size of the capsule is 1. In a particular embodiment, the size of the capsule is 4.

[0075] In one aspect, the oral dosage form is a tablet. In one aspect, the oral dosage form is a tablet with a non-functional polymer coating. In one aspect, the size of the tablet is 6.1 mm round biconvex, the size of tablet is 6.35 mm round biconvex, the size of tablet is 9.0 mm round biconvex, or the size of tablet is 9.5 mm round biconvex. In one aspect, the size of the tablet is 6.9 x 16.9 mm oval biconvex, the size of the tablet is 8x16 mm oval biconvex, the size of the tablet is 9x18mm oval biconvex, the size of tablet is 9.5x18.4mm oval biconvex, or the size of tablet is 10x19mm oval biconvex.

[0076] In one aspect, the oral dosage form as described herein comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 200 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 200 mg of Compound (I).

[0077] In one embodiment, the pharmaceutical composition or an oral dosage form (e.g., capsule) comprises about 10 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 10 mg of Compound (I).16MEl\59654703.vl

[0078] In one embodiment, the pharmaceutical composition or an oral dosage form (e.g., capsule) comprises about 50 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 50 mg of Compound (I).

[0079] In one embodiment, the pharmaceutical composition or an oral dosage form e.g., capsule) comprises about 100 mg of Compound (I), or a pharmaceutically acceptable salt thereof in an amount equivalent to 100 mg of Compound (I).

[0080] In one embodiment, the pharmaceutical composition or an oral dosage form (e.g., capsule) comprises about 13.1 mg of Compound (I) Sesqui-succinate.

[0081] In one embodiment, the pharmaceutical composition or an oral dosage form (e.g., capsule) comprises about 65.5 mg of Compound (I) Sesqui-succinate.

[0082] In one embodiment, the pharmaceutical composition or an oral dosage form (e.g., capsule) comprises about 131 mg of Compound (I) Sesqui-succinate.

[0083] In one aspect, the dosage form is a capsule, wherein the capsule is an immediate release capsule.

[0084] In one aspect, the capsule disintegrates in less than 15 minutes (e.g., 3 minutes, e.g., about 5 minutes, about 7 minutes, about 10 minutes, about 15 minutes) using USP <701>, wherein the procedure for uncoated or plain-coated tablets is used, wherein the capsule is placed in each of the 6 tubes of the basket (Basket type A) along with the disc and analytical grade water was added, and the temperature was maintained at 37 °C ± 2 °C. In a particular aspect, the capsule disintegrates in less than 15 minutes.

[0085] In one aspect, the dosage form is a capsule or a tablet, wherein at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, of Compound (I) or a pharmaceutically acceptable salt thereof is released in about 45 minutes, using Paddles USP II apparatus with a biorelevant media (simulated gastric fluid) with a media vessel volume of 900 mL, a paddle speed of 75 rpm ± 4 rpm and a temperature of 37.0 °C.

[0086] In a particular aspect, the dosage form is a capsule or a tablet, wherein at least 80% of Compound (I) or a pharmaceutically acceptable salt thereof is released in about 45 minutes.17MEl\59654703.vlMethod of Treatment

[0087] Another aspect of the present disclosure features a method of treating or ameliorating Fibrodysplasia Ossificans Progressiva (FOP) in a subject, comprising administering to the subject in need thereof a pharmaceutical composition or an oral dosage form disclosed herein.

[0088] The pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In a particular aspect, the orally acceptable dosage form is a capsule, herein the capsule is an immediate release capsule.

[0089] In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.

[0090] Mutations in ALK2 cause the kinase to be inappropriately active and are associated with various diseases. The pharmaceutical compositions disclosed herein inhibit a mutant ALK2 gene, e.g., a mutant ALK2 gene that results in the expression of an ALK2 enzyme having an amino acid modification. In another aspect, the pharmaceutical compositions disclosed herein inhibit both wild type (WT) ALK2 protein and mutant forms of ALK2 protein. For the purposes of this disclosure, sequence information for ALK2 is found on the National Center for Biological Information (NCBI) webpage (https: / / www.ncbi.nlm.nih.gov / ) under ACVR1 activin A receptor type 1 [ Homo sapiens (human) ]; Entrez Gene ID (NCBI): 90. It is also known as: FOP; ALK2; SKR1; TSRI; ACTRI; ACVR1 A; ACVRLK2; said sequence information is incorporated herein.

[0091] In one aspect, the disclosure provides a method of inhibiting aberrant ALK2 activity in a subject comprising the step of administering to the subject in need thereof a pharmaceutical composition described herein. In an embodiment, the aberrant ALK2 activity is caused by a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having an amino acid modification selected from one or more of L196P, PF197-8L, R202I, R206H, Q207E, R258S, R258G, R325A, G328A, G328V, G328W, G328E, G328R, G356D, and R375P. In an embodiment, the ALK2 enzyme has the amino acid modification R206H.18MEl\59654703.vl

[0092] Because of their activity against ALK2, the pharmaceutical composition described herein can be used to treat a subject with a condition associated with aberrant ALK2 activity. In an embodiment, the condition associated with aberrant ALK2 activity is fibrodysplasia ossificans progressive (FOP).

[0093] FOP diagnosis is based on the presence of congenital malformations of the great toes (hallux valgus) and the formation of fibrous nodules in soft tissues. The nodules may or may not transform into heterotopic bone. These soft tissue lesions are often first noted in the head, neck, or back. -97% of FOP subjects have the same c.617G>A; R206H mutation in the ACVR1 (ALK2) gene. There is a genetic test available through the University of Pennsylvania (Kaplan et al, Pediatrics 2008, 121(5): el295-el300).

[0094] Other common congenital anomalies include malformations of the thumbs, short broad femoral necks, tibial osteochondromas and fused facet joints of the cervical spine. The fused facet joints in the neck often cause toddlers to scoot on their buttocks rather than crawl.

[0095] FOP is commonly misdiagnosed (-80%; cancer or fibromatosis) and subjects are frequently subjected to inappropriate diagnostic procedures such as biopsies that exacerbate disease and cause permanent disability.

[0096] In one embodiment, the condition associated with aberrant ALK2 activity is fibrodysplasia ossificans progressiva (FOP) and the subject has a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having an amino acid modification selected from one or more of L196P, PF197-8L, R202I, R206H, Q207E, R258S, R258G, R325A, G328A, G328W, G328E, G328R, G356D, and R375P. In one aspect, the ALK2 enzyme has the amino acid modification R206H.

[0097] In an embodiment, the condition associated with aberrant ALK2 activity is a brain tumor, e.g., glial tumor. In an embodiment, the glial tumor is diffuse intrinsic pontine glioma (DIPG). In an embodiment, the disclosure provides a method of treating or ameliorating diffuse intrinsic pontine glioma in a subject, comprising administering to the subject in need thereof a pharmaceutical composition described herein.

[0098] In an embodiment, the condition associated with aberrant ALK2 activity is diffuse intrinsic pontine glioma and the subject has a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having an amino acid modification selected from one or more of R206H, G328V, G328W, G328E, and G356D. In one aspect of this embodiment, the ALK2 enzyme has the amino acid modification R206H.19MEl\59654703.vl

[0099] In an embodiment, the condition associated with aberrant ALK2 activity is anemia associated with inflammation, cancer or chronic disease.

[0100] In an embodiment, the condition associated with aberrant ALK2 activity is trauma-or surgery-induced heterotopic ossification.

[0101] In one aspect, the pharmaceutical composition or an oral dosage form of the disclosure is co-administered (either as part of a combination dosage form or as a separate dosage form administered prior to, sequentially with, of after administration) with a second therapeutic agent useful in treating the disease to be treated e.g., FOP. In one aspect, a compound of the disclosure is co-administered with a steroid e.g., prednisone) or other anti-allergenic agents such as omalizumab.

[0102] In one aspect, the pharmaceutical composition or an oral dosage form of the disclosure is co-administered with a RAR-g agonist or an antibody against activin for treating the disease to be treated e.g., FOP. In one aspect, the RAR-g agonist to be co-administered is palovarotene. In an aspect, the antibody against activin to be co-administered is REGN2477.

[0103] In one aspect, the pharmaceutical composition or an oral dosage form of the disclosure is co-administered with therapies that target mast cells useful in treating FOP. In an aspect, the pharmaceutical composition or an oral dosage form of the disclosure is coadministered with a mast cell inhibitor including, but not limited to a KIT inhibitor. In one aspect, the mast cell inhibitor to be co-administered is selected from cromolyn sodium (or sodium cromoglicate); brentuximab (ADCETRIS®); ibrutinib (IMBRUVICA®); omalizumab (XOLAIR®); anti-leukotriene agents (e.g, montelukast (SINGULAIR®) or zileuton (ZYFLO® or ZYFLO CR®)); and KIT inhibitors (e.g, imatinib (GLEEVEC®), midostaurin (PKC412A), masitinib (MASIVET® or KINAVET®), avapritinib, DCC-2618, PLX9486).

[0104] The precise amount of the pharmaceutical composition administered to provide an “therapeutically effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, a “therapeutically effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to20MEl\59654703.vlthe condition of the subject, the type of condition(s) being treated and the amount of a pharmaceutical composition being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57thEd., 2003).

[0105] ‘Treat”, “treatment” and “treating” such a disease or disorder refers to ameliorating at least one symptom of the disease or disorder described herein. These terms, when used in connection with a condition such as fibrodysplasia ossificans progressiva, refer to one or more of: controlling the rate of heterotopic bone growth; relieving pain and inflammation associated with development of new bone; extending the expected survival time of the patient; reducing the size or the number of heterotopic bone growth lesions; maintaining or improving mobility; preventing or treating new flare ups; inhibiting the development of new heterotopic bone lesions; enabling surgery to remove existing heterotopic ossifications to restore limb function and / or mobility; prolonging survival; prolonging progression-free survival; prolonging time to progression; inhibiting FOP related injury induced edema, and / or enhancing quality of life. When used in connection with a condition such as diffuse intrinsic pontine glioma, these terms refer to one or more of: impeding growth of the glioma, causing the glioma to shrink by weight or volume, extending the expected survival time of the patient, inhibiting glial tissue growth, reducing glial tumor mass, reducing size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonging survival, prolonging progression-free survival, prolonging time to progression, and / or enhancing quality of life.

[0106] A “subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like).

[0107] The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure.EXEMPLIFICATIONExample 1: Description of the Drug Product

[0108] / . / Composition of the Capsule

[0109] The disclosure provides a pharmaceutical composition that is prepared in an oral dosage form, such as, but not limited to a capsule or a tablet.21MEl\59654703.vl

[0110] The capsule is an immediate release drug product comprising of 10 mg, 50 mg or 100 mg of Compound (I) free base (which is the equivalent of 13.1 mg, 65.5 mg and 131 mg of the sesqui-succinate salt respectively).

[0111] The components and composition of the drug product are described in Table 1.The 10 mg strength was manufactured from the blend containing 10.0% w / w of Compound (I) Sesqui-succinate and was filled into a size 4 capsule. The 50 mg and 100 mg strengths were manufactured from the blend containing 40.0% w / w of Compound (I) Sesqui-succinate and was filled into size 4 and size 1 capsules respectively.Table 1: Composition of the Compound (I) Sesqui-succinate Capsules.

[0112] [a] Based on free base (1.000 mg Compound (I) free base is equivalent to 1.310 mg Compound (I) Sesqui-succinate ); [b] Compound (I) Sesqui-succinate amount may be adjusted based on the potency of the drug substance. The amount of Silicified Microcrystalline Cellulose is adjusted to compensate for this change; and [c] Silicified Microcrystalline Cellulose is composed of Microcrystalline Cellulose and Colloidal Silicon Dioxide.22MEl\59654703.vl

[0113] 1.2 Properties of Compound (I) Sesqui-succinate and Compound (I) hydrochloride monohydrate salts

[0114] The Compound (I) Sesqui-succinate drug substance was considered to be soluble over a wide range of pH as presented in Error! Reference source not found, and was highly permeable according to the Biopharmaceutics Classification System (BCS) criteria.

[0115] Table 2: Comparison of Relevant Physicochemical Properties of the Sesqui-succinate and Hydrochloride Salt Forms.> > >

[0116] [a] The monohydrate HC1 salt Pattern 6-A is a monohydrate salt and was used in the toxicology studies. This form was stable over a wide range of relative humidity and in water container solvent systems.Example 2: Excipients

[0117] 2.1 Excipient Compatibility

[0118] During the development of a capsule formulation comprising Compound (I) or a pharmaceutically acceptable salt thereof, several excipients were tested in a compatibility study. In this study, the API comprising Compound (I) or a pharmaceutically acceptable salt thereof was compressed at a 1:1 ratio to produce an intimate mixture of APLPolymer. The resulting compact was ground up and put onto stability. The excipients listed in Table 3 include those which may be required for the development of a capsule formulation, and those anticipated to be required for a paediatric coated minitablet formulation.

[0119] Table 3: Excipients for Compatibility Study.23MEl\59654703.vl

[0120] Compatibility was assessed after compacts were made of the formulations at T=0 and after storage for 2, 4, and 8 weeks at 25 °C / 60 % RH and 40 °C / 75 % RH. All samples were stored in borosilicate glass vials in an open configuration (a small hole was drilled into the vial lid). A further vial was also set down in a closed configuration.

[0121] The tests included visual appearance, assay performed in accordance with AM / 407 and related substances-performed in accordance with AM / 407.

[0122] There was no increase in the total impurities or visible degradation in the excipient compatibility programmes for either Compound (I) Sesqui-succinate salt (Table 4) or Compound (I) HC1 salt (Table 5) for T=0 to T=8 weeks. In addition to this, the appearance remained equivalent across all stability conditions and time points with an ‘Off White Powder’ .

[0123] Table 4: Compound (I) Sesqui-succinate Salt Excipient Compatibility, Reported as Total Impurities.

[0124] Table 5: Compound (I) HC1 Salt Excipient Compatibility, Reported as Total Impurities.24MEl\59654703.vl

[0125] 2.2 Excipients in Pharmaceutical Composition or an Oral Dosage Form

[0126] The pharmaceutical composition or an oral dosage form, such as a capsule or a table of the disclosure comprises of Compound (I) Sesqui-succinate and excipients, such as, silicified microcrystalline cellulose (SMCC), croscarmellose sodium and magnesium stearate. The excipients were identified based on function, application to dry granulation processes, and previous experience.

[0127] SMCC is composed of microcrystalline cellulose and colloidal silicon dioxide. SMCC was selected as the diluent because in addition to producing strong ribbons during granulation, the co-processed silicon dioxide can also help improve lubrication and flow. Croscarmellose sodium was selected as a disintegrant. Magnesium stearate was selected as a lubricant.

[0128] All excipients are official in United States Pharmacopeia / National Formulary (USP-NF), European Pharmacopoeia (Ph. Eur.) or Japanese Pharmacopoeia (JP).Croscarmellose sodium and magnesium stearate are official in United States Pharmacopeia-National Formulary (USP-NF), European Pharmacopoeia (Ph. Eur.), and Japanese Pharmacopoeia (JP). SMCC is official in the UPS-NF and JP, while SMCC complies with the Ph. Eur. monographs for microcrystalline cellulose and colloidal silicon dioxide. All the excipients are Generally Recognized as Safe (GRAS).25MEl\59654703.vl

[0129] The hard HPMC capsules are standard capsules used for solid oral dosage forms. Hard HPMC capsules have lower moisture content than hard gelatin capsules, therefore, they were selected to reduce potential moisture ingress into the formulation.Example 3: Drug Product

[0130] 3.1 Formulation Development

[0131] During the development of the drug product, solid-state characterization showed that Compound (I) hydrochloride salt (monohydrate) was a channel hydrate. Channel hydrates can be challenging to develop due to the uncontrolled dehydration within the crystal network. Limiting moisture content of the excipients and controlling humidity during manufacturing would most likely be required. Therefore, a reassessment of the salt screen was conducted.

[0132] Compound (I) Sesqui- succinate demonstrated comparable solid-state stability and solubility and was not a channel hydrate like the hydrochloride salt. Therefore, the sesqui-succinate salt was used for solid oral development. As shown by data presented in Table 4, there were no significant differences in solubility whatever the dissolution media, between the sesqui-succinate and the hydrochloride salt. Differences in solid state properties and hygroscopicity with the hydrochloride salt may impact drug substance and drug product stability as well as the drug product manufacturability.

[0133] Excipient compatibility studies were done with the sesqui-succinate salt. Excipient compatibility studies, using excipients chosen for a dry granulation, showed no increase in related substances after 2 weeks at 40°C / 75% RH in an open dish.

[0134] 3.2 Manufacturing Process Development

[0135] The manufacturing process begins with screening and blending excipients and drug substance prior to dry granulation using roller compaction. Post-roller compaction, the granules are blended with extragranular disintegrant and lubricant prior to encapsulation. FIG. 1 is a flow diagram depicting the dError! Reference source not found, for the process flow diagram.

[0136] 3.3 Dry Granulation

[0137] The desired target product profile for the adult formulation comprising Compound (I) or a pharmaceutically acceptable salt thereof is an immediate release capsule. Dry blends were produced for filling directly into capsules and were examined for the flow properties of26MEl\59654703.vlthe API and drug loading within the blends towards development of formulation. The desired product profile for a capsule of dosage strength such as, 10 mg and 100 mg, include, but not limited to, disintegration within 15 minutes, dissolution - an 80% release by 45 minutes, and good flow properties.

[0138] Blends were subjected to dry granulation trials within the development facility using the Vector Lab scale roller compactor and granulator. These trials were aimed to produce granules using a 1 mm screen. Prior to the production of blends, the compressibility of the API were tested using Heckel analysis, Strain rate sensitivity and true density measurement.

[0139] Granulated blends were characterized by Bulk / Tapped Density, Carr’s Index and the Hausner ratio and compared to the existing flow properties of the dry blend formulation strategy. The particle size distribution of the leading blends were characterized using sieve analysis, the range of sieves were decided based on if a granule is produced or a dry blend.

[0140] The increased bulk density of the formulations will improve the overall flow of the material as conventionally a denser granule will flow better. A dry granulation approach could also be beneficial for reducing the capsule size required for the 100 mg dose and in-tum make the administration of the formulation easier if this become a more apparent risk throughout formulation development.

[0141] The formulation development activities were conducted using the HC1 salt form, once a lead formulation candidate was identified all experimental activities were repeated using the Sesquisuccinate salt form to confirm equivalence in behavior.

[0142] Preliminary blends investigated the impact of various diluents and combinations of diluents. In order to the assess the impact of the diluents, the levels of disintegrants and lubricants were kept constant with 5% w / w Ac-Di-Sol SD-711 and 1% w / w Magnesium Stearate, both 1:1 intragranular vs extragranular. Varying grades of microcrystalline cellulose were investigated in the first instance, due to its good compression and flow properties. A summary of the initial formulations screened is provided in Table 6. In order to prevent the requirement for tamping, and therefore mitigate the potential for plug formation, 00 HPMC capsules were used for all formulations during the initial screen.27MEl\59654703.vl

[0143] Table 6: Formulation Composition of Formulations 1-5.

[0144] The same process was used for all formulations screened, where by all intragranular excipients were passed through a 1 mm sieve and blended at 34 rpm for 10 minutes. Granules were produced using the Vector lab scale roller compactor and granulator with a 1mm square screen. The parameters used on the Vector lab scale roller compactor are as follows: Roll force (12.00 kN), screw speed (35 rpm), and roll speed (1 rpm). These granules were then sieved through a 1mm screen with the extragranular excipients and blended at 34 rpm for 3 minutes.

[0145] The critical attributes of all the formulations screened were the bulk density and flow, as these would determine the final capsule size and have a negative impact moving to an automated process. It is convention that a blend with a higher bulk density will also flow better and therefore minimise risk on scale up. Formulations containing Prosolv SMCC 90 HD had the highest bulk / tapped density and so was selected as a potential lead formulation to investigate an increased drug loading. It was also noted that there was a degree of sticking during roller compaction for formulations containing Mannitol. Therefore, these were no longer investigated to prevent processing problems on scale up.

[0146] Increased drug loadings were investigated for formulations containing Prosolv SMCC 90 HD. As hypothesised an increased drug loading had an adverse impact on the bulk density of the final blend but were not significant as can be seen in Table 7.28MEl\59654703.vl

[0147] Table 7: Flow characteristics of Formulations 1-5.

[0148] Avicel 302 and Lactose were also investigated due to their increased bulk density with the same critical attributes being assessed as before in formulations 6-11, as shown in Table 8. The flow characteristics are shown in Table 9.

[0149] Table 8: Formulation Composition of Formulations 6-11.

[0150] Table 9: Flow characteristics of Formulations 6-11.

[0151] Based on the bulk density, and corresponding capsule fill volume, formulations containing either Prosolv SMCC 90 HD, or Avicel 302 were selected as the lead candidates.29MEl\59654703.vl

[0152] Due to concerns regarding the potential for segregation and uneven granule distribution within the 100 mg blend, a 10 mg granule approach was also assessed. The blend formulation prepared to achieve a 10 mg dosage form (10% w / w) with Prosolv SMCC 90 HD (84% w / w) and with the distribution of disintegrant (Ac-Di-Sol® Croscarmellose Sodium, 84% w / w) and lubricant (Magnesium stearate, 1% w / w) remaining at 1:1 intra vs extragranular as done for the 100 mg dose. The bulk density achieved for this granule was 0.62 g / mL.

[0153] 3.4 Container Closure System

[0154] The capsules comprising Compound (I) Sesqui- succinate were packaged in 60-cc high density polyethylene (HDPE) bottles with tamper evident, child resistant polyproplylene (PP) closure containing 4 g desiccant (silica gel). Each bottle contains 30 capsules.

[0155] 3.5 Microbiological Attributes

[0156] Microbial limit testing in accordance with USP <61> / Ph. Eur. 2.6.12 for total aerobic microbial count (TAMC) and total yeast and mold count (TYMC) and USP <62> / Ph. Eur. 2.6.13 for E. coli was performed for Compound (I) Sesqui-succinate capsules.

[0157] Microbial Limits and Absence of Specified Microorganism: The total aerobic microbial count and the total combined yeast and mold count is evaluated using industry standards by USP < 1111 > / Ph.Eur. 5.1.4 and USP <61> / Ph. Eur. 2.6.12. Additionally, the drug product is monitored to ensure that the bacterial strain, Escherichia coli, is not present per the USP < 1111 > / Ph. Eur. 5.1.4 and USP <62> / Ph. Eur. 2.6.13 standards (ICH Q4B Annex 4A and Annex 4B). These microbiological attributes are monitored at release and annually on stability at the long-term storage condition.

[0158] 3.6 Compatibility

[0159] 3.6.1 Compatibility in Soft Food

[0160] For pediatric patients and for patients that have difficulty swallowing a capsule as a whole unit, the drug product can be administered by opening the capsule and sprinkling its contents onto a soft food. To support this mode of administration, the stability of the capsule content in the presence of various food matrices was assessed. The study included soft foods covering a wide range of pH as shown in Table 10.30MEl\59654703.vl

[0161] Table 10: Soft Foods Studied and Their Apparent pH.

[0162] [a] Prepared as per package directions.

[0163] The stability study was conducted by sprinkling the content of 2 capsules of 10 mg or the content of 2 capsules of 100 mg onto the soft food and thus covering a dose ranging from 20 mg to 200 mg of Compound (I). The contents were added to a tablespoon of each soft food (approximately 15 g) and the sample was stored at room temperature under ambient lighting conditions for a maximum of 2 hours. The preparations were analyzed for Compound (I) content at time zero (TO), after 1 hour (Tl) and after 2 hours (T2) storage.

[0164] The results are presented in Table 11 and in Table 12 for the 20 mg and 200 mg dose, respectively. For the 20 mg dose, all results met the acceptance criteria except for the chocolate milk and chocolate mousse (pudding) where recovery results below 90% were observed at TO and at T2 for the chocolate mousse (pudding) and at Tl for the chocolate milk. For the 200 mg dose, all results met the acceptance criteria except for the porridge where recovery results below 90% were observed at TO and Tl.

[0165] It was concluded that drug product is compatible with apple sauce, raspberry yoghurt, strawberry milk drink and rice pudding and can thus be prepared with these soft foods and administered within 2 hours of preparation. The use of chocolate milk, porridge or chocolate mousse is not recommended at this time for administration of the drug product as a significant decrease in Compound (I) Sesqui-succinate content was observed immediately upon contact or after 1 hour.

[0166] Table 11: Stability in Soft Foods - 20 mg Dose.31MEl\59654703.vl

[0167] [a] Change in Compound (I) Sesqui-succinate content with respect to TO.

[0168] Table 12: Stability in Soft Foods - 200 mg Dose.

[0169] [a] Change in Compound (I) Sesqui-succinate content with respect to TO.

[0170] The method suitability was demonstrated by adding a known amount of the drug product into each food matrices and determining the recovered content (triplicate preparations). Extraction was achieved by adding the analytical method sample solvent to each the soft food-drug product preparations and sonicating with intermittent shaking. As shown in Table 13, the recovery results met the acceptance criteria of 90% to 110% of label claim for apple sauce, raspberry yoghurt, strawberry milk drink, chocolate milk drink and rice pudding. The recovery obtained with the chocolate mousse and porridge may be indicative of an extraction issue.

[0171] Table 13: Method Suitability - Recovery.<32MEl\59654703.vl

[0172] Food matrices (placebo) were also analyzed to confirm specificity of the method. The chromatographic profile did not show any interference at the retention time of Compound (I) Sesqui-succinate.

[0173] 3.6.2 Compatibility in Liquid

[0174] The liquid compatibility study included water and orange juice covering the range of pH as shown in Table 14.

[0175] Table 14: Vehicle Studied and Their Apparent pH.

[0176] The stability study was conducted by mixing the content of capsules into 30 mL of the vehicle using the following capsule strengths to achieve the minimum (5 mg) or maximum (120 mg) doses administered: 1 capsule of 5 mg , or 2 capsules each of 50 mg and 10 mg, or 4 capsules of 30 mg.

[0177] Although the 5 mg and 30 mg capsules are not currently proposed for use in the clinic, the strengths were developed from the same 10% blend used for the manufacture of the 10 mg capsule and are thus appropriate for this study.

[0178] Following mixing, the samples were stored at room temperature under ambient light for a maximum of 2 hours and analyzed for Compound (I) Sesqui-succinate content at time zero and after 2 hours (T2) storage.

[0179] From the results shown in Table 15, it was concluded that drug product is compatible with water and orange juice and can thus be prepared with these vehicles and administered within 2 hours of preparation.33MEl\59654703.vl

[0180] Table 15: Stability in Liquids - 5 mg and 120 mg Dose.

[0181] The analytical procedure used in this study was based on the UPLC procedure for identity, assay and related substances.

[0182] The method suitability was established by adding a known amount of the drug product into each vehicle and determine the content of Compound (I) Sesqui-succinate in % Label Claim.

[0183] 3.6.3 Tube Feeding Compatibility

[0184] Compound (I) Sesqui-succinate administration via a gastrostomy tube was assessed in line with the draft FDA Guidance for Industry “Oral Drug Products Administered Via Enteral Feeding Tube: In Vitro Testing and Labelling Recommendations”, dated June 2021.

[0185] The study was designed to evaluate the compatibility of Compound (I) Sesqui-succinate drug product with this mode of administration and define the volume required to guarantee a complete administration of the product using gastrostomy tubes of different diameter and type. The study covered an administration dose covering range of 5 mg to 120 mg using 1 capsule of 5 mg (worst case scenario for adsorption risk), 2 capsules each of 50 mg and 10 mg (equivalent to the 120 mg administration scheme in FALKON) and 4 capsules of 30 mg (worst-case scenario for clogging due to largest amount of insoluble excipient) to achieve dose of 120 mg as described in Table 16.

[0186] Table 16: Tube Feeding Compatibility: Administration System Evaluated.34MEl\59654703.vl

[0187] The capsules content was suspended in 30 mL of vehicle (water or orange juice) and dose recovery after flushing 3 times with 30 mL of vehicle was evaluated. Results are provided in Table 17, Table 18 and Table 19 respectively.

[0188] For the 5 mg lowest dose tested and 120 mg highest dose tested, all results with the orange juice remained within acceptance criteria with or without flushing 3 times with the vehicle. However, when Compound (I) Sesqui-succinate is suspended in water, flushing was required to guarantee >90% of dose administrated (flushing 3 times each with 30 mL of water).

[0189] Taken all together, Compound (I) Sesqui-succinate recovered was >90% for both the 5 mg and 120 mg doses thus meeting the acceptance criteria after 3 consecutive flushing with either water or orange juice.

[0190] Based on these results, Compound (I) Sesqui-succinate has thus been shown to be compatible for administration with enteral tube or in this case gastrostomy administration system described in Table 16. The drug product can then be administered via enteral tube using orange juice or water as vehicle followed by flushing of the tube with 3 times each of 30 mL of vehicle. The following administration system or equivalent are recommended: Silicone gastrostomy tube from 12 Fr to 22 Fr and Gastrostomy button 12 Fr (Silicone.Polyether imide. Polycarbonate. Barium Sulfate. Stainless Steel), with Gastrostomy extender (PVC (plasticizer: Citrate), Acrylonitrile Butadiene Styrene)35MEl\59654703.vl

[0191] Table 17: Evaluation of Administration with Gastrostomy Tubes - 5 mg Dose.

[0192] Table 18: Evaluation of Administration with Gastrostomy Tubes - 120 mg Dose.

[0193] Table 19: Evaluation of Administration with Gastrostomy Tubes - 120 mg Dose.

[0194] NP: Not performed.36MEl\59654703.vlExample 4. Manufacture

[0195] 4.1 Batch Formula

[0196] The batch formula for the manufacture of 1.5 kg of the 10% w / w blend and 4.00 kg of the 40% w / w blend is presented in Table 20.

[0197] The 10% w / w blend is encapsulated into a size 4 HPMC capsule at the specified target weight of 131 mg to deliver 10 mg of Compound (I) Sesqui-succinate per capsule. The 40% w / w blend is used to produce both the 50 mg and 100 mg capsules. The blend is encapsulated to the specified target weight of 163.75 mg into a size 4 HPMC capsule or 327.5 mg into a size 1 HPMC capsule to deliver 50 mg or 100 mg of Compound (I) Sesqui-succinate, respectively.

[0198] The number of capsules produced from the blends may be adjusted depending on the clinical needs. For the 10 mg capsule, the batch size may vary from approximately 11,450 capsules (1.50 kg) to 38,160 capsules (5.00 kg). For the 50 mg capsule, the batch size may vary from approximately 24,400 capsules (4.00 kg) to 73,280 capsules (12.00 kg). For the 100 mg capsule, the batch size may vary from approximately 12,200 capsules (4.00 kg) to 36,640 capsules (12.00 kg).

[0199] Table 20: Batch Formula for the 10% w / w (10 mg Capsule) and the 40% w / w Blend (50 mg and 100 mg Capsule).

[0200] [a] The amount of drug substance is adjusted based on the potency of Compound (I) Sesqui-succinate. The amount of silicified microcrystalline cellulose is adjusted to compensate for this change; [b] Approximate number of capsules based on an encapsulation target weight of 131.0 mg; [c] Approximate number of capsules based on an encapsulation target weight of 163.75 mg; and [d] Approximate number of capsules based on an encapsulation target weight of 327.5 mg.37MEl\59654703.vl

[0201] 4.2 Description of Manufacturing Process and Process Controls

[0202] Compound (I) Sesqui-succinate capsules were manufactured using standard process procedures and controls. The manufacturing process consists of blending of Compound (I) Sesqui-succinate drug substance and intragranular excipients followed by roller compaction and blending with extragranular excipients and encapsulation.

[0203] A flow diagram of the Compound (I) Sesqui-succinate capsule manufacturing process is provided in FIG. 1 followed by a brief step-by-step description of the manufacturing process.

[0204] (1) The drug substance, the silicified microcrystalline cellulose and the intragranular portion of croscarmellose sodium are sieved and then mixed together in a blender drum.

[0205] (2) The magnesium stearate is sieved and transferred into the blender drum and mixed with the other components.

[0206] (3) The blend is compacted by roller compaction and milled.

[0207] (4) The resulting granules are transferred to the blender drum and mixed with the extragranular portion of sieved croscarmellose sodium.

[0208] (5) Magnesium stearate is sieved and then transferred to the blender drum and the blend is mixed to produce the final blend.

[0209] (6) The final blend is then filled into capsules.

[0210] (7) The bulk capsules are de-dusted, weight-sorted and metal-checked and then packaged into the bottle container closure system.Example 5. Compound (I) Sesqui-succinate Capsules

[0211] 5.1 Specification for Capsules

[0212] The specification(s) for control of Compound (I) Sesqui-succinate capsules are presented in Table 21.38MEl\59654703.vl

[0213] Table 21: Specification(s) for Compound (I) Sesqui- succinate Capsules.< ><> <><><><>

[0214] [a] Test conducted at release and on stability; [b] Test conducted at release only; and [c] All impurities > 0.05% a / a are reported with relative retention time. NMT: no more than. The amount of impurity is expressed relative to the amount of active principle drug and is defined by the area to area (a / a) ratio. The % of impurity is calculated based on (integrated area of impurity) / (integrated area of API + integrated area of all impurities)* 100

[0215] 5.2 Assay, Identity and Related Substances by HPLC

[0216] The same assay / impurities method that is used for the drug substance is also used for the drug product. A reversed-phase high performance liquid chromatography (HPLC) method with gradient elution and ultraviolet (UV) detection is used for the determination of identity, assay, and impurities. The separation is performed using a mobile phase of trifluoroacetic acid (TFA) in water and TFA in acetonitrile / methanol as the strong diluent with a C8 column or equivalent. A brief description of the method conditions is presented in Table 22.39MEl\59654703.vl

[0217] Table 22: Analytical Procedure Summary - Identity, Assay and Related Substances by HPLC.

[0218] 5.3 Content Uniformity by HPLC

[0219] A reversed-phase HPLC method with gradient elution and ultraviolet (UV) detection is used for the determination of content uniformity of Compound (I) Sesqui-succinate drug product. The separation is performed using a mobile phase of trifluoroacetic acid (TFA) in water and TFA in acetonitrile as the strong diluent with a C18 column or equivalent. A brief description of the method conditions is provided in Table 23.

[0220] Table 23: Analytical Procedure Summary - Content Uniformity by HPLC.40MEl\59654703.vl

[0221] 5.4 Dissolution USP Apparatus II

[0222] The methodology to determine the dissolution of Compound (I) Sesqui- succinate capsules utilizes USP Apparatus II and performed as per USP <711> and Ph. Eur. 2.9.3. A dissolution medium of simulated gastric fluid at 37°C (900 mL per vessel) with a paddle rotation speed of 75 rpm ± 4 rpm is employed to determine the amount of Compound (I) Sesqui- succinate released by analysis using isocratic reverse phase HPLC method with UV detection. Profile sampling may be performed as deemed necessary, whereby sample solutions are withdrawn from each dissolution vessel at time intervals of 10, 15, 30, 45, and 60 minutes. A brief description of the chromatographic conditions is presented in Table 24.

[0223] Table 24: Analytical Procedure Summary - Dissolution HPLC Conditions.

[0224] 5.5 Impurities

[0225] Specified Impurities: Impurity 1 - NMT 1.0% a / a

[0226] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.01-1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0227] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.01-0.5% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0228] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.01-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0229] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.01-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.41MEl\59654703.vl

[0230] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.01-0.05% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0231] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.05-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0232] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.07-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0233] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.09-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0234] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.1-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0235] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.1-0.3% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0236] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.1-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0237] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.2-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0238] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 1) in an amount of 0.3-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0239] The structure of Impurity 1 is as follows.42MEl\59654703.vl"

[0240] (Impurity 1)

[0241] Impurity 1 is an Compound (I) Sesqui-succinate drug substance process impurity controlled at NMT 1.0% a / a in the drug substance specification. The same acceptance criterion has been implemented to monitor this impurity in the Compound (I) Sesqui-succinate drug product. This impurity is observed at similar levels in the drug substance and drug product and does not change stability. This impurity has been appropriately qualified in a 14-day repeat dose toxicity study (separate from GLP toxicology batch) at the level of 1.0% based on a maximum human daily dose of 1,000 mg / day.

[0242] Unspecified Impurities: Each NMT 0.5% a / a

[0243] Each unspecified impurity > 0.05% a / a is reported by relative retention time (RRT) to two decimal places and controlled at a limit of NMT 0.5% a / a. The proposed limit is the same as in the drug substance and for Phase 1 was justified using the modified Haber’s Rule (Harvey et al., Management of Organic Impurities in Small Molecule Medicinal Products: Deriving Safe Limits for Use in Early Development. Reg. Toxicology and Pharmacology. 2017, 84: 116-123) and a maximum of six months of dosing. The safe limit for non-mutagenic impurities was calculated using 5 mg of maximum allowable daily intake. The calculated threshold, which is appropriate for a healthy individual, is 1.1% (based on 300 mg max QD). The acceptance criterion of 0.5% (1.5 mg of degradation product) is a lower and more conservative approach.

[0244] Based on the proposed maximum daily dose of 120 mg for the Phase 2 study, this limit does not represent a safety issue and is appropriate for this stage in development.Considering the dose, the maximum exposure to any non-mutagenic impurity is controlled below 1 mg / day as applied in ICH Q3A for daily dose < 2 g / day (Harvey et al., 2017) which is below allowable limit of 2 mg prescribed in ICH Q3B for a maximum daily dose >10 mg to 2 g.

[0245] Total Impurities: NMT 3.0% a / a43MEl\59654703.vl

[0246] The total impurities acceptance criterion is set to NMT 3.0% a / a. This is congruent with the drug substance specification and appropriate at this stage of development.Example 6. Stability of Compound (I) Sesqui-succinate Capsules 5 mg

[0247] The disclosure provides an oral capsule comprising Compound (I) Sesqui-succinate that is intended for immediate release and will be administered (once a day) using weight-based dosing strategy for all patients (children, adolescents and adults).

[0248] The capsules of the disclosure selectively target the Activin receptor like-kinase-2 (ALK2), for the treatment of Fibrodysplasia Ossificans Progressiva (FOP).

[0249] Three capsules strengths, namely, 10 mg (10 % w / w API), 50 mg and 100 mg (40 % w / w API) capsules have been developed so far as well as matching placebo.

[0250] The clinical trial will involve the following products: 10 mg, 50 mg Compound (I) Sesqui-succinate active capsules and Compound (I) Sesqui-succinate Placebo formulation in size 4 capsules to match 10 mg and 50 mg.

[0251] Other capsule strengths, such as, but not limited to 5 mg and 30 mg could also be used for clinical requirements in treating Fibrodysplasia Ossificans Progressiva (FOP). The percentage of active ingredient in the blend as well as the type of capsules differ from one strength to another and is detailed in Table 25.

[0252] Table 25: Batches Comparison.

[0253] [a] Filling with Vcaps ©Plus Size 4 capsules not possible on IMA equipment (automatic filling).

[0254] The Compound (I) Sesqui-succinate batches dose 5 mg and 30 mg were monitored for stability following the process modifications: Increase in batch size of the 10 % w / w mixture from 1.5 kg to 7 kg; automatic filling on the IMA ZANASI 12E equipment; granulation 0.8mm instead of 1.0mm; change of capsule type for Compound (I) Sesqui-succinate 5 mg; and change of capsule size for Compound (I) Sesqui-succinate 30 mg.44MEl\59654703.vl

[0255] Three studies, namely, ICH stability study, In-use stability study and Under stressed conditions stability study were conducted on the Compound (I) Sesqui-succinate capsules 5 mg (Quali-V size 4) to monitor the stability.

[0256] The unit dose composition for Compound (I) Sesqui-succinate capsules 5 mg is provided in Table 26.

[0257] Table 26: Composition of the Compound (I) Sesqui-succinate Capsules 5 mg -Batch W07065.

[0258] [a] Based on free base (1.000 mg Compound (I) free base is equivalent to 1.310 mg Compound (I) Sesqui-succinate); [b] The amount of Compound (I) Sesqui-succinate is adjusted according to the purity of the material; [c] Silicified microcrystalline cellulose is composed of microcrystalline cellulose and colloidal silicone dioxide; and [d] The batch is packaged in sealed HDPE bottles containing 30 capsules.

[0259] The acceptance criteria at release and at shelf-life for the stability study is provided in Table 27. Acceptance criteria at shelf life are used to assess the stability of this batch monitored during the different studies (ICH, in-use and under stressed conditions).45MEl\59654703.vl

[0260] Table 27: Specification of Compound (I) Sesqui- succinate Capsule Dose 5 mg.< >< << << <<> < < < <<>

[0261] [a] When testing, specify whether the capsules are easy to open; [b] Report all impurities > 0.05 % a / a with relative retention time; [c] Report results to one decimal place.46MEl\59654703.vlExample 7. Evaluation Test Procedure

[0262] The analytical methods which have been validated for Compound (I) Sesqui-succinate 10 mg, 50 mg and 100 mg capsules were used for the 5 mg. However, some adjustments of the methods were needed as sample preparation and dilution volume.

[0263] To evaluate the impact of the 5 mg capsules strength’s introduction on the validated range of the analytical methods, an impact assessment has been performed for each analytical method. Based on the assessment, complementary validation activities were performed for the identification, assay and impurities test, the content uniformity test and the dissolution test. For the microbiological testing, the method verification was repeated for 5 mg capsules.

[0264] Compound (I) Sesqui- succinate identification, assay and impurities are determined according to the UPLC method 380360-INS. However, 2 replicates are performed for the assay of Compound (I) Sesqui-succinate according to sample preparation described in 380360-INS. One replicate is performed for the determination of impurities where only the powder of the capsules is introduced in the volumetric flask without the capsule shell due to interaction of the capsule’s components with impurities of Compound (I) Sesqui-succinate. The method has been validated.

[0265] Compound (I) Sesqui-succinate content uniformity test is determined according to European pharmacopoeia 2.9.40 and USP <905> harmonised methods and to the HPLC method 366179-INS. The method has been validated.

[0266] Dissolution test is determined according to apparatus type II (method with paddles) UV online 358026-INS. The method was optimized and has been validated.

[0267] Water content is determined according to the coulometric method with oven 362199-INS. The method has been validated.

[0268] European pharmacopoeia 2.6.12 and 2.6.13, and USP <61> and <62> harmonised methods are used for microbiological test. The methods are applied according to the current version of the European pharmacopoeia and USP, and the microbiological methods have been validated.Example 8. ICH Stability Study

[0269] 8.1 ICH Stability Study Design47MEl\59654703.vl

[0270] The ICH stability study is also known as the formal stability study. This study follows a formulation over time and verify its ability to keep its physical, chemical and microbiological characteristics under different storage conditions. A stability study makes it possible to determine the period of validity (shelf-life) and the storage conditions of a given formula in a given packaging. This study may also be initiated on the unconditioned product (bulk) to determine the stability of the product before packaging.

[0271] The stability of Compound (I) Sesqui- succinate capsule 5 mg was followed at 48 months at 25 °C / 60 %RH, 48 months at 30 °C / 65 %RH (optional intermediate condition), 48 months at 30 °C / 75 %RH and 6 months at 40 °C / 75 %RH.

[0272] The ICH stability plan is summarized in the Table 28 with the details of characteristics and time points according to the storage conditions.

[0273] Table 28: Plan and Studied Characteristics - ICH Stability.

[0274] Results at T18M, T24M, T30M, T36M, and T48M are not available, [a] Appearance, assay and impurities of Compound (I) Sesqui-succinate, dissolution and water content; [b] Microbial enumeration test and test for specified microorganisms; [c] Content uniformity, identification; ( ) The 30 °C / 65 %RH condition is optional. It will be performed only if the 30 °C / 75 %RH data are not compliant; and - No analysis.

[0275] The results of ICH stability study are presented in Table 29 to Table 31 respectively. Time-points not available are indicated therein.48MEl\59654703.vl

[0276] Table 29: Compound (I) Sesqui-succinate Capsules 5 mg Quali-V - Batch W07065 - ICH stability at 25 °C / 60 %RH.<<<49MEl\59654703.vl< < << < <

[0277] - Test not required; NP : Not performed; Results at T18M, T24M, T30M, T36M, and T48M are not available; [a] The ease of opening the capsule was not assessed at the T6M time-point (no impact, test is just only for information); [b] Difficult to open due to hardening of the capsule; [c] Results of retests after improvement of method (changes of media dissolution volume and sinker size) following investigation; and [d] The dissolution test was performed at 50 rpm to support the method development.

[0278] Table 30: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 - ICH stability at 30 °C / 75 %RH.50MEl\59654703.vl<<<51MEl\59654703.vl< < << < <

[0279] - Test not required; NP : Not performed; Results at T18M, T24M, T30M, T36M, and T48M are not available; [a] The ease of opening the capsule was not assessed at the T6M time-point (no impact, test is just only for information); [b] Difficult to open due to hardening of the capsule; [c] Results of retests after improvement of method (changes of media dissolution volume and sinker size) following investigation; and [d] The dissolution test was performed at 50 rpm to support the method development.

[0280] Table 31: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 - ICH stability at 40 °C / 75 %RH.52MEl\59654703.vl<<<< < << < <

[0281] - Test not required; [a] The ease of opening the capsule was not assessed at the T6M time-point (no impact, test is just only for information); and [b] Results of retests after improvement of method (changes of media dissolution volume and sinker size) following investigation.

[0282] 8.2 Discussion ofICH Stability Study

[0283] Appearance: No change of appearance is observed after 12-months storage at 25 °C / 60 %RH, 30 °C / 75 %RH and 6 months at 40 °C / 75 %RH. At T9 months of storage53MEl\59654703.vlat 25 °C / 60 %RH and at 30 °C / 75 %RH, the capsules have become difficult to open due to their hardening (Not confirm at 12 month-period). The coloration of the powder inside the capsules remains white to off white and the capsule coloration remain white also.

[0284] Identification: At TO, identification of Compound (I) Sesqui-succinate is positive.

[0285] Content Uniformity: At TO, content uniformity is compliant according to Eur. Ph.2.9.40 and USP <905>.

[0286] Assay: Whatever the storage conditions, all results remain within the acceptance criteria (90.0 % to 110.0 % of label claim) after 12 month period of storage. No real trend can be observed as show in FIG. 2.

[0287] Impurities: Specified Impurity (Impurity 1): Whatever the storage conditions, the specified impurity (Impurity 1) is well below the acceptance criteria (NMT 1.0 %) and does not evolve compared to the initial time point.

[0288] Unspecified Impurities: After 12 months at 25 °C / 60 %RH and at 30 °C / 75 %RH and 6 months at 40 °C / 75 %RH, all unspecified impurities remain well below the acceptance criteria (NMT 0.2 %).

[0289] The main impurities > 0.05 % were observed at RRT 0.48, RRT 0.53 and RRT 1.36.

[0290] After 12 months, whatever the storage conditions, the higher unspecified impurity is at RRT 1.36 and represents 0.07 %.

[0291] Total impurities: Whatever the storage conditions, the total impurities do not evolve compared to the initial time point and remain well below the acceptance criteria (NMT 3.0 %).

[0292] Water content: Compared to initial value, water content is quite stable after 12 months of storage at 25 °C / 60 %RH and at 30 °C / 75 %RH and after 6 months of storage at 40 °C / 75 %RH. The very slight variation observed is due to the method’s accuracy as shown in FIG. 3 and results remains between 2 and 3 %.

[0293] Dissolution at 75 rpm: At initial time, the results of dissolution are compliant for level S2 according to European Pharmacopoeia 2.9.3. The dissolution test was first performed on 6 units (level SI), the individual value for vessel 2 (74 %) was not compliant54MEl\59654703.vl(lower than Q+5 % (85 %)) consequently 6 additional capsules were tested, and the batch was found compliant at level S2.

[0294] An investigation was conducted, and the results showed an impact of the sinker and the dissolution volume (500 mL) on the dissolution of the Quali-V capsules, FIG. 4). The parameters of the dissolution method were therefore adapted to improve the dissolution of the Quali-V capsule (dissolution volume of 900 mL and Japanese sinkers). The dissolution testing was performed using the optimized parameters on capsules stored 1 month at 25 °C / 60 %RH. The dissolution results were compliant for level SI and were considerate as initial result. The method was validated with these new parameters.

[0295] After 12-month period, whatever the storage conditions, the dissolution tests meet specification (Q = 80 % dissolved at 30 minutes) despite a slight decrease of % dissolved, as shown in FIG. 5.

[0296] No significant differences have been observed on dissolution profiles for batch W07065 (dose 5 mg) compared to initial time point, as shown in FIG. 6A, FIG. 6B and FIG.6C.

[0297] However, on 6 samples, a heterogeneity of the dissolution curves is observed until 15 minutes. Phenomenon is due to the HPMC contained in the capsules and is linked to the time necessary for water molecules to diffuse into the HPMC chains and to initiate the disintegration of the shell.

[0298] There is no impact on the compliance of the test.

[0299] Dissolution at 50 rpm (to support the method development): The objective is to support the method development and to justify the rotation speed of the method. The USP and European Pharmacopoeia require to: Justify a speed greater than 50 rpm with paddles (cone effect, variability) and demonstrate the discriminance of the dissolution method.

[0300] The results obtained show that the speed of stirring at 50 rpm slow down the dissolution profiles whatever the condition of storage. And the % dissolved at 30 minutes remains similar at 25°C / 60%RH (94% vs 95 %) but is lower at 30°C / 75%RH (92 % vs 96 %) as shown in FIG. 7A and FIG. 7B.

[0301] Despite the change of speed stirring, at 12-months, whatever the storage conditions, the results of dissolution are compliant for level S2 according to European Pharmacopoeia 2.9.3 and USP <711>.55MEl\59654703.vl

[0302] Microbiological Tests: At initial time point, 6 months and 12 months, all microbiological tests are compliant.

[0303] 8.3 Conclusion ofICH Stability Study

[0304] All results from ICH stability are within specifications after 12 months under longterm conditions (25 °C / 60 %RH) and intermediate conditions (30 °C / 75 %RH) and after 6 months under accelerated conditions (40 °C / 75 %RH). They confirm the trend observed for the stability of Compound (I) Sesqui- succinate active formula demonstrated on the other strengths.Example 9. In-use Stability Study

[0305] 9.1 In-use Stability Study Design

[0306] This is a stability study under in-use conditions by simulating the number of openings during the treatment period.

[0307] In accordance with the CPMP / QWP / 2934 / 99 guideline, this evaluation was performed on bottles at beginning (TO) as well as at the end of the envisaged shelf-life for this product (48 months at 25 °C / 60 %RH and 30 °C / 75 %RH (30 °C / 65 %RH optional)).

[0308] The objective of this study was to evaluate the in-use stability of Compound (I) Sesqui-succinate capsules in HDPE bottles after the first opening and under the intended conditions of use, i.e., opening of the bottle once a day for a period of 30 days.

[0309] The In-use stability plan is summarized in the Table 32 with the details of characteristics and time points according to the storage conditions.

[0310] Table 32: Plan and Studied Characteristics - In-use Stability.

[0311] Results at T48M and T48M + 30 days of opening are not available, [a] Appearance, assay and impurities of Compound (I) Sesqui-succinate, dissolution and water56MEl\59654703.vlcontent; [b] Microbial enumeration test and test for specified microorganisms; ( ) The 30 °C / 65 %RH condition is optional. It will be performed only if the 30 °C / 75 %RH data are not compliant. * The time point corresponding to the time point of the ICH study.

[0312] For the in-use study at initial time point, 9 bottles were opened before placing them under both temperature conditions (25 °C / 60 %RH and 30 °C / 75 %RH).

[0313] All bottles used for this study, were opened only on working days, once each day, except for Monday and Friday, where all bottles were opened twice a day for a total of 30 openings (see Table 33).

[0314] For both temperature conditions, the bottles were opened during a few minutes and either one capsule was removed, or a sampling simulation was performed. For a total of 30 openings, 15 capsules were removed from each bottle (the recording of all openings HDPE bottle was kept with stability raw data).

[0315] Table 33: Sampling Simulation.

[0316] The results of In-use stability study are presented in Table 34 and Table 35 respectively. Time-points not available are indicated therein.

[0317] Table 34: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 - In-use Stability at 25 °C / 60 %RH.57MEl\59654703.vl<<<< < << < <

[0318] Results at T48M and T48M + 30 days of opening are not available, [a] Results of retests after improvement of method (changes of media dissolution volume and sinker size) following investigation.58MEl\59654703.vl

[0319] Table 35: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 - In-use Stability at 30 °C / 75 %RH.<<<< << < <59MEl\59654703.vl

[0320] Results at T48M and T48M + 30 days of opening are not available, [a] Results of retests after improvement of method (changes of media dissolution volume and sinker size) following investigation.

[0321] 9.2 Discussion of In-use Stability Study

[0322] At TO, all analytical and microbiological results after 30 openings and 30 days at 25 °C / 60 %RH and 30 °C / 75 %RH are compliant with the acceptance criteria.

[0323] No significant change for the different tests compared with reference values (TO) was observed, either at 25 °C / 60 %RH or at 30 °C / 75 %RH.

[0324] Therefore, the Compound (I) Sesqui-succinate capsules 5 mg (Quali-V size 4) packaged in the primary container closure system (HDPE bottle) is stable after 30 openings and 30 days at 25 °C / 60 %RH and 30 °C / 75 %RH.

[0325] 9.3 Conclusion of In-use Stability Study

[0326] At initial time-point, the Compound (I) Sesqui-succinate capsules 5 mg, batch W07065 is stable for 30 days at 25 °C / 60 %RH and 30 °C / 75 %RH after 30 openings of the HDPE bottle.

[0327] This study shows that opening the bottle once a day for 30 days, corresponding to the conditions simulating patient usage, does not have an impact on the stability of the drug product, at both 25 °C / 60 %RH and 30 °C / 75 %RH.Example 10. Under Stressed Conditions Stability Study

[0328] 10.1 Under Stressed conditions stability study Design

[0329] This study is related to the temperature excursion study (cycling) and the high-temperature study (at 50 °C).

[0330] These studies included the stress tests that the batch must undergo according to ICH QI A. They were complementary to the ICH study and allow to have supportive data such as the following.

[0331] Temperature excursion (cycling): After 3 freeze-thaw cycles of 2 days at -20 °C followed by 2 days at 40 °C / 75 %RH, the batch was analyzed. The results allow to define if a specific labelling regarding the risk of freezing should be applied to the clinical batches.60MEl\59654703.vl

[0332] High temperature study: Evaluation of the impact of a temperature rise that may occur during the life of the product. For this, the bottles containing the capsules are stored at 50 °C for 15 days.

[0333] For temperature excursion study, bottles initially placed at 25 °C / 60 %RH underwent 3 freeze-thaw cycles of 2 days at 20 °C followed by 2 days at 40 °C / 75 %RH. Details are described in the Table 36. The time-point 6 months at 25 °C / 60 %RH was used as reference time-point. Table 37 provides the cycle of excursion.

[0334] Table 36: Plan and Studied Characteristics for Temperature Excursion.0335] [a] Appearance, assay and impurities of Compound (I) Sesqui-succinate, dissolution and water content; [b] Microbial enumeration test and test for specified microorganisms; and * The number of days at -20 °C then at 40 °C / 75 %RH was at least 2 days per condition. Depending on the dates, the samples could have stayed longer.

[0336] Table 37: Cycle of Excursion.

[0337] For stressed conditions study, bottles initially placed 6 months at 25 °C / 60 %RH were placed 15 days at 50 °C. Details are described in the Table 38. The time-point 6 months at 25 °C / 60 %RH was used as reference time-point.

[0338] Table 38: Plan and Studied Characteristics for Stressed Conditions at 50 °C.61MEl\59654703.vl

[0339] [a] Appearance, assay and impurities of Compound (I) Sesqui-succinate, dissolution and water content.

[0340] The results of under stress conditions stability studies are presented in Table 39 and Table 40 respectively.

[0341] Table 39: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 - Temperature Excursion.<< << < < < < <

[0342] [a] The ease of opening the capsule was not assessed (no impact, test is only for information).

[0343] Table 40: Compound (I) Sesqui-succinate Capsules 5 mg - Batch W07065 -Stressed Study at 50 °C.62MEl\59654703.vl<< <

[0344] [a] The ease of opening the capsule was not assessed (no impact, test is only for information).

[0345] 10.2 Discussion of Under Stressed Conditions Stability Studies (cycling / 50 °C)

[0346] This experiment is carried out to simulate the variation / cycling in storage conditions potentially observed during overseas shipment or during clinical use.

[0347] After 3 freeze-thaw cycles of 2 days each (at minima) at -20 °C then at 40 °C / 75 %RH and after 15 days at 50 °C, all results are within the defined acceptance criteria and are similar to those obtained with samples stored 6 months at 25 °C / 60 %RH.

[0348] Therefore, the Compound (I) Sesqui-succinate active capsules can undergo variation in storage condition without specific degradation.63MEl\59654703.vl

[0349] 10.3 Conclusion of Under Stressed Conditions Stability Studies

[0350] None of the results generated after 15 days at 50 °C or after 3 freeze-thaw cycles of 2 days (at minima) each at -20 °C then at 40 °C / 75 %RH show any sign of degradation or other signs of instability.Example 11. Stability Study of 10 mg, 50 mg, and 100 mg of Compound (I) Sesqui-succinate Capsules

[0351] The stability data summary is presented in Table 41. The stability protocol for the Compound (I) Sesqui- succinate clinical batches is presented in Table 42.

[0352] Table 41: Compound (I) Sesqui-succinate Stability Data Summary.

[0353] It should be noted that Chiral Purity and X-ray Powder Diffraction (XRPD) were tests conducted historically for the drug product stability studies. These tests will no longer be evaluated on stability as batch analyses have shown that these attributes are not required for the drug product.

[0354] Additionally, in order to confirm batch compliance over shelf-life, additional microbial analyses were performed on stability samples stored for 20 months and 10 months at 25°C / 60%RH stability conditions. All results comply to specifications.

[0355] Table 42: Stability Protocol for Compound (I) Sesqui-succinate Capsules, 10 mg, 50 mg and 100 mg Clinical Batches.64MEl\59654703.vl

[0356] [a] Microbiological testing for 10 mg and 100 mg strengths only; [b] Stability protocol for the 50 mg strength does not include the 9-month time point; [c] Stability protocol for the 50 mg strength is up to 24 months only; M = total aerobic microbial count, total yeast and mould count, absence of E. coli; X = appearance, assay, related substances, dissolution and water content.

[0357] 11.1 Stability Data, 10 mg Capsules

[0358] Table 43 A: Drug Product Stability Data, 10 mg Capsules at 25°C / 60%RH.<<65MEl\59654703.vl

[0359] Table 43 A: Drug Product Stability Data, 10 mg Capsules at 25°C / 60%RH (continued).66MEl\59654703.vl

[0360] Table 43B: Drug Product Stability Data, 10 mg Capsules at 25°C / 60%RH.

[0361] Table 43B: Drug Product Stability Data, 10 mg Capsules at 25°C / 60%RH (continued).67MEl\59654703.vl

[0362] Table 43B: Drug Product Stability Data, 10 mg Capsules at 25°C / 60%RH (continued).68MEl\59654703.vl

[0363] [a] Dissolution testing performed with isocratic method starting at the 18-month time point; and [b] Following the internalization of microbial testing this batch was tested at the 20-month time point for TAMC, TYMC and E. coli. All microbial results were found compliant. NS = Not Scheduled.

[0364] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.01-1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0365] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.01-0.5% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0366] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.01-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0367] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.01-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0368] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.01-0.05% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0369] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.05-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.69MEl\59654703.vl

[0370] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.07-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0371] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.09-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0372] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.1-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0373] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.1-0.3% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0374] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.1-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0375] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.2-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0376] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 2) in an amount of 0.3-0.4% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0377] The structure of chiral (enantiomer S) impurity (Impurity 2) is as follows.

[0378] (Impurity 2)

[0379] In some embodiments, the pharmaceutical composition disclosed herein further comprises of unspecified individual impurity (Impurity 3).70MEl\59654703.vl

[0380] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.01-0.5% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0381] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.01-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0382] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.01-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0383] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.01-0.05% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0384] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.05-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0385] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.1-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0386] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.1-0.15% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0387] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 3) in an amount of 0.15-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0388] The structure of (Impurity 3) is as follows.

[0389] (Impurity 3)71MEl\59654703.vl

[0390] Table 44: Drug Product Stability Data, 10 mg Capsules at 40°C / 75%RH.<<

[0391] Table 44: Drug Product Stability Data, 10 mg Capsules at 40°C / 75%RH (continued).72MEl\59654703.vl<<

[0392] [a] The verification of the compendial methods for TAMC and TYMC (USP <61> / Ph. Eur. 2.6.12) and for E. coli (USP <62> / Ph. Eur. 2.6.13) is under completion at QMC. NS = Not Scheduled.

[0393] 11.2 Stability Data, 50 mg Capsules

[0394] In some embodiments, the pharmaceutical composition disclosed herein further comprises of unspecified individual impurity (Impurity 4).73MEl\59654703.vl

[0395] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.01-0.5% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0396] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.01-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0397] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.01-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0398] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.01-0.05% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0399] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.05-0.1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0400] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.1-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0401] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.1-0.15% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0402] In some embodiments, the pharmaceutical composition disclosed herein further comprises (Impurity 4) in an amount of 0.15-0.2% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

[0403] The structure of (Impurity 4) is as follows.

[0404] (Impurity 4)74MEl\59654703.vl

[0405] Table 45A: Drug Product Stability Data, 50 mg Capsules at 25°C / 60%RH.<<

[0406] Table 45A: Drug Product Stability Data, 50 mg Capsules at 25°C / 60%RH (continued).75MEl\59654703.vl

[0407] [a] Following the internalization of microbial testing, this batch was tested at the 10-month time point for TAMC, TYMC and E. coli. All microbial results were found compliant; [b] Dissolution testing performed with new isocratic method; and [c] The verification of the compendial methods for TAMC and TYMC (USP <61> / Ph. Eur. 2.6.12) and for E. coli (USP <62> / Ph. Eur. 2.6.13) is under completion at QMC.

[0408] Table 45B: Drug Product Stability Data, 50 mg Capsules at 25°C / 60%RH.76MEl\59654703.vl< << <

[0409] Table 45B: Drug Product Stability Data, 50 mg Capsules at 25°C / 60%RH (continued).77MEl\59654703.vl< << <

[0410] [a] Following the internalization of microbial testing, this batch was tested at the 10-month time point for TAMC, TYMC and E. coli. All microbial results were found compliant. NS = Not Scheduled.

[0411] Table 46: Drug Product Stability Data, 50 mg Capsules at 40°C / 75%RH.78MEl\59654703.vl<<

[0412] Table 46: Drug Product Stability Data, 50 mg Capsules at 40°C / 75%RH (continued).79MEl\59654703.vl

[0413] [a] Dissolution testing performed with new isocratic method; [b] The verification of the compendial methods for TAMC and TYMC (USP <61> / Ph. Eur. 2.6.12) and for E. coli (USP <62> / Ph. Eur. 2.6.13) is under completion at QMC. NS = Not Scheduled.

[0414] 11.3 Stability Data, 100 mg Capsules

[0415] Table 47A: Drug Product Stability Data, 100 mg Capsules at 25°C / 60%RH.80MEl\59654703.vl<<

[0416] Table 47A: Drug Product Stability Data, 100 mg Capsules at 25°C / 60%RH (continued).81MEl\59654703.vl

[0417] NS = Not Scheduled.

[0418] Table 47B: Drug Product Stability Data, 100 mg Capsules at 25°C / 60%RH.< 82MEl\59654703.vl<

[0419] Table 47B: Drug Product Stability Data, 100 mg Capsules at 25°C / 60%RH (continued).<83MEl\59654703.vl<

[0420] Table 47B: Drug Product Stability Data, 100 mg Capsules at 25°C / 60%RH (continued).< << <84MEl\59654703.vl

[0421] [a] Dissolution testing performed with isocratic method starting at the 18-month time point; [b] Following the internalization of microbial testing, this batch was tested at the 20-month time point for TAMC, TYMC and E. coli. All microbial results were found compliant. NS = Not Scheduled. NP = Not Performed.

[0422] Table 48: Drug Product Stability Data, 100 mg Capsules at 40°C / 75%RH.<<85MEl\59654703.vl

[0423] Table 48: Drug Product Stability Data, 100 mg Capsules at 40°C / 75%RH (continued).<<86MEl\59654703.vl

[0424] [a] The verification of the compendial methods for TAMC and TYMC (USP <61> / Ph. Eur. 2.6.12) and for E. coli (USP <62> / Ph. Eur. 2.6.13) is under completion at QMC. NS = Not Scheduled.

[0425] 11.4 Summary of Stability Data

[0426] The stability data for Compound (I) Sesqui-succinate capsules, 10 mg, 50 mg and 100 mg clinical batches stored at the long term 25°C / 60% RH and accelerated 40°C / 75%RH storage conditions, packaged in the clinical container closure system, showed no significant change through the available time points. The stability studies will be monitored throughout the clinical study and, if unacceptable changes are observed, the material will be withdrawn from the clinic or the results will be discussed with the health authority, as appropriate.

[0427] Example 12. Dissolution Testing of 10 mg of Compound (I) Sesqui-succinate Capsules

[0428] Capsules were subjected to dissolution testing at a minimum of n=3. The dissolution profile for the 10 mg capsules shown in FIG. 8 is consistent of immediate release properties. The variability seen at the 5-minute time point is attributed to the viability in capsule rupture time, as is expected with HPMC capsule shells.

[0429] Example 13. Bioequivalence (BE) Study of Capsule Strengths (5x10 mg or 1x50 mg)

[0430] A Phase I, open-label, single-centre, randomised, 2-sequence, 3-period, crossover study was desinged to investigate the relative bio availability of two Fidrisertib dosage strengths and the effect of food on the pharmacokinetics of Fidrisertib in healthy adult participants.

[0431] 13.1 Rationale

[0432] Fidrisertib is being developed for fibrodysplasia ossificans progressiva (FOP), an ultra-rare, severely disabling disease characterised by heterotopic ossification (HO) in muscles, tendons and ligaments, often associated with painful, recurrent episodes of soft tissue swelling. Eesions begin in early childhood and lead to progressive ankyloses of major joints with resultant loss of movement. Prognosis is poor and life expectancy is reduced.

[0433] All Fidrisertib capsule strengths have similar qualitative compositions (same excipient, hydroxypropyl methyl cellulose (HPMC) capsules) and are manufactured following a similar manufacturing process but quantitative composition varies as they are 87MEl\59654703.vlprepared from different blends. A relative bioavailability study is proposed to demonstrate the interchangeability of Fidrisertib capsule strengths (5x10 mg or 1x50 mg).

[0434] Food-drug interactions could have an impact on the pharmacokinetics (PK) of orally administered drugs and could thereby impact the safety and efficacy of the drug. The effect of food on Fidrisertib PK will be assessed in this study at a lower dose (50 mg single dose), using different capsules strength.

[0435] 13.2 Objectives and Endpoints

[0436] Table 49: Objectives and Endpoints.88MEl\59654703.vl

[0437] Abbreviations: AE = adverse event; AUGnf = area under the plasma concentrationtime curve from time zero to infinity; AUCiast = area under the plasma concentration-time curve from time zero to the last measurable concentration; CI = confidence interval; CL / F = apparent total clearance; Cmax = maximum (peak) plasma drug concentration; ECG = electrocardiogram; GMR = geometric mean ratio; PK = pharmacokinetic(s); SAE = serious adverse event; ti / 2 = elimination half-life; tmax = time to maximum observed drug concentration; Vd / F = apparent volume of distribution.

[0438] 13.3 Overall Study Design

[0439] This is a Phase I, open-label, single-centre, randomised, 2-sequence, 3-period crossover study designed to assess the relative bioavailability of single 50 mg Fidrisertib dose administered as 1x50 mg capsule and 5x10 mg capsules and assess the effect of food on the PK of single 50 mg (5x10 mg) Fidrisertib dose in healthy adult participants.

[0440] This study will compare how the body absorbs and processes a 50 mg dose of study intervention Fidrisertib as in different strength capsules and how having food impacts these processes. It will include healthy male and female volunteers. This study is what is known as a “3-period crossover study”. In this type of clinical study each participant goes through three different Treatment Periods. In each period, they will receive the same dose of 50 mg test drug delivered as a different treatment. The order in which they receive these treatments is mixed up.

[0441] This study will include 3 treatment groups:

[0442] - Treatment A: Participants will receive five 10 mg intact capsules of Fidrisertib (5x10 mg) under fasting condition (overnight; for at least 10 hours).

[0443] - Treatment B: Participants will receive one 50 mg intact capsule of Fidrisertib (1x50 mg) under fasting condition (overnight; for at least 10 hours).

[0444] - Treatment C: Participants will receive five 10 mg intact capsules of Fidrisertib (5x10 mg) under fed (high-fat, high-calorie meal) conditions.

[0445] The study will have 2 parts:

[0446] Screening Period'. Consenting participants will undergo Screening assessments (within 28 days before dosing) to be qualified for the study according to the eligibility criteria. A total of 22 participants will be treated in order to have at least 20 evaluable89MEl\59654703.vlparticipants for the capsule strength comparison (Treatment A vs B). Screening, that may take up to 4 weeks (28 days) and requires at least 1 visit.

[0447] Treatment Period'. After a Screening visit, participants will be admitted to clinical research unit (CRU) the day before Period 1 dosing (Day -1). Treatment period, that may take up to 21 days. Participants will stay in the research centre during this part. Participants in the study will take Fidrisertib on Day 1, Day 9 and Day 17. The strength of Fidrisertib capsules, the number of capsules and whether it should be taken on an empty stomach or after high-fat, high-calorie meal will vary depending on the Treatment Period.

[0448] All the 22 participants will be randomised on Day 1 in a 1 : 1 ratio to one of the two-treatment sequences:

[0449] - Sequence 1 (A-B-C) (n=ll): Participants will receive Treatment A on Day 1, Treatment B on Day 9 and Treatment C on Day 17.

[0450] - Sequence 2 (B-A-C) (n=ll): Participants will receive Treatment B on Day 1, Treatment A on Day 9 and Treatment C on Day 17.

[0451] The dosing between the subsequent Treatment Periods are separated by an 8-day Washout Period.

[0452] Participants will be admitted to clinical research unit (CRU) the day before first dosing (i.e. on Day -1) and discharged from the CRU after completing the PK sample collection and the end of study (EOS) visit on Day 20 (i.e. 72-hour after last dosing).

[0453] Participants will have an overnight fasting (at least 10 hours) before dosing in Treatment A and B and before the high-fat, high-calorie meal consumption of Treatment C.

[0454] At each intake, Fidrisertib will be administered with approximately 240 mL water. Water is allowed as desired except for one hour before and one hour after dosing and no food is allowed for at least 4 hours postdose.

[0455] Participants will undergo all assessments and blood collection. Safety assessments including AE assessments, vital signs, electrocardiograms (ECGs), clinical laboratory assessments and physical examinations will be conducted for all enrolled participants during the conduct of the study.

[0456] The schema of the study design is presented in FIG. 9.90MEl\59654703.vl

[0457] 13.4 Number of Participants

[0458] The total study duration for a participant will be up to 48 days (approximately 7 weeks) including Screening (within 28 days before dosing) and 3 Treatment Periods (up to 21 days). A total of 22 participants will be treated in order to have at least 20 evaluable participants for the capsule combination comparison (Treatment A vs Treatment B).

[0459] If participants prematurely discontinue the study, additional participants may be enrolled after consultation with the sponsor and the principal investigaor to ensure that the required number of evaluable participants complete the study.

[0460] 13.5 Visit Frequency

[0461] After a Screening visit, participants will be admitted to CRU the day before dosing (i.e. Day -1) and discharged from the CRU 72-hour after last dosing (i.e. on Day 20). The EOS visit will be completed on Day 20 before discharge.

[0462] 13.6 Statistical Methods

[0463] Sample Size Determination: Bioequivalence between 10 mg and 50 mg Fidrisertib capsule strength will be concluded if 90% confidence intervals (CI) for both area under concentration-time curve (AUClast) and maximum observed plasma (peak) concentration (Cmax) geometric means ratios (GMRs) are included in the 80% to 125% bioequivalence range.

[0464] The coefficient of variation (CV) was assumed to be 20% based on the observed intra-participant CV for Fidrisertib ranging approximately from 7% to 24% for relevant PK parameters in previous studies. Provided that the ratio of the expected GMR (test / reference) is 0.95 and type I error of 0.05, a total sample size of 20 study participants should allow 83.5% power for the bioequivalence assessment. A total of 22 participants will be randomised (assuming a drop-out rate <10%) to achieve at least 20 participants for the bioequivalence assessment.

[0465] No formal sample size calculation was performed for the food effect evaluation as there was no formal research hypothesis being tested. The proposed design with 22 participants enrolled is considered sufficient to characterise food effect based on prior studies.

[0466] Primary Analysis: All PK concentration and parameters will be listed and summarised using summary statistics (including number of participants, arithmetic mean,91MEl\59654703.vlstandard deviation (SD), coefficient of variation (CV), median, minimum, maximum and geometric mean) for each treatment. The evaluation of the effect of capsule strength (Treatment A vs Treatment B) and food effect (Treatment A vs Treatment C) on the natural log (In)-transformed Fidrisertib PK parameters will be assessed using an analysis of variance (ANOVA). Geometric least square (LS) means (and 90% CI) will be calculated for the main PK parameter of interest (Cmax, AUCiast) and GMRs will be derived comparing each test treatment to the reference treatment. Similar evaluation will be done for AUGnf for the food effect evaluation only and provided as supportive endpoint.

[0467] Secondary Analyses: Safety evaluations will include AE and serious adverse event (SAE) reporting, change from baseline in ECGs, vital signs (temperature, respiratory rate, blood pressure (BP), pulse oximetry and heart rate), physical examination, body weight, laboratory parameters (haematology, biochemistry and urinalysis) and serum pregnancy tests for Women of Childbearing Potential (WOCBP). The safety analysis will be descriptive in nature.

[0468] Adverse event severity will be assessed and reported according to criteria defined in the protocol (mild, moderate, severe). All AEs will be coded according to the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) and will be classified by MedDRA preferred term and system organ class.92MEl\59654703.vl

Claims

CLAIMS1. A pharmaceutical composition comprising:(i) Compound (I) or a pharmaceutically acceptable salt thereof;Compound (I)(ii) intragranular excipient, wherein the intragranular excipient comprises of a filler, a disintegrant, and a lubricant; and(iii) extragranular excipient, wherein the extragranular excipient comprises of a disintegrant and a lubricant.

2. The pharmaceutical composition of claim 1, wherein the Compound (I) is a sesqui-succinate salt, wherein the molar ratio between Compound (I) and succinic acid is 1:1.5.

3. The pharmaceutical composition of claim 1 or 2, wherein the Compound (I) is 5-50% w / w (e.g., 8-12% w / w, 9-11% w / w, 38-42% w / w, or 39-41% w / w) of the total weight of the pharmaceutical composition.

4. The pharmaceutical composition of claim 3, wherein the Compound (I) is 10% w / w of the total weight of the pharmaceutical composition or 40% w / w of the total weight of the pharmaceutical composition.

5. The pharmaceutical composition of any one of claims 1-4, wherein the filler is 45-90% w / w e.g., 82-86% w / w or 52-56% w / w) of the total weight of the pharmaceutical composition.

6. The pharmaceutical composition of claim 5, wherein the filler is microcrystalline cellulose, for example, silicified microcrystalline cellulose (SMCC).93MEl\59654703.vl7. The pharmaceutical composition of any one of claims 1-6, wherein the disintegrant in the intragranular excipient is 1-4% w / w (e.g., 1.5-3% w / w or 2-3% w / w) of the total weight of the pharmaceutical composition.

8. The pharmaceutical composition of any one of claims 1-7, wherein the disintegrant in the extragranular excipient is 1-4% w / w (e.g., 1.5-3% w / w or 2-3% w / w) of the total weight of the pharmaceutical composition.

9. The pharmaceutical composition of any one of claims 1-8, wherein the disintegrant in the intragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition and wherein the disintegrant in the extragranular excipient is 2.5% w / w of the total weight of the pharmaceutical composition.

10. The pharmaceutical composition of any one of claims 1-9, wherein the disintegrant in the intragranular excipient and in the extragranular excipient is the same.

11. The pharmaceutical composition of any one of claims 1-10, wherein the disintegrant in the intragranular excipient and in the extragranular excipient is croscarmellose sodium.

12. The pharmaceutical composition of any one of claims 1-11, wherein the lubricant in the intragranular excipient is 0.1-1% w / w (e.g., 0.2-0.7% w / w or 0.4-0.6% w / w) of the total weight of the pharmaceutical composition.

13. The pharmaceutical composition of any one of claims 1-11, wherein the lubricant in the extragranular excipient is 0.1-1% w / w (e.g., 0.2-0.7% w / w or 0.4-0.6% w / w) of the total weight of the pharmaceutical composition.

14. The pharmaceutical composition of any one of claims 1-13, wherein the lubricant in the intragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition and wherein the lubricant in the extragranular excipient is 0.5% w / w of the total weight of the pharmaceutical composition.

15. The pharmaceutical composition of any one of claims 1-14, wherein the lubricant in the intragranular excipient and in the extragranular excipient is the same.

16. The pharmaceutical composition of any one of claims 1-15, wherein the lubricant in the intragranular excipient and in the extragranular excipient is magnesium stearate.94MEl\59654703.vl17. A pharmaceutical composition comprising:(i) 8-12% w / w (e.g., 9-11% w / w) of Compound (I) or a pharmaceutically acceptable salt thereof;Compound (I)(ii) intragranular excipient, wherein the intragranular excipient comprises of 82-86% w / w (e.g., 83-85% w / w) of a filler, 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant; and(iii) extragranular excipient, wherein the extragranular excipient comprises of 1.5-3% w / w e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w e.g., 0.4-0.6% w / w) of a lubricant.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises:(i) 10% w / w of Compound (I) or a pharmaceutically acceptable salt thereof; (ii) intragranular excipient, wherein the intragranular excipient comprises of 84% w / w of a filler, 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant; and(iii) extragranular excipient, wherein the extragranular excipient comprises of 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant.

19. A pharmaceutical composition comprising:(i) 38-42% w / w (e.g., 39-41% w / w) of Compound (I) or a pharmaceutically acceptable salt thereof;95MEl\59654703.vlCompound (I) (ii) intragranular excipient, wherein the intragranular excipient comprises of 52-56% w / w (e.g., 53-55% w / w) of a filler, 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant; and(iii) extragranular excipient, wherein the extragranular excipient comprises of 1.5-3% w / w (e.g., 2-3% w / w) of a disintegrant, and 0.2-0.7% w / w (e.g., 0.4-0.6% w / w) of a lubricant.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises:(i) 40% w / w of Compound (I) or a pharmaceutically acceptable salt thereof; (ii) intragranular excipient, wherein the intragranular excipient comprises of 54% w / w of a filler, 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant; and(iii) extragranular excipient, wherein the extragranular excipient comprises of 2.5% w / w of a disintegrant, and 0.5% w / w of a lubricant.

21. The pharmaceutical composition of any one of claims 17-20, whereinthe filler is microcrystalline cellulose, for example, silicified microcrystalline cellulose (SMCC);the disintegrant in the intragranular excipient and in the extragranular excipient is croscarmellose sodium; andthe lubricant in the intragranular excipient and in the extragranular excipient is magnesium stearate.96MEl\59654703.vl22. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises of an amount of 5 mg to 100 mg of Compound (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to 5 mg to 100 mg of Compound (I).

23. The pharmaceutical composition of any one of claims 1-22, wherein the pharmaceutical composition further comprises<(impurity 1)in an amount of 0.01-1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

24. The pharmaceutical composition of any one of claims 1-23, wherein the pharmaceutical composition further comprises(Impurity 2)in an amount of 0.01-1% w / w relative to the amount of Compound (I) in the pharmaceutical composition.

25. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition is prepared in an oral dosage form.

26. The pharmaceutical composition of claim 25, wherein the oral dosage form is a capsule or a tablet.97MEl\59654703.vl27. A capsule comprising a capsule shell and a capsule formulation, wherein the capsule formulation comprises the pharmaceutical composition of any one of claims 1-26.

28. The capsule of claim 27, wherein the capsule is an immediate release capsule.

29. The capsule of claim 27 or 28, wherein the capsule is a hydroxypropyl methylcellulose (HPMC) capsule.

30. The capsule of any one of claims 27-29, wherein the capsule shell comprises of titanium dioxide and hypromellose.

31. The capsule of any one of claims 27-30, wherein the size of the capsule is 1 or 4.

32. A method of treating or ameliorating Fibrodysplasia Ossificans Progressiva (FOP) in a subject, comprising administering to the subject in need thereof a pharmaceutical composition of any one of claims 1-26.98MEl\59654703.vl

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