Use of somatostatin modulators for the treatment of carcinoid syndrome - Patent Application 20070233633

Abstract

Described herein is the use of the somatostatin modulator 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile, or a pharma- ceutically acceptable salt thereof, in the treatment of carcinoid syndrome.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,551, filed January 11, 2022, which is incorporated by reference herein in its entirety.

[0002] Described herein are pharmaceutical compositions and medicaments comprising somatostatin modulators for use in the treatment of carcinoid syndrome. [Background technology]

[0003] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six subtypes of somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of specific subtypes of somatostatin receptors or combinations of them is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity. Carcinoid syndrome is usually caused by well-differentiated NETs, ​​nearly 90% of which express somatostatin receptors (SSTRs). Summary of the Invention

[0004] In one aspect, described herein is the use of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt (e.g., Compound A-monohydrochloride) or solvate thereof, in the treatment of carcinoid syndrome in humans. In some embodiments, Compound A, or a pharma- ceutically acceptable salt (e.g., Compound A-monohydrochloride) or solvate thereof, is administered orally. In some embodiments, Compound A, or a pharma- ceutically acceptable salt (e.g., Compound A-monohydrochloride) or solvate thereof, treats symptoms of carcinoid syndrome in humans.

[0005] In one aspect, described herein is a method of treating carcinoid syndrome in a human, the method comprising orally administering to a human having carcinoid syndrome a daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, sufficient to achieve a trough plasma concentration of Compound A of at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, or at least about 60 ng / mL. and / or at least 30 ng / mL, at least 31 ng / mL, at least 32 ng / mL, at least 33 ng / mL, at least 34 ng / mL, at least 35 ng / mL, at least 36 ng / mL, at least 37 ng / mL, at least 38 ng / mL, at least 39 ng / mL, at least 40 ng / mL, at least 41 ng / mL, at least 42 ng / mL, at least 43 ng / mL, at least 44 ng / mL, at least 45 ng / mL, at least 46 ng / mL, at least 47 ng / mL, at least 48 ng / mL, at least 49 ng / mL, at least 50 ng / mL, at least 51 ng / mL, at least 52 ng / mL, at least 53 ng / mL, at least 54 ng / mL, at least 55 ng / mL, at least 56 ng / mL, at least 57 ng / mL, at least 58 ng / mL, at least 59 ng / mL, at least 60 ng / mL, at least 61 ng / mL, at least 62 ng / mL, at least 63 ng / mL, at least 64 ng / mL, at least 65 ng / mL, at least 66 ng / mL, at least 67 ng / mL, at least 68 ng / mL, at least 69 ng / mL, at least 70 ng / mL, at least 71 ng / mL, at least 72 ng / mL, at least 73 ng / mL, at least 74 ng / mL, at least 75 ng / mL, at least 76 ng / mL, at least 77 ng / mL, at least 78 ng / mL, at least 79 ng / mL, at least 80 ng / 2. The method of claim 1, wherein the serum concentration of the serotonin-dependent agonist is at least 41 ng / mL, at least 42 ng / mL, at least 43 ng / mL, at least 44 ng / mL, at least 45 ng / mL, at least 46 ng / mL, at least 47 ng / mL, at least 48 ng / mL, at least 49 ng / mL, at least 50 ng / mL, at least 51 ng / mL, at least 52 ng / mL, at least 53 ng / mL, at least 54 ng / mL, at least 55 ng / mL, at least 56 ng / mL, at least 57 ng / mL, at least 58 ng / mL, at least 59 ng / mL, or at least 60 ng / mL.In some embodiments, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, corresponds to about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, or about 120 mg / day of Compound A-monohydrochloride. In some embodiments, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, corresponds to about 40 mg / day, about 80 mg / day, or about 120 mg / day of Compound A-monohydrochloride.

[0006] In another aspect, described herein is a method of treating carcinoid syndrome in a human with carcinoid syndrome, the method comprising orally administering an initial daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, to the human with carcinoid syndrome, determining a plasma trough concentration of Compound A in the human, and increasing the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, if the human does not have at least a threshold trough plasma concentration of Compound A. In some embodiments, the threshold trough plasma concentration of Compound A is at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, at least about 30 ng / mL, at least about 31 ng / mL, at least about 32 ng / mL, at least about 33 ng / mL, at least about 34 ng / mL, at least about 35 ng / mL, at least about 36 ng / mL, at least about 37 ng / mL, at least about 38 ng / mL, at least about 39 ng / mL, g / mL, at least about 40 ng / mL, at least about 41 ng / mL, at least about 42 ng / mL, at least about 43 ng / mL, at least about 44 ng / mL, at least about 45 ng / mL, at least about 46 ng / mL, at least about 47 ng / mL, at least about 48 ng / mL, at least about 49 ng / mL, at least about 50 ng / mL, at least about 51 ng / mL, at least about 52 ng / mL, at least about 53 ng / mL, at least about 54 ng / mL, at least about 55 ng / mL, at least about 56 ng / mL, at least about 57 ng / mL, at least about 58 ng / mL, at least about 59 ng / mL, or at least about 60 ng / mL.In some embodiments, the initial daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, comprises an amount equivalent to about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, or about 120 mg / day of Compound A-monohydrochloride. In some embodiments, increasing the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, comprises increasing the daily dose by an amount equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, or about 80 mg / day of Compound A-monohydrochloride.

[0007] In another aspect, a method of treating carcinoid syndrome in a human having carcinoid syndrome, comprising orally administering to the human having carcinoid syndrome an initial daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, equivalent to about 40 mg or about 80 mg of Compound A-monohydrochloride, for an initial period of time; determining whether the frequency of symptoms of carcinoid syndrome has decreased during the initial period of time; and if the frequency of symptoms of carcinoid syndrome has decreased during the initial period of time, and, if the frequency of the symptoms of carcinoid syndrome is not reduced during the initial period, continuing the daily amount of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, administered during the initial period with the same daily amount of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, or, if the frequency of the symptoms of carcinoid syndrome is not reduced during the initial period, increasing the daily amount of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, administered during the initial period by an incremental daily amount of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, and subsequently administering to the human the increased daily amount of Compound A, or a pharma- ceutically acceptable salt or solvate thereof.

[0008] In some embodiments, the symptoms of carcinoid syndrome include the severity of diarrhea, the frequency and intensity of flushing episodes, or a combination thereof. In some embodiments, the severity of diarrhea includes the number of bowel movements per day, the number of watery stools measured by the Bristol stool scale, or both. In some embodiments, the initial daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, or about 40 mg / day. In some embodiments, the initial daily dose of Compound A, or a pharma-ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day. In some embodiments, the increased daily dose of Compound A, or a pharma-ceutically acceptable salt or solvate thereof, is equivalent to about 80 mg or about 120 mg of Compound A-monohydrochloride.

[0009] In another aspect, described herein is a method of treating carcinoid syndrome in a human having carcinoid syndrome, comprising orally administering to the human having carcinoid syndrome a pharmaceutical composition comprising 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, wherein the human having carcinoid syndrome is treatment naive or the human having carcinoid syndrome has been previously treated with a somatostatin analog, and treatment with the somatostatin analog has ceased and a sufficient period of time has elapsed to allow the somatostatin analog to be washed out of the human, and wherein treatment is initiated at a daily dose equivalent to at least about 40 mg / day of Compound A-monohydrochloride.

[0010] In some embodiments, the human with carcinoid syndrome is treatment naive to somatostatin analog therapy and is actively symptomatic. In some embodiments, active symptomatic includes an average of ≧4 bowel movements (BM) / day or ≧2 flushing episodes over at least 2 days over a 2-week period. In some embodiments, carcinoid syndrome in a human previously treated with a somatostatin analog is symptomatically controlled with a somatostatin analog. In some embodiments, symptomatic control includes an average of <4 BM / day with ≦5 bowel movements (BM) / day and an average of ≦2 flushing episodes / day over a 2-week period. In some embodiments, the somatostatin analog is octreotide, lanreotide, or pasireotide. In some embodiments, treatment is initiated with a daily dose equivalent to about 40 mg / day or 80 mg / day of Compound A-monohydrochloride. In some embodiments, if breakthrough symptoms are observed, the daily dose is increased by an amount equivalent to a daily dose of about 40 mg / day of Compound A-monohydrochloride. In some embodiments, breakthrough symptoms include a flushing frequency of ≧4 bowel movements (BM) / day on two consecutive days or ≧3 flushing episodes / day on at least one day.

[0011] In another aspect, described herein is a method of treating carcinoid syndrome in a human having carcinoid syndrome, the method comprising orally administering a daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, to a human having carcinoid syndrome, wherein treating carcinoid syndrome comprises managing the symptoms of carcinoid syndrome.

[0012] In some embodiments, managing a symptom of carcinoid syndrome comprises reducing the frequency of daily bowel movements, diarrhea episodes, fecal incontinence episodes, skin flushing, or a combination thereof. In some embodiments, managing a symptom of carcinoid syndrome comprises treating diarrhea, flushing episodes, or both in a human. In some embodiments, the diarrhea is severe diarrhea. In some embodiments, managing a symptom of carcinoid syndrome comprises reducing the number of bowel movements (BM) to less than 4 BM / day on two consecutive days, reducing flushing frequency to less than 3 flushing episodes / day on at least one day, or both.

[0013] In some embodiments, the daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is equivalent to about 40 mg or about 80 mg of compound A-monohydrochloride. In some embodiments, if the severity of diarrhea, flushing episodes, or both does not decrease during treatment with a daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, the daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, or about 40 mg / day. In some embodiments, the daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day. In some embodiments, the daily dose of Compound A, or a pharma- ceutically acceptable salt thereof, is increased by an incremental daily dose equivalent to about 40 mg / day, and treatment is continued with a daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, equivalent to about 80 mg or about 120 mg of Compound A-monohydrochloride.

[0014] In another aspect, described herein is a method of treating severe diarrhea, flushing episodes, or both in a human with carcinoid syndrome, comprising orally administering to a human in need thereof an initial daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the initial daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, corresponds to about 40 mg or about 80 mg of Compound A-monohydrochloride. In some embodiments, if the severity of the severe diarrhea, flushing episodes, or both does not decrease in severity during treatment with a daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, the initial daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, or about 40 mg / day. In some embodiments, the initial daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day. In some embodiments, the daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day, and treatment is continued with a daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, equivalent to about 80 mg or about 120 mg of compound A-monohydrochloride.

[0015] In some embodiments, the severity of the severe diarrhea is measured by the number of stools per day, the number of watery stools as measured by the Bristol Stool Scale, or both. In some embodiments, the severity of the flushing episodes is assessed by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, plasma serotonin levels, or both.

[0016] In another aspect, described herein is a method of treating carcinoid syndrome in a human with carcinoid syndrome, comprising orally administering to the human with carcinoid syndrome a daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, wherein the human with carcinoid syndrome has previously been treated with a somatostathione analog, and treatment is initiated with a daily dose equivalent to about 40 mg / day of Compound A-monohydrochloride.

[0017] In another aspect, described herein is a method of treating carcinoid syndrome in a human with carcinoid syndrome, comprising orally administering to the human with carcinoid syndrome a daily dose of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharma- ceutically acceptable salt or solvate thereof, wherein the human with carcinoid syndrome has previously been treated with a somatostathione analog, and treatment is initiated with a daily dose equivalent to about 80 mg / day of Compound A-monohydrochloride.

[0018] In some embodiments, the human with carcinoid syndrome has responded to and tolerated treatment with a somatostathione analog. In some embodiments, the symptoms of carcinoid syndrome were previously controlled on depot monotherapy with octreotide or lanreotide. In some embodiments, the human with carcinoid syndrome is refractory to treatment with a somatostathione analog. In some embodiments, the somatostathione analog is octreotide, lanreotide, or pasireotide.

[0019] In some embodiments, treating carcinoid syndrome comprises managing a symptom of carcinoid syndrome. In some embodiments, managing a symptom of carcinoid syndrome comprises reducing the frequency of daily bowel movements, diarrhea episodes, episodes of fecal incontinence, skin flushing, or a combination thereof. In some embodiments, managing a symptom of carcinoid syndrome comprises treating diarrhea, flushing episodes, or both in a human. In some embodiments, the diarrhea is severe diarrhea. In some embodiments, the severity of diarrhea comprises the number of bowel movements per day, the number of watery stools as measured by the Bristol Stool Scale, or both. In some embodiments, managing a symptom of carcinoid syndrome comprises reducing the number of bowel movements (BM) to less than 4 BM / day for 2 consecutive days, reducing the flushing frequency to less than 3 flushing episodes / day for at least 1 day, or both.

[0020] In some embodiments, if the severity of diarrhea, flushing episodes, or both does not decrease during treatment with a daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, or about 40 mg / day.

[0021] In some embodiments, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day. In some embodiments, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an incremental daily dose equivalent to about 40 mg / day, and treatment is continued with a daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, equivalent to about 80 mg or about 120 mg of Compound A-monohydrochloride.

[0022] In some embodiments, the neuroendocrine tumors (NETs) in humans are grade 1 or grade 2. In some embodiments, the neuroendocrine tumors (NETs) in humans comprise a positive SSTR tumor status.

[0023] In some embodiments, the serum 5-hydroxyindoleacetic acid (5-HIAA) concentration in the human prior to treatment with Compound A is greater than about >280 μmol / L.

[0024] In some embodiments, if a human cannot tolerate Compound A, or a pharma- ceutically acceptable salt or solvate thereof, treatment with Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is discontinued.

[0025] In some embodiments, if a human does not tolerate Compound A, or a pharma- ceutically acceptable salt or solvate thereof, the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is reduced. In some embodiments, if a human does not tolerate Compound A, or a pharma- ceutically acceptable salt thereof, the daily dose of Compound A, or a pharma- ceutically acceptable salt thereof, is reduced by an amount equivalent to about 40 mg of Compound A-monohydrochloride.

[0026] In some embodiments, Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is administered in the form of one or more tablets comprising a spray-dried solid dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride thereof, one or more additional pharma- ceutically acceptable ingredients, and, optionally, one or more film coating agents.

[0027] In some embodiments, the spray-dried solid dispersion comprises (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, and (b) a pharma- ceutically acceptable polymer, wherein the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, is dispersed in a polymer matrix formed from the pharma- ceutically acceptable polymer.

[0028] In some embodiments, the one or more pharma- ceutically acceptable ingredients are selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, In some embodiments, the one or more pharma-ceutically acceptable ingredients include microcrystalline cellulose, mannitol, pregelatinized starch croscarmellose sodium crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silicon dioxide, or magnesium stearate.

[0029] In some embodiments, each tablet contains about 2% to about 20% by weight of the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof. In some embodiments, each tablet contains about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight of the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof.

[0030] In some embodiments, each tablet comprises about 10% to about 35% by weight of a polymer matrix formed from a pharma- ceutically acceptable polymer. In some embodiments, each tablet comprises about 2% to about 15% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, dispersed in the polymer matrix, is about 20% to about 35% by weight of the tablet, and about 40% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and, optionally, less than about 5% by weight of one or more film coating agents. In some embodiments, the tablet comprises about 20% to about 40% by weight of a spray-dried dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer; about 60% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, one or more glidants; and, optionally, less than about 5% by weight of one or more film coating agents.

[0031] In some embodiments, the spray-dried dispersion has a ratio of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) of about 15 / 85 to about 35 / 65.

[0032] In some embodiments, each tablet comprises about 20% to about 35% by weight spray-dried dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer, the 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, and a hydroxypropyl methylcellulose acetate sucrose dispersion. The spray-dried dispersion comprises a polymer matrix of polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA) in a ratio of about 15 / 85 to about 35 / 65, about 60% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, and optionally less than about 5% by weight of one or more film coating agents.

[0033] In some embodiments, each tablet comprises about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer, A spray-dried dispersion comprising a ratio of about 15 / 85 or about 35 / 65 of [difluoro-phenyl-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), and about 60% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more disintegration aids, one or more lubricants, one or more glidants, and optionally about 5% by weight of one or more film coating agents.

[0034] In some embodiments, the tablet comprises about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride or a solvate thereof dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer; The spray-dried dispersion comprises a ratio of about 15 / 85 or about 35 / 65 of hydroxy-benzonitrile monohydrochloride, or a solvate thereof, to a polymer matrix of hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), about 60% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silicon dioxide, and magnesium stearate, and optionally less than about 5% by weight of one or more film coating agents.

[0035] In some embodiments, each tablet contains about 10 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof. In some embodiments, each tablet contains about 10 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof. In some embodiments, each tablet contains about 20 mg of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof.

[0036] In some embodiments, one or more tablets are administered at least 30 minutes before a meal. In some embodiments, one or more tablets are administered at least 60 minutes before a meal. In some embodiments, one or more tablets are administered on an empty stomach with a glass of water at least 30 minutes before a meal.

[0037] In some embodiments, the bioavailability of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or a solvate thereof, is not substantially affected by the co-administration of a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid. In some embodiments, compound A, or a pharma- ceutically acceptable salt or solvate thereof, is not co-administered with a drug that changes the pH of the upper gastrointestinal (GI) tract. In some embodiments, when compound A, or a pharma- ceutically acceptable salt or solvate thereof, is co-administered with a drug that changes the pH of the upper gastrointestinal (GI) tract, the amount of the daily dose of compound A, or a pharma- ceutically acceptable salt or solvate thereof, administered is increased. In some embodiments, the amount of the daily dose of Compound A, or a pharma- ceutically acceptable salt or solvate thereof, is increased by an amount equivalent to about 10 mg / day, about 20 mg / day, about 30 mg / day, or about 40 mg / day of Compound A-monohydrochloride. In some embodiments, the drug that alters the pH of the upper gastrointestinal (GI) tract comprises a proton pump inhibitor, a histamine H2 receptor antagonist, or an antacid.

[0038] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it should be understood that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0039] [Figure 1] 1 shows dose proportionality observed in humans administered HMG capsule or SDD tablet formulations of Compound A-HCl. [Diagram 2] 1 shows the performance of HMG capsule and SDD tablet formulations of Compound A-HCl in dogs with or without pentagastrin pretreatment. [Diagram 3]1 shows hormone levels observed in the primary analysis population of the Acrobat Edge clinical trial. [Figure 4] 1 shows evidence of dose response observed in the Acrobat Edge and Evolve clinical trials. [Diagram 5] The estimated trough plasma paltusotine concentrations required for therapeutic efficacy and the predicted dose-proportionality effect for the SDD tablet formulation are shown. [Figure 6] 1 shows predicted trough plasma paltusotine concentrations in acromegalic patients taking a PPI in a 60 mg SDD tablet (fasted for 1 hour after dosing) compared with those in acromegalic patients not taking a PPI and those in a 40 mg HMG capsule formulation (fasted for 2 hours after dosing). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Somatostatin (SST), also known as somatotropin-releasing inhibitory factor (SRIF), was originally isolated as a 14 amino acid peptide from sheep hypothalamus (Brazeau et al., Science 179, 77-79, 1973). An N-terminally extended 28 amino acid peptide with similar biological activity to the 14 amino acid somatostatin was subsequently isolated (Pradayrol et al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980). SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). SSTs are produced by various cell types in the central nervous system (CNS) and intestine and have multiple functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other hormones that are antiproliferative.

[0041] These pleiotropic actions of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All receptors are members of the class A subgroup of the G protein-coupled receptor (GPCR) superfamily. The SST2A receptor is the most widely expressed subtype in human tumors and is the dominant receptor that suppresses GH secretion. Unless otherwise specified, the term SSTR2 refers to SSTR2a.

[0042] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or a combination thereof. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes, or a combination thereof, relative to other somatostatin receptor subtypes is useful in various clinical applications. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to other somatostatin receptor subtypes reduces undesirable side effects in various clinical applications.

[0043] For example, modulation of SSTR2 activity mediates the inhibition of growth hormone (GH) release from the anterior pituitary gland and glucagon release from the pancreas. SSTR2 is also involved in many other biological functions, including, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, selective SSTR2 modulators are used to treat acromegaly, enteric neuroendocrine tumors, pain, neuropathy, nephropathy, and inflammation, as well as retinopathies resulting from abnormal blood vessel growth.

[0044] In some embodiments, SSTR3 agonists inhibit insulin secretion. In some embodiments, SSTR4 agonists exhibit anti-inflammatory and anti-nociceptive effects. In some embodiments, SSTR5 agonists inhibit insulin secretion. In addition, SSTR5 is involved in regulating the release of growth hormone.

[0045] In some embodiments, the somatostatin modulator 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride (Compound A) has utility across a broad range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used to treat a variety of diseases or conditions, including, but not limited to, acromegaly, neuroendocrine tumors, retinopathy and other eye disorders, neuropathy, nephropathy, respiratory diseases, cancer, pain, neurodegenerative diseases, inflammatory diseases, and psychiatric and neurodegenerative disorders. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of acromegaly, neuroendocrine tumors, or both in a mammal. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of neuroendocrine tumors.

[0046] The compound 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride (Compound A), or a solvate thereof, is a selective non-peptide SST2 biased agonist suitable for oral administration to a mammal in need of treatment with a somatostatin modulator. In some embodiments, the mammal in need of treatment with a somatostatin modulator has been diagnosed with a neuroendocrine tumor (NET). In some embodiments, the mammal in need of treatment with a somatostatin modulator has been diagnosed with a well-differentiated NET. In some embodiments, the mammal in need of treatment with a somatostatin modulator has been diagnosed with carcinoid syndrome.

[0047] Neuroendocrine tumors (NETs) are a heterogeneous group of tumors arising from enterochromaffin cells that have characteristics of both nervous and hormone-producing cells. NETs are primarily characterized by their site of origin, grade and stage, and functional status. Most NETs are found in the gastrointestinal (GI) tract, but NETs can occur in other sites, including the lung. Within the GI tract, the most common sites are the small intestine, rectum, and colon, followed by the pancreas, stomach, and appendix.

[0048] Well-differentiated NETs are commonly referred to as "carcinoid tumors," a term commonly used by clinicians and patients. To unify the various approaches to tumor characterization and staging, thereby allowing for greater international consistency in reporting, the World Health Organization (WHO) classification system was developed that does not recognize "carcinoid tumors."

[0049] Grading schemes for neuroendocrine tumors (NETs) use mitotic counts, levels of the nuclear protein Ki-67 associated with cell proliferation, and assessment of necrosis. Both the WHO and the European Neuroendocrine Tumor Society (ENETS) incorporate mitotic counts and Ki-67 proliferation for classification of gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs).

[0050] Tumors are classified into one of three grades: ●G1: Well-differentiated histology, low grade ●G2: Well-differentiated histology, intermediate grade ●G3: Poorly differentiated histology, high grade

[0051] Staging for NETs is from the American Joint Committee on Cancer staging for more common cancers with the same site of origin, although other staging systems are also used.

[0052] Neuroendocrine tumors can be functional or non-functional, each with a distinct clinical profile. Functional NETs are characterized by symptoms caused by the biologically active compounds they secrete. Neuroendocrine tumors produce peptides and hormones that are responsible for the characteristic symptoms. Known products of well-differentiated NETs include amines (e.g., serotonin, 5-hydroxytryptophan (5-HTP), norepinephrine, dopamine, histamine), polypeptides (e.g., kallikrein, pancreatic polypeptide, bradykinin, motilin, somatostatin, vasoactive intestinal peptide, neuropeptide K, substance P, neurokinin A and B), and prostaglandins (e.g., prostaglandin E and F).

[0053] Functional nonpancreatic NETs release excess serotonin and other hormonally active products (including histamine, tachykinins, kallikreins, and prostaglandins), resulting in symptoms collectively referred to as carcinoid syndrome (Vinik A, Hughes M, Feliberti E, et al. Carcinoid Tumors Endotext[Internet].Copyright MDText.com, Inc; 2000-2021. 2018). These symptoms most commonly include cutaneous flushing (seen in 85% of cases), and recurrent watery diarrhea and seizures (seen in 75%-85% of cases). Carcinoid syndrome is biochemically confirmed by documentation of elevated serum serotonin or the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA).

[0054] Nonfunctioning NETs are not associated with abnormal hormone secretion, are difficult to detect, and often present with secondary nonspecific symptoms at advanced stages. Up to 50%-75% of patients with nonfunctioning small intestinal NETs present with metastatic disease at the time of diagnosis.

[0055] Most patients with CS have intestinal NETs with liver metastases that make surgical cure very difficult in most patients.

[0056] Patients with diarrhea from CS experience multiple watery loose stools per day, sometimes with considerable urgency, which can be very difficult to manage. In addition to CS, patients with NETs may have other causes of diarrhea. Depending on the location, NETs can cause symptoms similar to common conditions such as irritable bowel syndrome, Crohn's disease, peptic ulcer disease, gastritis, other digestive disorders, asthma, or pneumonia. For these reasons, NETs are often only diagnosed at an advanced stage and are commonly misdiagnosed. Diagnosis is based on histopathology, imaging, and circulating biomarkers.

[0057] Carcinoid syndrome biomarkers include plasma 5-HIAA and pancreastatin, serum chromogranin A, and serotonin. Pancreastatin is a disease state biomarker for neuroendocrine tumors and can be used alone or in combination with plasma 5HIAA, chromogranin A, and serotonin levels in the exploratory evaluation of the efficacy of paltusotine in subjects with carcinoid syndrome.

[0058] Because the symptoms of CS are often nonspecific, delayed diagnosis is common. If detected early, NETs are often curable with surgery, but unfortunately, most eventually recur within 5-10 years after surgery. Most NETs are diagnosed with progressive metastatic disease, at which point surgical cure is not possible and treatment is focused on symptom management.

[0059] Increased frequency of bowel movements, diarrhea, fecal incontinence, and skin flushing correlate with decreased quality of life (QoL). Compared to non-NET cancer populations and population norms, patients with NETs have higher rates of depression and cognitive impairment, decreased overall physical function, sleep disorders, fatigue, and anxiety.

[0060] Diarrhea has a particularly significant negative impact on physical, emotional, and social health. Interventions to improve individual daily activities and productivity may improve health-related QoL and reduce stress in patients with NETs.

[0061] Diarrhea in carcinoid syndrome is primarily a result of tumor secretion of serotonin. In healthy individuals, serotonin is found primarily in the GI tract, where most of it is secreted by enterochromaffin cells, the cellular source of NETs. Circulating serotonin originates exclusively from the GI tract and is an important component of normal intestinal function. Excess serotonin increases peristalsis and reduces water and electrolyte absorption, leading to diarrhea. Patients with CS show significantly increased serotonin plasma levels and, consequently, increased levels of the water-soluble urinary metabolite 5-HIAA. Reduced serotonin production, reflected in reduced levels of 5-HIAA, is associated with improved diarrhea in CS.

[0062] The diarrhea associated with CS tends to be watery after the first one or two bowel movements, and the frequency of bowel movements can range from 2-5 to more than 20 times a day, which can be very debilitating and detrimental to QoL. The presence of watery diarrhea associated with cutaneous flushing (especially when associated with evidence of elevated serotonin blood levels), and radiographic evidence of malignancy, is almost always diagnostic of diarrhea in CS.

[0063] Diarrhea is described as an increase in the frequency of bowel movements or a decrease in the consistency of stool, resulting in the passage of loose, watery stools. The severity of diarrhea is determined by the size and number of stools passed within a given period of time.

[0064] Severe diarrhea means having more than 10 watery stools per day (24 hours). Moderate diarrhea means having several diarrheal stools per day, but no more than 10. Mild diarrhea means having several diarrheal stools per day.

[0065] In some embodiments, improvement in clinical symptoms is measured as a change from baseline in stool consistency according to the Bristol Stool Scale, a medical aid designed to classify feces on a scale of 1 to 7 according to increasing wateriness.

[0066] In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-HCl), is used to improve quality of life (QoL) in humans with CS. In some embodiments, improving QoL includes managing symptoms of hormonal excess associated with CS. In some embodiments, improving QoL includes reducing the frequency of bowel movements, reducing the frequency of diarrhea, reducing the frequency of fecal incontinence, reducing the frequency of skin flushing, or a combination thereof.

[0067] Nearly 90% of well-differentiated NETs causing CS express somatostatin receptors (SSTRs), and 80% of patients with carcinoid syndrome respond to octreotide. The predominant target of octreotide is the somatostatin type 2 receptor (SST2). Thus, somatostatin receptor imaging may be useful to localize NETs not visualized on CT or MRI, provide a whole-body picture of tumor burden, and document tumor expression of somatostatin receptors prior to treatment with SRLs. Currently, SSTR imaging combined with CT (e.g., 111-infrared CT) is used in comparison to infrared CT imaging for increased spatial resolution and sensitivity for the detection of small tumors. 68 Ga-Dotatate and 68 Ga-Dotatoc, and 64 A positron emission tomography (PET) tracer for Cu-Dotatate is preferred.

[0068] Long-acting somatostatin receptor ligand (SRL) therapy is the primary treatment for carcinoid syndrome, but palliation of carcinoid syndrome symptoms at labeled doses is inadequate for many patients. Long-acting SRL therapy has also demonstrated efficacy in extending progression-free survival in patients with non-functioning, metastatic, well- or moderately differentiated enteropancreatic NETs. Long-acting SRL therapy may be associated with significant dose exposure variability relative to dose exposure variability associated with injection technique. For example, nurses at MD Anderson Cancer Center successfully delivered only 52% of 328 octreotide long-acting repetitive (LAR) depot injections into the intramuscular space as assessed by computed tomography (Boyd AE, DeFord LL, Mares JE, et al. Improving the success rate of gluteal intramuscular injections. Pancreas. 2013;42(5):878-882. Negative experiences with long-acting SRL therapy, particularly chronic injections of octreotide LAR, including pain or soreness at the injection site, have also been identified in patients with carcinoid syndrome (Adams JR, Ray D, Willmon R, Pulgar S, Dasari A. Living With Neuroendocrine Tumors: Assessment of Quality of Life Through a Mobile Application. JCO Clin Cancer Inform. 2019;3:1-10).

[0069] Diarrhea that develops after initiation of selective somatostatin analogue (SSA) therapy is common and is most commonly due to poorly controlled CS. In such situations, the diarrhea retains the characteristics of the diarrhea that occurred before the initiation of treatment, but occurs less frequently.

[0070] The use of SSAs approved by the US Food and Drug Administration (FDA) for the management and control of CS may contribute to the worsening of diarrhea. One of the more common adverse reactions of chronic use of SSAs is steatorrhea, with a frequency of 26%-65% for lanreotide (dose related) and 36%-61% for octreotide. Steatorrhea associated with SSAs results from the inhibition of diet-stimulated digestive enzymes from the pancreas.

[0071] Despite the use of SSA, patients may become refractory to treatment and experience progression of symptoms. Treatment options used in clinical practice for refractory CS include SSA dose escalation, interferon, and surgical, embolization, and radiation therapy. Despite these treatment strategies, patients are likely to continue to experience progression of diarrhea symptoms of CS and continue to have 4 or more bowel movements per day. In some embodiments, compound A, or a pharmacologic acceptable salt thereof, is used to treat CS in a human with CS, the human with CS being refractory to treatment with somatostatin analogs (SSAs).

[0072] Daily oral treatments such as Compound A may achieve higher drug concentrations in the liver, the most common source of vasoactive substances that cause symptoms of carcinoid syndrome. Compound A, an orally administered non-peptide somatostatin type 2 receptor (SST2) agonist, has the potential to improve treatment outcomes, achieving symptom control while eliminating painful injections.

[0073] Compound A is a somatostatin modulator that is useful in the therapeutic methods described herein.

[0074] Compound A As used herein, Compound A refers to 3-(4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl)-2-hydroxy-benzonitrile, having the chemical structure shown below.

[0075] [ka]

[0076] Compound A is also known as "paltusotine." Other names may be known or given to Compound A.

[0077] Compound A is a selective non-peptide SST2 biased agonist. In clinical studies, Compound A has been shown to have an estimated bioavailability of about 70% and an observed half-life of about 42 to about 50 hours. In some embodiments, Compound A is used to treat acromegaly, neuroendocrine tumors, or both. In some embodiments, Compound A is used to treat acromegaly. In some embodiments, Compound A is used to treat neuroendocrine tumors.

[0078] In some embodiments, the free base form of Compound A is incorporated into the formulations described herein. In some embodiments, Compound A is incorporated into the formulations described herein as a pharma- ceutically acceptable salt. In some embodiments, Compound A is incorporated into the formulations described herein as a pharma- ceutically acceptable solvate.

[0079] As used herein, "pharmacologically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition containing it.

[0080] The term "pharmaceutical acceptable salt" refers to the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J.Pharm.Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and more rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior, and salt-forming molecules can be in equilibrium with neutral forms, allowing for tailored passage across biological membranes.

[0081] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, a compound disclosed herein (i.e., in free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and glucoheptonic acid (G). These include, but are not limited to, luconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0082] In some embodiments, Compound A is incorporated into the formulations described herein as a pharma- ceutically acceptable salt form selected from Compound A hydrochloride and Compound A methanesulfonic acid. In some embodiments, the Compound A salt form is Compound A monohydrochloride. In some embodiments, the Compound A salt form is Compound A dihydrochloride. In some embodiments, the Compound A salt form is Compound A monomethanesulfonic acid. In some embodiments, the Compound A salt form is Compound A dimethanesulfonic acid.

[0083] In one embodiment, Compound A monohydrochloride (Compound A-HCl) is incorporated into the pharmaceutical compositions described herein. Compound A monohydrochloride (Compound A-HCl), also known as 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride and paltusotine monohydrochloride, has the following structure:

[0084] [ka]

[0085] In some embodiments, the Compound A salt form is amorphous. In some embodiments, the Compound A monohydrochloride salt is amorphous.

[0086] In some embodiments, the Compound A salt form is crystalline. In some embodiments, the Compound A monohydrochloride salt is crystalline.

[0087] It should be understood that the reference to pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amount of solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0088] Therapeutic agents that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. Such government regulatory guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as, for example, the amount of residual solvents in the final product. Preferred solvents are those that are suitable for use in GMP facilities and are consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0089] Solvents are divided into three classes: Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that have limited use during the manufacture of therapeutic agents. Class 3 solvents are solvents that have low toxicity potential and pose lower risks to human health. Data for Class 3 solvents show low toxicity in acute or short-term studies and negative genotoxicity studies.

[0090] Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0091] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0092] Class 3 solvents, which possess low toxicity, include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0093] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the APIs. In most cases, the solvents are not completely removed by practical manufacturing techniques. The appropriate selection of solvents for the synthesis of APIs can enhance the yield or determine properties such as crystal morphology, purity, and solubility. Thus, the solvent is an important parameter in the synthesis process.

[0094] In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of a Class 2 or Class 3 solvent. In some embodiments, the composition comprising Compound A-HCl comprises a residual amount of a solvent selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, methanol, acetone, dimethylformamide, tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, toluene, and ethanol.

[0095] Unless otherwise stated, the following terms used in this application have the definitions set forth below. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0096] The term "modulate," as used herein, means to directly or indirectly interact with a target so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0097] The term "modulator" as used herein refers to a molecule that directly or indirectly interacts with a target. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0098] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes of administration. Those of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0099] Terms such as "concomitant administration," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0100] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered that relieves to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to bring about a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0101] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong either in potency or duration of a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, in either potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0102] The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, e.g., a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an auxiliary agent are administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an auxiliary agent are administered to a patient as separate entities, either simultaneously, contemporaneously, or sequentially, without specific intervening time restrictions, such administration providing effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0103] The terms "article of manufacture" and "kit" are used synonymously.

[0104] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs, and the like. In one aspect, the mammal is a human.

[0105] The terms "treat," "treating," or "treatment," as used herein, include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, reducing pathology caused by a disease or condition, or halting the symptoms of a disease or condition, either prophylactically and / or therapeutically.

[0106] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Appropriate formulations depend on the selected route of administration. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0107] In some embodiments, the compounds described herein are administered alone or in a pharmaceutical composition in combination with a pharma- ceutically acceptable carrier, excipient, or diluent. The administration of the compounds and compositions described herein can be performed by any method that allows the compound to be delivered to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient.

[0108] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, or as a powder or granules.

[0109] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface active agent or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide sustained or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets for identification or to characterize different combinations of doses of the active compound.

[0110] Conventional techniques for producing solid oral dosage forms include, but are not limited to, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, or (5) wet granulation. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spray, tableting, extrusion, etc.

[0111] It should be understood that in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0112] Provided herein is a tablet comprising Compound A, or a pharma- ceutically acceptable salt thereof. In some embodiments, the tablet comprises Compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer, and one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants, and optionally one or more film coating agents.

[0113] In some embodiments, described herein are spray-dried solid dispersions comprising (a) Compound A-HCl, or a solvate thereof, and (b) a pharma- ceutically acceptable polymer, wherein Compound A-HCl, or a solvate thereof, is dispersed in a polymer matrix formed from the pharma- ceutically acceptable polymer.

[0114] Described herein, in some embodiments, are tablets prepared with the spray-dried solid dispersions described herein.

[0115] Spray-dried solid dispersion (SDD) The amorphous state for most small molecule drugs is thermodynamically unstable and kinetically unstable unless the glass transition temperature (Tg) is sufficiently high. However, the amorphous state can be stabilized by dilution of the drug in an excipient matrix. When amorphous molecules are dispersed in a matrix of high Tg, the low molecular mobility provides a diffusion barrier that inhibits the molecular mobility required for phase separation upon storage. Phase separation into drug-rich domains forms crystalline nuclei and is ultimately a precursor to extensive crystallization, resulting in loss of solubility benefits. In some embodiments, pharma- ceutically acceptable polymers for use in the preparation of spray-dried solid dispersions are polymers with high Tg. When the active pharmaceutical ingredient (API) and excipients are not thermodynamically miscible with each other in the solid state, the spray-dried dispersion (SDD) is formulated such that the resulting Tg of the mixture, including adsorbed water, is at least 10°C to 20°C higher than typical storage conditions. Additionally, consideration must be given to moisture uptake during storage, either through the selection of a non-hygroscopic polymer or packaging format, since adsorbed water plasticizes the dispersion and lowers the Tg.

[0116] In some embodiments, Compound A-HCl or a solvate thereof in the spray-dried solid dispersions described herein is substantially amorphous.

[0117] In some embodiments, the pharma- ceutically acceptable polymer comprises a polymer of cellulose, vinyl alcohol, vinyl acetate, propylene glycol, pyrrolidone, vinylpyrrolidone, oxyethylene, oxypropylene, methacrylic acid, methyl methacrylate, ethylene glycol, ethylene glycol glyceride, ethylene oxide, propylene oxide, 2-ethyl-2-oxazoline, maleic acid, methyl vinyl ether, vinyl caprolactam, or combinations thereof, optionally functionalized with any combination of alkyl ethers, alkyl esters, phthalate esters.

[0118] In some embodiments, the pharma- ceutically acceptable polymer is hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, cellulose acetate poly(maleic acid / methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-alpha tocopheryl polyethylene glycol 1000 succinate, or combinations thereof.

[0119] In some embodiments, the spray-dried dispersion further comprises a dispersion polymer selected from hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate; HPMCAS, e.g., HPMCAS-H, HPMCAS-L, or HPMCAS-M), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA), polyethylene polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof.

[0120] HPMCAS is a cellulosic polymer with four types of semi-randomly substituted substituents on the hydroxyls: methoxy, hydroxypropyloxy, acetate, and succinate. The polymer is available in three grades: L, M, and H, based on the content (by weight) of acetyl and succinoyl groups in the HPMCAS molecule. Grade L: 5-9% by weight acetate, 14-18% by weight succinate, 20-24% by weight methoxy, 5-9% by weight hydroxypropyloxy. Grade M: 7-11% by weight acetate, 10-14% by weight succinate, 21-25% by weight methoxy, 5-9% by weight hydroxypropyloxy. Grade H: 10-14% by weight acetate, 4-8% by weight succinate, 22-26% by weight methoxy, 6-10% by weight hydroxypropyloxy.

[0121] In some embodiments, the pharma- ceutically acceptable polymer is selected from PVP / VA64, PVP30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, poly(methacrylic acid-co-methyl methacrylate) (PMMAMA, or trade name Eudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus.

[0122] In some embodiments, the pharma- ceutically acceptable polymer is selected from PVP / VA64 and HPMCAS-M. In some embodiments, the pharma- ceutically acceptable polymer is PVP / VA64. In some embodiments, the pharma- ceutically acceptable polymer is HPMCAS-M.

[0123] In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:10 to about 10:1. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:1 to about 1:10. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:3 to about 1:8. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4 to about 1:7. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4 to about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:5 to about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:10. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:9. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:8. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:7. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:6. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:5. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:4. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:3. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:2. In some embodiments, the weight ratio of Compound A-HCl or a solvate thereof to the dispersion polymer is about 1:1.

[0124] In some embodiments, the spray-dried solid dispersion comprises at least 5% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 10% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 15% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises at least 25% by weight of Compound A-HCl or a solvate thereof. The % amounts are calculated based on the free base, i.e., Compound A.

[0125] In some embodiments, the spray-dried solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 15% Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% Compound A-HCl or a solvate thereof. The % amount is calculated based on the free base, i.e., Compound A.

[0126] In some embodiments, the spray-dried solid dispersion comprises about 5% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 6% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 7% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 8% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 9% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 10% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 11% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 12% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 13% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 14% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 15% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 16% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 17% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 18% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 19% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 21% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 22% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 23% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 24% by weight of Compound A-HCl or a solvate thereof.In some embodiments, the spray-dried solid dispersion comprises about 25% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 26% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 27% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 28% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 29% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 30% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 31% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 32% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 33% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 34% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% by weight of Compound A-HCl or a solvate thereof. The % amount is calculated based on the free base, i.e., Compound A.

[0127] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is present in a detectable amount. In some embodiments, the spray-dried solid dispersion does not comprise a non-aqueous solvent.

[0128] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, and mixtures thereof. In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of methanol, acetone, and mixtures thereof. In some embodiments, the spray-dried solid dispersion further comprises methanol.

[0129] tablet In one aspect, described herein is a tablet comprising compound A-HCl, or a solvate thereof, dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer, and one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, and one or more glidants, and, optionally, one or more film coating agents.

[0130] In some embodiments, the Compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharma- ceutically acceptable polymer is a spray-dried solid dispersion as described herein.

[0131] In some embodiments, the tablet contains about 2% to about 20% by weight of Compound A-HCl or a solvate thereof. In some embodiments, the tablet contains about 2% to about 15% by weight of Compound A-HCl or a solvate thereof.

[0132] In some embodiments, the tablet comprises about 10% to about 30% by weight of a polymer matrix formed from a pharma- ceutically acceptable polymer, hi some embodiments, the tablet comprises about 20% to about 35% by weight of a polymer matrix formed from a pharma- ceutically acceptable polymer.

[0133] In some embodiments, the tablet comprises about 2% to about 10% by weight of Compound A-HCl or a solvate thereof dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharma- ceutically acceptable polymer.

[0134] In some embodiments, the tablet comprises about 2% to about 10% by weight of compound A-HCl, or a solvate thereof, dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharma- ceutically acceptable polymer, and about 40% to about 80% by weight of one or more pharma- ceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, and, optionally, less than about 5% by weight of one or more film coating agents.

[0135] In some embodiments, the additional excipients in the tablet, in addition to the spray-dried solid dispersion, include one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants, or any combination thereof. In some embodiments, the additional excipients in the tablet, in addition to the spray-dried solid dispersion, include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate.

[0136] In some embodiments, the tablet comprises one or more fillers / binders / diluents selected from cellulose (such as microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, and methylcellulose), starch, gelatin, sugars (such as sucrose, glucose, dextrose, mannitol, and lactose), natural and synthetic gums (such as acacia, sodium alginate, panwar gum, and ghatti gum), polyvinylpyrrolidinone, polyethylene glycol, waxes, and any combination thereof. In some embodiments, the tablet comprises microcrystalline cellulose and mannitol.

[0137] In some embodiments, one or more fillers / binders / diluents in the tablets described herein comprise about 20% to about 80% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in the tablets described herein comprise about 40% to about 65% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in the tablets described herein comprise about 50% to about 65% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in the tablets described herein comprise about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the total tablet weight. In some embodiments, one or more fillers / binders / diluents in the tablets described herein comprise about 58% by weight of the total tablet weight. In some embodiments, less than 70%, less than 65%, less than 60%, less than 55%, or less than 50% by weight of the total tablet weight comprises one or more fillers / binders / diluents. In some embodiments, less than 60% by weight of the total tablet weight comprises one or more fillers / binders / diluents.

[0138] In some embodiments, the tablet comprises one or more disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethylcellulose, and any combination thereof. In some embodiments, the tablet comprises crospovidone.

[0139] In some embodiments, one or more disintegrants in the tablets described herein comprise about 2% to about 30% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 5% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 10% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein comprise about 15% by weight of the total tablet weight. In some embodiments, less than 20% by weight of the total tablet weight comprises one or more disintegrants.

[0140] In some embodiments, the tablet comprises one or more lubricants selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, and any combination thereof. In some embodiments, the tablet comprises magnesium stearate.

[0141] In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 5% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1% to about 1% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.5% by weight of the total tablet weight. In some embodiments, less than 2% by weight of the total tablet weight comprises one or more lubricants. In some embodiments, less than 1% by weight of the total tablet weight comprises one or more lubricants.

[0142] In some embodiments, the tablet contains one or more glidants. Glidants are substances added to powders to improve their flowability. Examples of glidants include magnesium stearate, colloidal silicon dioxide, starch, and talc. In some embodiments, the tablet contains colloidal silicon dioxide.

[0143] In some embodiments, one or more lubricants in a tablet described herein comprises about 0.1% to about 5% by weight of the total tablet weight. In some embodiments, one or more lubricants in a tablet described herein comprises about 0.1% to about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in a tablet described herein comprises about 0.5% to about 1.5% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% by weight of the total tablet weight. In some embodiments, one or more lubricants in the tablets described herein comprise about 1% by weight of the total tablet weight. In some embodiments, less than 2% by weight of the total tablet weight comprises one or more lubricants. In some embodiments, less than 1.5% by weight of the total tablet weight comprises one or more lubricants.

[0144] Additional excipients In some embodiments, the tablets described herein contain additional excipients, including, but not limited to, buffering agents, glidants, preservatives, and coloring agents. Additional excipients such as bulking agents, isotonicity agents, and chelating agents are within the scope of the embodiments.

[0145] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, mixtures of amino acids and buffers, mixtures of aluminum glycinate and buffers, mixtures of acid salts of amino acids and buffers, and mixtures of alkali salts of amino acids and buffers. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0146] In some embodiments, the tablets described herein contain a preservative. Preservatives include antibacterial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[0147] In some embodiments, the tablets described herein contain a coloring agent for the identity of the resulting liquid form and / or for aesthetic purposes. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and mixtures thereof.

[0148] Additional excipients are contemplated in tablet embodiments. These additional excipients are selected based on function and compatibility with the tablet compositions described herein and can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975), Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980), and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.

[0149] In a further embodiment, the tablets described herein are coated tablets, such as enteric coated tablets, sugar coated tablets, or film coated tablets.

[0150] In one embodiment, the individual unit dosages also include a film coating, which disintegrates upon oral ingestion or upon contact with diluent, hi one embodiment, these formulations are manufactured by conventional techniques.

[0151] Compressed tablets are solid dosage forms prepared by compressing the bulk blend formulation described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings including Opadry® typically range from about 1% to about 5% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0152] Provided herein is a film-coated tablet formulation that includes a combination of an active ingredient (e.g., Compound A-HCl) and one or more tableting excipients to form a tablet core and then coat the core. The tablet core is produced using a conventional tableting process, followed by compression and coating.

[0153] An enteric coating is a coating that resists the action of stomach acid but dissolves or disintegrates in the intestine.

[0154] In one embodiment, the oral solid dosage form disclosed herein comprises an enteric coating.The enteric coating comprises one or more of the following: cellulose acetate phthalate; methyl acrylate-methacrylic acid copolymer; cellulose acetate succinate; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate); polyvinyl acetate phthalate (PVAP); methyl methacrylate-methacrylic acid copolymer; methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate versions); styrene maleic acid copolymer; polymethacrylic acid / acrylic acid copolymer; hydroxyethyl ethylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate tetrahydrophthalate; acrylic resin; shellac.

[0155] Enteric coating is a coating applied to tablets, pills, capsules, pellets, beads, granules, particles, etc., that keeps them from dissolving until they reach the small intestine.

[0156] Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up unpleasant tastes or odors and in protecting the tablets from oxidation.

[0157] Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by two or more compression cycles, including layered tablets, and press-coated or dry-coated tablets. In some embodiments, tablets are coated with a water-soluble, pH-independent film coating (e.g., Opadry products) that allows for immediate disintegration for rapid active release.

[0158] Dosage in tablets In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 100 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 80 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 5 mg to about 60 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 10 mg to about 40 mg.

[0159] In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 10 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 20 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 30 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 40 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 50 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 60 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 70 mg. In some embodiments, the amount of Compound A-HCl or a solvate thereof in the tablet is about 80 mg.

[0160] Methods of Administration and Treatment Regimens In one embodiment, the pharmaceutical compositions disclosed herein are used as medicaments for the treatment of carcinoid syndrome in a mammal. The method for treating carcinoid syndrome in a mammal involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising Compound A, or a pharma- ceutical acceptable salt thereof.

[0161] Long-acting somatostatin receptor ligands (LA-SRLs) are first-line therapy for neuroendocrine tumor (NET) syndromes, including acromegaly and carcinoid syndrome (CS). In the treatment of acromegaly, two phase 2 studies suggested that patients treated with SRLs could be switched to once-daily dosing of Compound A (see Acrombat EDGE (NCT03789656) and Acrobat EVOLVE (NCT03792555)). Dose and exposure response data from EDGE, EVOLVE, and in phase 1 studies in healthy volunteers suggest that a dose range of 40 mg to 60 mg once daily provides consistent IGF-1 suppression in patients with acromegaly.

[0162] In contrast to the effective dose of Compound A for acromegaly patients, CS patients may require higher doses due to the malabsorption associated with CS and potential differences in the clearance and volume of distribution of Compound A between CS and acromegaly patients. In addition, the pharmacokinetics (clearance and volume of distribution) of Compound A may be different in subjects with carcinoid syndrome compared to acromegaly due to differences in liver and body composition that affect metabolic activity.

[0163] The starting doses of approved long-acting SRL therapies for carcinoid syndrome are equal to or greater than the starting doses for acromegaly (Sandostatin LAR Prescribing Information, 2021; Somatuline Prescribing Information, 2018). The starting dose equivalent to 40 mg of Compound A-mono-HCl is expected to be a well-tolerated starting dose for subjects with carcinoid syndrome, as this dose has been well tolerated in studies of subjects with acromegaly.

[0164] In general, doses used to treat CS in adult humans typically range from about 40 mg to about 120 mg per day of Compound A. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0165] In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride salt) is administered once daily. In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride salt) is administered twice daily.

[0166] In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) is orally administered to a human on a continuous dosing schedule. In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) is administered to a human on a continuous daily dosing schedule.

[0167] The term "continuous dosing schedule" refers to the administration of a particular therapeutic agent on a regular basis. In some embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent on a regular basis without any drug-free period from the particular therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent in cycles. In some other embodiments, a continuous dosing schedule refers to the administration of a particular therapeutic agent in a cycle of drug administration followed by a drug-free period from the particular therapeutic agent (e.g., a washout period or other such period during which the drug is not administered). For example, in some embodiments, the therapeutic agent is administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, every other day, every third day, every fourth day, daily for one week followed by one week of no therapeutic agent, daily for two weeks followed by one or two weeks of no therapeutic agent, daily for three weeks followed by one, two, or three weeks of no therapeutic agent, daily for four weeks followed by one, two, three, or four weeks of no therapeutic agent, weekly therapeutic agent followed by one week of no therapeutic agent, or biweekly therapeutic agent followed by two weeks of no therapeutic agent. In some embodiments, the daily administration is once a day. In some embodiments, the daily administration is twice a day. In some embodiments, the daily administration is three times a day.

[0168] The term "continuous daily dosing schedule" refers to daily administration of a particular therapeutic agent at approximately the same time each day. In some embodiments, the daily administration is once per day.

[0169] In certain embodiments where no improvement in the state of the disease or condition in humans is observed, the daily dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride), is increased. In some embodiments, the frequency of administration is increased by repeating higher C max In some embodiments, the frequency of administration is increased to provide sustained or more regular exposure to Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride). In some embodiments, the frequency of administration is increased to provide sustained or more regular exposure to Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride). In some embodiments, the frequency of administration is increased to provide sustained or more regular exposure to Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride). max The concentration of Compound A in the blood is increased to provide a sustained or more regular exposure to Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride).

[0170] In general, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human with CS will be in the range of about 20 mg / day to about 160 mg / day, or about 40 mg / day to about 1200 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human will be about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, or about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, or about 160 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 40 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 50 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 60 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 70 mg / day. In other embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 80 mg / day. In some embodiments, the dosage is administered once per day. In some embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 90 mg / day. In some embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 100 mg / day. In some embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 110 mg / day.In some embodiments, a suitable dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) for administration to a human would be about 120 mg / day. In some embodiments, the above amounts refer to the amount of Compound A-monohydrochloride.

[0171] In some embodiments, the daily dosage or amount of active agent in the dosage form is lower or higher than the ranges set forth herein, based on several variables for the individual treatment regime. In various embodiments, the daily and unit dosage amounts vary depending on several variables, including, but not limited to, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, the identity of the person (e.g., body weight), and the particular additional therapeutic agent being administered (if any), and the judgment of the physician.

[0172] Symptom-Based Treatment of Carcinoid Syndrome In clinical practice, the primary therapeutic goals for the treatment of CS include managing symptoms of hormonal excess, such as bowel movement frequency, diarrhea, fecal incontinence, and skin flushing. In some embodiments, the therapeutic goal is to reduce the frequency of daily bowel movements, diarrhea episodes, fecal incontinence episodes, skin flushing, or a combination thereof.

[0173] Somatostatin inhibits hormone secretion and the growth of NETs. Therefore, metabolically stable SSAs are the cornerstone of treatment for patients with NETs due to their inhibition of secretion of multiple hormones and reduced disease progression rates. Guidelines recommend the use of SSAs (octreotide or lanreotide) as initial first-line treatment in patients with CS, and there is evidence that both long-acting and short-acting SSAs effectively control symptoms. Some patients with severe symptoms may require initial concomitant use of short-acting octreotide until the effects of the long-acting formulation are fully effective.

[0174] In some embodiments, compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) is administered via a titration schedule. In some embodiments, compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) is administered via a titration schedule to minimize adverse events associated with administration of compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride). In some embodiments, titration with compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) allows the subject to tolerate compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride), minimize adverse events associated with administration of compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride), maximize the likelihood that an optimized dose of compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) will be administered and tolerated by the subject, or a combination thereof. In some embodiments, titration includes upward titration. In some embodiments, uptitration is necessary to manage one or more symptoms of CS.

[0175] The possibility of up-titration with Compound A was based on a multicenter retrospective chart review, with the most common initial dose of octreotide LAR depot (40 mg to 60 mg every 4 weeks) then titrated up to 160 mg every 4 weeks (Strosberg JR et al., Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart study. The Oncologist. 2014, 19:930-936).

[0176] In some embodiments, treatment with Compound A, or a pharma- ceutically acceptable salt thereof (eg, Compound A-monohydrochloride salt), does not require titration.

[0177] As used herein, a subject is said to "tolerate" a dose of a compound if administration of that dose to the subject does not result in an unacceptable adverse event or an unacceptable combination of adverse events. Those skilled in the art will understand that tolerance is a subjective measure, and what may be acceptable to one patient may not be acceptable to a different patient. For example, one subject may not be able to tolerate headaches, whereas a second subject may be able to tolerate mild headaches but not moderate headaches, whereas a third subject may tolerate moderate headaches but not severe headaches. In some embodiments, a patient may not be able to tolerate treatment with an injectable somatostatin analogue due to injection site rejection.

[0178] As used herein, an "adverse event" is an adverse medical occurrence associated with treatment with Compound A, or a pharma- ceutically acceptable salt thereof. In some embodiments, the adverse event is headache, fatigue, diarrhea, pain, or a combination thereof.

[0179] As used herein, an "optimized dose" refers to a therapeutic dose optimized for the needs of a particular subject, and is the highest dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride), that elicits a biological or medicinal response in the subject that corresponds to the required dose of Compound A, is desired, and is tolerable by the subject, as determined by the subject, optionally in consultation with the subject's medical professional.

[0180] As used herein, "up-titration" of a compound refers to increasing the amount of the compound until the subject no longer tolerates the increased amount. Up-titration can be accomplished in one or more dose increments, which may be the same or different. In some embodiments, the method comprises administering Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) at an initial dose once a day for an initial period, followed by up-titrating to a higher dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) once a day thereafter. In some embodiments, the initial period comprises 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. In some embodiments, this cycle is repeated until an optimized dose is achieved.

[0181] In some embodiments, the titration method includes administering an initial dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) once a day for about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, followed by up-titrating to a higher dose of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) once a day thereafter. In some embodiments, this cycle is repeated until an optimized dose is achieved. In some embodiments, dose adjustments are made weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, dose adjustments are made and / or repeated to achieve consistent CS symptom management.

[0182] In some embodiments, the method of titration includes administering compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) at an initial dose once a day for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by up-titrating to a higher dose of compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) once a day thereafter. In some embodiments, this cycle is repeated until an optimized dose is achieved. In some embodiments, the method includes administering 40 mg of compound A-monohydrochloride once a day for a period of time, followed by up-titrating to about 80 mg of compound A-monohydrochloride once a day thereafter. In some embodiments, the method comprises administering 40 mg of compound A-monohydrochloride once a day for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by up-titrating to about 80 mg of compound A-monohydrochloride once a day thereafter. In some embodiments, the method comprises administering 80 mg of compound A-monohydrochloride once a day for a period of time, followed by up-titrating to about 120 mg of compound A-monohydrochloride once a day thereafter. In some embodiments, the method comprises administering 80 mg of compound A-monohydrochloride once a day for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks, followed by up-titrating to about 120 mg of compound A-monohydrochloride once a day thereafter.

[0183] In some embodiments, the method of titration includes an upward titration, or a downward titration, followed by an optional further upward titration of Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride).

[0184] In some embodiments, the titration schedule comprises administering Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride) at an initial dose for about 1, 2, 3, or 4 weeks, and increasing the dose by an amount equal to an increment value, provided that the patient tolerates the initial dose. In some embodiments, the increment value for increasing the daily dose corresponds to about 40 mg / day of Compound A-monohydrochloride.

[0185] In some embodiments, the initial dose corresponds to about 40 mg or about 80 mg of Compound A-monohydrochloride. In some embodiments, the initial dose corresponds to about 40 mg of Compound A-monohydrochloride. In some embodiments, the initial dose corresponds to about 80 mg of Compound A-monohydrochloride. In some embodiments, it is inappropriate to increase the daily dose of Compound A-monohydrochloride by 40 mg if CS symptoms are inadequately controlled at the initial daily dose.

[0186] In some embodiments, the titration schedule further comprises administering Compound A, or a pharma- ceutically acceptable salt thereof, at an increased dose for about 1 week, 2 weeks, 3 weeks, or 4 weeks, and further increasing the dose by an increment value, provided that the patient tolerates the increased dose. In some embodiments, the increment value for increasing the daily dose corresponds to about 40 mg / day of Compound A-monohydrochloride.

[0187] In some embodiments, the titration schedule is repeated until an optimized dose is obtained that provides therapeutic efficacy while minimizing side effects from Compound A treatment.

[0188] In some embodiments, treatment with Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride), does not require titration. In some embodiments, the optimized dose is administered without titration.

[0189] In some embodiments, the optimized dose corresponds to about 40 mg / day to about 160 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day, about 140 mg / day, or about 160 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 40 mg / day, about 80 mg / day, about 120 mg / day, or about 160 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 40 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 80 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 120 mg / day of compound A-monohydrochloride. In some embodiments, the optimized dose corresponds to about 160 mg / day of compound A-monohydrochloride.

[0190] In a Phase 2 clinical trial of acromegaly patients previously treated with LA-SRL, evaluation of steady-state IGF-1 change as a function of dose of Compound A-monohydrochloride showed that 10 and 20 mg per day resulted in IGF-1 levels above baseline, where baseline was the IGF-1 measured at the last LA-SRL injection. Switching to Compound A-monohydrochloride occurred 4 weeks after the last LA-SRL injection. Doses of 30 and 40 mg per day resulted in nearly zero change from baseline, indicating that doses of 30 and 40 mg per day were equally effective as previous monotherapy with injected LA-SRL in suppressing IGF-1.

[0191] A dose-response relationship was observed when assessing the magnitude of IGF-1 elevation during washout of Compound A in these acromegaly studies. Exposure-response modeling estimated the Compound A concentration at which 80% of the maximum pharmacological response (EC80) was achieved. In some embodiments, administering the SDD tablets described herein in an amount of about 30 mg / day to about 60 mg / day of Compound A-monohydrochloride provides daily trough concentrations that exceed the EC80, resulting in consistent IGF-1 suppression in patients with acromegaly.

[0192] In some embodiments, the trough concentration of compound A required to provide a therapeutic effect equivalent to that of long-acting SRL in CS patients is about 20 ng / mL to about 150 ng / mL. In some embodiments, the trough concentration of compound A required to provide a therapeutic effect equivalent to that of long-acting SRL in CS patients is about 25 ng / mL to about 80 ng / mL. In some embodiments, the trough concentration of compound A required to provide a therapeutic effect equivalent to that of long-acting SRL in CS patients is about 30 ng / mL to about 80 ng / mL. In some embodiments, the trough concentration of compound A required to provide a therapeutic effect equivalent to that of long-acting SRL in CS patients is about 30 ng / mL to about 60 ng / mL.

[0193] In some embodiments, the trough concentration of Compound A required to provide a therapeutic effect in CS equivalent to that of a long-acting SRL is at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, or at least about 50 ng / mL. In some embodiments, paltusotine is at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, at least about 30 ng / mL, at least about 31 ng / mL, at least about 32 ng / mL, at least about 33 ng / mL, at least about 34 ng / mL, at least about 35 ng / mL, at least about 36 ng / mL, at least about 37 ng / mL, at least about 38 ng / mL, at least about 39 ng / mL, at least about 40 ng / mL, at least about 41 ng / mL, at least about 42 ng / mL, at least about 43 ng / mL, at least about 44 ng / mL, at least about 45 ng / mL, at least about 46 ng / mL, at least about 47 ng / mL, at least about 48 ng / mL, mL, at least about 49 ng / mL, at least about 50 ng / mL, at least about 51 ng / mL, at least about 52 ng / mL, at least about 53 ng / mL, at least about 54 ng / mL, at least about 55 ng / mL, at least about 56 ng / mL, at least about 57 ng / mL, at least about 58 ng / mL, at least about 59 ng / mL, at least about 60 ng / mL, at least about 61 ng / mL, at least about 62 ng / mL, at least about 63 ng / mL, at least about 64 ng / mL, at least about 65 ng / mL, at least about 66 ng / mL, at least about 67 ng / mL, at least about 68 ng / mL, at least about 69 ng / mL, at least about 70 ng / mL, at least about 71 ng / mL, at least about 72 ng / mL, at least about 73 ng / mL, at least about 74 ng / mL, at least about 75 ng / mL, at least about 76 ng / mL, at least about 77 ng / mL, at least about 78 ng / mL,The therapeutic agent is administered at a dose sufficient to provide a trough concentration of paltusotine that is at least about 79 ng / mL, at least about 80 ng / mL, at least about 81 ng / mL, at least about 82 ng / mL, at least about 83 ng / mL, at least about 84 ng / mL, at least about 85 ng / mL, at least about 86 ng / mL, at least about 87 ng / mL, at least about 88 ng / mL, at least about 89 ng / mL, at least about 90 ng / mL, at least about 91 ng / mL, at least about 92 ng / mL, at least about 93 ng / mL, at least about 94 ng / mL, at least about 95 ng / mL, at least about 96 ng / mL, at least about 97 ng / mL, at least about 98 ng / mL, at least about 99 ng / mL, or at least about 100 ng / mL.

[0194] In some embodiments, the trough concentration of Compound A required to provide a therapeutic effect in CS patients is greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, or greater than 40 ng / mL. In some embodiments, the trough concentration of Compound A required to provide a therapeutic effect in CS patients is at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, or at least about 50 ng / mL. In some embodiments, paltusotine is administered at a dose sufficient to provide a trough concentration of paltusotine that is at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, at least about 30 ng / mL, at least about 31 ng / mL, at least about 32 ng / mL, at least about 33 ng / mL, at least about 34 ng / mL, at least about 35 ng / mL, at least about 36 ng / mL, at least about 37 ng / mL, at least about 38 ng / mL, at least about 39 ng / mL, or at least about 40 ng / mL. In some embodiments, paltusotine is administered at a dose sufficient to provide a trough concentration of paltusotine that is at least about 32 ng / mL.

[0195] In some embodiments, treating CS involves administering a sufficient amount of compound A to obtain a trough plasma level of compound A in the CS patient that is between about 20 ng / mL and about 150 ng / mL. In some embodiments, treating CS involves administering a sufficient amount of compound A to obtain a trough plasma level of compound A in the CS patient that is between about 25 ng / mL and about 80 ng / mL. In some embodiments, treating CS involves administering a sufficient amount of compound A to obtain a trough plasma level of compound A in the CS patient that is between about 30 ng / mL and about 80 ng / mL. In some embodiments, treating CS involves administering a sufficient amount of compound A to obtain a trough plasma level of compound A in the CS patient that is between about 30 ng / mL and about 60 ng / mL.

[0196] In some embodiments, treating CS comprises administering a sufficient amount of Compound A to obtain a trough plasma level of Compound A in the CS patient that is greater than 10 ng / mL, greater than 15 ng / mL, greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, greater than 40 ng / mL, greater than 45 ng / mL, greater than 50 ng / mL, greater than 55 ng / mL, greater than 60 ng / mL, greater than 65 ng / mL, greater than 70 ng / mL, greater than 75 ng / mL, or greater than 80 ng / mL.

[0197] In some embodiments, the treatment of CS includes administering to a patient a trough plasma level of Compound A of about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, or at least about 80 ng / mL to obtain a trough plasma level of Compound A in the CS patient. mL, or at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, or at least about 150 ng / mL.

[0198] In some embodiments, Compound A, or a pharma- ceutically acceptable salt thereof (e.g., Compound A-monohydrochloride), has a concentration of about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL, about 31 ng / mL, about 32 ng / mL, about 33 ng / mL, about 34 ng / mL, about 35 ng / mL, about 36 ng / mL, about 37 ng / mL, or about 38 ng / mL. g / mL, approximately 38ng / mL, approximately 39ng / mL, approximately 40ng / mL, approximately 41ng / mL, approximately 42ng / mL, approximately 43ng / mL, approximately 44ng / mL, approximately 45ng / mL, approximately 46ng / mL, approximately 47ng / mL, approximately 48ng / mL , about 49ng / mL, about 50ng / mL, about 51ng / mL, about 52ng / mL, about 53ng / mL, about 54ng / mL, about 55ng / mL, about 56ng / mL, about 57ng / mL, about 58ng / mL, about 59ng / mL, about 60 ng / mL, approximately 61ng / mL, approximately 62ng / mL, approximately 63ng / mL, approximately 64ng / mL, approximately 65ng / mL, approximately 66ng / mL, approximately 67ng / mL, approximately 68ng / mL, approximately 69ng / mL, approximately 70ng / mL, approximately 71ng / mL, about 72ng / mL, about 73ng / mL, about 74ng / mL, about 75ng / mL, about 76ng / mL, about 77ng / mL, about 78ng / mL, about 79ng / mL, about 80ng / mL, about 81ng / mL, about 82ng / mL, about The compound is administered at a dose sufficient to provide a trough concentration of Compound A that is 83 ng / mL, about 84 ng / mL, about 85 ng / mL, about 86 ng / mL, about 87 ng / mL, about 88 ng / mL, about 89 ng / mL, about 90 ng / mL, about 91 ng / mL, about 92 ng / mL, about 93 ng / mL, about 94 ng / mL, about 95 ng / mL, about 96 ng / mL, about 97 ng / mL, about 98 ng / mL, about 99 ng / mL, about 100 ng / mL, or greater than about 100 ng / mL.

[0199] In some embodiments, compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) is administered at a dose sufficient to provide a trough concentration of compound A that is about 32 ng / mL. In some embodiments, compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) is administered at a dose sufficient to provide a trough concentration of compound A that is at least about 32 ng / mL. In some embodiments, compound A, or a pharma- ceutically acceptable salt thereof (e.g., compound A-monohydrochloride) is administered at a dose sufficient to provide a trough concentration of compound A that is greater than about 32 ng / mL.

[0200] In some embodiments, once daily administration of the SDD tablets described herein to a CS patient at a total daily dose of about 40 mg to about 160 mg of Compound A-monohydrochloride provides a dose of greater than 10 ng / mL, greater than 15 ng / mL, greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, greater than 40 ng / mL, greater than 45 ng / mL, greater than 50 ng / mL, greater than 55 ng / mL, greater than 60 ng / mL, greater than 65 ng / mL, greater than 70 ng / mL, greater than 80 ng / mL, greater than 90 ng / mL, greater than 100 ng / mL, greater than 150 ng / mL, greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, greater than 40 ng / mL, greater than 45 ng / mL, greater than 50 ng / mL, greater than 55 ng / mL, greater than 60 ng / mL, greater than 65 ng / mL, greater than 70 ng / mL, greater than 80 ng / mL, greater than 90 ng / mL, greater than 100 ng / mL, greater than 100 ng / mL, greater than 150 ng / mL, greater than 200 ng / mL, greater than 250 ng / mL, greater than 300 ng / mL, greater than 350 ng / mL, greater than 400 ng / mL, greater than 450 ng / mL, greater than 500 ng / mL, greater than 550 ng / mL, greater than 600 ng / mL, greater than 650 ng / mL, greater than 900 ng / mL, greater than 10 In one embodiment, a trough concentration of Compound A is provided that is greater than 100ng / mL, greater than 115ng / mL, greater than 120ng / mL, greater than 125ng / mL, greater than 130ng / mL, greater than 135ng / mL, greater than 140ng / mL, greater than 145ng / mL, greater than 150ng / mL, or greater than 150ng / mL.

[0201] In some embodiments, once daily administration of an SDD tablet described herein to a CS patient at a total daily dose of about 40 mg to about 120 mg of Compound A-monohydrochloride provides a trough concentration of about 10 ng / mL to about 150 ng / mL of Compound A. In some embodiments, once daily administration of an SDD tablet described herein to a CS patient at a total daily dose of about 40 mg to about 120 mg of Compound A-monohydrochloride provides a trough concentration of about 20 ng / mL to about 150 ng / mL of Compound A.

[0202] In any of the foregoing aspects, there are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which the compound is administered once daily. EXAMPLES

[0203] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0204] Example 1: Oral Capsules Representative capsules are set forth in Table 1 below.

[0205] [Table 1]

[0206] A typical description of the manufacturing process for hot melt granulated capsules follows.

[0207] Step 1: High shear wet granulation: Vitamin E polyethylene glycol succinate (TPGS) is melted. Compound A-HCl, mannitol, microcrystalline cellulose, croscarmellose sodium, and silicon dioxide are charged into a high shear wet granulator and mixed. The melted Vitamin E TPGS is sprayed onto the granulation components.

[0208] Stage 2: Milling: The wet granulation is milled through a screening mill using an appropriately sized screen.

[0209] Stage 3: Blending: Sift the sodium stearyl fumarate using an appropriate size screen. Charge the milled granulation into a diffusion mixer (tumble) along with the sodium stearyl fumarate and blend.

[0210] Step 4: Encapsulation: The 10 mg capsules were automatically encapsulated into size 2 gelatin capsules.

[0211] Example 2: Spray-dried solid dispersion Spray dried solid dispersions were prepared with the following formulations: 15 wt% Compound A-HCl: 15 / 85 Compound A-HCl / HPMCAS-M and 15 / 85 Compound A-HCl / PVP VA64. Manufacturing was completed using a Bend Lab Dryer, BLD-150, with a drying gas capacity of 150 kg / hr. The parameters that were modified were the solution solids loading for the HPMCAS-M SDD formulation to help reduce nozzle bearding, and the dryer outlet temperature for the PVP VA64 SDD to reduce the risk of variability that may occur during clinical manufacturing. The original process parameter screening plan specified producing reduced dryer outlet temperature conditions with a larger orifice nozzle to generate larger particles, but based on the results of the first spray, it was determined that the atomization pressure required to achieve the desired solution flow rate was too low to fully atomize the solution with the larger orifice. Dryer outlet temperature tends to be more variable than solution flow rate, so the parameter screen was shifted to focus on mitigating risk of dryer outlet temperature alone while ensuring complete atomization of the droplets. Variation in dryer outlet temperature can affect residual solvent levels in the SDD, which can affect physical and chemical stability. All sprays were successfully completed with good yields, demonstrating a robust process space for both formulations.

[0212] 15 / 85 Compound A HPMCAS-M SDD Formulation Manufacturing Details Three sub-batches of 15 / 85 Compound A-HCl / HPMCAS-M SDD were sprayed to explore the manufacturing process space and prepare for clinical trial manufacturing. When the sub-batches were first sprayed at 10 wt% solids, significant nozzle bearin g was observed after approximately 45 minutes on the solution, which likely affected the spray plume.

[0213] The solution was diluted to 8 wt% and sub-batches were made for 1 hour duration to ensure reduced bearding. A very small amount of bearding was observed in this batch after approximately 50 minutes on solution, but it did not appear to affect the atomization plume, so the 8 wt% solids loading was chosen.

[0214] Chilled water at 2 GPM and approximately 7°C was run through the spray dryer lid throughout all sprays to keep the lid cool and prevent sticking and browning. No significant lid build-up or browning was observed throughout production. No cleaning was performed between sprays and all sprays were completed from one solution with additional solvent added prior to production of Batches 2A and 2C. The production parameters used for all three sub-batches are outlined in Table 2.

[0215] [Table 2]

[0216] 15 / 85 Compound A-HCl / PVP VA64 SDD Formulation Manufacturing Details A process parameter screening spray and FPN demonstration batch was also completed for the 15 / 85 Compound A-HCl / PVP VA64 SDD formulation. Dryer outlet temperature was modified to mitigate the risk of process parameter variability in preparation for clinical trial manufacturing.

[0217] The process space was limited by the maximum dryer outlet temperature, dryer outlet temperature, and the minimum desired solution flow rate. A maximum inlet temperature of 160° C. was specified to avoid adhesion or browning of SDD on the spray dryer lid, and the minimum flow rate was set at 100 g / min to ensure sufficient throughput. The minimum and maximum dryer outlet temperatures were selected to be 40° C. and 65° C., respectively, to ensure that the particles were sufficiently dried and that the dryer outlet temperature did not exceed the Tg of the wet particles.

[0218] Process parameter screening sprays on the PVP VA64 formulation explored the manufacturing space by varying the dryer outlet temperature, which allowed for investigation of the effect of dryer relative saturation on particle residual solvent content, morphology, density, and stability.

[0219] Cooling water was run at 2 GPM and approximately 7°C throughout all sprays to prevent cap buildup and browning, neither of which were observed. No nozzle bearing was observed throughout all three runs. All sprays were completed from one solution. Production details for each sub-batch are summarized in Table 3.

[0220] [Table 3]

[0221] Characterizing SDD Particle properties: Particle size distribution and bulk and tapped densities were measured for each batch of Compound A-HCl SDD. The HPMCAS-M SDD has a larger particle size, which is expected because the HPMCAS-M solution is more viscous than the PVP VA64 solution, resulting in larger droplets for a given nozzle configuration. Increasing the solid loading in the solution of Lot 2B results in a larger particle size than Batches 2A and 2C, again due to the higher viscosity of the spray solution. The particle size distribution of all PVPVA-64 batches is similar as expected.

[0222] The bulk and tapped densities of 2A and 2C are similar, with batch 2B having a slightly lower density, potentially due to larger particles. The bulk and tapped densities of all PVPVA-64 batches are similar, indicating a robust process with respect to the effect of dryer outlet temperature on powder properties.

[0223] Residual solvent and water content: Residual methanol and water in the six SDDs were measured using GC and KF, respectively. All SDDs contained residual methanol below the ICH guideline of 0.3 wt% after secondary drying, suggesting sufficient drying at 40°C / 15% RH.

[0224] Morphology by SEM: Particle morphology of all six SDDs was evaluated via SEM. Each SDD showed typical morphology with no evidence of irregular particles, suggesting sufficient micronization for all conditions tested. HPMCAS-M particles were predominantly crushed spherical, while the PVP VA64 SDD contains a larger fraction of spherical particles.

[0225] Crystallinity by PXRD: All six SDDs were assessed for crystallinity using PXRD. All SDDs were amorphous by PXRD, as evidenced by the absence of sharp diffraction peaks.

[0226] Thermal properties by DSC: All six SDDs were characterized by moderated DSC. The results are tabulated in Table 4. The SDDs produced were all amorphous and homogeneous by DSC, as evidenced by the presence of a single glass transition in the inversion heat signal. None of the formulations showed signs of crystallization after Tg, suggesting low propensity for Compound A to crystallize at those temperatures for both formulations. Additionally, both formulations showed high Tg compared to ambient temperature, suggesting low physical stability risk under dry conditions. The PVP VA64 formulation will require packaging to minimize humidity.

[0227] [Table 4]

[0228] overview Physical stability observations: PVP VA64 SDD appeared to deliquesce upon storage and crystals were observed at 3 months (open at 40°C / 75% RH). Storage with a desiccant is recommended. HPMCAS-M SDD was physically stable over 6 months at 40°C / 75% RH.

[0229] Chemical stability observations: Potential for acid catalyzed degradation in the HPMCAS-M formulation versus stability. Some degradation in the PVP VA64 formulation as well, but less pronounced than in the HPMCAS-M SDD. Packaging is required for the PVPVA SDD, which is driven by physical stability concerns.

[0230] Compound A / PVP VA64 at 15% by weight was selected as the primary SDD formulation.

[0231] 12-month stability: 15% Compound A-HCl / PVP-VA64 SDD The 12-month SDD samples were kept with desiccant at 5°C, 25°C / 60% RH, and 40°C / 75% RH. Samples were prepared for water analysis by Karl Fischer titration and analyzed immediately. The remaining samples were dried overnight under vacuum to remove residual moisture and preserve the physical state of the SDD for further characterization. The list of analytical tests performed for characterization included appearance, moisture content by Karl Fischer titration, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermal properties by modulated differential scanning calorimetry (mDSC), dissolution performance by microcentrifuge (MCT) test, assay and related substances by HPLC.

[0232] Conclusions from PXRD analysis on the 12 month SDD stability samples: There was no evidence of crystallinity in the samples stored for 12 months at each of the stability conditions.

[0233] Conclusions from SEM analysis on the 12 month SDD stability samples: No particle fusion was observed across all stability conditions at 12 months. There was no evidence of crystallinity in the samples stored at 12 months in each of the stability conditions.

[0234] Conclusions from SEM analysis on the 12 month SDD stability samples: No particle fusion is observed across all stability conditions at 12 months. There was no evidence of crystallinity in the samples stored at 12 months in each of the stability conditions.

[0235] Conclusions from mDSC analysis on 12-month SDD stability samples: Repeated analysis of the 12-month SDD sample held at 5°C provided irreproducible thermograms and the cause for this result is currently unknown. The 5°C sample was determined to be physically stable by all other characterization techniques. The 12-month SDD samples held at 25°C / 60% RH and 40°C / 75% RH showed a single, reproducible Tg at 124-125°C, supporting the conclusion that SDD is stable after 12 months of storage with desiccant at these conditions.

[0236] Conclusions from the MCT dissolution analysis on the 12 month SDD stability samples: The non-sink dissolution performance of the 12 month stability samples is consistent with the initial (t0) samples stored at -20°C.

[0237] 35 / 65 Compound A-HCl / PVP VA64 SDD Formulation Manufacturing Details A spray dried solid dispersion was prepared with 35 wt% Compound A-HCl: 35 / 65 Compound A-HCl / PVP VA64 formulation.

[0238] The preparation of SDD was completed using an SD-180 laboratory dryer. Secondary drying was completed using a Binder Convection Dryer. Preparation details are summarized in Table 5.

[0239] The spraying was completed successfully with good yield.

[0240] [Table 5]

[0241] Example 3: Oral Tablet Representative 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg spray dried dispersion tablets are provided in Tables 6, 7, 8, 9, 10, 11, 12, and 13.

[0242] Typical excipients used to prepare tablets include microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate, and Opadry White 03K184116 (film coating).

[0243] [Table 6]

[0244] [Table 7]

[0245] [Table 8]

[0246] [Table 9]

[0247] [Table 10]

[0248] [Table 11]

[0249] [Table 12]

[0250] [Table 13]

[0251] [Table 14]

[0252] A representative, non-limiting description of the manufacturing process for SDD tablets follows.

[0253] Step 1: Spray drying: Compound A-HCl and Copovidone are dissolved in MeOH. The solution is spray dried. The spray dried dispersion (Compound A-HCl SDD) is collected.

[0254] Stage 2: Roller Compaction: A granulation blend consisting of Compound A-HCl SDD, fillers, disintegrants, glidants, and lubricants is blended. In some embodiments, a granulation blend consisting of Compound A-HCl SDD, mannitol, microcrystalline cellulose, crospovidone, colloidal silicon dioxide is prepared and blended. The intragranular portion of magnesium stearate is screened and added to the granulation blend. The resulting blend is blended. The granulation blend is loaded into the hopper of a roller compactor and compressed into ribbons. The ribbons are passed through a mesh screen using an in-line vibratory mill to break up the ribbons and mill them into granules.

[0255] In some embodiments, the granulated blend comprises about 20% to about 35% (w / w of final tablet weight) Compound A-HCl SDD. In some embodiments, the granulated blend comprises about 21%, about 22%, about 28%, 29%, about 33%, about 34% (w / w of final tablet weight) Compound A-HCl SDD. In some embodiments, the Compound A-HCl SDD comprises 15 / 85 Compound A-HCl / HPMCAS-M, 15 / 85 Compound A-HCl / PVPVA64, or 35 / 65 Compound A-HCl / PVPVA 64 SDD.

[0256] Stage 3: Blending: The intragranular material is mixed with the extragranular excipients. The extragranular excipients include one or more excipients selected from fillers, disintegrants, glidants, and lubricants. The extragranular components include microcrystalline cellulose, crospovidone, colloidal silicon dioxide. The extragranular lubricant, magnesium stearate, is sieved using a suitable size screen and then added to the blend and mixed.

[0257] Step 4: Compression: The final blend is compressed into tablets.

[0258] Step 5: Pan Coating: A film coating suspension of Opadry White 03K18416 is prepared in purified water and the tablets are coated with Opadry White 03K18416 in a perforated coating pan.

[0259] Example 4: Evaluation of formulation performance in dogs research design Two conditions evaluated in dogs * : +Pg pretreatment (mimicking the fasting human stomach, pH 1-2) and -Pg pretreatment (mimicking humans taking PPIs or antacids, pH 3-5). * (1 week washout between conditions, Pg = pentagastrin.)

[0260] Compound A-HCl solution N=4 non-naive dogs. Vehicle: propylene glycol. Condition: -Pg.

[0261] Compound A-HCl HMG Capsules N=4 non-naive dogs. Conditions: +Pg, -Pg.

[0262] Compound A-HCl spray dried dispersion tablet: PVPVA Two groups of N=6 non-naive male dogs. Conditions: +Pg, -Pg.

[0263] The results from this study are presented in Tables 15 and 16.

[0264] [Table 15]

[0265] As shown in Table 15 and Figure 2, in dogs not pretreated with pentagastrin, the HMG capsule formulation performed poorly, whereas the spray-dried dispersion tablet performed well. For the HMG capsule formulation, the AUC without pentagastrin was only 11% of the AUC with pentagastrin (917 ng / kg). * 98.2 ng / mL compared with * In comparison, the AUC for the PVPVA SDD tablet formulation without pentagastrin was 185% and 124%, respectively, of that with pentagastrin. These data indicate that the PVPVA SDD tablet formulation is superior in high gastric pH environments (e.g., as in subjects taking PPIs or antacids).

[0266] [Table 16]

[0267] Example 5: A Phase 1, Multi-Cohort, Single-Dose Study to Evaluate the Relative Bioavailability, Performance, and Safety of Two Formulations of Compound A The study will be conducted in up to three cohorts, each with a specific primary objective.

[0268] Cohort 1: To characterize the performance of 10 mg tablets prepared by spray dried dispersion (SDD) of Compound A-HCl salt.

[0269] Cohort 2: To evaluate the relative bioavailability of 10 mg SDD tablets compared to Compound A-HCl hot melt granulation (HMG) formulation, 10 mg capsules. To determine the effect of timing of food administration on the pharmacokinetics of low dose 10 mg SDD tablets.

[0270] Cohort 3: To determine the effect of timing of food administration on the pharmacokinetics and dose proportionality of SDD tablets at doses higher than 20 mg. To determine the optimal dosing regimen that provides sufficient systemic exposure with a short post-dose fasting period.

[0271] Cohort 4: To determine the effect of timing of food administration on the pharmacokinetics of SDD tablets at doses higher than 20 mg. To determine the optimal dosing regimen of paltusotine that results in high systemic exposure with a low post-dose fasting period.

[0272] Cohort 5: To determine the effect of the proton pump inhibitor (PPI), lansoprazole, on the pharmacokinetics of SDD tablets at a dose of 60 mg.To determine the effect of a low-fat meal on the pharmacokinetics of SDD tablets at a dose of 60 mg.

[0273] Research design: A maximum of thirty-six (36) healthy male and female subjects were enrolled. Cohorts 1-2 each consisted of four periods, and Cohort 3 consisted of three periods.

[0274] Cohort 1: SDD tablets were evaluated. Up to twelve (12) healthy male and female subjects were enrolled in each cohort. Cohort 1 consisted of four periods. In period 1, subjects were administered a proton pump inhibitor (lansoprazole, 15 mg BID, taken orally for three days (starting on day -3), at least 30 minutes before a meal, once in the morning, and once in the evening). On day 4 (day 1 of the study), fasted subjects received their final dose of lansoprazole (15 mg) 60 minutes prior to 20 mg of Compound A (2 x 10 mg of SDD tablets). In period 2, fasted subjects were administered 20 mg of Compound A (2 x 10 mg of SDD tablets). In period 3, fasted subjects were administered 20 mg of Compound A (2 x 10 mg of SDD tablets) with a high-fat, high-calorie meal. In period 4, fasted subjects will receive 80 mg of Compound A (maximum 8 x 10 mg SDD tablet). The actual dose was selected based on pharmacokinetic data from period 2.

[0275] For Period 1: In the evening prior to dosing (day -1), subjects were administered an evening dose of 15 mg lansoprazole, served dinner at least 30 minutes after administration of lansoprazole, and then asked to fast overnight (10 hours or more) on day -1. On day 1, subjects were administered a morning dose (last dose) of 15 mg lansoprazole at least 60 minutes prior to administration of Compound A (2 x 10 mg SDD tablets). After Compound A, subjects continued to fast for 2 hours, after which they were allowed to consume a standard meal.

[0276] For Period 2: Subjects were asked to fast overnight (≥10 hours) on day 7. On day 8, 20 mg of Compound A (2 x 10 mg SDD tablets) was orally administered. After Compound A, subjects continued fasting for 2 hours and were then allowed to consume a standard meal.

[0277] For Period 3: Subjects were asked to fast overnight (≥10 hours) on Day 14. On Day 15, subjects were allowed to consume a high-fat, high-calorie meal within 30 minutes. Once meal intake was completed, Compound A (2 x 10 mg SDD tablets) was administered (within 30 minutes after the start of the meal). No additional food was provided for at least 4 hours following administration of Compound A.

[0278] For 3 days prior to Day -1 and throughout the study, subjects were not permitted to engage in strenuous exercise >30 min / day.

[0279] PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, Holter and telemetry monitoring (Period 4 only), and physical examinations, were performed at scheduled times throughout the study.

[0280] Cohort 2: The cohort consisted of four periods, each of which received a single dose of 20 mg Compound A (2×10 mg SDD) administered orally.

[0281] For Period 1: Subjects were asked to fast overnight (≥10 hours) on day -1. On day 1, subjects were given a low-fat meal 2 hours after administration of 20 mg of Compound A (2 x 10 mg HMG capsules, reference formulation).

[0282] For Period 2: Subjects were asked to fast overnight (≥10 hours) on day 7. On day 8, subjects were fed a low-fat meal 2 hours after administration of 20 mg of Compound A (2 x 10 mg SDD tablets, test formulation).

[0283] For Period 3: Subjects were asked to fast overnight (≥10 hours) on day 14. On day 15, subjects were fed a low-fat meal 1 hour after administration of 20 mg of Compound A (2 x 10 mg SDD tablets).

[0284] For Period 4: Subjects were asked to fast overnight (≥10 hours) on day 21. On day 22, subjects were fed a low-fat meal 0.5 hours after administration of 20 mg of Compound A (2 x 10 mg SDD tablets).

[0285] The final study visit occurred on Day 29. Subjects were not permitted to engage in vigorous exercise >30 min / day for 3 days prior to Day -1 and throughout the study. PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, and physical examinations, were performed at scheduled times throughout the study.

[0286] Cohort 3: The cohort consisted of three periods. In each period, a single dose of SDD (40, 60, or 80 mg) of Compound A was orally administered (4 x 10 mg SDD tablets, 6 x 10 mg SDD tablets, or 8 x 10 mg SDD tablets). There was a washout period of at least 10 days between each dose of Compound A.

[0287] For Period 1: Subjects were asked to fast overnight (≥10 hours) on day -1. On day 1, subjects were fed a standard meal 1 hour after administration of 40 mg of Compound A (4 x 10 mg SDD tablets).

[0288] For Period 2: Subjects were asked to fast overnight (≥10 hours) on Day 10. On Day 11, subjects were fed a standard meal 1 or 2 hours after administration of 80 Compound A (8 x 10 mg SDD tablets). The timing of the meal (1 or 2 hours after administration of Compound A) was correlated with the mean AUC 0-24 Dependent on.

[0289] For Period 3: Subjects were asked to fast overnight (≥10 hours) on Day 20. On Day 21, subjects received a standard meal 1 or 4 hours after administration of 60 or 80 mg of Compound A (6 x 10 mg SDD tablets or 8 x 10 mg SDD tablets). The dose and timing of the standard meal were determined based on the mean AUC 0-24 Dependent on.

[0290] The final study visit occurred on Day 29. Subjects were not permitted to engage in vigorous exercise >30 min / day for 3 days prior to Day -1 and throughout the study. PK and safety assessments, including adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, 12-lead ECG, and physical examinations, were performed at scheduled times throughout the study.

[0291] Cohort 4: Cohort 4 consisted of three periods:

[0292] In period 1, fasted subjects were given a standard meal 1 hour after administration of 40 mg (4×10 mg) paltusotine SDD tablets.

[0293] In period 2, fasted subjects were given a standard meal 1 hour after administration of 80 mg (8×10 mg) paltusotine SDD tablets.

[0294] In period 3, fasted subjects were given a standard meal 4 hours after administration of 80 mg (8×10 mg) paltusotine SDD tablets.

[0295] Cohort 5: The cohort consisted of 3 periods. The PK of 60 mg paltusotine administered as 3 × 20 mg SDD tablets was assessed using the following criteria: effect of a low-fat meal on the PK of paltusotine (Period 1 and Period 3), and effect of the PPI lansoprazole on the PK of paltusotine (Period 2).

[0296] In period 1, fasted subjects were given a low-fat meal 1 hour after administration of 60 mg (3 × 20 mg) paltusotine SDD tablets: Low-fat meal: 400-500 calories, with 25% of calories coming from fat (11-14 grams).

[0297] In period 2, subjects were administered lansoprazole (15 mg BID for 3 days, taken orally at least 30 minutes before a meal). On day 4, fasted subjects were administered a final dose of lansoprazole (15 mg) 60 minutes prior to administration of 60 mg paltusotine (3 x 20 mg SDD tablets). Following administration of paltusotine, subjects continued to fast for 1 hour, after which they were offered a low-fat meal. Subjects remained fasted until 4 hours after dose administration.

[0298] In period 3, fasted subjects consumed a low-fat meal within 30 minutes. Once meal intake was completed (but not later than 30 minutes after the start of the meal), subjects received 60 mg of paltusotine (3 x 20 mg SDD tablets). Subjects remained fasting until 4 hours after dose administration.

[0299] Study population: Up to 36 healthy male or female subjects aged between the inclusive endpoints of 18 and 55 years were enrolled. For cohort 2 only, male and female subjects aged between the inclusive endpoints of 18 and 65 years at screening.

[0300] Inclusion criteria Each subject had to meet all of the following inclusion criteria to be enrolled in the study: Male and female subjects aged between 18 and 55 years, inclusive, at screening. For cohort 2 only, male and female subjects aged between 18 and 65 years, inclusive, at screening. 18 to 30 kg / m 2 Body Mass Index (BMI) with endpoints of - Willingness to refrain from strenuous unaccustomed exercise and sports, defined as more than 30 minutes per day, for 3 days prior to Day 1 and throughout the study. If subjects are heterosexual or bisexual women, they must be non-fertile or agree to use two highly effective or clinically tolerated methods of contraception.

[0301] Exclusion criteria Healthy subjects who met any of the following criteria were excluded from the study: - Previous treatment with Compound A. - Any uncontrolled or active major systemic disease that may compromise study participation or interfere with the assessment of study endpoints. - History or presence of malignancy within the past 5 years, except for adequately treated basal or squamous cell carcinoma of the skin. - Active acute or chronic infection. - Use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer, prior to the first dose of study drug. - Use of tobacco and / or nicotine-containing products, recreational drugs, or alcohol within 48 hours prior to admission and agreement to abstain from use throughout the study. - History of alcohol abuse and / or other drug dependence or current abuse and / or dependence <1 year prior to screening. - Use of any prescription or over-the-counter (OTC) medication or alternative medicine within 14 days prior to Day 1. - Use of caffeine-containing beverages or foods within 48 hours prior to Day 1 and 48 hours prior to each medical examination day in all subsequent periods. Consuming poppy seed-containing foods within 7 days prior to screening until study assessments were completed. Taking moderate or strong CYP3A4 inhibitors or inducers. Vigorous exercise >30 min / day for 3 days prior to Day 1 and throughout the study. Blood loss of ≥500 mL or blood donation within 3 months prior to admission. Amylase and / or lipase levels >2×ULN, alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) >2×ULN, total bilirubin >1.5×ULN (except in cases of known Gilbert's syndrome), and / or serum creatinine above the upper limit of normal. History of hypersensitivity reactions to any excipients in the study drug. Testing positive at screening or having a history of positive results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab). Female subjects who have a positive serum pregnancy test or are breastfeeding.For Cohort 1 only, subjects classified as poor or extremely rapid metabolizers of CYP2C19.

[0302] Test product, dose, and mode of administration: 10 mg tablets (SDD). Depending on the dose specified for a given period / cohort, multiple tablets were swallowed with water.

[0303] 20 mg tablets (SDD). Depending on the dose specified for a given period / cohort, multiple tablets were swallowed with water.

[0304] Reference therapy, dose, and mode of administration: A 10 mg HMG capsule formulation was provided as the reference formulation. Multiple capsules were swallowed with water depending on the dose assigned for a given period / cohort.

[0305] Plasma Pharmacokinetic Parameters: Blood PK samples were collected to assess Compound A plasma concentrations.

[0306] PK parameters were calculated for Compound A and are shown in the table below: Area under the plasma concentration curve from 0 to 24 hours (AUC 0-24 ), maximum plasma concentration (C max ), and the time to achieve maximum plasma concentration (T max ).

[0307] result Results from this clinical trial showed that coadministration of a proton pump inhibitor had only a small effect on the pharmacokinetics observed with administration of the SDD tablet, and that the shorter fasting period achieved with the SDD tablet provided better dose-proportional pharmacokinetics.

[0308] Results from Cohort 1 are presented in Table 17.

[0309] [Table 17]

[0310] Cohort 1 (SDD 10 mg × 2 under different conditions): The observed exposures with or without PPI are nearly equivalent. Cohort 1 (SDD 10 mg × 2 vs. 10 mg × 6): A relatively dose-proportional increase in exposure was observed.

[0311] The SDD tablets demonstrated a dose-proportional increase in total systemic exposure (AUC) up to the 80 mg dose.

[0312] No relatively dose-proportional increase in exposure was observed with the HMG capsule compared to the SDD tablet. See Figure 1. Dose proportionality data for the HMG capsule from previous clinical studies are presented in Table 18.

[0313] [Table 18]

[0314] Results from Cohort 2 are presented in Table 19.

[0315] [Table 19]

[0316] Cohort 2 (SDD 10 mg × 2 vs. HMG, and under different post-dose fasting periods): The SDD tablet did not appear to have a better exposure than the HMG capsule, and the two formulations were relatively comparable. For the SDD tablet, the AUC 0-24 (a measure of the extent of absorption) was reduced to 82% of the AUC observed with fasting 2 hours post-dose, a relatively small reduction in exposure.

[0317] Compared with the performance of SDD tablets under different post-dose fasting period scenarios, HMG capsules showed poor performance under different post-dose fasting period scenarios in a previously completed clinical study. Pharmacokinetic data obtained after administration of a 20 mg dose (2 x 10 mg HMG capsules) to 12 subjects (N = 4 males, N = 8 females) are presented in Table 20.

[0318] [Table 20]

[0319] For the HMG capsule formulation, an approximately 30% loss in the extent of absorption was observed with a 1 hour post-dose fast versus a 2 hour post-dose fast.

[0320] HMG capsules with a 2-hour fast were evaluated in a Phase 2 clinical study. A 1-hour fast is preferred over a 2-hour fast. Compared to a 2-hour fast, a 1-hour fast increases AUC (0-24) Loss of only 18% was observed. A 1-hour fasting SDD will be utilized in Phase 3. Importantly, the SDD tablet appears to have better dose proportionality than the HMG capsule, allowing for a 3.0-fold dose (i.e., 60 mg) to be administered in the Phase 3 clinical study.

[0321] Results from Cohort 5 are presented in Table 21.

[0322] [Table 21]

[0323] Compound A exposure (C max and AUC) appeared to be decreased by approximately 40% when administered with a PPI.

[0324] Additional results from Cohort 5 are presented in Table 22.

[0325] [Table 22]

[0326] Compound A exposure (C max and AUC) appeared to be reduced by approximately 60% when administered with a low-fat meal, compared with a reduction of >80% when administered with a high-fat meal.

[0327] Example 6: Phase 2 Study to Evaluate Compound A in Patients with Acromegaly Treated with Somatostatin Analogue-Based Therapeutic Regimens (Acrobat Edge) An open-label, exploratory study designed to evaluate the safety, efficacy, and pharmacokinetics of Compound A (also known as paltusotine) in subjects with acromegaly treated with a somatostatin analog (SSA)-based therapeutic regimen.

[0328] Research design: Intervention model: Single-group assignment. Shielding: None (open label). Primary purpose: Treatment.

[0329] Test product, dose, and mode of administration: 10 mg HMG capsule formulation. Multiple capsules were swallowed with water depending on the dose specified for a given period / cohort.

[0330] Measurement of outcome items Primary endpoint measure: Change from baseline (mean of screening values) in insulin-like growth factor-1 (IGF-1) levels [time frame: 13 weeks].

[0331] Secondary endpoint measures: 1) Percentage of subjects with a final IGF-1 measurement ≦upper limit of normal (ULN) [time frame: 13 weeks]. 2) Percentage of subjects with a final IGF-1 measurement ≦1.5×ULN [time frame: 13 weeks].

[0332] Eligibility Criteria Inclusion criteria Male and female subjects aged 18-70 years. Confirmed diagnosis of acromegaly with either partial or complete response to a protocol-defined somatostatin analog therapy regimen. Women must be non-pregnant and non-lactating and either surgically sterilized, postmenopausal, or using an effective method of birth control. Willing to provide signed informed consent.

[0333] Exclusion criteria Treatment naive acromegalic subjects. Previous treatment with paltusotine. Pituitary surgery within 6 months prior to screening. Subjects undergoing radiation therapy may be eligible with some restrictions. History or presence of malignancy within the past 5 years, except for fully treated basal and squamous cell carcinoma of the skin. Use of any investigational drug within the past 30 days or 5 half-lives, whichever is longer. Positive test at screening, or history of positive result, for HIV, Hepatitis B surface antigen (HBsAg), or Hepatitis C antibody (HCV-Ab). History of alcohol or substance abuse in the past 12 months. Any condition that, in the opinion of the investigator, would jeopardize the subject's proper participation in the study. Cardiovascular conditions or drugs associated with QT prolongation or that predispose the subject to heart rhythm abnormalities. Subjects with symptomatic cholelithiasis. Subjects with clinically significant abnormal findings during the Screening Period and any other medical condition or laboratory finding that, in the opinion of the Investigator, may jeopardize the subject's safety or ability to complete the study.Subjects taking Octreotide LAR at a dose greater than 40 mg, or Lanreotide Depot at a dose greater than 120 mg, or Pasireotide LAR at a dose greater than 60 mg.Subjects who normally take Octreotide LAR or Lanreotide Depot less frequently than every 4 weeks (e.g., every 6 or 8 weeks).

[0334] Example 7: Phase 2 Study to Evaluate the Safety and Efficacy of Compound A for the Treatment of Acromegaly (Acrobat Evolve) This Phase 2, double-blind, placebo-controlled, randomized withdrawal study is designed to evaluate the safety, efficacy, and pharmacokinetics of Compound A in subjects with acromegaly who are responders to octreotide LAR or lanreotide depot.

[0335] Research design: Allocation: Randomized. Intervention models: Parallel group comparisons. Shielding: Triple (participant, healthcare provider, investigator). Primary purpose: Treatment.

[0336] Test product, dose, and mode of administration: 10 mg HMG capsule formulation. Multiple capsules were swallowed with water depending on the dose specified for a given period / cohort.

[0337] Measurement of outcome items Primary endpoint measurement: Proportion of subjects meeting responder criteria (based on the mean of two consecutive insulin-like growth factor-1 [IGF-1] measurements ≤ upper limit of normal [ULN]) (time frame: 13 weeks).

[0338] Secondary endpoint measures: 1) Change in IGF-1 levels [time frame: weeks 10-13]. 2) Change in growth hormone (GH) levels [time frame: weeks 8-13]. 3) Change in patients' assessment of acromegaly symptoms [time frame: weeks 10-13]. A total score calculated by adding the intensity of each of the individual acromegaly symptoms (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness, or tingling).

[0339] Eligibility Criteria Inclusion criteria Male and female subjects aged 18-70 years. Confirmed diagnosis of acromegaly controlled on a stable dose of octreotide LAR or lanreotide depot. Women must be non-pregnant and non-lactating and either surgically sterilized, post-menopausal, or using an effective method of birth control. Willing to provide signed informed consent.

[0340] Exclusion criteria Treatment naive acromegalic subjects. Previous treatment with Compound A. Pituitary surgery within 6 months prior to screening or radiation therapy at any time prior to study entry. Pituitary radiation therapy with recent documented IGF-1 elevation (within 3-4 years or >4 years prior to study entry) may be eligible. History or presence of malignancy within the past 5 years, except for adequately treated basal and squamous cell carcinoma of the skin. Use of any investigational drug within the past 30 days or 5 half-lives, whichever is longer. Positive test at screening or history of positive result for HIV, Hepatitis B surface antigen (HBsAg), or Hepatitis C antibody (HCV-Ab). History of alcohol or substance abuse in the past 12 months. Any medical condition that, in the opinion of the investigator, would jeopardize the subject's proper participation in this study. Cardiovascular conditions or medications associated with QT prolongation or that predispose the subject to heart rhythm abnormalities. Subjects with symptomatic cholelithiasis. Subjects with clinically significant abnormal findings during the screening period and any other medical conditions or laboratory findings that, in the opinion of the Investigator, may jeopardize the subject's safety or ability to complete the study.Subjects previously taking the following medications: pegvisomant (within the past 3 months), dopamine agonists (within the past 3 months), and pasireotide LAR (within the past 6 months).Subjects taking octreotide LAR at a dose greater than 40 mg, or lanreotide depot at a dose greater than 120 mg.Subjects who normally take octreotide LAR or lanreotide depot less frequently than every 4 weeks (e.g., every 6 or 8 weeks).

[0341] Results from Phase 2 Study Twenty-five patients were enrolled: those treated with octreotide or lanreotide and with baseline IGF-1 (×ULN):>1 and <2.5.

[0342] Pre-specified primary analysis population: Patients treated with SRL (octreotide or lanreotide) with elevated IGF-1 at baseline - representing the majority of patients in clinical practice. The primary hypothesis was that the groups would show no change in median IGF-1 at week 13 versus baseline.

[0343] As shown in FIG. 3, paltusotine maintained IGF-1 and GH levels after switching from injected SRL peptide depot (data presented are median (interquartile range [IQR]: 25th percentile, 75th percentile) end of treatment defined as EoT=week 13 (visit 14), or last on treatment value carried forward (LOCF). Week after WD defined as week 17, or at least 22 days after the last dose. Note: p-values ​​are based on non-parametric Wilcoxon signed rank test of whether the median change differed from zero). IGF-1 levels after 13 weeks of paltusotine treatment did not change significantly from baseline in patients previously treated with injected SRL depot. Rise in IGF-1 after withdrawal (within 2 weeks) characterizes the magnitude of therapeutic activity for oral paltusotine. GH levels after 13 weeks of paltusotine treatment did not change significantly from baseline levels when patients were previously treated with injected SRL depots. The rise in GH after withdrawal characterized the magnitude of therapeutic activity of oral paltusotine.

[0344] Figure 4 shows evidence of a dose response observed from the Acrobat and Evolve studies. However, the HMG capsule formulation used lacked dose-proportional pharmacokinetics above 40 mg.

[0345] As shown in FIG. 5, administration of SDD tablets at 40 mg / day and 60 mg / day is predicted to produce trough concentrations consistently within the therapeutic range.

[0346] In some embodiments, the trough concentration of paltusotine required to provide a therapeutic effect equivalent to that of a long-acting SRL in patients with acromegaly is greater than 20 ng / mL, greater than 25 ng / mL, greater than 30 ng / mL, greater than 35 ng / mL, or greater than 40 ng / mL. In some embodiments, the trough concentration of paltusotine required to provide a therapeutic effect equivalent to that of a long-acting SRL in patients with acromegaly is at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, or at least about 50 ng / mL. In some embodiments, paltusotine is administered at a dose sufficient to provide a trough concentration of paltusotine that is at least about 20 ng / mL, at least about 21 ng / mL, at least about 22 ng / mL, at least about 23 ng / mL, at least about 24 ng / mL, at least about 25 ng / mL, at least about 26 ng / mL, at least about 27 ng / mL, at least about 28 ng / mL, at least about 29 ng / mL, at least about 30 ng / mL, at least about 31 ng / mL, at least about 32 ng / mL, at least about 33 ng / mL, at least about 34 ng / mL, at least about 35 ng / mL, at least about 36 ng / mL, at least about 37 ng / mL, at least about 38 ng / mL, at least about 39 ng / mL, or at least about 40 ng / mL. In some embodiments, paltusotine is administered at a dose sufficient to provide a trough concentration of paltusotine that is at least about 32 ng / mL.

[0347] As shown in Figure 6, the median “predicted” steady-state trough concentrations in acromegalic patients taking a PPI at 60 mg SDD (fasted 1 hour after dosing) are similar to the median steady-state trough concentrations in acromegalic patients at 40 mg HMG (fasted 2 hours after dosing).

[0348] Example 8: A Phase 2, Randomized, Parallel-Group Study to Evaluate the Safety, Pharmacokinetics, and Dose-Response of Paltusotine Treatment in Subjects with Carcinoid Syndrome The objective of this study was to evaluate the safety, pharmacokinetics (PK), and dose-response of paltusotine treatment in subjects with carcinoid syndrome.

[0349] Overall design This is a phase 2, randomized, open-label, parallel-group, multicenter study. The study will include a screening period of up to 12 weeks. After completion of screening, subjects will be randomly assigned to receive open-label doses of 40 mg QD versus 80 mg QD for up to 8 weeks, referred to as the randomized treatment phase.

[0350] Subjects who complete the randomized treatment phase may be eligible to enter the open-label extension (OLE) phase of the study in which subjects will receive paltusotine for 50 weeks. The total duration of paltusotine treatment will be up to 58 weeks or up to 15 months.

[0351] Duration and intervention group The study consists of two phases: a randomized treatment phase and an OLE phase. Subjects participating in both phases will complete the study in approximately 58-70 weeks or 14-16 months. The study consists of the following: Screening period: up to 12 weeks, Randomized treatment phase: 8 weeks, 1:1 randomization to 40 mg or 80 mg for 8 weeks, OLE phase: 50 weeks.

[0352] Study Drugs Paltusotine is provided as a 20 mg tablet. During the randomized treatment phase, subjects assigned to 40 mg will take two 20 mg tablets daily, subjects assigned to 80 mg will take four 20 mg tablets daily, and subjects requiring 120 mg will take six 20 mg tablets daily.

[0353] screening The screening period will vary from 2 to 12 weeks, depending on when subjects meet the randomization eligibility criteria described below.

[0354] Subjects who are naïve to SRL, actively symptomatic (an average of ≥ 4 bowel movements (BM) / day for at least 2 days (≥ 3 consecutive days) or > 2 flushing episodes per day over a 2-week period) or currently symptomatically controlled (≤ 5 bowel movements (BM) per day, an average of < 4 BM / day, and an average of ≤ 2 flushing episodes / day over a 2-week period while treated with lanreotide, octreotide LAR, or short-acting octreotide (immediate-release octreotide injection or oral octreotide)) and willing to wash out of the drug are eligible for screening.

[0355] Completion of the electronic symptom diary will continue throughout screening and throughout the 12-week study (throughout the randomized treatment phase and 4 weeks into the OLE), followed by daily for the selected period of the OLE phase. Stool consistency according to the Bristol Scale and abdominal pain according to the NRS will also be recorded in the electronic symptom diary. Some evaluation items will use a baseline defined from the screening period, which is defined as the last 7 days before the start of randomized treatment. Otherwise, the baseline will be defined as the last value before the start of randomized treatment.

[0356] Subjects naïve to SRL: For subjects naïve to SRL, two screening visits (S1 and S2) are scheduled during the screening period. After completing the initial eligibility assessment at S1, a 2-week evaluation of the frequency of untreated symptoms (BM and flushing episodes) begins. At the S1 visit, plasma 5HIAA levels are assessed. If the plasma 5-HIAA result is ≧2× the upper limit of normal (ULN), the 2-week evaluation is completed, and the subject demonstrates that they meet the symptomatic eligibility criteria (an average of ≧4 BMs / day over a 2-week period, or >2 flushing episodes per day), a randomization visit is scheduled on Day 1.

[0357] SRL before the test, Subjects with symptom control using lanreotide or octreotide LAR: For subjects using pre-study lanreotide or octreotide LAR, two screening visits (S1 and S2) will be scheduled during the screening period. Screening Visit 1 (S1) should be scheduled such that the interval between the last pre-study injection of lanreotide or octreotide LAR and S2 is not longer than the subject's usual interval between injections. S2 will occur up to 4 weeks after the last pre-study lanreotide or octreotide LAR injection. These subjects will not receive lanreotide or octreotide LAR after informed consent is given at S1. Electronic symptom diary completion should commence during day 1 of S1.

[0358] At the S2 visit, symptom control from pre-study lanreotide or octreotide LAR is assessed. Subjects who are symptomatically controlled between S1 and S2 (having a mean of <4 BMs / day, or >2 flushing episodes / day, with ≦5 BMs / day (on ≥3 consecutive days) over a 2-week period) will have plasma 5HIAA levels assessed and continue the screening period for up to 10 weeks after S2. During this time, subjects must meet symptom eligibility criteria (an increase of ≧2 BMs above the daily treatment mean from the documented period between S1 and S2, or an increase in daily mean flushing episodes of ≧3 episodes in at least one day, during a 7-day period). If a subject is not eligible for the Day 1 randomization visit within 10 weeks of S2, the subject will fail screening.

[0359] Short-acting octreotide: For subjects using regular doses of short-acting octreotide (immediate release octreotide injection or oral octreotide) for carcinoid syndrome symptom prophylaxis, two screening visits (S1 and S2) are scheduled during the screening period. After S1, a 2-week assessment of the frequency of treated symptoms (BM and flushing episodes) begins. Subjects continue pre-study administration of short-acting octreotide at the most recent pre-study dose and dosing frequency during this period. Electronic symptom diary completion should begin within 1 day after informed consent is given at S1. S2 occurs approximately 2 weeks after S1.

[0360] At the S2 visit, symptom control from short-acting octreotide will be assessed. Plasma 5-HIAA will be sampled for subjects with ≤5 BMs per day, an average of <4 BMs / day, or an average of >2 flushing episodes / day over the 2 weeks between S1 and S2 and continuing through the screening period. During the screening period, subjects must demonstrate adequate washout of short-acting octreotide by meeting symptomatic eligibility criteria (an increase of ≥2 BMs above the daily treatment average from the documented period between S1 and S2, or an increase in daily average flushing episodes of ≥3 episodes in at least one day during a 7-day period). If day 1 cannot be scheduled within 10 weeks of S2, the subject will be considered a screening failure.

[0361] Antidiarrheal medications may be used during screening as recommended by the investigator. Exemplary guidelines for recommending oral antidiarrheal medications to subjects during the screening period are as follows:

[0362] [Table 23]

[0363] Diphenoxylate or loperamide may be used as needed to improve symptom control at any time during the study, except when short-acting octreotide is being used for rescue therapy. At screening, if a subject meets symptom criteria that make them eligible for randomization, and there is a delay in the schedule of the subject's Day 1 Randomization Visit, the subject may be initiated on short-acting octreotide. Short-acting octreotide must be stopped no later than 12 hours prior to the randomization visit.

[0364] [Table 24]

[0365] Randomized Treatment Phase Once all screening assessments are completed and subject eligibility is verified, subjects will be randomized to 40 mg QD vs. 80 mg QD for the 8-week randomized treatment phase. Subjects will be provided with enough paltusotine 20 mg tablets for 40 mg QD or 80 mg QD for 14 days on Day 1 and will return to the site on Day 14 to perform PK evaluations. Scheduled study visits will occur on Days 28, 42, and 56. A decision on Day 56 (referred to as Week 8 in the SOA) will be made regarding potential enrollment in the OLE phase.

[0366] Rescue treatment of symptoms of breakthrough carcinoid syndrome during the randomized treatment phase

[0367] Diphenoxylate or loperamide may be used as needed to improve symptom control at any time during the study, except when short-acting octreotide is being used for rescue therapy.Possible treatment regimens for breakthrough symptoms of carcinoid syndrome that arise during the study are shown in Table C.

[0368] On Day 1, all subjects who have not already received instructions for short-acting octreotide 200 μg up to three times daily as directed by the investigator during the screening period will receive instructions for rescue therapy when criteria are met (Table D). Short-acting octreotide should not be administered at least 12 hours prior to biomarker sample collection.

[0369] [Table 25]

[0370] [Table 26]

[0371] If a subject experiences symptoms of carcinoid syndrome that meet the protocol criteria for short-acting octreotide rescue, the respective dose may be increased by 40 mg QD once during the first 28 days to a maximum dose of 80 or 120 mg QD based on symptomatology. No dose escalations will be permitted after day 28 throughout the remaining 4 weeks of the parallel-arm phase of the study. Table E summarizes the dose adjustments for the randomized, parallel-arm portion of the study.

[0372] [Table 27]

[0373] Open-label expansion phase The final dose of the randomized treatment phase will be administered at the study site at the Week 8 visit. Subjects who complete the 8-week randomized treatment phase may begin the OLE phase of the study if, in the investigator's opinion, the subject would benefit from OLE phase participation. Subjects who do not complete the randomized treatment phase but for whom the investigator recommends continued treatment with paltusotine may be eligible to participate in the OLE phase.

[0374] For subjects who roll over into OLE, the initial OLE dose will be selected by the investigator based on frequency of rescue treatment and study drug tolerability, beginning on Day 57 (Table F).

[0375] [Table 28]

[0376] Breakthrough Carcinoid Syndrome Symptoms Rescue Treatment Diphenoxylate or loperamide may be used as needed to improve symptom control at any time during the study, except when short-acting octreotide is being used for rescue therapy. Possible treatment regimens for breakthrough symptoms of carcinoid syndrome occurring during the study are shown in Table C. Short-acting octreotide should not be administered for at least 12 hours prior to biomarker sample collection.

[0377] If a subject experiences symptoms of carcinoid syndrome that meet the protocol criteria for short-acting octreotide rescue, the respective dose may be increased by 40 mg QD once during the first 28 days to a maximum dose of 80 or 120 mg QD based on symptomatology. No dose escalations will be permitted after day 28 throughout the remaining 4 weeks of the parallel-arm phase of the study. Table E summarizes the dose adjustments for the randomized, parallel-arm portion of the study.

[0378] Completion and Early Termination of Research Completion and early termination (ET) of the study are defined separately for the randomized treatment and OLE phases, respectively. Completion of the randomized treatment and OLE phases of the study requires that subjects complete the final visit within each phase (End of Study [EOS] visit for the Randomized Treatment and OLE Phases). Subjects who do not complete the randomized treatment phase may be eligible to participate in the OLE phase, at the request of the investigator and after discussion with the Medical Monitor. Subjects who prematurely discontinue from the randomized treatment or OLE phases of the study should be treated with standard of care recommended by the investigator and attend an ET visit.

[0379] End of randomized treatment phase and end of treatment Completion of the last scheduled dose in the randomized treatment phase is defined as the end of the randomized treatment phase (EOR), and completion of the last scheduled dose in the OLE phase is defined as the end of treatment (EOT).

[0380] End of Study An EOS visit (follow-up visit) will be conducted to collect safety data 28 days after the last dose of paltusotine.

[0381] The EOS visit is 28 days after the last dose of the randomized treatment phase for subjects who do not enter the OLE phase. For subjects who complete the OLE phase, the EOS visit is at Week 62.

[0382] Study objectives and evaluation items To evaluate the safety and tolerability of paltusotine at doses of 40, 80, and 120 mg QD. Endpoints include incidence of TEAEs, including serious TEAEs and TEAEs leading to discontinuation, change from baseline to EOR in safety parameters: clinical laboratory tests, physical examination findings, vital signs, 12-lead ECG, and 24-hour continuous cardiac monitoring (120 mg dose subjects only).

[0383] To evaluate the PK of paltusotine at 40, 80, and 120 mg. Endpoints included steady-state trough levels at each dose in the EOR.

[0384] Exploratory Efficacy of the Randomized Treatment Phase Response rates for the different dose arms will be derived. Endpoints include the proportion of clinical responders by dose during the last week of the randomized treatment phase: ●Only in subjects who meet the enrollment criteria for diarrhea: having an average of less than 4 bowel movements per day; having a >20% reduction in average number of daily bowel movements compared to baseline. ●Only in subjects who meet the flushing enrollment criterion: have a >30% reduction in the average number of daily flushing episodes compared to baseline. ● In subjects who meet the enrollment criteria for both diarrhea and flushing episodes: having an average of less than 4 bowel movements per day compared to baseline; having a >20% reduction in the average number of daily bowel movements; having a reduction from baseline in the average number of daily flushing episodes compared to baseline.

[0385] To evaluate the effect of paltusotine treatment on the frequency of BM / day. Outcomes include change in mean daily BM from the screening baseline period to the last week of the randomized treatment phase.

[0386] To evaluate the effect of paltusotine treatment on the frequency of flushing episodes / day. Outcomes include the change in mean daily flushing episodes from the screening baseline period to the last week of the randomized treatment phase

[0387] To evaluate the effect of paltusotine treatment on biochemical markers of carcinoid syndrome.End points included change from baseline to EOR: plasma 5-HIAA, plasma pancreastatin, serum chromogranin A, serum serotonin.In some subjects, plasma pancreastatin will not be collected and analyzed.

[0388] To evaluate the effect of paltusotine treatment on the use of protocol-defined rescue with short-acting octreotide injections.Evaluation measures include change in short-acting octreotide use: change in the percentage of days on short-acting octreotide in the screening period after subjects met the enrollment criteria relative to the percentage of days on short-acting octreotide in the last week of the randomized treatment phase, and change in the mean daily dose of short-acting octreotide in the screening period after subjects met the enrollment criteria relative to the mean daily dose of short-acting octreotide during the last week of the randomized treatment phase.

[0389] To evaluate the effect of paltusotine treatment on incontinence. Outcomes include the change in mean daily faecal incontinence episodes (defined as the passage of unintentional bowel movements containing solid stool, liquid stool, or mucus) from the screening baseline period to the last week of the randomized treatment period.

[0390] To evaluate the effect of paltusotine treatment on the severity of abdominal pain. Outcomes included change in worst abdominal pain in the last 24 hours (using a NRS of 0 to 10), from the mean baseline period at screening to the mean of the last week of the randomized treatment phase, and from the highest score during the baseline period at screening to the highest score during the last week of the randomized treatment phase.

[0391] To evaluate the effect of paltusotine treatment on stool consistency. Outcomes included: change in worst (highest) stool score (Bristol scale) in the last 24 hours, from the mean baseline period at screening to the mean of the last week of the randomized treatment phase, and from the highest score during the baseline period at screening to the highest score during the last week of the randomized treatment phase.

[0392] To evaluate the effect of paltusotine treatment on health-related quality of life: change from baseline to EORTC QLQ-C30, EORTC QLQ-GI.NET21 scores, EQ-5D-5L, FACT-CSI.

[0393] To assess the severity and change in carcinoid syndrome as perceived by the subjects. Evaluation items include change from baseline to EOR in Patient Global Impression of Status (PGI-S) and change in EOR in Patient Global Impression of Severity (PGI-C).

[0394] To assess treatment preferences. Outcomes include change in treatment preferences from baseline to EOR.

[0395] To evaluate the effect of paltusotine treatment on bowel urgency. Outcomes include the change in mean daily urgency episodes (defined as BMs that force the subject to rush to the toilet) from the screening baseline period to the last week of the randomized treatment phase.

[0396] Open Label Extension (OLE) Phase To evaluate the safety and tolerability of paltusotine. Endpoints included incidence of TEAEs, including serious TEAEs and TEAEs leading to discontinuation, safety parameters: clinical laboratory tests, physical examination findings, vital signs, and change from EOR to EOT on 12-lead ECG.

[0397] To evaluate the PK of paltusotine at 40, 80, and 120 mg. Endpoints included steady-state trough levels at each dose at EOT.

[0398] To evaluate the effect of paltusotine on tumor progression. Outcomes include the incidence of NET progression at EOT using imaging assessments at 6-month intervals during paltusotine treatment.

[0399] To evaluate the durability of the effect of paltusotine. Endpoints include: a) Proportion of clinical responders by dose during the last week of the OLE phase: i) Only in subjects who meet the entry criteria for diarrhea: having an average of less than 4 bowel movements per day and having a reduction in the average number of daily bowel movements of >20% compared to baseline. ii) Only in subjects who meet the entry criteria for flushing: having a reduction in the average number of daily flushing episodes of >30% compared to baseline. iii) Only in subjects who meet the entry criteria for both diarrhea and flushing episodes: having an average of less than 4 bowel movements per day and having a reduction in the average number of daily bowel movements of >20% compared to baseline, and having a reduction from baseline in the average number of daily flushing episodes compared to baseline. b) Change in daily BM frequency from the average of the last week before baseline to the average of the last week of OLE phase participation. c) Change in daily flushing episode frequency from the average of the last week before baseline to the average of the last week of OLE phase participation. d) Change from baseline to EOT in biochemical markers of carcinoid syndrome. e) Change from baseline to EOT: EORTC QLQ-C30, EORTC QLQ-GI.NET21 score, EQ-5D-5L, FACT-CSI.

[0400] To evaluate the effect of paltusotine treatment on the use of protocol-defined rescue with short-acting octreotide injections.Outcomes included change in number of days treated with short-acting octreotide, change in percentage of days on short-acting octreotide in the last week before baseline compared with 1 week before EOT, and change in mean daily dose of octreotide from the last week before baseline to 1 week before EOT.

[0401] To evaluate the effect of paltusotine treatment on incontinence. Outcomes include the change in mean daily faecal incontinence episodes (defined as the passage of unintentional bowel movements containing solid stool, liquid stool, or mucus) from the last week before baseline to the last week before EOT.

[0402] To evaluate the effect of paltusotine treatment on the severity of abdominal pain. Outcomes included: change in worst abdominal pain in the last 24 hours (using a NRS of 0 to 10), from the mean of the last week before baseline to the last week of OLE; from the highest score in the last week before baseline to the last week of OLE.

[0403] To evaluate the effect of paltusotine treatment on bowel urgency. Outcomes included the change in mean daily urgency episodes (defined as BMs that forced the subject to rush to the toilet) from the last week before baseline to the last week before EOT.

[0404] Number of targets Approximately 30 subjects (15 subjects / arm) will be enrolled in the study. Subjects taking proton pump inhibitors (PPIs) at screening may contribute up to 6 subjects enrolled in the study.

[0405] Inclusion criteria Willingness and ability to provide written informed consent prior to any study-related procedures. Willingness and ability to comply with study procedures as specified in the protocol, including at least 70% compliance with an electronic symptom diary for 2 weeks prior to the Day 1 visit.

[0406] Male or female subjects aged ≥18 years at screening.

[0407] Documented carcinoid syndrome requiring medical therapy, including at least one prior instance of biomarker elevation. Eligible subjects will be classified into one of the following categories: Naïve to SRL and actively symptomatic (average of ≥4 bowel movements (BM) on at least 2 days or ≥2 flushing episodes over a 2-week period) Subjects currently treated with lanreotide, octreotide LAR, or short-acting octreotide (subcutaneous or oral), currently symptomatically controlled (≦5 BMs per weekday, mean <4 BMs / day, and mean ≦2 flushing episodes / day over a 2-week period), and willing to wash out the medication. Subjects must demonstrate worsening of symptoms after washout.

[0408] Evaluable documentation of locally advanced or metastatic histopathologically confirmed well-differentiated NETs. Tumors must be grade 1 or grade 2 (Ki-67 ≤ 20%, or ≤ 20 mitoses per 10 high-power fields if Ki-67 index is not available) according to the World Health Organization classification of neuroendocrine neoplasms (Rindi G, Inzani F. Neuroendocrine neoplasm update: towards universal nomenclature Endocr Relat Cancer. 2020;27(6):R211-R218). Grade 3 tumors are not eligible.

[0409] [Table 29]

[0410] Absence of tumor progression in the investigator's opinion documented by standard surveillance within the last 6 months prior to initiation of study drug treatment.

[0411] Previous documentation of positive SSTR tumor status by PET or somatostatin receptor scintigraphy.

[0412] Plasma 5-HIAA ≥ 2 × ULN during screening in naïve subjects without washout of SRL.

[0413] Women who engage in heterosexual intercourse must be non-fertile, postmenopausal with at least 1 year of amenorrhea, or agree to use highly effective contraception from the start of screening until the final study visit. In addition to these contraception methods, male partners must use condoms from the start of screening until the final study visit.

[0414] If the subject is male, he or she must agree to use condoms if sexually active or to abstain.

[0415] Exclusion criteria Medical History and Medications: Diarrhea due to any condition other than carcinoid syndrome (including but not limited to fat malabsorption, bile acid malabsorption, short bowel syndrome, exocrine pancreatic insufficiency, infection, VIPoma, Zollinger-Ellison syndrome). Exceptions to these are subjects who have had a previous cholecystectomy or small bowel resection, but only if diarrhea is controlled prior to washout or native to the SRL. Uncontrolled / severe diarrhea associated with significant volume shrinkage, dehydration, or hypotension. In the investigator's opinion, need for second-line therapy (e.g., telotristat) to control symptoms of carcinoid syndrome. Tumor-directed therapy <4 weeks prior to screening, treatment with hepatic embolization, radiation therapy, peptide receptor radionuclide therapy (PRRT) and / or cytoreduction <12 weeks prior to screening. Karnofsky performance status <60%. Major surgery within 8 weeks prior to screening. Malignant tumors, excluding eligible NETs, ​​basal or squamous cell carcinoma considered clinically cured, or cervical carcinoma in situ. Life expectancy <12 months from screening. Diabetes mellitus treated with insulin less than 6 weeks prior to study enrollment or with a change in total daily insulin dose of >15% within 6 weeks prior to screening. Poorly controlled diabetes defined as having a hemoglobin A1c (HbA1c) that is ≥8.5% (i.e., ≥69.5 mmol / mol) or an estimated HbA1c based on fructosamine if HbA1c is not evaluable (e.g., due to a hemoglobinopathy). Current use of medications that are strong inducers of cytochrome P450 3A4 (CYP3A4) within 2 weeks prior to screening, which may reduce systemic exposure to paltusotine. Inability to receive short-acting octreotide (octreotide acetate injection). Known allergy or hypersensitivity to any of the test materials or related compounds. Any other medical condition that may interfere with the study, as determined by the investigator.

[0416] Screening Tests and Evaluations: Confirmed or suspected active COVID-19 based on SARS-CoV-2 PCR testing and clinical symptoms: Corrected QT interval (QTcF) >480 ms using Fridericia's formula (or QTcF >500 ms in the presence of complete bundle branch block), or PR interval >240 ms during screening, based on the median reading of the mean of three ECGs, each separated by approximately 1 minute in duration, after the subject has rested quietly in the supine position for at least 10 minutes without significant stimuli (noise, television, etc.).

[0417] Other criteria: cardiovascular disease, estimated glomerular filtration rate <60 mL / min / 1.73 m 2 Clinically significant comorbidities including, but not limited to, cirrhosis, baseline AST and / or ALT >2xULN, and / or total bilirubin >1.5xULN. Subjects with previously diagnosed Gilbert's syndrome without other hepatic and biliary disorders and associated with a total bilirubin <3.5mg / dL (<51.3μmol / L) are allowed.

[0418] Subject reported rating Planned time points for all subjects are noted in the SOA. If these assessments are performed at the same visit, the order is as follows: (1) electronic symptom diary, (2) Patient Global Impression Severity (PGI-S), (3) Patient Global Impression Change (PGI-C), (4) EuroQol 5 Dimensions 5 Level (EQ-5D-5L, (5) EORTC QLQ-C30 quality of life questionnaire, (6) EORTC QLQ-GI.NET21 quality of life questionnaire, (7) Functional Assessment of Carcinoid Syndrome Symptom Index (FACT-CSI) (Shaunfield S, Webster KA, Kaiser K, et al. (2021) Development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index. Neuroendocrinology 111: 850-862), and (8) Treatment Preference Questionnaire.

[0419] Electronic Symptom Diary: Subjects will be asked to complete a daily home electronic symptom diary, a short symptom diary, starting after the initial screening, throughout screening, from weeks 1 to 12 (throughout the randomized treatment phase, and until the start of the OLE phase), and then daily for 2 weeks during the remainder of the OLE phase prior to the clinic visits at weeks 18, 24, 36, 48, and 58 (or simply during weeks 17-18, 23-24, 35-36, 47-48, and 57-58). This electronic symptom diary will be used to assess subject comprehension and compliance and to measure baseline symptoms of bowel movement (BM) frequency and frequency of flushing, fecal urgency and incontinence episodes, abdominal pain severity, and stool consistency. Baseline symptoms of stool consistency will be assessed according to the Bristol Scale, and abdominal pain by NRS.

[0420] Subjects will be instructed to complete the diary at approximately the same time each evening during the time period specified above. Site staff will review subjects' compliance with completing the self-reported electronic diary as outlined in the electronic diary manual.

[0421] Subjects will be asked to record the use of all breakthrough symptom medications in a daily electronic symptom diary.

[0422] Global Impression of Change and Severity: The PGI-S assesses the subject's perception of overall disease severity using a 4-point verbal rating scale (no symptoms, mild symptoms, moderate symptoms, and severe symptoms). The PGI-C assesses the subject's perception of change in disease severity using a 7-point verbal rating scale (much better, moderately better, slightly better, no change, slightly worse, moderately worse, and much worse).

[0423] EQ-5D-5L: The EQ-5D-5L (EQ-5D Five Severity Levels), developed by the European Quality of Life (EuroQoL), is a standardized instrument completed by subjects for use as a measure of health outcomes applicable to a wide range of health conditions. The EQ-5D-5L includes five dimensions of health: mobility, self-care ability, ability to perform usual activities, pain and discomfort, and anxiety and depression. Based on qualitative and quantitative studies conducted by the EuroQoL Group, each domain has five options (levels): "no problems", "slight problems", "moderate problems", "severe problems", and "impossible / extreme problems". Responses to all five dimensions can be converted into a single summary index, utility (range: 0-1), by using a value set. Higher index values ​​represent better health status.

[0424] EORTC QLQ-C30 Quality of Life Questionnaire: The EORTC QLQ-C30 Quality of Life Questionnaire is used to assess health-related quality of life in subjects with cancer. The questionnaire involves 28 questions to assess health-related quality of life, and each question can be answered on a scale of 1 to 4. A lower score indicates a better quality of life. There are two additional questions, one to assess the subject's "overall health in the past week" and one to assess the subject's "overall quality of life in the past week." Each of these two questions can be answered on a scale of 1 to 7. A higher score indicates a better quality of life.

[0425] EORTC QLQ-GI.NET21 Quality of Life Questionnaire: The EORTC QLQ-GI.NET21 Quality of Life Questionnaire is used for symptom follow-up in subjects with neuroendocrine carcinoids. It has about 21 questions divided into the categories "during the past week" and "during the past 4 weeks" and is used for symptom follow-up in subjects. Each of the questions can be answered on a scale of 1 to 4. A lower score indicates a better quality of life.

[0426] FACT-CSI: The FACT-CSI is a 24-item instrument that can be scored as a single multidimensional symptom index consisting of the following domains: disease-related physical symptoms, disease-related emotional symptoms, side effects of treatment, and functional health. Subjects select a response to each statement on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much). A lower total score indicates a better quality of life (Shaunfield S, Webster KA, Kaiser K, et al. (2021) Development of the Functional Assessment of Cancer Therapy-Carcinoid Syndrome Symptom Index. Neuroendocrinology 111:850-862).

[0427] Treatment Preference Question: The treatment preference question is a single question regarding the subject's preferred form of treatment, ie, injectables previously used, or oral investigational drug (or no preference).

[0428] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are within the spirit and scope of this application and the appended claims.

Claims

1. 1. A pharmaceutical composition for use in treating carcinoid syndrome in a human, comprising 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile (Compound A), or a pharmaceutically acceptable salt thereof, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally; The pharmaceutical composition, wherein treating carcinoid syndrome comprises managing the symptoms of carcinoid syndrome.

2. Managing the symptoms of carcinoid syndrome includes reducing the frequency of daily bowel movements, diarrheal episodes, fecal incontinence episodes, skin flushing, or a combination thereof; 10. The pharmaceutical composition of claim 1, wherein managing the symptoms of carcinoid syndrome comprises treating diarrhea, flushing episodes, or both in the human.

3. The pharmaceutical composition described in claim 2, wherein the diarrhea is severe diarrhea, and the severity of the severe diarrhea is measured by the number of bowel movements (BM) per day, the number of watery stools measured by the Bristol Stool Scale, or both.

4. The pharmaceutical composition of claim 1, wherein managing the symptoms of carcinoid syndrome includes reducing the number of bowel movements (BMs) to fewer than four BMs / day on two consecutive days, reducing the flushing frequency to fewer than three flushing episodes / day on at least one day, or both.

5. The pharmaceutical composition of claim 2, wherein the severity of the flushing episode is assessed by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) levels, plasma serotonin levels, or both.

6. The pharmaceutical composition of claim 1, wherein the treatment comprises administering to the human a daily dose of Compound A, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 1, wherein the human is administered 20 mg / day to 160 mg / day of Compound A, or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 1, wherein the human is administered 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, or 160 mg / day of Compound A, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 1, wherein the human is administered 40 mg / day of Compound A, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 1, wherein the human is administered 80 mg / day of Compound A, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 1, wherein the human is administered 120 mg / day of Compound A, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 6, wherein the daily dose of Compound A, or a pharmaceutically acceptable salt thereof, is increased by an incremental daily dose equivalent to about 40 mg / day.

13. The pharmaceutical composition of claim 1, wherein the serum 5-hydroxyindoleacetic acid (5-HIAA) concentration in the human prior to treatment with Compound A is greater than about >280 μmol / L.

14. Compound A, or a pharmaceutically acceptable salt thereof, comprising a spray-dried solid dispersion of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride; one or more additional pharmaceutically acceptable ingredients; and and optionally one or more film coatings; Optionally, the spray-dried solid dispersion comprises: (a) 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, (b) a pharmaceutically acceptable polymer; 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer; 2. The pharmaceutical composition of claim 1, wherein the amount of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride administered is based on Compound A.

15. The one or more tablets are administered at least 30 minutes before a meal; the one or more tablets are administered at least 60 minutes before a meal; 15. The pharmaceutical composition of claim 14, wherein the one or more tablets are administered in an empty stomach at least 30 minutes before a meal with a glass of water.

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