Uses of a somatostatin modulator for the treatment of disease

Abstract

This article describes formulations of somatostatin regulators, methods for manufacturing such formulations, and methods for treating conditions, diseases, or symptoms that will benefit from regulation of somatostatin activity using such formulations.

Description

[Technical Field]

[0001] This article describes pharmaceutical compositions and preparations containing somatostatin regulators, methods for manufacturing such pharmaceutical compositions and preparations, and uses of such pharmaceutical compositions and preparations for treating conditions, diseases, or ailments that would benefit from regulation of somatostatin activity. [Previous Technology]

[0002] 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 various secondary hormones. Six somatostatin receptor protein subtypes (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5) have been identified and are encoded by five different somatostatin receptor genes. Regulation of specific somatostatin receptor subtypes or combinations thereof is attractive for treating conditions, diseases, or symptoms that would benefit from regulation of somatostatin activity. [Summary of the Invention]

[0003] In one embodiment, this article describes a method for treating acromegaly in humans, comprising orally administering to the human suffering from acromegaly a daily dose of 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzonitrile (compound A) or a pharmaceutically acceptable salt or solvate thereof sufficient to achieve a glutar plasma concentration 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 or at least about 40 ng / mL of compound A. In some embodiments, the plasma concentration of compound A is 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, about 38 ng / mL, about 39 ng / mL, or about 40 ng / mL.

[0004] In another embodiment, this article describes a method for treating acromegaly in humans, comprising: orally administering a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof to the human suffering from acromegaly; determining the plasma trough concentration of compound A in the human; and if the human does not have at least a critical trough plasma concentration of compound A, increasing the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the critical trough plasma concentration of compound A is approximately 20 ng / mL, approximately 21 ng / mL, approximately 22 ng / mL, approximately 23 ng / mL, approximately 24 ng / mL, approximately 25 ng / mL, approximately 26 ng / mL, approximately 27 ng / mL, approximately 28 ng / mL, approximately 29 ng / mL, approximately 30 ng / mL, approximately 31 ng / mL, approximately 32 ng / mL, approximately 33 ng / mL, approximately 34 ng / mL, approximately 35 ng / mL, approximately 36 ng / mL, approximately 37 ng / mL, approximately 38 ng / mL, approximately 39 ng / mL, approximately 40 ng / mL, approximately 41 ng / mL, approximately 42 ng / mL, approximately 43 ng / mL, approximately 44 ng / mL, approximately 45 ng / mL, approximately 46 ng / mL, approximately 47 ng / mL, approximately 48 ng / mL, approximately 49 ng / mL. ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL, or about 60 ng / mL. In some embodiments, the critical trough plasma concentration of compound A is 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, about 38 ng / mL, about 39 ng / mL, or about 40 ng / mL. In some embodiments, increasing the daily dose of compound A or its pharmaceutically acceptable salts or solvates comprises increasing the daily dose by an amount equivalent to about 10 mg of compound A monohydrochloride.

[0005] In some embodiments, a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is equivalent to about 10 mg / day to about 80 mg / day of compound A monohydrochloride. In some embodiments, a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is equivalent to about 20 mg / day to about 60 mg / day of compound A monohydrochloride. In some embodiments, a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is 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. In some embodiments, a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is equivalent to 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, or about 60 mg / day of compound A monohydrochloride.

[0006] In another embodiment, this document describes a method for treating acromegaly in humans, comprising modifying serum insulin-like growth factor-1 (IGF-1) concentrations, growth hormone (GH) concentrations, or both, wherein the method comprises orally administering, once daily, to the human suffering from acromegaly a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, modification of serum insulin-like growth factor-1 (IGF-1) concentrations, growth hormone (GH) concentrations, or both comprises a reduction in IGF-1 concentrations, GH concentrations, or both. In some embodiments, modification of serum insulin-like growth factor-1 (IGF-1) concentrations comprises achieving less than about 2.5 times the upper limit of normal (ULN) for IGF-1. In some embodiments, serum insulin-like growth factor-1 (IGF-1) concentration, growth hormone (GH) concentration, or a modification thereof comprises achieving a glutar 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, or at least about 40 ng / mL. In some embodiments, serum insulin-like growth factor-1 (IGF-1) concentration, growth hormone (GH) concentration, or a modification thereof comprises achieving a trough plasma concentration of compound A of the following: 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, about 38 ng / mL, about 39 ng / mL, or about 40 ng / mL. In some embodiments, modified serum insulin-like growth factor-1 (IGF-1) concentrations, growth hormone (GH) concentrations, or both, comprise compound A administered at a daily dose equivalent to about 10 mg / day to about 80 mg / day of compound A monohydrochloride, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, modified serum insulin-like growth factor-1 (IGF-1) concentrations, growth hormone (GH) concentrations, or both, comprise compound A administered at a daily dose 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, or a pharmaceutically acceptable salt or solvate thereof.

[0007] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered orally according to a titration schedule.

[0008] In another embodiment, this document describes a method for treating acromegaly in humans, comprising orally administering to a human suffering from acromegaly a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt or solvate thereof via a titration schedule. In some embodiments, the titration schedule comprises administering an initial dose of compound A or a pharmaceutically acceptable salt or solvate thereof daily for an initial period, followed by administering doses of compound A or a pharmaceutically acceptable salt or solvate thereof daily at doses higher than the initial dose. In some embodiments, the initial period comprises one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the initial period comprises about two weeks.

[0009] In some embodiments, the titration schedule includes incremental titration or down-titration of compound A or a pharmaceutically acceptable salt or solvate thereof, followed optionally by re-incremental titration. In some embodiments, the titration schedule includes administering compound A or a pharmaceutically acceptable salt or solvate thereof at an initial dose for about one to about four weeks, increasing the dose by an amount equal to a first increment if the patient tolerates the initial dose, or decreasing the dose by an amount equal to a first increment if the patient does not tolerate the initial dose.

[0010] In some embodiments, the titration schedule further includes: administering compound A or a pharmaceutically acceptable salt or solvate thereof at an increased dose for about one to about four weeks, and if the patient tolerates the increased dose, further increasing the dose by an amount equal to a second increment; or administering compound A or a pharmaceutically acceptable salt or solvate thereof at a decreased dose for about one to about four weeks, and if the patient tolerates the decreased dose, increasing the dose by an amount equal to a second increment as appropriate. In some embodiments, the initial dose of compound A or a pharmaceutically acceptable salt or solvate thereof is equivalent to about 10 mg / day or about 20 mg / day of compound A monohydrochloride. In some embodiments, the first increment is equivalent to an amount of compound A or a pharmaceutically acceptable salt or solvate thereof equivalent to about 10 mg of compound A monohydrochloride. In some embodiments, the first increment is equal to a second increment. In some embodiments, the method further comprises: evaluating serum insulin-like growth factor-1 (IGF-1) concentrations in humans with acromegaly before each dose increase; and increasing the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof if the serum IGF-1 concentration is above the upper limit of normal (ULN). In some embodiments, the method further comprises: evaluating serum insulin-like growth factor-1 (IGF-1) concentrations in humans with acromegaly before each dose increase; and increasing the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof if the serum IGF-1 concentration is approximately 1.1 times, approximately 1.2 times, approximately 1.3 times, approximately 1.4 times, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, or greater than 2.5 times the upper limit of normal (ULN).

[0011] In some embodiments, the titration schedule is repeated until an optimal dose is obtained. In some embodiments, the optimal dose is equivalent to 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. In some embodiments, the optimized dose provides steady-state plasma trough concentrations of compound A at 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, about 38 ng / mL, about 39 ng / mL, or about 40 ng / mL.

[0012] In another embodiment, this document describes a method for treating acromegaly in humans, comprising orally administering to a human suffering from acromegaly a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt or solvate thereof, wherein the human is unresponsive to treatment with a somatostatin analogue, resistant to the therapy, or has lost the response to treatment. In some embodiments, the somatostatin analogue is octreotide, lanreotide, or pasireotide.

[0013] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered orally according to a titration schedule.

[0014] In another embodiment, this article describes a method for assessing the clinical response of individuals with acromegaly to treatment with compound A or its pharmaceutically acceptable salts or solvates, comprising: (a) evaluating serum insulin-like growth factor-1 in individuals with acromegaly before initiating treatment with compound A. (a) IGF-1 concentration; (b) administering compound A or its pharmaceutically acceptable salt or solvate at an initial daily dose for an initial period; (c) re-evaluating serum IGF-1 concentration in individuals with acromegaly; and (d) continuing daily administration of compound A or its pharmaceutically acceptable salt or solvate, and if the serum IGF-1 concentration in step (a) is higher than the serum IGF-1 concentration in step (c), increasing the daily dose of compound A or its pharmaceutically acceptable salt or solvate as appropriate, or if the serum IGF-1 concentration in step (c) is substantially similar to the serum IGF-1 concentration in step (a), discontinuing daily administration of compound A or its pharmaceutically acceptable salt or solvate as appropriate. In some embodiments, the initial period is approximately two weeks, approximately three weeks, or approximately four weeks. In some embodiments, the initial period is approximately two weeks.

[0015] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered to an individual following a titration schedule. In some embodiments, the titration schedule comprises one or more cycles of: administering compound A or a pharmaceutically acceptable salt or solvate thereof at a first daily dose for approximately two weeks, followed by: administering compound A or a pharmaceutically acceptable salt or solvate thereof at an increased daily dose or administering compound A or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, if the serum IGF-1 concentration is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2 times, about 2.1 times, about 2.2 times, about 2.3 times, about 2.4 times, about 2.5 times, or greater than 2.5 times the upper limit of normal (ULN), the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased.

[0017] In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased in increments equivalent to about 10 mg / day of compound A monohydrochloride. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased at a frequency of about two weeks.

[0018] In some embodiments, the incremental dose increase cycle is repeated until an optimal dose is obtained. In some embodiments, the optimal dose is equivalent to 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. In some embodiments, the optimized dose provides steady-state plasma trough concentrations of compound A at approximately 20 ng / mL, approximately 21 ng / mL, approximately 22 ng / mL, approximately 23 ng / mL, approximately 24 ng / mL, approximately 25 ng / mL, approximately 26 ng / mL, approximately 27 ng / mL, approximately 28 ng / mL, approximately 29 ng / mL, approximately 30 ng / mL, approximately 31 ng / mL, approximately 32 ng / mL, approximately 33 ng / mL, approximately 34 ng / mL, approximately 35 ng / mL, approximately 36 ng / mL, approximately 37 ng / mL, approximately 38 ng / mL, approximately 39 ng / mL, or approximately 40 ng / mL. In some embodiments, the optimized dose maintains normal serum IGF-1 concentrations in the individual.

[0019] In some embodiments, the normal serum IGF-1 concentration in an individual is less than about 1 times the upper limit of normal (ULN).

[0020] In another embodiment, this document describes a method for treating acromegaly in humans, comprising orally administering to a human suffering from acromegaly a pharmaceutical composition comprising 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzonitrile (compound A) or a pharmaceutically acceptable salt or solvate thereof; wherein the human suffering from acromegaly has previously been treated with a somatostatin analog; and wherein the treatment is initiated with a daily dose equivalent to about 40 mg / day of compound A monohydrochloride. In some embodiments, the human suffering from acromegaly responds to and tolerates treatment with a somatostatin analog. In some embodiments, the somatostatin analog is octreotide, lanreotide, or parreotide. In some embodiments, signs and symptoms of acromegaly have previously been controlled with a reservoir-type monotherapy of octreotide or lanreotide. In some embodiments, the control of acromegaly signs and symptoms by octreotide or lanreotide reservoir-type monotherapy includes IGF-1 ≤ 1.0 × ULN. In some embodiments, IGF-1 levels and acromegaly signs and symptoms are evaluated at a frequency of approximately one month. In some embodiments, if IGF-1 > 0.9 × ULN, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased to an equivalent daily dose of approximately 60 mg / day of compound A monohydrochloride. In some embodiments, if a human is intolerant to the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof, the daily dose is reduced to an equivalent amount of approximately 20 mg / day of compound A monohydrochloride.

[0021] In another embodiment, this document describes a method for treating acromegaly in humans, comprising orally administering to a human with acromegaly a pharmaceutical composition comprising 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzonitrile (compound A) or a pharmaceutically acceptable salt or solvate thereof; wherein the human with acromegaly has not received prior treatment; or wherein the human with acromegaly has not received treatment for acromegaly in the past 4 months; or wherein the human with acromegaly was previously treated with a somatostatin analog and has discontinued treatment with a somatostatin analog and allowed sufficient time for the somatostatin analog to be flushed out of the body; and wherein treatment is initiated with a daily dose equivalent to about 20 mg / day of compound A monohydrochloride. In some embodiments, the somatostatin analog is octreotide, lanreotide, or parreotide. In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased over periods of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or about 9 weeks to a daily dose equivalent to about 40 mg / day of compound A monohydrochloride. In some embodiments, IGF-1 levels and signs and symptoms of acromegaly are evaluated at a frequency of about one month. In some embodiments, if IGF-1 > 0.9 × ULN, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased to a daily dose equivalent to about 60 mg / day of compound A monohydrochloride. In some embodiments, if a person with acromegaly is intolerant to a daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof, the daily dose is reduced to an amount equivalent to about 20 mg / day of compound A monohydrochloride. In some embodiments, the daily dose provides steady-state plasma trough concentrations of the following compounds A: approximately 20 ng / mL, approximately 21 ng / mL, approximately 22 ng / mL, approximately 23 ng / mL, approximately 24 ng / mL, approximately 25 ng / mL, approximately 26 ng / mL, approximately 27 ng / mL, approximately 28 ng / mL, approximately 29 ng / mL, approximately 30 ng / mL, approximately 31 ng / mL, approximately 32 ng / mL, approximately 33 ng / mL, approximately 34 ng / mL, approximately 35 ng / mL, approximately 36 ng / mL, approximately 37 ng / mL, approximately 38 ng / mL, approximately 39 ng / mL, or approximately 40 ng / mL. In some embodiments, if IGF-1 levels remain above the upper limit of normal after treatment with a daily dose of compound A monohydrochloride or solvate equivalent to approximately 60 mg / day or more, then treatment with compound A is discontinued.

[0022] In some embodiments, treatment with compound A or its pharmaceutically acceptable salts or solvates is interrupted if a human is intolerant to compound A, compound A monohydrochloride, or a solvate thereof.

[0023] In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased by an incremental dose equivalent to about 10 mg / day of compound A monohydrochloride.

[0024] In some embodiments, in any of the methods of treatment using compound A described herein, the method further includes measuring serum glucose levels in the individual. In some embodiments, serum glucose levels in the individual are measured when initiating treatment with compound A or a pharmaceutically acceptable salt or solvate thereof; when adjusting the dose of compound A or a pharmaceutically acceptable salt or solvate thereof; or in both cases. In some embodiments, the method further includes measuring serum glucose levels in the individual when initiating treatment with compound A or a pharmaceutically acceptable salt or solvate thereof; when increasing the dose of compound A or a pharmaceutically acceptable salt or solvate thereof; or in both cases. In some embodiments, measuring serum glucose levels in the individual includes administering an oral glucose tolerance test (OGTT). In some embodiments, if the peak serum glucose concentration in the individual is >150 mg / dL, as measured by an oral glucose tolerance test (OGTT), antidiabetic treatment is initiated as appropriate, or antidiabetic treatment is adjusted as appropriate.

[0025] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more capsules or tablets.

[0026] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more capsules. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more capsules, wherein the capsules are HMG capsules as described herein.

[0027] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more tablets. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more tablets, wherein the tablets are as described herein.

[0028] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered in the form of one or more tablets, each tablet comprising: a spray-dried solid dispersion of compound A monohydrochloride or a solvate thereof; one or more additional pharmaceutically acceptable ingredients; and, where applicable, one or more film coating agents. In some embodiments, the spray-dried solid dispersion comprises: (a) compound A monohydrochloride or a solvate thereof; and (b) a pharmaceutically acceptable polymer; wherein compound A monohydrochloride or a solvate thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer. In some embodiments, one or more pharmaceutically acceptable ingredients are selected from the group consisting of: one or more diluents, one or more disintegrants, one or more lubricants, and one or more flow aids. In some embodiments, one or more pharmaceutically acceptable ingredients comprise microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium, crospovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, colloidal silica, and magnesium stearate.

[0029] In some embodiments, each tablet comprises about 2% to about 20% by weight of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet comprises 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 compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet comprises about 10% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, each tablet comprises: about 2% to about 15% by weight of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, wherein the dispersed compound A monohydrochloride or a solvate thereof in the polymer matrix comprises about 20% to about 35% by weight of the tablet; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0030] In some embodiments, the tablet comprises: a spray-dried dispersion of about 20% to about 40% by weight of a monohydrochloride salt of compound A or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0031] In some embodiments, the spray-dried dispersion comprises a polymer matrix of compound A monohydrochloride or its solvates in a ratio of about 15 / 85 to about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA).

[0032] In some embodiments, each tablet comprises: a spray-dried dispersion of about 20% to about 35% by weight of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; wherein the spray-dried dispersion comprises a polymer matrix of compound A monohydrochloride or a solvate thereof in a ratio of about 15 / 85 to about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: microcrystalline cellulose, mannitol, pregelatinized starch, cross-linked sodium carboxymethyl cellulose, crosspovidone, sodium chloride, 1:1 sodium chloride:potassium chloride, silica, and magnesium stearate; and, where applicable, 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 a spray-dried dispersion of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; wherein the spray-dried dispersion comprises about 15 / 85 or about 3 A polymer matrix of compound A monohydrochloride or its solvates in a 5 / 65 ratio with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0034] 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 a spray-dried dispersion of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; wherein the spray-dried dispersion comprises a polymer matrix of compound A monohydrochloride or a solvate thereof in a ratio of about 15 / 85 or about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically 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; less than about 5% by weight of one or more film coating agents, depending on the situation.

[0035] In some embodiments, each tablet comprises: about 2% to about 15% by weight of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer, wherein the dispersed compound A monohydrochloride or a solvate thereof in the polymer matrix is ​​about 20% to about 35% by weight of the tablet; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0036] In some embodiments, each tablet comprises: a spray-dried dispersion of about 20% to about 40% by weight of a monohydrochloride salt of compound A or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0037] In some embodiments, the spray-dried dispersion comprises a polymer matrix of compound A monohydrochloride or a solvate thereof in a ratio of about 15 / 85 to about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA).

[0038] In some embodiments, each tablet comprises: a spray-dried dispersion of about 20% to about 35% by weight of compound A monohydrochloride or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; wherein the spray-dried dispersion comprises a polymer matrix of compound A monohydrochloride or a solvate thereof in a ratio of about 15 / 85 to about 35 / 65 with hydroxypropyl methylcellulose acetate succinate (HPMCAS) or polyvinylpyrrolidone polyvinyl acetate copolymer (PVP / VA); about 60% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more disintegrant aids, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0039] In some embodiments, each tablet contains about 10 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 10 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 20 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 30 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 40 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 50 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 60 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 70 mg of compound A monohydrochloride or a solvate thereof. In some embodiments, each tablet contains about 80 mg of compound A monohydrochloride or a solvate thereof.

[0040] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered once daily at least 30 minutes before a meal. In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is administered once daily at least 60 minutes before a meal. In some embodiments, compound A is administered once daily on an empty stomach. In some embodiments, compound A is administered at least 30 minutes before a meal. In some embodiments, compound A is administered at least 60 minutes before a meal. In some embodiments, compound A is administered at least 180 minutes after a meal. In some embodiments, compound A is administered at least 60 minutes before a meal and at least 180 minutes after a meal. In some embodiments, compound A is administered at bedtime. In some embodiments, compound A is administered once daily on an empty stomach with a glass of water at least 30 minutes before a meal.

[0041] In some embodiments, the bioavailability of compound A monohydrochloride or its solvates is substantially unaffected by co-administration with proton pump inhibitors, histamine H2-receptor antagonists, or antacids. In some embodiments, compound A or its pharmaceutically acceptable salts or solvates are not co-administered with drugs that alter the pH of the upper gastrointestinal (GI) tract.

[0042] In some embodiments, if compound A or a pharmaceutically acceptable salt or solvate thereof is co-administered with a drug that alters the pH of the upper gastrointestinal (GI) tract, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased.

[0043] In some embodiments, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof is increased to an amount equivalent to about 10 mg / day or about 20 mg / day of compound A monohydrochloride.

[0044] 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.

[0045] In some embodiments, compound A or a pharmaceutically acceptable salt or solvate thereof is co-administered with a dopamine agonist. In some embodiments, the dopamine agonist is cabergoline or a pharmaceutically acceptable salt thereof. In some embodiments, the dopamine agonist is cabergoline and is administered at a dose and frequency of about 0.5 mg / week to about 0.5 mg / day.

[0046] In one embodiment, this article describes a method for treating acromegaly or neuroendocrine tumors or both in humans, comprising orally administering to a human suffering from acromegaly or neuroendocrine tumor any of the spray-dried dispersion tablets described herein.

[0047] In some embodiments, the tablets are taken once daily. In some embodiments, the tablets are taken at least 30 minutes before a meal. In some embodiments, the tablets are taken at least 60 minutes before a meal. In some embodiments, the tablets are taken at least 180 minutes after a meal. In some embodiments, the tablets are taken at least 60 minutes before a meal and at least 180 minutes after a meal. In some embodiments, the tablets are taken on an empty stomach. In some embodiments, the tablets are taken with a glass of water on an empty stomach at least 30 minutes before a meal. In some embodiments, the tablets are taken at bedtime. In some embodiments, the bioavailability of compound A monohydrochloride or its solvates from the tablets is substantially unaffected by co-administration with proton pump inhibitors, histamine H2-receptor antagonists, or antacids.

[0048] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that although the detailed description and specific examples indicate particular embodiments, they are given by way of illustration only, so that those skilled in the art will understand from this detailed description the various changes and modifications within the spirit and scope of this disclosure.

Implementation Method

[0059] Cross-reference to related applications

[0060] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 193,010, filed May 25, 2021; and U.S. Provisional Patent Application No. 63 / 274,409, filed November 1, 2021; each of which is incorporated herein by reference in its entirety.

[0061] Somatostatin (SST) (also known as growth hormone-releasing inhibitory factor (SRIF)) was initially isolated from the sheep hypothalamus as a 14-amino acid peptide (Brazeau et al., Science 179, 77-79, 1973). Subsequently, an N-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was 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 various 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 the secretion of other hormones, most notably growth hormone (GH). It is produced by a variety of cell types in the central nervous system (CNS) and the intestine, and has multiple functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other anti-proliferative hormones.

[0062] The pleiotropic effects of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5). These 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 Metab8, 398-405, 1997). All receptors are members of the class A subset of the G protein-coupled receptor (GPCR) superfamily. SSTR2A is the most widely expressed subtype in human tumors and is the major receptor for inhibiting GH secretion. Unless otherwise stated, the term SSTR2 refers to SSTR2a.

[0063] Selective modulation of any one of the somatostatin receptor subtypes or combinations thereof may be possible in various clinical applications, relative to other somatostatin receptor subtypes or combinations thereof. In some embodiments, selective modulation of any one of the somatostatin receptor subtypes reduces undesirable side effects in various clinical applications, relative to other somatostatin receptor subtypes.

[0064] For example, regulation 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, such as, but not limited to, cell proliferation, pain sensation, inflammation, and angiogenesis. In some embodiments, selective SSTR2 modulators are used to treat acromegaly, pituitary gigantism, enteroendocrine tumors, pain, neuropathy, nephropathy, and inflammation, as well as retinopathy caused by abnormal angiogenesis. In some other embodiments, selective SSTR2 modulators are particularly used to treat arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, Cushing's disease, acute lung injury, acute respiratory distress syndrome, and ophthalmic conditions such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmology.

[0065] 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. Additionally, SSTR5 is also involved in regulating growth hormone release.

[0066] Somatostatin peptides and their receptor subtypes are also widely expressed in the brain, and disruption or attenuation of their activity is potentially associated with several mental illnesses and neurodegenerative diseases. For example, in patients with schizophrenia, the concentration of somatostatin in the cerebral cortex and hippocampus is reduced, and one of the most consistent neuropathological findings in this patient group is the lack of cortical inhibitory interneurons expressing somatostatin. Somatostatin is also highly expressed in brain regions associated with seizures and is also considered to play an important role in epilepsy. The reduced levels of somatostatin in the hippocampus of patients with Alzheimer's and Parkinson's diseases suggest that the restoration of its signaling is a potential drug target for neurodegeneration.

[0067] In one state, compound A is a selective non-peptide SST2-biased agonist suitable for oral administration to mammals requiring treatment with somatostatin regulators.

[0068] In some embodiments, the somatostatin receptor modulators described herein are effective in a wide range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used to treat a variety of diseases or conditions, such as (but not limited to) acromegaly, pituitary gigantism, neuroendocrine tumors, retinopathy and other ophthalmic conditions, neuropathy, nephropathy, respiratory diseases, cancer, pain, neurodegenerative diseases, inflammatory diseases, and mental and neurodegenerative diseases. In some embodiments, the somatostatin receptor modulators described herein are used to treat acromegaly, neuroendocrine tumors, or both in mammals. In some embodiments, the somatostatin receptor modulators described herein are used to treat acromegaly in mammals. In some embodiments, the somatostatin receptor modulators described herein are used to treat neuroendocrine tumors. In some embodiments, the somatostatin receptor modulators described herein are used to treat pituitary gigantism in mammals.

[0069] In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals. In some embodiments, the somatostatin receptor modulators described herein are used to inhibit certain endocrine substances, such as (but not limited to) GH, insulin, glucagon, and prolactin. Inhibition of certain endocrine substances can be used to treat conditions such as acromegaly; endocrine tumors, such as carcinoid tumors, VIPomas, insulinomas, and glucagonomas; or diabetes and diabetes-related complications, including retinopathy, neuropathy, and nephropathy. In some embodiments, the somatostatin receptor modulators described herein are used to inhibit exocrine secretions from the pancreas, stomach, and intestines to treat conditions such as pancreatitis, fistulas, hemorrhagic ulcers, and diarrhea associated with diseases such as AIDS or cholera. Conditions involving autocrine or paracrine secretions of trophic factors (such as IGF-1) (and some endocrine factors) that can be treated by administration of the compounds described herein include breast cancer, prostate cancer, and lung cancer (small cell and non-small cell epidermoid carcinoma), as well as hepatocellular carcinoma, neuroblastoma, colon and pancreatic adenocarcinoma (ductal type), chondrosarcoma and melanoma, diabetic retinopathy, and atherosclerosis associated with restenosis after vascular grafts and angioplasty.

[0070] In some embodiments, the somatostatin receptor modulators described herein are used to inhibit mediators that suppress neuroinflammatory reactions (e.g., substance P or tachykinin) and can be used to treat rheumatoid arthritis; psoriasis; localized inflammation, such as that associated with sunburn, eczema, or other sources of itching; inflammatory bowel disease; irritable bowel syndrome; and allergies, including asthma and other respiratory illnesses. In some other embodiments, the somatostatin receptor modulators described herein act as neuromodulators in the central nervous system and can be used to treat Alzheimer's disease and other forms of dementia, pain, and headaches. In some embodiments, the somatostatin receptor modulators described herein provide cellular protection in conditions involving visceral blood flow, including sclerosis and esophageal varices.

[0071] Compound A is a somatostatin regulator, which can be used in the treatment methods described herein. Compound A

[0072] As used herein, compound A refers to 3-(4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl)-2-hydroxybenzonitrile, which has the chemical structure shown below.

[0073] Compound A is also known as "patostine". Other names may be known or given to compound A.

[0074] Compound A is a selective non-peptide SST2-biased agonist. In clinical studies, Compound A showed 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. In some embodiments, Compound A is used to treat pituitary gigantism.

[0075] 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 pharmaceutically acceptable salt. In some embodiments, compound A is incorporated into the formulations described herein as a pharmaceutically acceptable solvate.

[0076] As used herein, "medically acceptable" means a material such as a carrier or diluent that does not eliminate the biological activity or properties of a compound and is relatively nontoxic, that is, a material that, when administered to an individual, will not cause undesirable biological effects or will not interact in a harmful manner with any component of a composition containing it.

[0077] The term "pharmaceutically acceptable salt" refers to a form of therapeutic agent consisting of a combination of a cationic form of the therapeutic agent and a suitable anion, or, in alternative embodiments, a combination of an anionic form of the therapeutic agent and 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, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than nonionic species and are therefore suitable for use in solid dosage forms. Furthermore, since its solubility is generally a function of pH, selective dissolution in one or more parts of the digestive tract is possible, and this ability can be manipulated as a form of delayed and sustained release behavior. Moreover, since salt-forming molecules can reach equilibrium in a neutral state, the channels across biological membranes can be modulated.

[0078] In some embodiments, pharmaceutically acceptable salts are obtained by reacting the compounds disclosed herein with an acid. In some embodiments, the compounds disclosed herein (i.e., in their free base form) are basic and react with organic or inorganic acids. Inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include (but are not limited to) 1-hydroxy-2-naphthylcarboxylic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-sidektoglutaric acid; 4-acetaminobenzoic 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; caproic acid; caproic acid; octanoic acid; carbonic acid; cinnamic acid; citric acid; cyclamic acid. (acid); dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactosic acid; gentian acid; glucohepanoic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; glycerophosphate; 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; pyruvic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid (p); and undecanoic acid.

[0079] In some embodiments, compound A is incorporated into the formulations described herein as a pharmaceutically acceptable salt form selected from compound A hydrochloride and compound A methanesulfonic acid. In some embodiments, the salt form of compound A is compound A monohydrochloride. In some embodiments, the salt form of compound A is compound A dihydrochloride. In some embodiments, the salt form of compound A is compound A monomethanesulfonic acid. In some embodiments, the salt form of compound A is compound A dimethanesulfonic acid.

[0080] In one state, compound A monohydrochloride (compound A-HCl) is incorporated into the pharmaceutical composition described herein. Compound A monohydrochloride (compound A-HCl) (also known as 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxy-benzonitrile monohydrochloride and paltostine monohydrochloride) has the following structure:

[0081] In some embodiments, the salt form of compound A is amorphous. In some embodiments, the monohydrochloride salt of compound A is amorphous.

[0082] In some embodiments, the salt form of compound A is crystalline. In some embodiments, the monohydrochloride salt of compound A is crystalline.

[0083] It should be understood that references to pharmaceutically acceptable salts include solvation forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during a crystallization process with a pharmaceutically acceptable solvent (e.g., water, ethanol, and the like). A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is alcohol. The solvates described herein are conveniently prepared or formed during the processes described herein. Additionally, the compounds provided herein may be present in both non-solventized and solvated forms, as appropriate.

[0084] Therapeutic agents that can be administered to mammals (e.g., humans) must be prepared in accordance with regulatory guidelines. These government regulatory guidelines are known as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, such as the amount of residual solvent in the final product. Preferred solvents are those suitable for use in GMP facilities and that meet industrial safety requirements. Solvent classifications 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).

[0085] Solvents are classified into three types. Class 1 solvents are toxic and must be avoided. Class 2 solvents are those whose use is restricted during the manufacture of therapeutic agents. Class 3 solvents are those with low toxicity potential and pose a low risk to human health. Data on Class 3 solvents indicate that they have low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0086] Class 1 solvents that must be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0087] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, cyclobutane, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene.

[0088] The three classes of solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, methyl tert-butyl methyl ether (MTBE), cumene, dimethyl methoxide, 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.

[0089] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing of the APIs. In most cases, the solvents cannot be completely removed by actual manufacturing techniques. Appropriate selection of the solvent used to synthesize APIs can enhance yield or determine characteristics such as crystal form, purity, and solubility. Therefore, the solvent is a key parameter in the synthesis process.

[0090] In some embodiments, the composition comprising compound A-HCl includes a residual amount of an organic solvent. In some embodiments, the composition comprising compound A-HCl includes a residual amount of a Class 2 or Class 3 solvent. In some embodiments, the composition comprising compound A-HCl includes 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.

[0091] Unless otherwise stated, the following terms as used in this application have the definitions given below. The use of the term "including" and other forms (e.g., "include, includes, included") is not limited. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0092] As used herein, the term “modulation” means an interaction with a target, directly or indirectly, 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 expanding the activity of the target.

[0093] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, anti-agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0094] As used herein, the terms "administer," "administering," and similar terms refer to methods that enable the delivery of compounds or compositions to a desired site of biological action. These methods include, but are not limited to, oral administration. Those skilled 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.

[0095] As used herein, the term “co-administration” or similar terms are intended to cover the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which such agents are administered via the same or different routes of administration or at the same or different times.

[0096] As used herein, the terms "effective amount" or "therapeutic effective amount" mean an adequate amount of a drug or compound administered to a patient that will reduce one or more symptoms of the disease or condition being treated to a certain degree. Results include reduction and / or alleviation of the signs, symptoms, or any other desired changes in the cause or biological system of the disease. For example, for therapeutic use, an "effective amount" is the amount of a composition containing the compounds disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in any individual case is determined as appropriate using techniques such as dose escalation studies.

[0097] As used herein, the term "enhance" means to increase or prolong the efficacy or duration of a desired effect. Therefore, in relation to enhancing the effect of a therapeutic agent, the term "enhancement" means to increase or prolong the efficacy or duration of the effect of another therapeutic agent on the system. As used herein, "enhancing effective amount" means an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

[0098] As used herein, the term "medical combination" means a product derived from mixing or combining one or more active ingredients and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means the simultaneous administration of an active ingredient (e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof) and an adjuvant to a patient in the form of a single entity or dose. The term "non-fixed combination" means the simultaneous, parallel, or sequential administration of an active ingredient (e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof) and an adjuvant to a patient as separate entities without a specific time interval, wherein the administration provides an effective amount of the two compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0099] The terms “product” and “set” are used as synonyms.

[0100] The terms “individual” or “patient” encompass mammals. Examples of mammals include (but are not limited to) any member of the class Mammalia: humans; non-human primates such as chimpanzees and other apes and monkeys; agricultural animals such as cattle, horses, sheep, goats, and 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 category, the mammal is human.

[0101] As used herein, the term "treatment" includes the reduction, weakening or improvement of at least one symptom of a disease or condition by means of prevention and / or treatment, prevention of additional symptoms, suppression of a disease or condition, such as preventing the development of a disease or condition, reducing a disease or condition, causing a disease or condition to subside, reducing the condition caused by a disease or condition, or terminating the symptoms of a disease or condition.

[0102] In some embodiments, the treatment of acromegaly using compound A or a pharmaceutically acceptable salt or solvate thereof comprises growth hormone inhibitory (GH), insulin-like growth factor 1 (IGF-1), or both. Pharmaceutical composition

[0103] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more active compounds to treat a pharmaceutically acceptable inactive ingredient in a pharmaceutically used formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. editions, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh edition (Lippincott Williams & Wilkins 1999), the disclosure of which is incorporated herein by reference.

[0104] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein may be carried out by any method capable of delivering the compounds to the site of action. Such methods include (but are not limited to) administration via the enteral route (including oral administration), but the most suitable route may depend, for example, on the condition and disease of the recipient.

[0105] In some embodiments, the pharmaceutical composition is suitable for oral administration in the form of discrete units, such as capsules or tablets, each containing a predetermined amount of active ingredient; or powder or granules.

[0106] Orally administered pharmaceutical compositions include tablets, push-fit capsules made from gelatin, and soft-sealable capsules made from gelatin and plasticizers (such as glycerin or sorbitol). Tablets may be prepared by compression or molding, as appropriate, with one or more excipients. Compressed tablets may be prepared by compressing an active ingredient in a free-flowing form (e.g., powder or granules) in a suitable machine, the active ingredient being mixed, as appropriate, with a binder, inert diluent, or lubricant, surfactant, or dispersant. Molded tablets may be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations intended for oral administration should have a dosage suitable for that administration. The push-in compound capsule may contain a mixture of active ingredient and filler (e.g., lactose), binder (e.g., starch), and / or lubricant (e.g., talc or magnesium stearate), and, where appropriate, stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid (e.g., fatty oil, liquid paraffin, or liquid polyethylene glycol). In some embodiments, a stabilizer is added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may contain, where appropriate, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets to identify or characterize different combinations of active compound dosages.

[0107] Conventional techniques for manufacturing solid oral dosage forms include (but are not limited to) one or a combination of the following methods: (1) dry mixing, (2) direct pressing, (3) milling, (4) dry or anhydrous granulation, or (5) wet granulation. For example, see 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 spraying, ingot making, extrusion, and the like.

[0108] It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may also include other reagents commonly used in this art, taking into account the type of formulation. For example, compounds and compositions suitable for oral administration may include flavoring agents.

[0109] This document provides a tablet comprising compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises: compound A-HCl or a solvate thereof dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more lubricants and one or more flow aids; and, where appropriate, one or more film coating agents.

[0110] In some embodiments, a spray-dried solid dispersion comprising (a) a compound A-HCl or a solvate thereof; and (b) a pharmaceutically acceptable polymer; wherein the compound A-HCl or a solvate thereof is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

[0111] In some embodiments, this document describes the preparation of tablets using the spray-dried solid dispersions (SDDs) described herein.

[0112] The amorphous state of 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 diluting the drug in an excipient matrix. When amorphous molecules are dispersed in a high-Tg matrix, the low molecular mobility provides a diffusion barrier that inhibits the molecular mobility required for phase separation during storage. Phase separation is a precursor to the formation of crystal nuclei and eventual extensive crystallization of the drug-rich structural domains, leading to a loss of solubility advantage. In some embodiments, the pharmaceutically acceptable polymer used to prepare the spray-dried solid dispersion is a polymer with a high Tg. In cases where the active pharmaceutical ingredient (API) and the excipient are thermodynamically immiscible in the solid state, the spray-dried dispersion (SDD) is formulated such that the resulting Tg of the mixture (including absorbed water) is at least 10°C to 20°C higher than typical storage conditions. In addition, water absorption during storage must be considered, whether by selecting non-hygroscopic polymers or packaging configurations, because absorbed water will plasticize the dispersion and reduce Tg.

[0113] In some embodiments, the compound A-HCl or its solvate in the spray-dried solid dispersion described herein is substantially amorphous.

[0114] In some embodiments, the pharmaceutically acceptable polymer comprises the following polymers: cellulose, which, where applicable, is functionalized with alkyl ethers, alkyl esters, or phthalates; vinyl alcohol; vinyl acetate; propylene glycol; pyrrolidone; vinylpyrrolidone; ethylene oxide; propylene oxide; methacrylic acid; methyl methacrylate; ethylene glycol; ethylene glycol glycerol; ethylene oxide; propylene oxide; 2-ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam; or combinations thereof.

[0115] In some embodiments, pharmaceutically acceptable polymers include 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, and o-acetic acid. Cellulose phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), copolymers of methacrylic acid and methyl methacrylate, polyethylene glycol glycerides composed of monoglycerides, diglycerides and triglycerides and polyethylene glycol monoesters and diesters, hydroxypropyl cellulose, copolymers of ethylene oxide and propylene oxide blocks, poly(2-ethyl-2-oxazoline), poly(maleic acid / methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide / propylene oxide tetrafunctional block copolymer, d-α-tocopherol polyethylene glycol 1000 succinate or combinations thereof.

[0116] In some embodiments, the spray-dried dispersion further comprises a dispersion polymer. The dispersion polymer is selected from hydroxypropyl methylcellulose (HPMC), 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.

[0117] HPMCAS is a cellulose polymer with four types of substituents that are semi-randomly substituted at the hydroxyl group: methoxy, hydroxypropyloxy, acetate, and succinate. Based on the content (wt%) of acetyl and succinate in the HPMCAS molecule, the polymer can be obtained in three grades: L, M, and H. L grade: 5-9 wt% acetate, 14-18 wt% succinate, 20-24 wt% methoxy, 5-9 wt% hydroxypropyloxy. M grade: 7-11 wt% acetate, 10-14 wt% succinate, 21-25 wt% methoxy, 5-9 wt% hydroxypropyloxy. H grade: 10-14 wt% acetate, 4-8 wt% succinate, 22-26 wt% methoxy, 6-10 wt% hydroxypropyloxy.

[0118] In some embodiments, pharmaceutically acceptable polymers are selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, poly(comethyl methacrylate) (PMMAMA or the trade name Eudragit L100), Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus.

[0119] In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M.

[0120] In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:10 and about 10:1. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:1 and about 1:10. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:3 and about 1:8. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:4 and about 1:7. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:4 and about 1:6. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is between about 1:5 and about 1:6. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is about 1:10. In some embodiments, the weight ratio of compound A-HCl or its solvate to the dispersion polymer is about 1:9. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:8. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:7. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:6. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:5. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:4. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:3. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:2. In some embodiments, the weight ratio of compound A-HCl or its solvate to the polymer dispersion is about 1:1.

[0121] 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 percentages are calculated based on the free base (i.e., compound A).

[0122] 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% of compound A-HCl or a solvate thereof. In some embodiments, the spray-dried solid dispersion comprises about 35% of compound A-HCl or a solvate thereof. The percentages are calculated based on free base (i.e., compound A).

[0123] 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 percentages are calculated based on the free base (i.e., compound A).

[0124] 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 contain a non-aqueous solvent.

[0125] In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent selected from the group consisting of: 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. Tablets

[0126] In one embodiment, this document describes an tablet comprising: a compound A-HCl or a solvate thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from the group consisting of: one or more diluents, one or more disintegrants, one or more lubricants and one or more flow aids; and, where appropriate, one or more film coating agents.

[0127] In some embodiments, the compound A-HCl or its solvates dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer are the spray-dried solid dispersions described herein.

[0128] In some embodiments, the tablets contain about 2% to about 20% by weight of compound A-HCl or a solvate thereof. In some embodiments, the tablets contain about 2% to about 15% by weight of compound A-HCl or a solvate thereof.

[0129] In some embodiments, the tablets comprise about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, the tablets comprise about 20% to about 35% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0130] In some embodiments, the tablets contain about 2% to about 10% by weight of the compound A-HCl or a solvate thereof, dispersed in about 10% to about 30% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0131] 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 pharmaceutically acceptable polymer; about 40% to about 80% by weight of one or more pharmaceutically acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants and one or more flow aids; and, where applicable, less than about 5% by weight of one or more film coating agents.

[0132] In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablets also include one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids, or any combination thereof. In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablets also include microcrystalline cellulose, mannitol, crosspovidone, colloidal silica, and magnesium stearate.

[0133] In some embodiments, the tablets comprise one or more fillers / binders / diluents. The fillers / binders / diluents are selected from cellulose (e.g., microcrystalline cellulose, carboxymethyl cellulose, ethyl cellulose, and methyl cellulose), starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, mannitol, and lactose), natural and synthetic gums (e.g., gum arabic, sodium alginate, panwar gum, and ghatti gum), polyvinylpyrrolidone, polyethylene glycol, waxes, and any combination thereof. In some embodiments, the tablets comprise microcrystalline cellulose and mannitol.

[0134] In some embodiments, the one or more fillers / binders / diluents in the tablets described herein account for between about 20% and about 80% by weight of the total tablet weight. In some embodiments, the one or more fillers / binders / diluents in the tablets described herein account for between about 40% and about 65% by weight of the total tablet weight. In some embodiments, the one or more fillers / binders / diluents in the tablets described herein account for between about 50% and about 65% by weight of the total tablet weight. In some embodiments, the one or more fillers / binders / diluents in the tablets described herein account for about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the total tablet weight. In some embodiments, the one or more fillers / binders / diluents in the tablets described herein account for about 58% by weight of the total tablet weight. In some embodiments, less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, or less than 50% by weight of the total tablet weight contains one or more fillers / binders / diluents. In some embodiments, less than 60% by weight of the total tablet weight contains one or more fillers / binders / diluents.

[0135] In some embodiments, the tablets contain one or more disintegrants. The disintegrants are selected from croscarmellose sodium, crospovidone, sodium hydroxyacetic acid starch, Veegum HV, methylcellulose, agar, bentonite, cellulose, carboxymethyl cellulose, and any combination thereof. In some embodiments, the tablets contain crospovidone.

[0136] In some embodiments, the one or more disintegrants in the tablets described herein account for between about 2% and about 30% by weight of the total tablet weight. In some embodiments, the one or more disintegrants in the tablets described herein account for between about 5% and about 20% by weight of the total tablet weight. In some embodiments, the one or more disintegrants in the tablets described herein account for between about 10% and about 20% by weight of the total tablet weight. In some embodiments, the one or more disintegrants in the tablets described herein account for 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, the one or more disintegrants in the tablets described herein account for about 15% by weight of the total tablet weight. In some embodiments, less than 20% by weight of the total tablet weight includes one or more disintegrants.

[0137] In some embodiments, the tablets comprise one or more lubricants. The lubricant is selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl betaine, hydrogenated vegetable oil, polyethylene glycol, and any combination thereof. In some embodiments, the tablets comprise magnesium stearate.

[0138] In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.1% and about 5% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.1% and about 2% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.1% and about 1% by weight of the total tablet weight. In some embodiments, the one or more lubricants in the tablets described herein account for 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, the one or more lubricants in the tablets described herein account for 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.

[0139] In some embodiments, the tablets contain one or more flow aids. A flow aid is a substance added to a powder to improve its flowability. Examples of flow aids include magnesium stearate, colloidal silica, starch, and talc. In some embodiments, the tablets contain colloidal silica.

[0140] In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.1% and about 5% by weight of the total tablets. In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.1% and about 2% by weight of the total tablets. In some embodiments, the one or more lubricants in the tablets described herein account for between about 0.5% and about 1.5% by weight of the total tablets. In some embodiments, the one or more lubricants in the tablets described herein account for 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 tablets. In some embodiments, the 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. Additional excipients

[0141] In some embodiments, the tablets described herein contain additional excipients, including (but not limited to) buffers, flow aids, preservatives, and colorants. Additional excipients (e.g., build-up agents, tensioning agents, and chelating agents) are within the scope of the embodiments.

[0142] Non-limiting examples of buffers include (but are not limited to) sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitates, mixtures of amino acids and buffers, mixtures of aluminum glycate and buffers, mixtures of acidic salts of amino acids and buffers, and mixtures of alkali metal salts of amino acids and buffers. Additional buffers 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.

[0143] In some embodiments, the tablets described herein contain preservatives. Preservatives include antimicrobial agents, antioxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, isoascorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[0144] In some embodiments, the tablets described herein contain a colorant for identification and / or aesthetic purposes of the resulting liquid form. Suitable colorants illustratively include FD&C Red 3, FD&C Red 20, FD&C Red 40, FD&C Yellow 6, FD&C Blue 2, D&C Green 5, D&C Orange 5, caramel, ferric oxide, and mixtures thereof.

[0145] Additional excipients are included in the tablet examples. These additional excipients were selected based on functionality and compatibility with the tablet compositions described herein and can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (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, 7th edition (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference in their entirety.

[0146] In other embodiments, the tablets described herein are coated tablets, such as sausage-coated tablets, sugar-coated tablets, or film-coated tablets.

[0147] In one embodiment, individual unit doses also include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. In one embodiment, such formulations are manufactured using conventional techniques.

[0148] Compacted tablets are solid dosage forms prepared by compacting the aforementioned bulk blend formulation. In various embodiments, the compacted tablets, designed to dissolve in the oral cavity, will include one or more flavoring agents. In other embodiments, the compacted tablets will include a film encapsulating the final compacted tablet. In some embodiments, film coating contributes to patient compliance (e.g., Opadry® coating or sugar coating). The film coating contains Opadry®, which is typically in the range of about 1% to about 5% of the tablet weight. In other embodiments, the compacted tablets include one or more excipients.

[0149] This document provides a film-coated tablet form comprising: an active ingredient (e.g., compound A-HCl) and a combination of one or more tablet-making excipients to form a tablet core and subsequently a coating core. The tablet core is produced using a conventional tablet-making process and subsequently pressed and coated.

[0150] The casing is a coating that resists the action of gastric acid but dissolves or disintegrates in the intestine.

[0151] In one embodiment, the oral solid dosage form disclosed herein includes casings. Casings include one or more of the following: cellulose acetate; methyl acrylate-methacrylic acid copolymer; cellulose acetate succinate; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate (hydroxypropyl methyl cellulose acetate succinate); polyvinyl acetate phthalate (PVAP); methyl methacrylate-methacrylic acid copolymer; methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate forms); styrene-maleic acid copolymer; polymethacrylic acid / acrylic acid copolymer; hydroxyethyl ethyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; tetrahydrophthalic acid cellulose; acrylic resin; shellac.

[0152] Intestinal casing is a coating applied to tablets, pills, capsules, pellets, beads, granules, or particles to prevent them from dissolving before reaching the small intestine.

[0153] Sugar-coated tablets are compressed tablets coated with sugar, which can help mask unpleasant tastes or atmospheres and protect the tablets from oxidation.

[0154] Film-coated tablets are pressed tablets coated with a thin layer or film of a water-soluble material. Film coatings include (but are not limited to) hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multiple pressed tablets are pressed tablets produced from more than one pressing cycle, including layered tablets and pressed-coated or dry-coated tablets. In some embodiments, the tablets are coated with a water-soluble, pH-independent film coating, which allows for immediate disintegration for rapid activity release (e.g., Opadry products). Dosage in the tablets

[0155] In some embodiments, the amount of compound A-HCl or its solvate in the tablet is between about 5 mg and about 100 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is between about 5 mg and about 80 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is between about 5 mg and about 60 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is between about 10 mg and about 40 mg.

[0156] In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 10 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 20 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 30 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 40 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 50 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 60 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 70 mg. In some embodiments, the amount of compound A-HCl or its solvate in the tablet is about 80 mg. Administration method and treatment regimen

[0157] In one embodiment, the pharmaceutical composition disclosed herein is used as a medicament for treating a disease or condition in a mammal that would benefit from regulation of somatostatin activity. A method of treating any of the diseases or conditions described herein in a mammal requiring such treatment involves administering a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof to the mammal in a therapeutically effective amount.

[0158] In some embodiments, the composition containing compound A described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The effective amount for this application depends on the severity and course of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount is determined as appropriate by methods including, but not limited to, dose-escalation and / or dose-differentiation clinical trials.

[0159] Generally, however, the dosage used for treatment in adults is typically in the range of about 10 mg to about 100 mg of compound A per day. In one embodiment, it is desirable that the dosage be conveniently available as a single dose or as separate doses administered simultaneously or at appropriate intervals, such as two, three, four or more sub-dose per day.

[0160] In one embodiment, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered daily to a human requiring therapy, together with an SST2 agonist. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered once daily. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered twice daily. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered every other day.

[0161] In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered orally to humans on a continuous dosing schedule. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered to humans on a continuous daily dosing schedule.

[0162] The term "continuous dosing schedule" refers to the administration of a specific therapeutic agent at regular intervals. In some embodiments, a continuous dosing schedule refers to the administration of a specific therapeutic agent at regular intervals without any drug holidays for that specific therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the periodic administration of a specific therapeutic agent. In some other embodiments, a continuous dosing schedule refers to the administration of a specific therapeutic agent during a drug administration cycle, followed by a drug holiday for that specific therapeutic agent (e.g., a washout period or other such period during which no drug is administered). For example, in some embodiments, the treatment agent is administered once daily, twice daily, three times daily, 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 two days, every three days; once daily for one week, followed by a week without treatment; once daily for two weeks, followed by one or two weeks without treatment; once daily for three weeks, followed by one, two, or three weeks without treatment; once daily for four weeks, followed by one, two, three, or four weeks without treatment; once a week, followed by a week without treatment; or once every two weeks, followed by two weeks without treatment. In some embodiments, the daily administration is once daily. In some embodiments, the daily administration is twice daily. In some embodiments, the daily administration is three times daily.

[0163] The term "continuous daily dosing schedule" refers to administering a particular therapeutic agent at approximately the same time each day. In some embodiments, daily dosing means once a day.

[0164] In some embodiments in which no improvement in the state of disease or condition in humans is observed, the daily dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is increased. In some embodiments, the dosing frequency is increased to provide repetitive high Cmax levels on a more regular basis (e.g., changing a once-daily dosing schedule to a twice-daily dosing schedule). In some embodiments, the dosing frequency is increased to provide sustained or more regular exposure to compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride). In some embodiments, the dosing frequency is increased to provide repetitive high Cmax levels and sustained or more regular exposure to compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) on a more regular basis.

[0165] Typically, the appropriate dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be in the range of about 0.01 mg / day to about 100 mg / day; about 10 mg / day to about 100 mg / day; or about 10 mg / day to about 80 mg / day. In other embodiments, the appropriate dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be 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, about 80 mg / day, about 90 mg / day, or about 100 mg / day. In some embodiments, the appropriate dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 10 mg / day. In some embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 20 mg / day. In some embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 30 mg / day. In other embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 40 mg / day. In other embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 50 mg / day. In other embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 60 mg / day. In other embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans will be about 70 mg / day. In other embodiments, a suitable dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) administered to humans would be approximately 80 mg / day. In some embodiments, the dose is administered once daily. In some embodiments, the amount mentioned above refers to the amount of compound A monohydrochloride.

[0166] In some embodiments, compound A is administered at least 30 minutes before a meal. In some embodiments, compound A is administered at least 60 minutes before a meal. In some embodiments, compound A is administered at least 180 minutes after a meal. In some embodiments, compound A is administered at least 60 minutes before a meal and at least 180 minutes after a meal. In some embodiments, compound A is administered on an empty stomach. In some embodiments, compound A is administered with a glass of water on an empty stomach at least 30 minutes before a meal. In some embodiments, compound A is administered at bedtime. In some embodiments, compound A is administered using a dosing regimen that includes one or more of the administration steps mentioned above.

[0167] In some embodiments, the amount of active agent in the daily dose or dosage form is below or above the range indicated herein, based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dose and unit dose vary depending on a number of variables, including (but not limited to) the disease or condition to be treated, the method of administration, the individual's requirements, the severity of the disease or condition being treated, human characteristics (e.g., weight), and any specific additional therapeutic agent administered (if applicable), as well as the practitioner's judgment. Treatment based on biomarker detection

[0168] Plasma concentrations of GH and IGF-1 are typically increased in active acromegaly and decrease during effective treatment. Therefore, both biomarkers are used in clinical practice to monitor biochemical control in acromegaly and determine treatment effectiveness. Due to the underlying biological mechanisms of acromegaly, the latest guidelines issued by the Endocrine Society and the American Association of Clinical Endocrinologists (AACE) for the diagnosis and treatment monitoring of acromegaly emphasize three key biomarkers: (a) IGF-1, (b) (mean) GH, and (c) the inhibitory level of GH concentration during the oral glucose tolerance test (OGTT).

[0169] In clinical practice, the primary treatment goal is to reduce insulin-like growth factor-1 (IGF-1) concentrations to clinically acceptable "normal" values ​​for age and sex, which is associated with modified / regularized mortality. The guidelines introduce an upper limit of normal (ULN) as an alternative to "safe" IGF-1 levels, which can be used to monitor biochemical control in individual acromegaly patients. This ULN is typically defined as 2 × the standard deviation (SD) of normal values ​​for age and sex, where age-related changes have the greatest impact on IGF-1 concentrations. Additionally, ULN correction values ​​offer the added benefit of serving as a comparable measure of IGF-1 concentrations between individuals.

[0170] Growth hormone (GH) is the primary pathological factor in acromegaly. Therefore, randomized GH measurement is implemented to provide an indication of the actual endogenous 24-hour GH profile. However, monitoring treatment efficacy using randomized GH levels or the average of multiple samples presents numerous challenges (e.g., highly pulsating GH profile, analytical variability, lack of a safety margin), but requires minimal clinical effort compared to obtaining a complete 24-hour GH profile with short sampling intervals that are impractical in clinical practice. Therefore, IGF-1 is generally considered a better and more stable biomarker.

[0171] Clinical manifestations caused by excessively high GH and IGF-I concentrations include cardiovascular, cerebrovascular, and respiratory diseases, as well as metabolic abnormalities. GH has an antagonistic effect on insulin's carbohydrate metabolism, and impaired glucose tolerance and diabetes are common complications reported in up to 50% of acromegaly patients. There is ample documentation demonstrating that normalizing GH and IGF-I levels in acromegaly patients improves glucose homeostasis. Somatostatin analogs alter glucose homeostasis by inhibiting GH and insulin secretion. Pegvisomant is a specific GH receptor antagonist that does not directly affect insulin secretion. In two pilot studies (one in healthy volunteers and the other in patients with acromegaly), octreotide treatment tended to deteriorate glucose homeostasis (Parkinson C et al., J. Clin. Endocrinol. Metab. 87:1797-1804, 2002; Quabbe HJ et al., J. Clin. Endocrinol. Metab. 68:873-881, 1989), while pevesole treatment had a neutral or positive effect. In patients with acromegaly, the presence of diabetes has been observed to contribute to premature death, and impaired glucose tolerance has been found to be associated with the severity of acromegaly-related cardiomyopathy.

[0172] An oral glucose tolerance test (OGTT) is performed to differentiate between healthy individuals and patients with active acromegaly. Furthermore, the OGTT can be performed one week post-surgery to evaluate whether GH secretion has been successfully reduced. In healthy individuals, increased plasma glucose levels suppress GH secretion to well below 1 ng / mL. Insufficient GH suppression indicates a disruption of the hypothalamic-pituitary-gonadal axis. A "standard" OGTT is performed by administering 75 g of glucose orally and monitoring the GH concentration in the blood sample every 30 minutes for 2 hours.

[0173] In healthy volunteers, two treatment-emergent adverse effects (TEAEs) of asymptomatic hyperglycemia occurred during repeated daily administration of compound A-HCl capsules for 7 days (5 mg) and 10 days (10 mg, 20 mg, and 30 mg) in a previous Phase 1 clinical trial. Both events occurred 1 hour after oral glucose administration and subsided 2 hours after loading during the scheduled OGTT following completion of the 10-day course of compound A. One individual receiving the 20 mg dose experienced a peak glucose concentration of 12.2 mmol / L (220 mg / dL) 1 hour after the oral glucose challenge, which normalized to 5.8 mmol / L (104 mg / dL) 2 hours after the challenge. One individual receiving the 10 mg dose experienced a peak glucose concentration of 12.4 mmol / L (223 mg / dL) 1 hour after the oral glucose challenge, which normalized to 4.3 mmol / L (77 mg / dL) 2 hours after the challenge. No hyperglycemic symptoms or other sequelae were reported in these cases. Compared with baseline, there was a small but significant increase in glucose AUC0–3hr after a 75 g oral glucose challenge at the highest multiple dose of 30 mg (3.2 h·mmol / L; 95% CI 1.8–4.6), compared with the small and insignificant change in placebo (1.5 h·mmol / L; 95% CI 1.5–4.6). Fasting plasma glucose showed no significant change.

[0174] In some embodiments, hyperglycemia includes peak serum glucose concentrations of >100 mg / dL, >110 mg / dL, >120 mg / dL, >130 mg / dL, >140 mg / dL, >150 mg / dL, >160 mg / dL, >170 mg / dL, >180 mg / dL, >190 mg / dL, >200 mg / dL, >210 mg / dL, >220 mg / dL, >230 mg / dL, >240 mg / dL, or >250 mg / dL. In some embodiments, hyperglycemia includes peak serum glucose concentrations >100 mg / dL, >110 mg / dL, >120 mg / dL, >130 mg / dL, >140 mg / dL, >150 mg / dL, >160 mg / dL, >170 mg / dL, >180 mg / dL, >190 mg / dL, or >200 mg / dL. In some embodiments, hyperglycemia includes peak serum glucose concentrations >100 mg / dL, >110 mg / dL, >120 mg / dL, >130 mg / dL, >140 mg / dL, >150 mg / dL, >160 mg / dL, >170 mg / dL, >180 mg / dL, >190 mg / dL, or >200 mg / dL, as measured by an oral glucose tolerance test (OGTT).

[0175] Mild postprandial hyperglycemia confirmed by oral glucose tolerance test, with no change in fasting glucose or HbA1c, has been previously described using this pharmacological category (Mazziotti G et al., (2009) J. Clin. Endocrinol. Metab. 94(5):1500-1508). This contrasts with the less selective parretin, which has strong activity against the SST5 receptor and is associated with decreased insulin secretion and hyperglycemia (Henry RR et al., (2013) J. Clin. Endocrinol. Metab. 98(8):3446-3453).

[0176] In some embodiments, hypoglycemia or hyperglycemia may occur during treatment with compound A. In some embodiments, hypoglycemia may occur during treatment with compound A. In some embodiments, hyperglycemia may occur during treatment with compound A. In some embodiments, glucose monitoring is recommended when compound A is administered as described herein, and adjustments or initiation of antidiabetic treatment may be necessary.

[0177] In some embodiments, blood glucose levels are monitored when treatment with compound A is initiated or when the dose of compound A is changed. Antidiabetic treatment should be initiated or adjusted accordingly.

[0178] In some embodiments, blood glucose levels are monitored when treatment with compound A is initiated or when the dose of compound A is changed, and antidiabetic treatment is adjusted or initiated accordingly. In some embodiments, hyperglycemia is treated with insulin and / or an insulin sensitizer. In some embodiments, hyperglycemia is treated with an agent for treating diabetes. In some embodiments, hyperglycemia is treated with metformin, insulin, sulfonylurea, GLP-1 receptor agonists, thiazolidinediones, meglitinide, SGLT2 inhibitors, DPP-4 inhibitors, α-glucosidase inhibitors, pramlintide, or combinations thereof. In some embodiments, hyperglycemia is treated by adjusting an individual's dietary intake.

[0179] In some embodiments, the administration of a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is based on a patient's serum insulin-like growth factor-1 (IGF-1) level, serum growth hormone (GH) level, or both. In some embodiments, the administration of a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is based on a patient's serum IGF-1 level. In some embodiments, the administration of a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is based on a patient's serum GH level. In some embodiments, a composition comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered to a patient with abnormal serum IGF-1 levels, serum GH levels, or both for the treatment of any of the diseases or conditions described herein.

[0180] In some embodiments, the administration of a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is based on achieving a serum IGF-1 value comparable to that of LA-SRL therapy. For many patients, non-enteral administration of LA-SRL is painful and inconvenient, and therapy using compound A is desirable. These patients would be willing to switch from painful injections of LA-SRL to oral administration of compound A.

[0181] In clinical practice, the primary treatment goal is to reduce IGF-1 concentrations to clinically acceptable "normal" values ​​for age and sex, which is associated with modified / regularized mortality. The guidelines introduce an upper limit of normal (ULN) as an alternative to a "safe" IGF-1 level, which can be used to monitor biochemical control in individual acromegaly patients. This ULN is typically defined as 2 × the standard deviation (SD) of the normal values ​​for age and sex, where age-related changes have the greatest impact on IGF-1 concentrations. Additionally, a ULN correction value has the added benefit of serving as a comparable measure of IGF-1 concentrations between individuals.

[0182] In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 2.5. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 2. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 1.8. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 1.5. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 1.3. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of less than about 1.2. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of greater than 0.5 and less than about 2.5. In some embodiments, treatment with compound A aims to achieve serum IGF-1 (x ULN) levels of > 1 and < about 2.5.

[0183] In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered via a titration schedule. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered via a titration schedule to minimize adverse events associated with the administration of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride). In some embodiments, titration with compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) enables: individual tolerance to compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride); minimization of adverse events associated with the administration of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride); maximizing the likelihood that an optimal dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered to an individual and tolerated; or a combination thereof. In some embodiments, the titration includes incremental titration.

[0184] In some embodiments, treatment with compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) does not require titration.

[0185] As used herein, an individual is said to be "tolerant" to a certain dose of a compound if administering such a dose to an individual 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 is tolerable to one patient may be intolerable to another. For example, one individual may be intolerant of headaches, a second may tolerate mild headaches but not moderate headaches, and a third may tolerate moderate headaches but not severe headaches. In some embodiments, a patient may be intolerant of treatment with injectable somatostatin analogs due to injection site rejection. In some embodiments, a patient may be intolerant of treatment with oral somatostatin analogs because multiple doses of somatostatin analogs must be taken more than once daily. In some embodiments, a patient may be intolerant of treatment with oral somatostatin analogs due to contraindications reported in patients receiving octreotide (e.g., hypersensitivity or anaphylactic reactions to octreotide, including anaphylactic shock).

[0186] As used herein, an "adverse event" is an adverse medical event associated with treatment using compound A or its pharmaceutically acceptable salts. In some embodiments, an adverse event is headache, fatigue, diarrhea, pain, or a combination thereof.

[0187] As used herein, “optimized dose” refers to the highest dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) that is equivalent to the required dose of compound A for a particular individual and that elicits the desired biological or medical response in the individual and is tolerable to the individual, as determined by the individual in consultation with the individual’s healthcare practitioner.

[0188] As used herein, "incremental titration" of a compound refers to increasing the amount of the compound until an individual cannot tolerate the increased amount. Incremental titration can be achieved with one or more dose increments that may be the same or different. In some embodiments, the method includes administering compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) once daily for an initial period of time, followed by incremental titration to a higher dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) once daily thereafter. In some embodiments, the initial period of time includes one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, or about twelve weeks. In some embodiments, this cycle is repeated until an optimal dose is achieved.

[0189] In some embodiments, the titration method comprises administering compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) once daily at an initial dose for about one week, about two weeks, about three weeks, or about four weeks, followed by incremental titration to a higher dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) once daily thereafter. In some embodiments, this cycle is repeated until an optimal dose is achieved. In some embodiments, dose adjustments are performed weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, dose adjustments are performed and / or repeated to achieve consistent IGF-1 inhibition. In some embodiments, dose adjustments are performed and / or repeated to achieve consistent IGF-1 inhibition and less than about 2.5 IGF-1 (x ULN).

[0190] In some embodiments, the titration method comprises administering compound A or a pharmaceutically acceptable salt thereof (e.g., compound A-HCl) once daily at an initial dose for about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks, followed by incremental titration to a higher dose of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A-HCl) once daily thereafter. In some embodiments, this cycle is repeated until an optimal dose is achieved. In some embodiments, the method comprises administering 10 mg of compound A-HCl once daily for about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks, followed by incremental titration to about 20 mg of compound A-HCl once daily thereafter.

[0191] In some embodiments, the titration method comprises incremental titration of compound A or a pharmaceutically acceptable salt thereof (e.g., compound A-HCl), or decremental titration followed by optional re-incremental titration.

[0192] In some embodiments, the titration schedule includes administering compound A or a pharmaceutically acceptable salt thereof (e.g., compound A-HCl) at an initial dose for about 1, 2, 3, or 4 weeks, and increasing the dose by an amount equal to the increment if the patient tolerates the initial dose. In some cases, the increment used to increase the daily dose is equivalent to about 10 mg of compound A-HCl.

[0193] In some embodiments, the initial dose is equivalent to about 10 mg to about 40 mg of compound A-HCl. In some embodiments, the initial dose is equivalent to about 10 mg, about 20 mg, about 30 mg, or about 40 mg of compound A-HCl. In some embodiments, the initial dose is equivalent to about 10 mg of compound A-HCl. In some embodiments, the initial dose is equivalent to about 20 mg of compound A-HCl.

[0194] In some embodiments, the titration schedule further includes administering compound A or its pharmaceutically acceptable salt at an increased dose for about one, two, three, or four weeks, and further increasing the dose increment if the patient tolerates the increased dose. In some embodiments, the increment for increasing the daily dose is equivalent to about 10 mg / day of compound A monohydrochloride.

[0195] In some embodiments, the titration schedule is repeated until an optimal dose is obtained. The optimal dose provides therapeutic efficacy while minimizing side effects from treatment with compound A. In some embodiments, treatment with compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) does not require titration. In some embodiments, the optimal dose is administered without titration.

[0196] In some embodiments, the optimized dose is equivalent to about 10 mg / day to about 80 mg / day of compound A monohydrochloride. In some embodiments, the optimized dose is 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. In some embodiments, the optimized dose is equivalent to about 30 mg / day, about 40 mg / day, about 50 mg / day, or about 60 mg / day of compound A monohydrochloride. In some embodiments, the optimized dose is equivalent to about 30 mg / day of compound A monohydrochloride. In some embodiments, the optimized dose is equivalent to about 40 mg / day of compound A monohydrochloride. In some embodiments, the optimized dose is equivalent to about 50 mg / day of compound A monohydrochloride. In some embodiments, the optimized dose is equivalent to about 60 mg / day of compound A monohydrochloride.

[0197] In a previous phase 2 clinical trial of acromegaly patients treated with LA-SRL, an assessment of steady-state IGF-1 changes with compound A monohydrochloride dose showed that daily doses of 10 and 20 mg resulted in IGF-1 levels above baseline, where baseline IGF-1 was measured at the time of the last LA-SRL injection. Switching to compound A monohydrochloride occurred 4 weeks after the last LA-SRL injection. Doses of 30 mg / day and 40 mg / day resulted in changes from near-zero baseline, indicating that doses of 30 mg / day and 40 mg / day were as effective as prior monotherapy with injectable LA-SRL in inhibiting IGF-1.

[0198] In some embodiments, patients who do not achieve a treatment goal with 40 mg / day patostine monotherapy are given an additional treatment. In some embodiments, achieving a treatment goal with 40 mg / day patostine monotherapy includes an IGF-1 level of -1 ≤ 1 x ULN. In some embodiments, achieving a treatment goal with 40 mg / day patostine monotherapy includes an IGF-1 level less than or approximately equal to a prior LA-SRL monotherapy. In some embodiments, achieving a treatment goal with 40 mg / day patostine monotherapy includes an IGF-1 level less than a prior LA-SRL monotherapy. In some embodiments, the combination therapy comprises compound A monohydrochloride and a dopamine agonist and / or a growth hormone (GH) receptor antagonist. In some embodiments, the dopamine agonist is cabergoline or a pharmaceutically acceptable salt thereof. In some embodiments, the GH receptor antagonist is pevesolement. In some embodiments, the combination therapy comprises compound A monohydrochloride and cabergoline or a pharmaceutically acceptable salt thereof. In some embodiments, cabergoline is administered at a dose and frequency of about 0.5 mg / week to about 0.5 mg / day. In some embodiments, cabergoline is administered at a dose of about 0.5 mg / week, 0.5 mg every other day, 0.5 mg every two days, 0.5 mg every three days, 0.5 mg every four days, and 0.5 mg every five days. In some embodiments, cabergoline is administered at a dose of about 0.5 mg / day.

[0199] A dose-response relationship was observed when assessing the rise in IGF-1 during the flushing of compound A. Exposure-response modeling estimated the concentration of compound A at which the maximum pharmacological response (EC80) was achieved (80%). In some embodiments, administration of SDD tablets containing approximately 30 mg / day to approximately 60 mg / day of compound A monohydrochloride, as described herein, provides daily trough concentrations exceeding EC80 and resulting in consistent IGF-1 inhibition in patients with acromegaly.

[0200] In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, is between about 20 ng / mL and about 150 ng / mL in patients with acromegaly. In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, is between about 25 ng / mL and about 80 ng / mL in patients with acromegaly. In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, is between about 30 ng / mL and about 80 ng / mL in patients with acromegaly. In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, is between about 30-60 ng / mL in patients with acromegaly.

[0201] In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, 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 in patients with acromegaly.

[0202] In some embodiments, the glutar plasma concentration of compound A, which provides consistent IGF-1 inhibition, in patients with acromegaly is at least 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, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, or at least about 100 ng / mL.

[0203] In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered in doses sufficient to provide the following trough concentrations of compound A: 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, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL. ng / mL, about 46 ng / mL, about 47 ng / mL, about 48 ng / mL, about 49 ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL, about 60 ng / mL, about 61 ng / mL, about 62 ng / mL, about 63 ng / mL, about 64 ng / mL, about 65 ng / mL, about 66 ng / mL, about 67 ng / mL, about 68 ng / mL, about 69 ng / mL, about 70 ng / mL, about 71 ng / mL, about 72 ng / mL, about 73 ng / mL, about 74 ng / mL, about 75 ng / mL, about 76 ng / mL, about 77 ng / mL, about 78 ng / mL, about 79 ng / mL, about 80 ng / mL, about 81 ng / mL, about 82 ng / mL, about 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.

[0204] In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered at a dose sufficient to provide a trough concentration of about 32 ng / mL for compound A. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered at a dose sufficient to provide a trough concentration of at least about 32 ng / mL for compound A. In some embodiments, compound A or a pharmaceutically acceptable salt thereof (e.g., compound A monohydrochloride) is administered at a dose sufficient to provide a trough concentration of compound A greater than about 32 ng / mL for compound A.

[0205] In some embodiments, the total daily dose of compound A monohydrochloride, from about 20 mg to about 80 mg, is administered once daily to the SDD tablets described herein to provide doses 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, greater than 80 ng / mL, greater than 85 ng / mL, greater than 90 ng / mL, greater than 95 ng / mL, greater than 100 ng / mL, greater than 115 ng / mL, greater than 120 ng / mL, greater than 125 ng / mL, greater than 130 ng / mL, greater than 135 ng / mL, and greater than 140 ng / mL. Valley concentrations of compound A at ng / mL, greater than 145 ng / mL, greater than 150 ng / mL, or greater than 150 ng / mL.

[0206] In some embodiments, a total daily dose of about 20 mg to about 60 mg of compound A monohydrochloride is administered once daily to the SDD tablets described herein to provide a valley concentration of about 10 ng / mL to about 150 ng / mL of compound A. In some embodiments, a total daily dose of about 40 mg to about 60 mg of compound A monohydrochloride is administered once daily to the SDD tablets described herein to provide a valley concentration of about 20 ng / mL to about 150 ng / mL of compound A. In some embodiments, a total daily dose of about 40 mg of compound A monohydrochloride is administered once daily to the SDD tablets described herein to provide a valley concentration of about 20 ng / mL to about 110 ng / mL of compound A. In some embodiments, a total daily dose of about 40 mg of compound A is administered once daily to the SDD tablets described herein to provide a valley concentration of at least 30 ng / mL of compound A. In some embodiments, a total daily dose of about 40 mg of compound A monohydrochloride is administered once daily with the SDD tablets described herein to provide a valley concentration of at least 32 ng / mL of compound A.In some embodiments, the following trough concentrations of compound A are provided by once-daily administration of the SDD tablets described herein at a total daily dose of about 40 mg of compound A monohydrochloride: 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, about 38 ng / mL, about 39 ng / mL, about 40 ng / mL, about 41 ng / mL, about 42 ng / mL, about 43 ng / mL, about 44 ng / mL, about 45 ng / mL. ng / mL, about 46 ng / mL, about 47 ng / mL, about 48 ng / mL, about 49 ng / mL, about 50 ng / mL, about 51 ng / mL, about 52 ng / mL, about 53 ng / mL, about 54 ng / mL, about 55 ng / mL, about 56 ng / mL, about 57 ng / mL, about 58 ng / mL, about 59 ng / mL, about 60 ng / mL, about 61 ng / mL, about 62 ng / mL, about 63 ng / mL, about 64 ng / mL, about 65 ng / mL, about 66 ng / mL, about 67 ng / mL, about 68 ng / mL, about 69 ng / mL, about 70 ng / mL, about 71 ng / mL, about 72 ng / mL, about 73 ng / mL, about 74 ng / mL, about 75 ng / mL, approximately 76 ng / mL, approximately 77 ng / mL, approximately 78 ng / mL, approximately 79 ng / mL, or greater than approximately 80 ng / mL but less than 150 ng / mL.

[0207] In any of the states mentioned above, further embodiments include a single dose of an effective amount of the compound, including further embodiments in which the compound is administered once daily. Examples

[0208] These examples are provided for illustrative purposes only and do not limit the scope of the patent applications provided herein. Example 1: Oral capsules

[0209] Representative capsules are described in Table 1 below. Table 1. Component Name Function Quantity / Unit (mg) % w / w Compound A-HCl a raw materials 10.00 5.00 microcrystalline cellulose diluent 85.5 42.77 Mannitol diluent 85.5 42.77 Cross-linked carboxymethyl cellulose sodium Disintegrant 7.4 3.70 Vitamin E polyethylene glycol succinate (TPGS) Solubilizer 8.5 4.27 Colloidal silicon dioxide Flow aid 2.0 1.00 Sodium stearyl fumarate lubricant 1.0 0.50 No. 2 Gelatin Capsules c Capsule shell NA NA Total 200.00 b 100.00 a) Quantities corrected for analysis and moisture, chloride, and isopropanol content; b) Capsule filling weight adjusted based on admixture analysis; c) Composed of red iron oxide, titanium dioxide, and gelatin.

[0210] The following is a representative description of the manufacturing process used for hot melt granulation capsules:

[0211] Stage 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 packed into a high-shear wet granulator and mixed. The molten vitamin E TPGS is sprayed onto the granulated component.

[0212] Stage 2: Grinding: The wet particles are ground using a screening mill with a screen of appropriate size.

[0213] Stage 3: Blending: The sodium stearyl fumarate is screened using a sieve of appropriate size. The milled particles are then packed together with the sodium stearyl fumarate into a diffusion mixer (drum) and blended.

[0214] Stage 4: Encapsulation: 10 mg capsules were automatically encapsulated into No. 2 gelatin capsules. Example 2: Spray-dried solid dispersion

[0215] Spray-dried solid dispersions containing 15 wt% compound A-HCl were prepared: 15 / 85 compound A-HCl / HPMCAS-M and 15 / 85 compound A-HCl / PVP VA64 formulations. Manufacturing was performed using a BLD-150 (Bend Lab Dryer with a drying gas capacity of 150 kg / hr). The parameters varied were the solid solution loading of the HPMCAS-M SDD formulation to help reduce nozzle bearding and the dryer outlet temperature of the PVP VA64 SDD to eliminate the risk of fluctuations that might occur during clinical manufacturing. The initial process parameter screening plan specified manufacturing with a larger orifice nozzle at a reduced dryer outlet temperature to produce larger particles; however, based on the results of the first spray, it was determined that the atomization pressure required to achieve the desired solution flow rate would be too low to adequately atomize the solution using the larger orifice. Since the dryer outlet temperature tends to be more variable than the solution flow rate, the parameter screening shifted to focusing solely on eliminating the risk of dryer outlet temperature while ensuring adequately atomized droplets. Variations in dryer outlet temperature will affect the residual solvent content in the SDD, which can impact its physical and chemical stability. All sprays were successfully completed in good yields, indicating robust processing margins for both formulations. Manufacturing details for Compound A HPMCAS-M SDD formulation (15 / 85).

[0216] Three sub-batch samples of compound A-HCl / HPMCAS-M SDD (15 / 85) were sprayed to explore manufacturing processing potential and prepare for clinical trial manufacturing. One sub-batch was first sprayed with 10 wt% solids, and significant nozzle stubble that appeared to affect the spray plume was observed on the solution after approximately 45 minutes.

[0217] The solution was diluted to 8 wt%, and a sub-batch was produced for a duration of 1 hour to ensure reduced snagging. During this batch, a very small amount of snagging was observed on the solution after about 50 minutes, but it did not appear to affect the atomized plume, and an 8 wt% solids loading was selected.

[0218] Throughout all sprays, cooling water at 2 GPM and approximately 7°C was flowed through the spray dryer cap to keep the cap cool and prevent adhesion and browning. No significant cap buildup or browning was observed throughout the manufacturing process. No cleaning was performed between sprays, and all sprays were completed from a single solution, with additional solvent added prior to manufacturing batches 2A and 2C. A summary of the process parameters used for all three sub-batches is shown in Table 2. Table 2. Manufacturing Summary of Compound A-HCl / HPMCAS-M SDD (15 / 85) parameter Batch Material 2A Batch 2B Batch Material 2C The collected block SDD (g) 5316 2231 624 Solid loading in solution (wt%) 8 10 8 solvent methanol atomizer Pressure vortex: Steinen A75 Nebulization pressure (psig) 370 301 345 Solution flow rate (g / min) 131 132 131 Dry gas flow rate (g / min) 1848 1848 1848 Dryer inlet temperature (°C) 146 145 144 Dryer outlet temperature (°C) 45 45 45 Secondary tray drying of bulk materials 16 hours at 40℃ / 15%RH 17 hours at 40℃ / 15%RH Dry yield (%) 1 96 96 93 Spray duration (hours) 8 3 1 Calculation of relative saturation (%) of the dryer 11 Calculated dew point (°C) 3 1. Dry yield is calculated as the SDD sample and collected dry bulk material divided by the amount of sprayed solids. 15 / 85 Compound A-HCl / PVP VA64 SDD formulation manufacturing details.

[0219] Process parameter screening spray and FPN demonstration batches for compound A-HCl / PVP VA64 SDD formulation 15 / 85 were also completed. The dryer outlet temperature was changed to eliminate the risk of process parameter variability in preparation for clinical trial manufacturing.

[0220] The process space is limited by the maximum dryer outlet temperature, the dryer outlet temperature, and the minimum desired solution flow rate. A maximum inlet temperature of 160°C is specified to prevent SDD from adhering to or browning on the spray dryer cover, and the minimum flow rate is set to 100 g / min to ensure sufficient throughput. The minimum and maximum dryer outlet temperatures are selected as 40°C and 65°C, respectively, to ensure adequate drying of the particles, and the dryer outlet temperature will not exceed the wet particle Tg.

[0221] Screening process parameters for PVP VA64 formulations: Spray drying explores manufacturing potential by varying the dryer outlet temperature. This allows for the study of the effects of dryer relative saturation on the residual solvent content, morphology, density, and stability of particles.

[0222] Throughout all sprays, cooling water was operated at 2 GPM and approximately 7°C to prevent cap buildup and browning, and neither was observed. Nozzle snagging was observed in any of the three manufacturing processes. All sprays were completed from a single solution. Manufacturing details for each sub-batch are summarized in Table 3. Table 3. 15 / 85 Compound A-HCl* / PVP VA64 SDD Process Parameters parameter Batch Material 4A Batch 4B Batch material 4C The collected block SDD (g) 5285 623 624 Solid loading in solution (wt%) 8 solvent methanol atomizer Pressure vortex: Steinen A75 Nebulization pressure (psig) 422 449 445 Solution flow rate (g / min) 128 133 132 Dry gas flow rate (g / min) 1845 1848 1849 Dryer inlet temperature (°C) 143 153 132 Dryer outlet temperature (°C) 45 49 40 Secondary tray drying of bulk materials 18 hours at 40℃ / 15%RH 26 hours at 40℃ / 15%RH Dry yield (%) 1 92 86 91 Spray duration (hours) 8 1 1 Calculation of relative saturation (%) of the dryer 11 9 14 Calculated dew point (°C) 3 *Compound A-HCl, based on free alkali formulation. 1. Dry yield is calculated as the SDD sample and collected dry bulk divided by the amount of sprayed solids. SDD characterization.

[0223] Particle Properties: Particle size distribution, packing density, and tap density were measured for each batch of compound A-HCl SDD. HPMCAS-M SDD exhibited larger particle sizes, as expected, due to the higher viscosity of the HPMCAS-M solution compared to the PVP VA64 solution, resulting in larger droplets for the given nozzle configuration. The increased solids loading in batch 2B resulted in larger particles than batches 2A and 2C, also due to the higher viscosity of the spray solution. As expected, the particle size distribution was similar across all PVPVA-64 batches.

[0224] The packing and tap densities of 2A and 2C are similar, while batch 2B may have a slightly lower density due to larger particles. The packing and tap densities of all PPVVA-64 batches are similar, indicating a robust process regarding the effect of dryer outlet temperature on powder properties.

[0225] Residual solvent and water content: Residual methanol and water in the six SDDs were measured using GC and KF, respectively. All SDDs contained less than 0.3 wt% residual MeOH after secondary drying, which indicates that they were adequately dried at 40°C / 15%RH.

[0226] Morphology by SEM: The particle morphology of all six SDDs was evaluated by SEM. Each SDD showed a typical morphology with no signs of irregular particles, indicating adequate atomization under all tested conditions. HPMCAS-M particles were mainly collapsed spheres, while PVP VA64 SDD contained a larger fraction of spherical particles.

[0227] Crystallization by PXRD: The crystallinity of all six SDDs was evaluated using PXRD. All SDDs were found to be amorphous by PXRD, which was evident in the absence of sharp diffraction peaks.

[0228] Thermal Properties by DSC: All six SDDs were characterized by modulated DSC. The results are listed in Table 4. All manufactured SDDs were amorphous and homogeneous by DSC, as evidenced by the presence of a single glass transition in the reverse thermal signal. Neither formulation showed any signs of crystallization after Tg, indicating that compound A has a lower tendency to crystallize at those temperatures for both formulations. Furthermore, both formulations showed high Tg relative to ambient temperature, indicating a lower risk of physical stability under dry conditions. The PVP VA64 formulation will require packaging to minimize humidity. Table 4. Tabulated thermal properties of the six batches as measured by DSC. Sample Wholesale materials Tg (°C) Std Dev* Δ Cp (J / (g*℃)) Std Dev* 15 / 85 compound A-HCl / HPMCAS-M SDD 2A 135.2 0.35 0.27 0.03 2B 134.7 0.36 0.25 0.02 2C* 134.5 0.95 0.26 0.00 15 / 85 compound A-HCl / PVP VA64 SDD 4A* 125.5 0.04 0.31 0.01 4B 125.6 0.26 0.30 0.01 4C 125.6 0.17 0.35 0.08 The mean is derived from n=2 replicates. Therefore, the standard deviation is actually calculated as range / 2. Summarize

[0229] Physical stability observation: PPVVA64 SDD showed deliquescence during storage, with crystals observed at 3 months (40℃ / 75%RH, open). Storage with a desiccant is recommended. HPMCAS-M SDD was physically stable after 6 months at 40℃ / 75%RH (open).

[0230] Chemical Stability Observation: The impact of potential acid-catalyzed degradation in the HPMCAS-M formulation on stability. Some degradation was observed in the PVPVA64 formulation, but not as significant as in the HPMCAS-M SDD. The PVPVA SDD will require packaging, driven by physical stability concerns. 15% w / w compound A / PVPVA64 was selected as the lead SDD formulation. 12-month stability: 15% compound A-HCl / PVP-VA64 SDD

[0231] 12-month-old SDD samples were stored with desiccant at 5°C, 25°C / 60% RH, and 40°C / 75% RH. Water analysis samples for Karl Fischer titration were prepared and analyzed immediately; the remaining samples were vacuum-dried overnight 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, water content in Karl Fischer titration, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermal characterization by modulation differential scanning calorimetry (mDSC), dissolution performance by microcentrifugation (MCT), analysis by HPLC, and related substances.

[0232] Conclusion of PXRD analysis on SDD stability samples after 12 months: There was no evidence of crystallinity in the samples stored for 12 months under each stability condition.

[0233] Conclusions of SEM analysis of SDD stability samples after 12 months: No particle fusion was observed under all stability conditions at 12 months. There was no evidence of crystallinity in the samples stored for 12 months under each stability condition.

[0234] Conclusions of SEM analysis of SDD stability samples after 12 months: No particle fusion was observed under all stability conditions at 12 months. There was no evidence of crystallinity in the samples stored for 12 months under each stability condition.

[0235] Conclusions of mDSC analysis on SDD stability samples after 12 months: Repeated analysis of SDD samples maintained at 5°C for 12 months yielded non-reproducible temperature records, the cause of which is currently unclear. All other characterization techniques confirmed that the 5°C samples are physically stable. SDD samples maintained at 25°C / 60%RH and 40°C / 75%RH for 12 months showed a single, reproducible Tg at 124-125°C, supporting the conclusion that SDD is stable after 12 months of storage with a desiccant under these conditions.

[0236] Conclusion of MCT dissolution analysis on 12-month SDD stability samples: The non-leaking dissolution performance of the 12-month stability samples was consistent with that of the initial (t0) samples stored at -20°C. Details of manufacturing 35 / 65 compound A-HCl / PVP VA64 SDD formulation.

[0237] Preparation of a spray-dried solid dispersion containing 35 wt% compound A-HCl: 35 / 65 compound A-HCl / PVP VA64 formulation. SDD manufacturing was performed using an SD-180 laboratory desiccator. Secondary drying was performed using a Binder Convection desiccator. Manufacturing details are shown in Table 5. Spray drying was successfully completed in good yield. Table 5. 35 / 65 compound A-HCl* / PVP VA64 SDD process parameters parameter value The collected block SDD (g) 2796 Solid loading in solution (wt%) 10.8 solvent methanol atomizer SD-90 with pressure swirl Nebulization pressure (psig) 320 Solution flow rate (g / min) 115 Drying gas rate (acfm) 80 Dryer inlet temperature (°C) 100 Dryer outlet temperature (°C) 45 Condenser set point (°C) -20 Secondary tray drying of bulk materials 48 hours at 40°C / ambient pressure *Compound A-HCl, based on free base formulation example 3: oral tablets

[0238] Representative 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg tablets are shown in Tables 6 to 13. Excipients used include: microcrystalline cellulose, mannitol, cropovidone, colloidal silica, magnesium stearate, and Opadry White 03K184116 (film coated). Table 6. Representative 10 mg spray-dried dispersion tablets. Component Name Function Quantity / Unit (mg) % w / w Spray-dried dispersion Compound A-HCl raw materials 10.00 3.20 PVP / VA 64 Film-forming agent 56.67 18.15 methanol a solvent NA NA Rolling / blending microcrystalline cellulose diluent 130.31 41.74 Mannitol diluent 53.04 16.99 Chloroprene Disintegrant 30.29 9.71 Colloidal silicon dioxide Flow aid 1.53 0.49 magnesium stearate lubricant 0.76 0.24 Blending / Pressing Chloroprene Disintegrant 18.18 5.82 Colloidal silicon dioxide Flow aid 1.52 0.49 magnesium stearate lubricant 0.76 0.24 Film coating Opadry ® White 03K18416 b film coating agent 9.09 2.91 Purified water c solvent NA NA Total 312.15 100.0 a. Methanol is removed during the spray drying process. b. Composed of hydroxypropyl methylcellulose 2910, titanium dioxide, and triacetin. c. Purified water is removed during the membrane coating process. Table 7. Representative 20 mg spray-dried dispersion (HPMCAS-M) tablets. Mixture number A1 A2 A3 Tablet dosage / tablet weight (mg / mg) 20 / 400 20 / 400 20 / 400 Function Element % w / w of the blend Pre-granulation Surfactant Compound 15 / 85 A-HCl / HPMCAS-M 33.33% 33.33% 33.33% Local pH modifier Citric acid - - 5.00% filler Microcrystalline cellulose (Avicel PH-102) 38.11% 40.11% 36.78% filler Mannitol (Mannogem EZ, spray dried) 19.06% 20.06% 18.39% Disintegration aids Sodium chloride (NaCl powder) - - - Disintegrant Sodium hydroxyacetic acid starch (Explotab) 5.00% - - Disintegrant Povidone (PVP-XL) - 5.00% 3.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Particle exterior Disintegrant Sodium hydroxyacetic acid starch (Explotab) 3.00% - - Disintegrant Povidone (PVP-XL) - - 2.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Table 8. Representative 20 mg spray-dried dispersion (PVPVA 64) tablets. Mixture number B1 B2 B3 Tablet dosage / tablet weight (mg / mg) 20 / 400 20 / 400 20 / 400 Function Element % w / w of the blend Pre-granulation Surfactant 15 / 85 Compound A-HCl / PVPVA 64 33.33% 33.33% 33.33% Local pH modifier Citric acid 5.00% - - filler Microcrystalline cellulose (Avicel PH-102) 43.17% 33.17% 33.17% filler Mannitol (Mannogem EZ, spray dried) - 20.00% - Disintegration aids Sodium chloride (NaCl powder) 5.00% - 20.00% Disintegrant Sodium hydroxyacetic acid starch (Explotab) 6.00% - - Disintegrant Povidone (PVP-XL) - 6.00% 6.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Particle exterior Disintegrant Sodium hydroxyacetic acid starch (Explotab) 6.00% - - Disintegrant Povidone (PVP-XL) - 6.00% 6.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Table 9. Additional representative 20 mg spray-dried dispersion tablets. Mixture number A4 B4 B5 B6 Tablet dosage / tablet weight (mg / mg) 20 / 400 20 / 606.1 20 / 400 20 / 606.1 Function Element % w / w of the blend Pre-granulation Surfactant 15 / 85 compound A-HCl / HPMCAS-M 33.33% - - - Surfactant 15 / 85 Compound A-HCl / PVPVA 64 - 22.00% 33.33% 22.00% Local pH modifier Citric acid 5.00% 5.00% - - filler Microcrystalline cellulose (Avicel PH-102) 35.61% 40.50% 33.17% 43.00% filler Mannitol (Mannogem EZ, spray dried) 16.56% 15.00% 16.00% 17.50% Disintegrant Povidone (PVP-XL) 5.00% 10.00% 10.00% 10.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% 0.25% Particle exterior Disintegrant Povidone (PVP-XL) 3.00% 6.00% 6.00% 6.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% 0.25% Table 10. Representative 30 mg and 40 mg spray-dried dispersions (PVPVA 64) tablets. Mixture number D1 D2 Tablet dosage / tablet weight (mg / mg) 30 / 909.2 40 / 1212.3 Function Element % w / w of the blend Surfactant 15 / 85 Compound A-HCl / PVPVA 64 22.00 22.00 filler Microcrystalline cellulose (Avicel PH-101) 43.00 43.00 filler Mannitol (Parteck M100) 17.50 17.50 Disintegrant Povidone (PVP-XL) 10.00 10.00 Flow aid Silicon dioxide (Syloid 244 FP) 0.50 0.50 lubricant magnesium stearate 0.25 0.25 Disintegrant Povidone (PVP-XL) 6.00 6.00 Flow aid Silicon dioxide (Syloid 244 FP) 0.50 0.50 lubricant magnesium stearate 0.25 0.25 Table 11. Additional representative 40 mg spray-dried dispersion (PVPVA 64) tablets. Mixture number E1 E2 E3 Tablet dosage / tablet weight (mg / mg) 40 / 500 40 / 600 40 / 600 Function Element % w / w of the blend Pre-granulation Surfactant 35 / 65 Compound A-HCl / PVPVA 64 34.29% 28.57% 28.57% filler Microcrystalline cellulose (Avicel PH-101) 32.14% 28.18% 22.18% filler Mannitol (Parteck M100) 16.07% 14.09% 11.09% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 5.00% 5.00% 7.81% Disintegrant Povidone (PVP-XL) 5.00% 5.00% 7.81% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Particle exterior filler Microcrystalline cellulose (Avicel PH-101) - 11.67% 11.67% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 3.00% 3.00% 4.69% Disintegrant Povidone (PVP-XL) 3.00% 3.00% 4.69% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Table 12. Representative 60 mg spray-dried dispersion (PVPVA 64) tablets. Mixture number C1 C2 C3 Tablet dosage / tablet weight (mg / mg) 60 / 500 60 / 600 60 / 600 Function Element % w / w of the blend Pre-granulation Surfactant 35 / 65 Compound A-HCl / PVPVA 64 34.29% 28.57% 28.57% filler Microcrystalline cellulose (Avicel PH-101) 32.14% 28.18% 22.18% filler Mannitol (Parteck M100) 16.07% 14.09% 11.09% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 5.00% 5.00% 7.81% Disintegrant Povidone (PVP-XL) 5.00% 5.00% 7.81% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Particle exterior filler Microcrystalline cellulose (Avicel PH-101) - 11.67% 11.67% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 3.00% 3.00% 4.69% Disintegrant Povidone (PVP-XL) 3.00% 3.00% 4.69% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Table 13. Additional representative 60 mg spray-dried dispersion (PVPVA 64) tablets. Mixture number C4 C5 C6 Tablet dosage / tablet weight (mg / mg) 60 / 600 60 / 600 60 / 600 Function Element % w / w of the blend Pre-granulation Surfactant 35 / 65 Compound A-HCl / PVPVA 64 28.57% 28.57% 28.57% filler Microcrystalline cellulose (Avicel PH-101) 15.08% 18.41% 18.41% filler Mannitol (Parteck M100) 7.54% 9.21% 9.21% Disintegrant Pregelatinized starch (Starch 1500) 20.00% - - Disintegration aids Sodium chloride (NaCl powder) - 10.00% - Disintegration aids 1:1 Sodium chloride:potassium chloride - - 10.00% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 5.00% 5.00% 5.00% Disintegrant Povidone (PVP-XL) 5.00% 5.00% 5.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% lubricant magnesium stearate 0.25% 0.25% 0.25% Particle exterior filler Microcrystalline cellulose (Avicel PH-101) 11.31% 11.31% 11.31% Disintegrant Cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) 3.00% 3.00% 3.00% Disintegrant Povidone (PVP-XL) 3.00% 3.00% 3.00% Flow aid Silicon dioxide (Syloid 244 FP) 0.50% 0.50% 0.50% Disintegration aids Sodium chloride (NaCl powder) - 5.00% - Disintegration aids 1:1 Sodium chloride:potassium chloride - - 5.00% lubricant magnesium stearate 0.25% 0.25% 0.25% Table 14. Examples of spray-dried dispersion tablets. Function Instance components % w / w of tablets Pre-granulation Surfactant (SDD) 15 / 85 compound A-HCl / HPMCAS-M, or 15 / 85 compound A-HCl / PVPVA 64, or 35 / 65 Compound A-HCl / PVPVA 64 20 to 35% filler Microcrystalline cellulose, mannitol 20% to 60% Disintegrant Pregelatinized starch, croscarmellose sodium, Chloroprene 5% to 30% Disintegration aids Sodium chloride (NaCl powder) 1:1 Sodium chloride:potassium chloride 0 to 10% Flow aid Silicon dioxide 0.25% to 1% lubricant magnesium stearate 0.25% to 1% Total pre-granulation 70% to 85% Particle exterior filler microcrystalline cellulose 0 to 20% Disintegrant Cross-linked carboxymethyl cellulose sodium, crosspovidone 3 to 10% Disintegration aids Sodium chloride (NaCl powder) 1:1 Sodium chloride:potassium chloride 0 to 5% Flow aid Silicon dioxide 0.25% to 1% lubricant magnesium stearate 0.25% to 1% Total particulate matter 15% to 30%

[0239] The following are representative non-limiting descriptions of the manufacturing process used for SDD tablets:

[0240] Stage 1: Spray drying: Dissolve compound A-HCl and crospovidone in MeOH. Spray dry the solution. Collect the spray-dried dispersion (compound A-HCl SDD).

[0241] Stage 2: Compaction: A granulated blend consisting of compound A-HCl SDD, filler, disintegrant, flow aid, and lubricant is blended. In some embodiments, a granulated blend consisting of compound A-HCl SDD, mannitol, microcrystalline cellulose, crosspovidone, and colloidal silica is prepared and blended. The internal fraction of magnesium stearate particles is sieved and added to the granulated blend. The resulting blend is then processed. The granulated blend is loaded into the hopper of a compactor and compacted into strips. An inline vibratory mill is used to pass the strip through a screen to break it up and grind it into granules.

[0242] In some embodiments, the granulated blend comprises about 20% to about 35% (w / w by weight of the final tablet) of compound A-HCl SDD. In some embodiments, the granulated blend comprises about 21%, about 22%, about 28%, 29%, about 33%, or about 34% (w / w by weight of the final tablet) of compound A-HCl SDD. In some embodiments, compound A-HCl SDD comprises 15 / 85 compound A-HCl / HPMCAS-M, 15 / 85 compound A-HCl / PVPVA64, or 35 / 65 compound A-HCl / PVPVA64 SDD.

[0243] Stage 3: Blending: The intraparticle material is mixed with the extraparticle excipient. The extraparticle excipient includes one or more of the following: fillers, disintegrants, flow aids, and lubricants. Extraparticle components include microcrystalline cellulose, crosspovidone, and colloidal silica. The extraparticle lubricant magnesium stearate is sieved using an appropriately sized sieve, then added to the blend and mixed.

[0244] Stage 4: Compression: The final blend is compressed into tablets.

[0245] Stage 5: Pan Coating: A film-coated suspension of Opadry White 03K18416 was prepared in purified water, and the tablets were coated with Opadry White 03K18416 in a perforated coating pan. Example 4: Study Design for Evaluating the Performance of the Formulation in Dogs

[0246] Evaluate two conditions* in dogs: +Pg pretreatment (simulating fasted humans, pH 1-2) and -Pg pretreatment (simulating humans taking PPIs or antacids, pH 3-5). (*: There is a 1-week flushing period between each condition; Pg = pentagastrin.) Compound A - HCl solution

[0247] N=4 untreated dogs. Mediator: Propylene glycol. Conditions: -Pg. Compound A-HCl HMG capsules

[0248] N=4 untreated dogs. Conditions: +Pg, -Pg. Spray-dried dispersion tablets of compound A-HCl: PVPVA

[0249] Group 2, N=6 untreated female dogs. Conditions: +Pg, -Pg.

[0250] The results from this study are presented in Tables 15 and 16. Table 15. Dog PK evaluation of formulations of compound A-HCl PK parameters Solution (-Pg) 20 mg HMG capsules 20 mg PVPVA SDD Tablets Fasting + Pg Fasting - Pg Fasting + Pg Fasting - Pg C max (ng / mL) 191 ± 55.2 126 ± 99.6 14.2 ± 2.9 67.5 ± 41.3 125 ± 72.6 AUC 0-t (ng*hr / mL) 1390 ± 559 874 ± 623 85.2 ± 32.6 366 ± 243 454 ± 226

[0251] As shown in Table 15 and Figure 2, the HMG capsule formulation performed poorly in dogs not pretreated with pentagastrin, while the spray-dried dispersion tablets performed better; for the HMG capsule formulation, the AUC without pentagastrin was only 11% of the AUC with pentagastrin (98.2 ng*hr / mL vs. 917 ng*hr / mL). In contrast, the AUC of the PVPVA SDD tablet formulation without pentagastrin was 185% and 124% of that under pentagastrin conditions, respectively. These data indicate that the PVPVA SDD tablet formulation performs well in high gastric pH environments (e.g., as is generally the case in individuals taking PPIs or antacids). Table 16. Dog PK evaluation of 60 mg 35 / 65 PVP-VA SDD tablets of compound A-HCl. PK parameters 35% SDD suspension 60 mg PVPVA SDD tablets Tablet C3 Tablet C4 Tablet C5 C max (ng / mL) 437 ± 140 377 ± 129 329 ± 144 357 ± 146 AUC 0-t (ng*hr / mL) 3630 ± 1990 3110 ± 1360 2540 ± 1120 2560 ± 1140 Example 5: Double-blind, randomized, placebo-controlled, single-dose and multiple-dose studies to evaluate the safety, pharmacokinetics and pharmacodynamics of compound A in healthy volunteers.

[0252] A phase 1, randomized, double-blind, placebo-controlled, single-dose and multiple-escalation-dose study was conducted at a single research center using oral compound A. Inclusion criteria included age 18 to 50 years; body mass index of 18-30 kg / m2; and, if female, a history of postmenopause or surgery. Exclusion criteria included a significant medical history.

[0253] In both the single-dose and multiple-dose cohorts, screening occurred within 28 days prior to the first dose (Day 1). Administration of patostine or placebo began on Day 1 after baseline. Participants fasted overnight for ≥10 h before each dose and maintained this fast until 4 h after administration (after the collection of the last GH sample following the growth hormone-releasing hormone [GHRH] challenge). For the food effect cohort, the study drug was administered 30 minutes after a high-fat, high-calorie breakfast.

[0254] The investigational drug used for administration was provided as an oral solution of compound A-HCl (prepared on-site at the Phase 1 unit) or capsules (placebo, 5 mg and 20 mg).

[0255] Participants received the study drug or placebo orally according to the protocol shown in Figure 1. During the single-dose period, participants were randomized 6:2 in seven cohorts (S1 to S7) to either compound A (1.25, 2.5, 5, 10, 20, 40, and 60 mg) or placebo. The cohorts comparing the oral bioavailability of the solution to the capsule and the effect of a standardized high-fat, high-calorie breakfast on the oral bioavailability of the capsule formulation used a 10 mg dose level. During the multiple-dose period, participants were randomized 6:3 in a single-dose period to either oral compound A-HCl capsules or placebo once daily at a dose of 5 mg for 7 days (M1, last day = day 7) or 10, 20, and 30 mg daily for 10 days (M2, M3, M4, last day = day 10).

[0256] Pharmacokinetic Sampling: Single-dose cohort: Plasma samples were collected on day 1 (before administration, every 15 min up to 90 min after administration, and then at 2, 3, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, and 144 h after administration). Multiple-dose cohort: For the 5 mg cohort, plasma samples were collected on day 1 (before administration, every 15 min up to 90 min after administration, and then at 2, 3, 4, 6, 8, 10, 12, and 18 h after administration), days 2–6 (before administration and 2 h after administration), and day 7 (at the same time points as day 1, followed by samples at 18, 24, 48, 72, 96, 120, and 144 h after administration). For all other multi-dose cohorts, plasma samples were collected on day 1 (before administration, every 15 min up to 90 min after administration, and then at 2, 3, 4, 6, 8, 10, 12, and 18 h after administration), days 2–6 (before administration and 2 h after administration), and day 10 (at the same time point as day 1, followed by samples at 18, 24, 48, 72, 96, 120, 144, 192, and 240 h after administration). The final time point for collecting blood samples for pharmacokinetics and terminal elimination half-life (t1 / 2) determinations was 144 h after administration for the single-dose cohort and cohort M1, and 240 h after administration for cohorts M2–M4.

[0257] Evaluation of GH: To evaluate the ability of patostine to inhibit GHRH-stimulated GH secretion, GHRH challenges were performed in single-dose cohorts S1, S2, S3, S4, and S5 (oral solution). On day 1, 2 h after patostine (or placebo) and at approximately the same time (± 10 min) as on day -1, 50 µg of recombinant human GHRH (1-44)-NH2 (somatorelin; Ferring Pharmaceuticals, Parsippany, NJ) was administered intravenously. Blood samples for serum GH were collected at -60 min, -30 min, before the GHRH challenge, and at 15, 30, 45, 60, 90, and 120 minutes after the challenge. Serum GH was also evaluated in cohort M1. Serum GH samples were collected on days -1, 1 and 7 (before administration, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 18 h after administration), days 2-6 (before administration and 12 h after administration), and days 8, 10 and 14 (at approximately the same time as administration).

[0258] Evaluation of IGF-1: To evaluate serum IGF-1 in single-dose cohorts, serum IGF-1 was collected on days -1 and 1 (before administration to 18 h post-administration) and on days 2 and 7 (at approximately the same time as administration to GHRH on day 1). In the M1 cohort, IGF-1 samples were obtained at the following times: before administration and 6 and 12 h post-administration on days -1, 1, and 7; before administration and 12 h post-administration on days 2–6; and at approximately the same time as administration on days 8, 10, and 14. For the M2 and subsequent cohorts, IGF-1 samples were obtained at the following times: before administration and 6 and 12 h post-administration on days -1, 1, and 10; before administration and 12 h post-administration on days 2–9; and at approximately the same time as administration on days 11, 14, and 21.

[0259] Safety Assessment: Safety assessment includes monitoring of scheduled clinical laboratory tests, cardiovascular safety monitoring (continuous Holter monitoring, ECG, telemetry), and physical examinations throughout the study period at the study facility and post-discharge (up to 9 days after a single dose, or up to 11 days after the last dose for the multiple-dose cohort). Adverse events and concomitant medications should be recorded. Laboratory samples for clinical chemistry, hematology, coagulation tests, and urinalysis should be collected under fasting conditions.

[0260] In the multi-dose cohort, baseline serum TSH, ACTH, and prolactin samples were collected on day -2, and the oral glucose tolerance test (OGTT) was performed on day -7 or earlier. These assessments were repeated on day 8 (M1) or day 11 (M2 and subsequent cohorts).

[0261] An oral glucose tolerance test (75 g glucose load) was administered to healthy individuals at baseline and after repeated administration of compound A. At baseline (day -7), no individuals exhibited abnormal blood glucose levels prior to the glucose challenge. At baseline assessment (day -7), one individual in cohort M3 (compound A-HCl - day 10, 20 mg / day) experienced clinically significant hypoglycemia at 2 and 3 hours after the glucose challenge, and one individual in cohort M4 (compound A-HCl - day 10, 30 mg / day) experienced hypoglycemia at 3 hours after the glucose challenge.

[0262] Two cases of TEAE with asymptomatic hyperglycemia occurred. Both events occurred 1 hour after oral glucose administration and subsided 2 hours after loading during the scheduled OGTT, following completion of the 10-day course of compound A. One individual in cohort M3 experienced a peak glucose concentration of 12.2 mmol / L (220 mg / dL) 1 hour after the oral glucose challenge, which normalized to 5.8 mmol / L (104 mg / dL) 2 hours after the challenge. One individual in cohort M2 (compound A-HCl - 10 days, 10 mg / day) experienced a peak glucose concentration of 12.4 mmol / L (223 mg / dL) 1 hour after the oral glucose challenge, which normalized to 4.3 mmol / L (77 mg / dL) 2 hours after the challenge. No symptoms of hyperglycemia or other sequelae were reported in either case. The clinical significance of isolated 1-hour post-oral glucose challenge hyperglycemia is unclear.

[0263] Compared with placebo, treatment with up to 30 mg of compound A was associated with an increase in serum glucose AUC0-3hr (up to 36% increase from baseline). This effect was not dose-dependent and was not associated with significant changes in fasting plasma glucose.

[0264] From baseline to the day after the last administration of the study drug, the difference in glucose AUC0-3 hr was significant for both M3 (compound A-HCl - 10 days, 20 mg / day; 95% CI 1.8, 8.4; p = 0.0104) and M4 (compound A-HCl - 10 days, 30 mg / day; 95% CI 1.8, 4.6; p = 0.0021). However, this finding was limited by the small number of individuals and observations (see table below). Comparison of oral glucose tolerance test AUC (multiple doses) - safety cohort Parameters (units) Treatment group N Difference (SE) 95% CI of the difference p-value Glucose AUC (0-3 hr) (h*mmol / L) Compound A-HCl 7 days - 5 mg / day 5 3.8 (4.00) (-1.2, 8.8) 0.1013 Compound A-HCl 10 days - 10 mg / day 6 2.4 (3.19) (-1.0, 5.7) 0.1294 Compound A-HCl 10 days - 20 mg / day 6 5.1 (3.12) (1.8, 8.4) 0.0104 Compound A-HCl 10 days - 30 mg / day 6 3.2 (1.34) (1.8, 4.6) 0.0021 All placebos 12 1.5 (4.85) (-1.5, 4.6) 0.2956 Note: Paired t-tests are used for within-group comparisons, where difference = (AUC on day -7) minus (AUC on day 2 after the last administration of compound A). SEM = Standard error of the mean.

[0265] Analytical method: IGF-1 and GH were isolated, stored and analyzed from the serum according to the manufacturer’s instructions (IGF-1 and human GH diagnostic analysis, Siemens Immulite® 1000 system).

[0266] Plasma pharmacokinetic analysis of compound A was performed using a validated procedure by CPR Pharma Services (Thebarton, Australia). In short, plasma compound A concentrations were determined by a combination of high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS / MS). Deuterated compound A was used as an internal standard. Supported liquid extraction was used to extract compound A and the internal standard. Analytes were analyzed by HPLC using an ACE C18-AR column (Advanced Chromatography Technologies, Ltd), and the precipitate was monitored using an API 4000™ LC-MS / MS system (Sciex, Framingham, MA) in positive ion multiple reaction monitoring mode. The extracts were then analyzed against a calibration curve. Data were acquired and integrated using Analyst® (Sciex) data acquisition software, which is directly linked to the API 4000™ LC-MS / MS, and then processed using Watson LIMS™ software (Thermo Scientific), where applicable. When using 100 μL of plasma, the calibration range is 0.100 to 100 ng / mL, with a lower limit of quantification of 0.100 ng / mL. The interanalytical accuracy is 94% to 100%, and the interanalytical precision (%CV) is between 6.1% and 15%.

[0267] Statistical Analysis: The study endpoints were the effects of compound A on GH and IGF-1 stimulation (pharmacodynamics), pharmacokinetics (including formulation and food effects), safety, and tolerability. To analyze the effects of compound A on GH and IGF-1 stimulation, the pharmacodynamic cohort included all randomized participants in the single-dose cohorts of 1.25 mg, 2.5 mg, 5 mg, 10 mg, and 20 mg (S1, S2, S3, S4, and S5) who received any dose of the study drug and had at least one post-baseline pharmacodynamic assessment. ANOVA was used to compare the percentage change in the area under the curve (AUC) of serum GH from baseline at 0 to 2 h (AUC0-2) between each administered cohort and all participants receiving placebo. The single-dose pharmacodynamic cohort included 39 participants from the S1, S2, S3, S4, and S5 cohorts (patostatin n = 29; placebo n = 10). One participant from each of the M1, M3, and M4 cohorts, and two placebo-treated participants were ineligible for inclusion in the pharmacodynamic cohort because they did not receive all doses. For the multi-dose cohort, only participants who received all doses were included. ANOVA was used to compare changes from baseline (mean of 3 or 4 measurements) of IGF-1 levels 12 h after the last dose between each dosing cohort and all participants receiving placebo. The multi-dose pharmacodynamic cohort consisted of 31 participants from the M1, M2, M3, and M4 cohorts (compound A n = 21; placebo n = 10).

[0268] To evaluate the pharmacokinetics of compound A, the single-dose pharmacokinetic cohort included all randomized cohorts that received any dose of the study drug and had sufficient plasma concentration data. For the multiple-dose cohort, only participants who received all doses were included. The relative bioavailability of the capsule formulation was determined by comparing its pharmacokinetic parameters with those of the solution formulation at a 10 mg dose. Food effects were determined at the same dose by comparing the pharmacokinetic parameters at a fasting state with those of compound A administered with a high-fat, high-calorie diet. For both formulation and food effects, ANOVA was performed, with treatment as a fixed effect and individuals as randomized effects. Peak concentration (Cmax), AUC0-last, and AUC0-inf data were transformed using the natural logarithm. Example 6: Phase 1, multiple-cohort, single-dose study to evaluate the relative bioavailability, performance, and safety of two formulations of compound A.

[0269] This study was conducted in up to five similar groups, each with a specific primary objective:

[0270] Group 1: Characterization of the performance of 10 mg tablets prepared by spray drying dispersion (SDD) of compound A-HCl salt.

[0271] Group 2: Evaluate the relative bioavailability of 10 mg SDD tablets compared to the thermally melted granulated (HMG) formulation of compound A-HCl, i.e., 10 mg capsules. Determine the effect of food administration time on the pharmacokinetics of low-dose 10 mg SDD tablets.

[0272] Group 3: Determine the effect of food administration time on the pharmacokinetics of SDD tablets and the dose-proportionality of doses above 20 mg. Determine the optimal dosing regimen that results in sufficient systemic exposure with a short post-dose fasting duration.

[0273] Group 4: Determining the effect of food administration time on the pharmacokinetics of SDD tablets at doses higher than 20 mg. Determining the optimal dosing regimen for patostane that results in high systemic exposure with a short post-dose fasting duration.

[0274] Group 5: To determine the pharmacokinetics of the proton pump inhibitor (PPI) lansoprazole on a 60 mg dose of SDD tablets. To determine the pharmacokinetics of a low-fat diet on a 60 mg dose of SDD tablets. Study Design:

[0275] Up to thirty-six (36) healthy male and female individuals were included. Groups 1 and 2 each consisted of four periods, and Group 3 consisted of three periods. Group 1:

[0276] Evaluation of SDD tablets. Up to twelve (12) healthy male and female individuals were enrolled in each cohort. Cohort 1 consisted of four periods: In period 1, individuals were given a proton pump inhibitor (lansoprazole, 15 mg BID for 3 days (from day -3), orally at least 30 minutes before meals, once in the morning and once in the evening). On day 4 (day 1 of the study), fasting individuals took the last dose of lansoprazole (15 mg) 60 minutes before 20 mg of compound A (2 x 10 mg SDD tablets). In period 2, fasting individuals were given 20 mg of compound A (2 x 10 mg SDD tablets). In period 3, fasting individuals were given 20 mg of compound A (2 x 10 mg SDD tablets) and a high-fat, high-calorie diet. In period 4, fasting individuals took up to 80 mg of compound A (up to 8 x 10 mg SDD tablets). The actual dose was selected based on pharmacokinetic data from Phase 2.

[0277] For Period 1: On the evening before administration (Day -1), the individual is given an evening dose of 15 mg lansoprazole, followed by dinner at least 30 minutes after administration of lansoprazole, and is then required to fast overnight (≥ 10 hr) on Day -1. On Day 1, the individual is given a morning dose of 15 mg lansoprazole (last dose) at least 60 minutes before administration of Compound A (2 x 10 mg SDD tablets). The individual continues to fast for 2 hr after Compound A, after which a standard diet is permitted.

[0278] For period 2: Individuals were required to fast overnight (≥ 10 hours) on day 7. On day 8, 20 mg of compound A (2 x 10 mg SDD tablets) was administered orally. Individuals continued to fast for 2 hours after compound A, after which they were allowed to consume a standard diet.

[0279] For Period 3: Individuals are required to fast overnight (≥ 10 hours) on Day 14. On Day 15, they are allowed to consume a high-fat, high-calorie diet over 30 minutes. After completing the meal, administer Compound A (2 x 10 mg SDD tablets) (no more than 30 minutes after the start of the meal). No additional food should be provided for at least 4 hours after administering Compound A. <0}

[0280] Individuals were not allowed to engage in strenuous exercise for more than 30 minutes per day for 3 days prior to day -1 and throughout the study.

[0281] Throughout the study, pharmacokinetic (PK) and safety assessments were performed at scheduled times, including adverse event (AE) monitoring, clinical laboratory testing, vital sign measurement, 12-lead ECG, Holter monitoring, and telemetry monitoring (period 4 only), and physical examination. Similar group 2:

[0282] The cohort consisted of four periods. In each period, a single oral dose of 20 mg of compound A (2 x 10 mg SDD) was administered.

[0283] For Period 1: Individuals are required to fast overnight (≥ 10 hr) on Day 1. On Day 1, a low-fat diet is given 2 hours after administration of 20 mg of Compound A (2 x 10 mg HMG capsules; reference formulation).

[0284] For period 2: Individuals were required to fast overnight (≥ 10 hr) on day 7. On day 8, they were given a low-fat diet 2 hours after administration of 20 mg of compound A (2 x 10 mg SDD tablets; test formulation).

[0285] For period 3: Individuals were required to fast overnight (≥ 10 hr) on day 14. On day 15, they were given a low-fat diet 1 hr after administration of 20 mg of compound A (2 x 10 mg SDD tablets).

[0286] For period 4: Individuals were required to fast overnight (≥ 10 hr) on day 21. On day 22, they were given a low-fat diet 0.5 hr after administration of 20 mg of compound A (2 x 10 mg SDD tablets).

[0287] The final study visit occurred on day 29. Individuals were not permitted strenuous exercise exceeding 30 minutes per day for the three days prior to day -1 and throughout the study period. Throughout the study, pharmacokinetic (PK) and safety assessments were performed at scheduled times, including adverse event (AE) monitoring, clinical laboratory testing, vital sign measurement, 12-lead ECG, and physical examination. Similar group 3:

[0288] The same group consists of three periods. In each period, a single oral dose of compound A SDD (40, 60 or 80 mg) (4 x 10 mg SDD tablets, 6 x 10 mg SDD tablets or 8 x 10 mg SDD tablets) is administered. There is a washout period of at least 10 days between each dose of compound A.

[0289] For Period 1: Individuals were required to fast overnight (≥ 10 hr) on Day 1. On Day 1, they were given a standard diet 1 hr after administration of 40 mg of Compound A (4 x 10 mg SDD tablets).

[0290] For Period 2: Individuals were required to fast overnight (≥ 10 hours) on Day 10. On Day 11, they were given a standard diet 1 or 2 hours after administration of 80 mg of Compound A (8 x 10 mg SDD tablets). The timing of the meal (1 or 2 hours after administration of Compound A) depended on the mean AUC0-24 determined in Period 1.

[0291] For Period 3: Individuals are required to fast overnight (≥ 10 hours) on day 20. On day 21, they are given a standard diet 1 hour 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 dosage and timing of the standard diet depend on the mean AUC0-24 determined in Period 2.

[0292] The final study visit occurred on day 29. Individuals were not permitted strenuous exercise exceeding 30 minutes per day for the three days prior to day -1 and throughout the study. Throughout the study, pharmacokinetic (PK) and safety assessments were performed at scheduled times, including adverse event (AE) monitoring, clinical laboratory testing, vital sign measurement, 12-lead ECG, and physical examination. Similar group 4:

[0293] Group 4 of the same type consists of the following 3 periods:

[0294] During period 1, fasting individuals were given a standard diet 1 hour after administration of 40 mg (4 × 10 mg) patostine SDD tablets.

[0295] In period 2, fasting individuals were given a standard diet 1 hour after administration of 80 mg (8 × 10 mg) patostine SDD tablets.

[0296] In period 3, fasting individuals were given a standard diet 4 hours after administration of 80 mg (8 × 10 mg) patostine SDD tablets. Similar group 5:

[0297] The cohort consisted of three periods. The pharmacokinetic (PK) response of 3 x 20 mg SDD tablets to 60 mg paltosterine was evaluated using the following criteria: the effect of a low-fat diet on the PK response of paltosterine (periods 1 and 3) and the effect of the PPI lansoprazole on the PK response of paltosterine (period 2), as follows:

[0298] In period 1, fasting individuals were given a low-fat diet 1 hour after administration of 60 mg (3 x 20 mg) patostine SDD tablets. Low-fat diet: 400-500 calories, of which 25% of the calories came from fat (11-14 grams).

[0299] During period 2, individuals were given lansoprazole (15 mg BID for 3 days, orally at least 30 minutes before meals). On day 4, the fasting individuals received the final dose of lansoprazole (15 mg) 60 minutes before receiving 60 mg paltostrtin (3 x 20 mg SDD tablets). Individuals continued to fast for 1 hour after paltostrtin administration, after which they were provided with a low-fat diet. Individuals remained fasted until 4 hours after dose administration.

[0300] During period 3, fasting individuals consumed a low-fat diet over 30 minutes. After completing the meal (but no more than 30 minutes after the start of the meal), individuals took 60 mg of patostine (3 x 20 mg SDD tablets). Individuals remained fasting until 4 hours after dose administration. Study population:

[0301] Up to 36 healthy male or female individuals aged 18 to 55 (inclusive) were selected. Only for Group 2, male and female individuals aged 18 to 65 (inclusive) at the time of selection were included. Inclusion Criteria

[0302] Each individual must meet all of the following inclusion criteria for inclusion in the study: male and female individuals aged 18 to 55 years (inclusive) at screening. For cohort 2 only, male and female individuals aged 18 to 65 years (inclusive) at screening. Body mass index (BMI) of 18 to 30 kg / m², inclusive. Willingness to avoid strenuous, unfamiliar exercise and physical activity (defined as more than 30 minutes per day) for 3 days prior to Day-1 and throughout the study period. If the individual is a heterosexual or bisexual woman, she must be of reproductive potential or must consent to the use of one or two clinically acceptable methods of contraception. Exclusion Criteria

[0303] Healthy individuals meeting any of the following criteria will be excluded from the study: Prior treatment with Compound A. Any uncontrolled or active major systemic disease that would make the study unsafe or interfere with the assessment of the study endpoint. History of or presence of malignancy within the past 5 years, except for adequately treated basal cell carcinoma or squamous cell carcinoma of the skin. Acute or chronic active infection. Use of any study drug within the past 60 days or 5 half-lives (whichever is longer) prior to the first administration of the study drug. Use of tobacco and / or nicotine-containing products, recreational drugs, or alcohol within the 48 hours prior to admission and agreement to abstain from use throughout the study. History of alcohol abuse and / or other drug addiction within < 1 year prior to screening. Use of any prescription or over-the-counter (OTC) medication or alternative medicine within 14 days from Day-1. Consumption of caffeinated beverages or foods within 48 hours prior to Day-1 and within 48 hours prior to each registration date for all subsequent periods. Consuming food containing poppy seeds within 7 days prior to screening until the completion of study evaluation. Taking moderate or strong CYP3A4 inhibitors or inducers. Engaging in strenuous exercise >30 min / day for 3 days prior to Day-1 and throughout the study period. Losing ≥500 mL of blood or donating blood within 3 months prior to admission. Amylase and / or lipase levels >2xULN, alanine transaminase (ALT) and / or aspartate transaminase (AST) >2xULN, total bilirubin >1.5xULN (except in cases of known Gilbert's syndrome), and / or serum creatinine above the upper limit of normal. History of allergic reaction to any excipient in the study drug. Positive or a history of positive tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab) at screening. Positive serum pregnancy test or currently breastfeeding female individuals. This study was conducted only on individuals in Group 1 classified as CYP2C19 poor metabolizers or ultra-rapid metabolizers. Test product, dosage, and administration method:

[0304] 10 mg tablets (SDD). Take multiple tablets with water, depending on the dosage specified for the given period / group.

[0305] 20 mg tablets (SDD). Take multiple tablets with water, depending on the dosage specified for the given period / group. Reference therapy, dosage, and administration method:

[0306] A 10 mg HMG capsule formulation is used as a reference formulation. Swallow multiple capsules with water, depending on the dose specified for the given period / group. Plasma pharmacokinetic parameters:

[0307] Collect blood PK samples to assess the plasma concentration of compound A.

[0308] The PK parameters of compound A were calculated and displayed in the following table: area under the plasma concentration curve from 0 to 24 hours (AUC0-24); maximum plasma concentration (Cmax); time to reach maximum plasma concentration (Tmax). Results

[0309] The results of this clinical trial show that co-administration of proton pump inhibitors has a small effect on the pharmacokinetics observed with SDD tablets, which achieve shorter fasting times and provide better dose-ratio pharmacokinetics.

[0310] The results for Group 1 are presented in Table 17. Table 17. Results for Group 1 average SD CV% Phase 1 (SDD 20 mg + PPI) T max (hr) 2 (1.5-3) C max (ng / mL) 92.5 21.6 23.3 AUC 0-24 (hr*ng / mL) 891 240 26.9 Phase 2 (SDD 20 mg alone) T max (hr) 3 (1.5-6) C max (ng / mL) 114 40.6 35.5 AUC 0-24 (hr*ng / mL) 1140 337 29.5 Phase 3 (SDD 20 mg + food) T max (hr) 1.8 (1.3-4) C max(ng / mL) 16.7 6.82 40.9 AUC 0-24 (hr*ng / mL) 155 46.3 29.9 Phase 4 (SDD 60 mg) T max (hr) 3 (1-6) C max (ng / mL) 305 139 45.4 AUC 0-24 (hr*ng / mL) 2900 1240 42.6 P4 / P2 ratio C max 3.0 (1.7-3.4) AUC 0-24 2.8 (1.6–3.7) Report the median and range of Tmax. Report the mean and range of the P4 / P2 ratio. All doses were administered after an overnight fast and a 2-hour fast following administration. Food: High-fat diet.

[0311] Group 1 (SDD 10 mg x 2, under different conditions): The observed exposures with and without PPI were comparable. Group 1 (SDD 10 mg x 2 vs. 10 mg x 6): The relative dose of exposure was observed to increase proportionally.

[0312] SDD tablets showed a proportional increase in total systemic exposure (AUC) at doses up to 80 mg.

[0313] Compared with SDD tablets, no proportional increase in relative exposure was observed with HMG capsules. See Figure 1. Dose-proportionality data for HMG capsules obtained from previous clinical studies are presented in Table 18. Table 18. Comparative data: Dose-proportionality of HMG capsule formulations observed after a single dose (fasting for 4 h after administration). Parameter (average) sky 5 mg (n=5) 10 mg (n=6) 20 mg (n=5) 30 mg (n=5) 40 mg (n=6) 60 mg (n=6) T max (hr) 1 1.2 ± 0.11 1.8 ± 0.94 2.4 ± 0.82 1.4 ± 0.91 3.4 ± 1.1 3.0 ± 1.2 C max (ng / mL) 1 16.8 ± 7.22 78.7 ± 45.3 88.7 ± 43.3 78.2 ± 60.7 185 ± 118 154 ± 77.6 AUC 0-24 (ng hr / mL) 1 167 ± 73.4 661 ± 340 811 ± 409 578 ± 411 1770 ± 888 The data shown as 1450 ± 656 represents the mean ± standard deviation.

[0314] The results for group 2 are presented in Table 19. Table 19. Results for group 2 average SD CV% Phase 1 (HMG 2h fast) T max (hr) 2 (0.75-3) C max (ng / mL) 123 54.4 44.4 AUC 0-24 (hr*ng / mL) 1060 462 43.6 Phase 2 (SDD 2h fasting) T max (hr) 2 (1-3) C max (ng / mL) 97.2 32.8 33.7 AUC 0-24 (hr*ng / mL) 877 320 36.5 Phase 3 (SDD 1h fast) T max (hr) 1.4 (0.75-4) C max (ng / mL) 89.3 37.0 41.4 AUC 0-24 (hr*ng / mL) 721 319 44.2 Phase 4 (SDD 30 min fasting) T max (hr) 1.3 (0.75-4) C max (ng / mL) 81.3 26.8 32.9 AUC 0-24 (hr*ng / mL) 630 212 33.6 P3 / P2 ratio (%) C max 92% AUC 0-24 82% of all doses were administered after an overnight fast.

[0315] Group 2 (SDD 10 mg x2 vs. HMG at different post-dose fasting durations): SDD tablets did not show better exposure than HMG capsules and the two formulations were relatively comparable. For SDD tablets, the AUC0-24 (a measure of absorption extent) after 1 hour of fasting was reduced to 82% of that observed after 2 hours of fasting, which is a relatively small reduction in exposure.

[0316] Compared with the performance of SDD tablets under different post-dose fasting duration scenarios, HMG capsules performed poorly under different post-dose fasting duration scenarios in previously completed clinical studies. Pharmacokinetic data obtained from 12 individuals (N=4 males, N=8 females) after administration of a 20 mg dose (10 mg HMG capsules x 2) are presented in Table 20. Table 20. Comparative Data: Performance of HMG Capsules under Different Post-Dose Fasting Durations Duration of fasting after administration T max (Hr) C max (ng / mL) AUC 0-24 (Hr*ng / mL) 4 hours 0.75-6 134 (48.9) 1280 (344) 2 hours 0.75-3 104 (35.5) 930 (293) 1 hour 0.75-3 92.2 (30.6) 654 (244) Ratio (%): 2hr / 1hr - 89% 70% The Cmax and AUC shown 0-24 The data represents the average (standard deviation). The range of Tmax is displayed.

[0317] When using HMG capsule formulations, compared with fasting for 2 hours after administration, approximately 30% of the absorption was lost.

[0318] HMG capsules with a 2-hour fast were evaluated in a Phase 2 clinical trial. A 1-hour fast was more promising than a 2-hour fast. Only an 18% AUC(0-24) loss was observed with a 1-hour fast compared to a 2-hour fast. SDD tablets with a 1-hour fast will be used in Phase 3. Importantly, SDD tablets showed better dose-proportioning than HMG capsules, which allows for a 3.0x dose (i.e., 60 mg) in a Phase 3 clinical trial.

[0319] The results for cohort 5 are presented in Table 21. Table 21. Results for cohort 5 (PPI) period treat N C max (ng / mL) AUC 0-inf (hr*ng / mL) T max (hr) 1 60 mg 12 250 (47.5%) 4050 (46.4%) 2.0 [1.0-4.0] 2 60 mg + PPI 12 153 (48.8%) 2450 (58.2%) 2.0 [1.3-6.0] Average value (CV%), except for the Tmax report value [range].

[0320] When administered with a PPI, the exposure (Cmax and AUC) of compound A was reduced by approximately 40%.

[0321] Additional results for group 5 are presented in Table 22. Table 22. Results for group 5 (low-fat diet) period treat N C max (ng / mL) AUC 0-inf (hr*ng / mL) Tmax (hr) 1 60 mg 11 256 (47.8%) 4140 (46.8%) 2.0 [1.0-4.0] 3 60 mg + low-fat diet 11 104 (63.9%) 1650 (55.1%) 2.0 [1.3-4.0] Average value (CV%), except for the Tmax report value [range].

[0322] Compared to the >80% reduction when administered with a high-fat diet, the exposure (Cmax and AUC) of compound A was reduced by approximately 60% when administered with a low-fat diet. Example 7: A phase 2, open-label exploratory study to evaluate the safety, pharmacokinetics, and efficacy of compound A in patients with acromegaly treated with a somatostatin analogue-based therapy (ACROBAT Edge).

[0323] Design of an open-label exploratory study to evaluate the safety, efficacy, and pharmacokinetics of compound A (also known as paltostine) in individuals with acromegaly treated with somatostatin analogues (SSA). Study design:

[0324] Intervention Model: Single-group allocation. Masking: None (open label). Primary Objective: Treatment. Test Product, Dosage, and Administration Method:

[0325] 5 mg or 10 mg HMG capsule formulation. Take multiple capsules with water, depending on the dose specified for the given period / group. Enrolled patients begin treatment with oral patostine 10 mg / day. Based on IGF-1 levels measured at weeks 2, 5, and 8, the dose is titrated in 10-mg increments in a double-blind manner at weeks 4, 7, and 10 to a maximum of 40 mg / day. Incremental titration is performed if the investigator confirms that the patient tolerates the current dose and the unblinding center IGF-1 reader determines that IGF-1 is >0.9 × ULN at weeks 2 and 5, or >1.0 × ULN at week 8. If the patient does not tolerate the current dose, the dose is reduced to the previous dose level (e.g., 20 mg to 10 mg, 10 mg to 5 mg). If IGF-1 inhibition within the normal range is achieved with a tolerated dose, the dose is not changed. Outcome Measurement

[0326] Main outcome measurement: Change in insulin-like growth factor-1 (IGF-1) levels from baseline (mean of screening values) [Timeframe: 13 weeks].

[0327] Secondary Outcome Measurements: 1) Percentage of individuals whose last IGF-1 measurement was ≤ Upper Limit of Normal (ULN) [Timeframe: 13 weeks]. 2) Percentage of individuals whose last IGF-1 measurement was ≤ 1.5 × ULN [Timeframe: 13 weeks]. Acceptance Criteria Incorporated into Standards

[0328] Male and female individuals aged 18 to 70. A confirmed diagnosis of acromegaly with a partial or complete response to a somatostatin analogue therapy regimen as defined in the agreement. Women must be non-pregnant and non-lactating, and surgically sterilized, postmenopausal, or using effective contraception. Willing to provide informed consent. Exclusion criteria.

[0329] Individuals with untreated acromegaly. Those previously treated with patostine. Those who underwent pituitary surgery within the past 6 months. Individuals who received radiation therapy may be eligible, but with some restrictions. Those with a history of malignancy or existing malignancy within the past 5 years, excluding adequately treated basal cell carcinoma and squamous cell carcinoma of the skin. Those who used any investigational drug within the past 30 days or 5 half-lives (whichever is longer). Those who tested positive for HIV, hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab) at the time of screening, or have a history of positive results. Those with a history of alcohol or substance abuse within the past 12 months. Any condition that the investigator believes may jeopardize the individual's proper participation in this study. Cardiovascular conditions or medications associated with prolonged QT or that are likely to cause cardiac arrhythmias in the individual. Individuals with symptomatic gallstones. Individuals with clinically significant abnormalities during the screening period, and any other medical conditions or laboratory results that the investigator believes may jeopardize the individual's safety or ability to complete the study. Individuals taking octreotide LAR at doses higher than 40 mg, lanreotide reservoir at doses higher than 120 mg, or parreotide LAR at doses higher than 60 mg. Individuals regularly taking octreotide LAR or lanreotide reservoir at a frequency of less than every 4 weeks (e.g., every 6 or 8 weeks). Patient-reported outcomes.

[0330] Patients reported acromegaly symptoms daily using a nine-item Acromegaly Symptom Diary (ASD). The ASD was a measure of nine patient-reported symptoms associated with acromegaly, including headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness / tingling, difficulty sleeping, and short-term memory difficulties. Symptoms experienced in the past 24 hours were rated on an 11-point scale, from 0 (no symptoms) to 10 (worst symptoms). The Patient Overall Modified Impression-I (PGI-I) scale was completed at week 13 (end of treatment).

[0331] The overall impression of acromegaly symptom scores and symptom improvement was maintained or improved with patostane treatment. Twenty patients in the study completed the final version of the acromegaly symptom diary (ASD). Among the 70 highest symptom scores, the median baseline total ASD score was low [median (IQR) = 12.00 (4.21, 23.93) n = 20], indicating a low symptom burden at baseline in this study population. Scores showed a slight decrease from baseline to week 13 / EoT [median (IQR) = -0.43 (-5.0, 2.4) n = 18]. After patostane flushing, the total ASD score increased numerically compared to EoT; however, the changes during treatment and flushing were not statistically significant.

[0332] Regarding the response to PGI-I, while receiving reservoir-type SRL therapy, at week 13 / EoT, compared to baseline, 11 patients (23.4%) showed "significant improvement" or "major improvement," while 26 patients (55.3%) showed "minimum improvement" or reported "no change." No patients reported any degree of worsening. Example 8: A phase 2 study evaluating the safety and efficacy of compound A for the treatment of acromegaly (ACROBAT Evolve).

[0333] A phase 2 double-blind, placebo-controlled, randomized discontinuation study was designed to evaluate the safety, efficacy, and pharmacokinetics of compound A in individuals with acromegaly who responded to octreotide LAR or lanreotide reservoirs. Study design:

[0334] Allocation: Randomization. Intervention Model: Parallel allocation. Masking: Tripartite (participant, care provider, researcher). Primary Objective: Treatment. Test Product, Dosage, and Administration Mode:

[0335] 10 mg HMG capsule formulation. Swallow multiple capsules with water, depending on the dosage specified for the given period / group. Result measurement.

[0336] Main outcome measurement: Percentage of individuals meeting the responder criteria (based on the mean of two consecutive insulin-like growth factor-1 [IGF-1] measurements ≤ Upper limit of normal [ULN]) (Timeframe: 13 weeks).

[0337] Secondary Outcome Measurements: 1) Changes in IGF-1 levels [Timeframe: Week 10 to Week 13]. 2) Changes in growth hormone (GH) levels [Timeframe: Week 8 to Week 13]. 3) Changes in patient-reported acromegaly symptoms [Timeframe: Week 10 to Week 13]. The total score is calculated by summing the intensity of each individual acromegaly symptom (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness, or tingling). Eligibility criteria are included in the standard.

[0338] Male and female individuals aged 18 to 70. A confirmed diagnosis of acromegaly controlled by a stable dose of octreotide LAR or lanreotide reservoir. Women must be non-pregnant and non-lactating, and surgically sterilized, postmenopausal, or using effective contraception. Willing to provide signed informed consent. Exclusion criteria.

[0339] Untreated acromegaly. Previous treatment with compound A. Pituitary surgery within the 6 months prior to screening or radiation therapy at any time prior to study entry. Pituitary radiation therapy with recently recorded elevated IGF-1 (within 3 to 4 years or more prior to study entry) is acceptable. History of malignancy or presence of malignancy within the past 5 years, excluding adequately treated basal cell carcinoma 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 or a history of positive HIV, hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab) tests at screening. History of alcohol or substance abuse within the past 12 months. Any condition that the investigator believes would jeopardize the individual's appropriate participation in this study. Cardiovascular conditions or medications associated with prolonged QT or that could predispose the individual to arrhythmias. Individuals with symptomatic gallstones. Individuals with clinically significant abnormalities found during the screening period, and any other medical condition or laboratory result that the investigator believes may jeopardize the individual's safety or ability to complete the study. Individuals who have previously taken the following medications: pevisomone (within the past 3 months), dopamine agonists (within the past 3 months), and parreptide LAR (within the past 6 months). Individuals taking doses higher than 40 mg of octreotide LAR or higher than 120 mg of lanreptide reservoir. Individuals who regularly take octreotide LAR or lanreptide reservoir at a frequency of less than every 4 weeks (e.g., every 6 or 8 weeks). Results from a Phase 2 trial.

[0340] 25 patients were included: patients treated with octreotide or lanreotide and whose baseline IGF-1 (x ULN) was >1 and <2.5.

[0341] Pre-specified primary analysis cohort: 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 median IGF-1 level in this group showed no change from baseline at week 13.

[0342] As shown in Figure 3, patostine maintains IGF-1 and GH levels after switching from the injectable SRL peptide reservoir (data presented are median (interquartile range [IQR]: 25th percentile, 75th percentile). EoT = End of treatment, defined as week 13 (14th visit) or last on treatment value carried forward (LOCF). Weeks after WD are defined as week 17 or at least 22 days after the last dose. Note: p-values ​​are based on a nonparametric Wilcoxon sign rank test to determine whether the change in median is non-zero). Patients previously treated with the injectable SRL reservoir showed no significant change in IGF-1 levels from baseline after 13 weeks of patostine treatment. IGF-1 increases after discontinuation (within 2 weeks), which describes the therapeutic activity of oral patostine. When patients had previously received treatment with an injectable SRL reservoir, GH levels did not change significantly from baseline after 13 weeks of patostatin treatment. The increase in GH after discontinuation of the drug describes the therapeutic activity of oral patostatin.

[0343] Figure 4 illustrates the evidence of dose-response observed from the Acrobat Edge and Evolve trials. However, the HMG capsule formulations used lacked dose-proportional pharmacokinetics at doses above 40 mg.

[0344] As shown in Figure 5, administration of SDD tablets at 40 mg / day and 60 mg / day is expected to produce consistent trough concentrations within the therapeutic range.

[0345] In some embodiments, the valence concentration of paltostetin required to provide a therapeutic effect equivalent to 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 valence concentration of paltostetin required to provide a therapeutic effect equivalent to 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, patostine is administered at a dose sufficient to provide the following trough concentrations of patostine: 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, patostine is administered at a dose sufficient to provide a trough concentration of patostine of at least about 32 ng / mL.

[0346] As shown in Figure 6, the median "predicted" steady-state trough concentration (1 h after fasting) in acromegaly patients taking a PPI with 60 mg SDD was similar to the median steady-state trough concentration in acromegaly patients taking 40 mg HMG (2 h after fasting). Example 9: Long-term study to evaluate the safety and efficacy of compound A-HCl (patostatin) for the treatment of acromegaly (ACROBAT Advance)

[0347] ACROBAT Advance is an ongoing open-label, long-term (5-year) safety and efficacy study of patostine in patients transferred from the ACROBAT Evolve & Edge study.

[0348] Eligible patients who have completed ACROBAT Edge and Evolve should enter ACROBAT Advance immediately after the washout period of their parent study, or after a break between treatments in which they resume their standard of care. Patoxetine therapy: Start with 10 mg / day and titrate to a maximum dose of 40 mg / day based on IGF-1 and tolerability. Patients are given 10 mg HMG capsules. Combination therapy is permitted for patients who do not achieve their treatment goals with 40 mg / day patoxetine monotherapy.

[0349] IGF-1 is a centralized measurement system calibrated using IDS-ISYS based on WHO recombinant reference standard 02 / 254.

[0350] Baseline characteristics of patients with ACROBAT Advance: 41 patients were included. The mean (SD) age for these patients was 129.7 (79.8) months since diagnosis. The mean (SD) age was 53.2 (11.5). 23 patients were female. 35 patients had previously undergone pituitary surgery.

[0351] Pre-trial medical treatment (defined as before the parent trial for those undergoing rollover and before ACROBAT Advance for those undergoing delayed rollover) includes: Pre-trial medical treatment Number of patients (n) Lanreitide, n - 60 / 90 / 120 mg / month 1 / 2 / 13 Octreotide, n - 20 / 30 / 40 mg / month 3 / 16 / 3 Paretaide, n - 40 / 60 mg / month 1 / 1 SRL + Cabernet Sauvignon, n 10 Pevisoxam, n - 20 mg / week 1

[0352] Camembert was administered at a frequency of approximately 0.5 mg / week to approximately 0.5 mg / day.

[0353] The results of the Phase 2 trial are shown in Figures 7a, 7b, 8a and 8b.

[0354] Once-daily oral patostine reduced and maintained IGF-1 levels comparable to those of previous injectable SRL therapy for up to 51 weeks.

[0355] Patostine was well tolerated and had a similar safety profile to SRL, including when used in combination with cabergoline. Example 10: A phase 3 study to evaluate the safety and efficacy of compound A in treating acromegaly in patients with acromegaly treated with long-acting somatostatin receptor ligands.

[0356] This is a randomized, controlled, multicenter study to evaluate the safety and efficacy of compound A (also known as paltostine) in patients with acromegaly who are being treated with long-acting somatostatin receptor ligands.

[0357] Individuals will switch from the stable octreotide / lanreotide regimen to 40 mg patostine, with the dose titrated up to 60 mg based on biochemical status and tolerability. Titration reduction will be permitted based on tolerability. It is anticipated that at the end of the titration period (week 24), the residual pre-test concentration of octreotide or lanreotide will be too low to contribute to efficacy. Overall Design

[0358] The study includes a screening period of 15 to 19 weeks. At the start of the screening period, individuals will receive either long-acting octreotide or lanreotide provided by the trial commissioner. At the end of the screening period, eligible individuals will be randomly assigned in a 1:1 ratio to receive paltostrtin or placebo. At the end of the treatment period, individuals who appear to benefit from paltostrtin treatment will be enrolled in a long-term open-label extension (OLE) lasting up to 96 weeks. During the OLE, all individuals will receive paltostrtin. Inclusion criteria

[0359] Adults aged ≥18 years with medically stable, confirmed active acromegaly who have been taking an approved stable dose of long-acting octreotide or lanreotide for at least 12 weeks prior to screening. Continuous treatment with octreotide or lanreotide monotherapy must have been administered for at least 12 weeks prior to screening. The following prior treatment regimens are eligible for inclusion in this study: long-acting octreotide: 10, 20, 30, or 40 mg every 4 weeks, or long-acting lanreotide: 60, 90, or 120 mg every 4 weeks, or 120 mg every 6 or 8 weeks.

[0360] Prior diagnosis of acromegaly. This requires evaluable documentation of a pituitary tumor diagnosed by pituitary imaging or histopathological confirmation of a pituitary adenoma at least 24 weeks prior to screening.

[0361] For individuals who have undergone pituitary surgery, there must be a record of IGF-1 concentration ≥1.3×ULN at least 12 weeks after the last pituitary surgery. The surgery must be performed ≥24 weeks prior to screening. For individuals who have not undergone pituitary surgery, there must be a record of IGF-1 concentration ≥1.3×ULN administered ≥24 weeks prior to screening. Screening and testing assessment

[0362] An individual's IGF-1 level must be ≤1.2 × ULN before they can begin treatment with medication provided by the trial sponsor. At the end of the screening period (weeks -8 and -4), the individual will undergo two IGF-1 tests to reconfirm eligibility. The average of the two measurements must meet the IGF-1 eligibility criteria. If a third IGF-1 test is required (week -2), the average of the three measurements must meet the IGF-1 eligibility criteria. Exclusion Criteria

[0363] Individuals with untreated or discontinued acromegaly. Individuals with a history of pituitary radiation therapy. Individuals with adrenal insufficiency who did not receive appropriate adrenal replacement therapy at the time of screening.

[0364] The high-risk pituitary tumor pattern is defined as: compression of the optic chiasm or invasion of adjacent brain structures (except for the sphenoid sinus or cavernous sinus); a history of tumor growth within 1 year after surgery (unless it occurred during a period of interruption of medical therapy); anticipated need for neurosurgical intervention or radiation therapy during the study period; and a pituitary adenoma at present or at any time in the past.

[0365] A history of major surgery / surgical treatment for any reason within 4 weeks prior to screening.

[0366] Has had an active malignant disease within the past 5 years.

[0367] The following medications were used: paretide LAR (within 24 weeks prior to screening), pevisole (within 12 weeks prior to screening), dopamine agonists (within 12 weeks prior to screening), or short-acting somatostatin analogs (SA-SSA) within the most recent 12 weeks prior to the first dose of the study drug. Discontinuation of these medications is part of the individual's pre-screening healthcare plan.

[0368] Medicines that will interfere with research if used currently or in the near future. Screening

[0369] The study includes a screening period of 15 to 19 weeks. Individuals must have an IGF-1 level ≤1.2 × ULN to begin treatment with the long-acting octreotide or lanreotide provided by the trial sponsor. During the screening period, the dosing interval of the lanreotide / octreotide injection used prior to the study should be maintained (every 4 weeks, every 6 weeks, or every 8 weeks). This dosing will be performed at the study site. If IGF-1 fails to reach ≤1.2 × ULN, the individual is considered a screening failure.

[0370] Near the end of the screening period (weeks -8 and -4), individuals will undergo two IGF-1 tests to reconfirm their eligibility. The average of the two tests must meet the IGF-1 eligibility criteria. If a third IGF-1 test is required (week -2), the average of the three tests must meet the IGF-1 eligibility criteria.

[0371] The dosing intervals for octreotide / lanreotide provided by the trial client are presented below. Lanreotide / octreotide dosing during the screening period... Lanreotide / Octreotide dosing interval Injection time Every 4 weeks Three injections: First injection at week -12, second injection at week -8, third injection at week -4. The interval between the third injection and day 1 is 4 weeks ± 3 days. Every 6 weeks Two injections: First injection at week -12, second injection at week -6. The interval between the second injection and day 1 is 6 weeks ± 3 days. Every 8 weeks Two injections: First injection at week -16, second injection at week -8. Interval between the second injection and day 1 = 8 weeks ± 3 days. Treatment period (randomized, control period [RC phase]).

[0372] Individuals who met all eligibility criteria and whose average screening period IGF-1 ≤ 1.0 × ULN were randomized (1:1) to patostine (n=26) or placebo (n=26).

[0373] Octreotide / Lanreotide injection is a critical transient event. If an individual receives octreotide / lanreotide every 4 weeks or 6 weeks respectively, Day 1 (treatment start) must be 4 weeks (±3 days) or 6 weeks (±3 days) after the last dose of lanreotide. Alternatively, if an individual receives lanreotide every 8 weeks, Day 1 (treatment start) must be 8 weeks (±3 days) after the last dose of lanreotide.

[0374] The treatment period will be approximately 36 weeks, with 11 planned visits.

[0375] Individuals will not receive the octreotide / lanreotide provided by the trial commissioner on Day 1. Instead, individuals will receive their first dose of the study drug on-site.

[0376] If salvage therapy is required during the RC period, the individual will discontinue either patostine or placebo, initiate salvage therapy, and continue the study for the remainder of the 36-week RC period. Open-label extension period

[0377] Individuals who have completed the 36-week RC phase may continue to participate in the OLE phase if they wish to participate and would benefit from continued participation and use of patosine treatment. The OLE treatment period is 96 weeks, with 11 planned visits. Unless otherwise specified, data from EOR visits during the RC phase will be used as the baseline for OLE. Primary Objectives and Endpoints of the Control Section of the Study

[0378] Evaluate the effect of patostine relative to placebo on IGF-1 response. The primary endpoint of this objective was the proportion of individuals who maintained a biochemical response to IGF-1 (≤1.0 × upper limit of normal [ULN]) at the end of the randomization-controlled period (EOR). Secondary objectives

[0379] Evaluate the effect of patostine relative to placebo on IGF-1 levels. The endpoint of this objective includes the change in IGF-1 (in ULN) from baseline to EOR.

[0380] Evaluate the effect of patostine relative to placebo on GH response. The endpoint of this objective was the proportion of individuals with GH <1.0 ng / mL at week 34 among those with GH <1.0 ng / mL at screening.

[0381] Evaluate the effect of patostine relative to placebo on acromegaly symptoms. The endpoint of this objective included the change in total acromegaly symptom diary (ASD) score from baseline to EOR. Exploration Objective

[0382] Evaluate the effect of patostine relative to placebo on GH levels. The endpoint of this objective includes the change in GH from baseline to EOR.

[0383] Assess the effect of patostine relative to placebo on the need for salvage therapy. The endpoint of this objective includes the proportion of individuals receiving salvage therapy.

[0384] Evaluate the effect of patostine relative to placebo on biochemical response. The endpoints for this objective included the proportion of individuals achieving an IGF-1 ≤1.3 × ULN in the effective response rate (EOR); and the proportion of individuals achieving a GH <2.5 ng / mL at week 34 among those with GH <2.5 ng / mL at screening. Safety objectives

[0385] To evaluate the safety and tolerability of patostine relative to placebo in individuals with acromegaly. Endpoints for this objective included: the incidence of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and TEAEs leading to discontinuation; changes in safety parameters; the incidence of clinically significant changes in abdominal (gallbladder) ultrasound compared to baseline; and changes in residual pituitary tumor volume from baseline. Open-label extended endpoints.

[0386] Safety endpoints: incidence of TEAEs, including serious adverse events (SAEs) and TEAEs that lead to discontinuation of the study drug; changes in safety parameters; changes in residual pituitary tumor volume from baseline.

[0387] Additional efficacy endpoints: changes in IGF-1 and GH levels from baseline; proportion of individuals with IGF-1 ≤ 1.0 × ULN; proportion of individuals with IGF-1 ≤ 1.3 × ULN; proportion of individuals receiving permissible adjunctive standard acromegaly treatment. Number of individuals

[0388] The total sample size was 52 individuals (26 in the patostine arm and 26 in the placebo arm). Duration and intervention groups.

[0389] The study comprises two phases: the RC phase and the long-term OLE phase. Individuals participating in both phases will complete approximately 144 weeks (nearly 3 years) of treatment and observation. The study will consist of the following: • Screening phase: 15 or 19 weeks; from week -19 / -15 to day -1. • RC phase (36 weeks): Treatment phase: from day 1 to week 36; the end of week 36 is defined as EOR. Weeks 1 to 24 will be the dose titration period. • OLE (96 weeks): Eligible individuals who complete the RC phase can enter the OLE and continue or start patostine treatment until the end of treatment (EOT); the end of the 96-week OLE phase is the planned EOT.

[0390] During the RC and OLE periods, paltostetin will be provided as a 20 mg tablet. The matched placebo tablets will be visually identical. The starting dose will be 40 mg (active paltostetin or 2 x 20 mg matched placebo tablets) once daily by oral administration. Dosage adjustments during the RC period

[0391] The dose of the investigational drug can be titrated up to 60 mg once daily (QD). The dose will be increased from 40 mg (2 × 20 mg tablets) to 60 mg (3 × 20 mg tablets) based on the IGF-1 response. A fixed or stable dose is considered to be established when the IGF-1 content is ≤0.9 × ULN, confirmed by two consecutive IGF-1 measurements collected at approximately 4-week intervals.

[0392] Dose increment titration will be based on two criteria: • Tolerability at the current dose, as assessed by the investigator, and • The individual's most recent IGF-1 result is >0.9×ULN. Dosage titration / adjustment IGF-1 criteria Tolerance criteria 40 mg to 60 mg The latest IGF-1 results for individuals at 40 mg are >0.9×ULN. Increases are permitted due to acceptable tolerability of 40 mg. 40 mg to 20 mg A dose reduction is required due to unacceptable tolerability to 40 mg. 20 mg to 40 mg The latest IGF-1 results for individuals with 20 mg IGF-1 were >0.9×ULN. Tolerability to 20 mg is acceptable. 60 mg to 40 mg A dose reduction is required due to unacceptable tolerability to 60 mg.

[0393] Due to poor tolerability, the individual's dose may be reduced during the RC period. Generally, there is a reasonable probability that a severe TEAE (Training-Action Effective) caused by (or related to) the study drug will lead to a dose reduction of the study drug. If tolerability improves after dose reduction, the dose may be increased in 20 mg increments up to a maximum of 60 mg (3 × 20 mg tablets) if necessary, based on agreed dose titration guidelines. When the study drug is intolerable, the study drug may be suspended for a maximum of 14 days per year, but not for more than 7 consecutive days per year during the study period, and then resumed at the same or reduced dose (if appropriate). RC Period Salvage Guidelines

[0394] During the RC phase, treatment of acromegaly other than the study drug is prohibited during the study period. The criteria for salvage treatment with pre-trial acromegaly medications (long-acting injectable octreotide or lanreotide) consist of the following: 1) significant worsening of one or more acromegaly symptoms or development of new acromegaly symptoms, sustained at the highest dose (60 mg) for at least 2 weeks ("significant worsening" can be defined as a symptom requiring a substantial increase in the level of clinical care or a substantial clinical deterioration; and 2) IGF-1 values ​​≥1.3 × ULN measured at two consecutive visits at the highest dose (60 mg). Dosage and dose adjustments during the open-label extension period.

[0395] The initial dose regimen for all individuals participating in OLE will be patostane 40 mg QD. Dose escalation during OLE will typically occur when the first IGF-1 result is available. At this point, the investigator may decide whether the dose escalation can be titrated to 60 mg. Open-label extended adjuvant therapy

[0396] During OLE, non-SRL acromegaly treatment (e.g., oral dopamine agonists (e.g., cabergoline) or GH receptor antagonists pevisolemones) may be permitted as adjunctive therapy when patostine is at the highest tolerated dose for at least 4 weeks and IGF-1 remains ≥1.3×ULN or is otherwise not at the individual’s treatment target in the investigator’s judgment.

[0397] If adjuvant therapy is determined to be needed, dopamine agonists (such as cabergoline) will be used as first-line adjuvant therapy. If, after a sufficient evaluation period, the investigational drug in combination with a dopamine agonist fails to achieve the treatment goal, pevisolemon can be added as a second-line adjuvant therapy. Pevisolemon can be added to the patostine + dopamine agonist combination. If there is no evidence of treatment response to the combination of patostine + dopamine agonist, the dopamine agonist should be discontinued and pevisolemon added to patostine therapy. Example 11: A phase 3 study was conducted to evaluate the safety and efficacy of compound A in treating acromegaly in patients with acromegaly who had not received pharmacological treatment.

[0398] This is a randomized, controlled, multicenter study to evaluate the safety and efficacy of compound A (also known as patostine) in patients with acromegaly who have not received pharmacological treatment. Overall design

[0399] This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study in which individuals with acromegaly who have not received pharmacological treatment will be randomly assigned to receive patostine or placebo. A total of 70 individuals will be enrolled as the target group.

[0400] The screening period for this study may be approximately 4, 8, or 12-16 weeks, depending on prior treatment. Following the screening period, individuals will be enrolled in a 12-week randomized controlled (RC) period and randomly assigned 1:1 to receive compound A or a matched placebo, stratified by prior treatment (medically untreated or previously treated relative to flushing). At the end of the RC period (EOR), individuals may be enrolled in the long-term open-label extension (OLE) study, during which they will receive patostine for up to 96 weeks. Inclusion Criteria

[0401] Individuals aged ≥18 years at screening who have undergone at least one pituitary surgery but have persistent active acromegaly and belong to one of the following three groups are eligible to participate in the study: • Medically Untreated Group: Individuals who have not previously been treated with acromegaly medications (including long-acting somatostatin receptor ligand [LA-SRL]) and have IGF-1 > 1.1 × Upper Limit of Normal (ULN) at screening. • Previously Treated Group (No Treatment in the Previous 4 Months): Individuals who last received acromegaly medication at least 4 months prior to screening and have IGF-1 > 1.1 × ULN at screening. • Washout Group: Individuals who are receiving appropriate treatment with octreotide monotherapy at screening (without dose changes in the previous 3 months), have IGF-1 ≤ 1.0 × ULN at the first screening visit, and are willing to wash out their medication during the screening period. Pre-trial octreotide monotherapy of any form (long-acting or short-acting octreotide [subcutaneous (SC) or oral]) can be flushed out and will determine the duration of the screening period. After providing informed consent, individuals will not receive any other experimental acromegaly medications. IGF-1 must increase by at least 30% from the first screening visit to the last screening visit and reach >1.1 × ULN to be eligible for enrollment.

[0402] Prior diagnosis of acromegaly. This requires evaluable documentation of a pituitary adenoma at least 24 weeks prior to screening. Additionally, documentation of IGF-1 concentration >1.1×ULN at least 12 weeks after the last pituitary surgery is required. Exclusion criteria

[0403] History of ineffective or significant intolerance to octreotide or lanreotide treatment.

[0404] History of pituitary radiation therapy within screening 3. Individuals with adrenal insufficiency who did not receive appropriate adrenal replacement therapy at screening time, as determined by the investigator. High-risk pituitary tumor pattern is defined as: compression of the optic chiasm or invasion of adjacent brain structures; history of tumor growth within 1 year after surgery or radiation; anticipated need for neurosurgical intervention or radiation therapy during the study period. Current or past history of pituitary adenoma.

[0405] A history of major surgery / surgical treatment for any reason within 4 weeks of screening.

[0406] Has had an active malignant disease within the past 5 years.

[0407] The following medications were used: lanreotide (within 16 weeks prior to screening), parreotide LAR (within 24 weeks prior to screening), pevisole (within 16 weeks prior to screening), dopamine agonists (within 16 weeks prior to screening), any combination of two or more acromegaly medications at the time of screening, and proton pump inhibitors (from the start of screening until the end of the study). Discontinuation of these medications was part of the individual's pre-screening medical care plan.

[0408] Current or near-term use of medicines that will interfere with the study. Treatment period (randomization, control (RC) period)

[0409] Once all screening evaluations are completed, individuals will be randomized on day 1 of the treatment period to begin treatment. The treatment period will last approximately 12 weeks. Individuals will receive their first dose of the investigational drug (patostatin or placebo) on day 1.

[0410] If rescue is required during the RC phase, the individual will discontinue patostine or placebo and will be considered a nonresponder. They will undergo an early termination (ET) visit and will be offered open-label extended (OLE) participation. If the individual does not participate in OLE, they will return to standard acromegaly care.

[0411] Open-label extension (approximately 100 weeks, including 4 weeks of follow-up)

[0412] Individuals who complete the 12-week RC phase or meet the salvage criteria may continue to participate in the OLE phase if they would benefit from continued participation and use of patostine treatment and are willing to participate. The OLE treatment period is 96 weeks. (Investigational drug)

[0413] Patostreptine will be available as a 20 mg tablet. The matched placebo tablet will be identical in appearance to the patostreptine tablet. The starting daily dose will be 20 mg (1 x 20 mg tablet of active patostreptine or matched placebo) for oral self-administration.

[0414] The investigational drug should be taken in the morning with at least 8 ounces (237 mL) of water after fasting for at least 6 hours overnight. Food or beverages (except water) or other medications should be avoided for at least 1 hour after administration.

[0415] Special precautions for antacid therapy: Famotidine should not be taken later than dinner time. Other H2 blockers and antacids can be taken before bedtime. The aim is to minimize the increase in gastric pH the next morning, thereby reducing the absorption of patostine.

[0416] The final dose of study drug during the RC phase will be auto-administered the day before the 12-week / EOR visit. For individuals continuing into OLE, the first dose of the OLE phase will be administered during the 12-week / EOR visit. Dosage titration and adjustments.

[0417] From the 6th week visit to the 11th week visit, dose increment titration will be based on two criteria: • Tolerability at the current dose, as assessed by the investigator, and • The individual's most recent IGF-1 result is >0.9×ULN. Dosage titration / adjustment IGF-1 criteria Tolerance criteria 20 mg to 40 mg If 20 mg is well tolerated, a dose increase is required one week after administration (day 8). 40 mg to 60 mg IGF-1 > 0.9 × ULN in week 4 or at any time before the week 11 visit. The 40 mg dose was well tolerated. 60 mg to 40 mg Due to unacceptable tolerability of 60 mg, a dose reduction is required. 40 mg to 20 mg Due to unacceptable tolerability of 40 mg, a dose reduction is required.

[0418] If acromegaly worsens during the RC period and requires salvage therapy, the individual will discontinue patostine or placebo and enter OLE or withdraw from the study. The salvage criteria are as follows: • Significant worsening of one or more acromegaly symptoms or development of new acromegaly symptoms, persisting for at least 2 weeks at the highest dose (60 mg) (“significant worsening” can be defined as a symptom requiring a substantial increase in the level of clinical care or a substantial clinical deterioration; and • An increase of >30% in IGF-1 levels from baseline at the highest dose (60 mg), measured twice at the scheduled visit or at an unscheduled visit (if earlier results are required); and

[0419] If rescue is required during the RC period, the individual will discontinue either patostine or placebo and will be considered a nonresponder. Dosage and dose adjustments during the open-label extension period.

[0420] The starting daily dose regimen for all individuals participating in OLE will be patostine 20 mg (1 x 20 mg tablets). Individuals will be instructed to take one tablet daily for the first week, and then, if tolerated, increase to 40 mg QD (2 x 20 mg tablets) until the next study visit.

[0421] When the first IGF-1 result is available, further incremental titrations in OLE may occur (e.g., to 60 mg QD (3 × 20 mg tablets)). Open-label extended adjuvant therapy.

[0422] During OLE, when patostine is at the highest tolerated dose for at least 4 weeks and IGF-1 is consistently ≥1.3×ULN or otherwise not at the individual’s treatment target, non-SRL acromegaly treatment (e.g., oral dopamine agonists (e.g., cabergoline) or GH receptor antagonists (i.e., pevisom)) may be permitted and may be initiated as adjuncts.

[0423] If adjuvant therapy is determined to be necessary, dopamine agonists (such as cabergoline) will be used as first-line adjuvant therapy. If, after a sufficient evaluation period, the investigational drug in combination with a dopamine agonist fails to achieve the treatment goal, pevesolemon may be added as a second-line adjuvant therapy. Pevesolemon can be added to the patostine + dopamine agonist combination. If there is no evidence of treatment response to the patostine + dopamine agonist combination, the dopamine agonist should be discontinued and pevesolemon added to patostine therapy. Contraindicated Drugs

[0424] Prohibited medications include: proton pump inhibitors; fenmotidine used at night; oral estrogens, except for monophasic estrogen-progestin oral contraceptives or stable estrogen replacements; strong inducers of the drug-metabolizing enzyme CYP3A4; any standard acromegaly medications during the RC phase of the study; octreotide (in any form), lanreotide, or parreotide during OLE; and any other investigational drugs. Primary objective

[0425] Evaluate the effect of patostine relative to placebo on IGF-1 response. The endpoint of this objective includes the proportion of individuals achieving a biochemical response to IGF-1 (≤1.0 × ULN) at the end of the randomization-controlled period (EOR). Secondary objectives

[0426] Evaluate the effect of patostine relative to placebo on IGF-1 levels. The endpoint of this objective includes the change in IGF-1 (in ULN) from baseline to EOR.

[0427] The biochemical response following patostine treatment was assessed using different definitions. The endpoints included the proportion of individuals achieving IGF-1 ≤1.3×ULN at EOR; the proportion of individuals achieving GH <2.5 ng / mL at EOR; and the proportion of individuals achieving GH <1 ng / mL at EOR.

[0428] Evaluate the effect of patostine relative to placebo on acromegaly symptoms. The endpoint of this objective includes the change in the total acromegaly symptom diary (ASD) score from baseline to the effective rate (EOR). Exploration Objective

[0429] Evaluate the effect of patostine relative to placebo on GH levels. The endpoint of this objective includes the change in GH from baseline to EOR.

[0430] Assess the effect of patostine relative to placebo on the need for salvage therapy. The endpoint of this objective includes the proportion of individuals requiring salvage therapy from the start of treatment to the end of the illness (EOR). Safety objectives.

[0431] Assess the safety and tolerability of patostine relative to placebo. Endpoints for this objective include: the incidence of treatment-emergency adverse events (TEAEs), including serious TEAEs and TEAEs leading to discontinuation; changes in safety parameters from baseline; and the incidence of clinically significant changes in abdominal (gallbladder) ultrasound compared to baseline. Open-label extension (OLE) endpoints.

[0432] Safety endpoints: incidence of TEAEs, including serious adverse events (SAEs) and TEAEs that lead to discontinuation of the study drug; changes in safety parameters; changes in residual pituitary tumor volume from baseline.

[0433] Additional efficacy endpoints: changes in IGF-1 and GH levels from baseline; proportion of individuals with IGF-1 ≤ 1.0 × ULN; proportion of individuals who discontinued RC (with salvage) and entered OLE and then achieved IGF-1 ≤ 1.0 × ULN during OLE; proportion of individuals who received permissible adjunctive standard acromegaly treatment. Individual-reported evaluation

[0434] Individually reported assessments include: (1) Acromegaly Symptom Diary (ASD), (2) Acromegaly Quality of Life (AcroQoL), (3) EQ-5D-5L, (4) Patient's Overall Impression of Severity (PGI-S), (5) Patient's Overall Improved Impression (PGI-I), and (6) Treatment Preference Questionnaire. These assessments will be completed using electronic devices (either the individual's electronic device or an application on a device provided by the trial commissioner). Acromegaly Symptom Diary

[0435] Individuals will be asked to complete an ASD (Short Symptom Diary) daily at home for the duration of the randomization control period, starting approximately two weeks before administration of the study drug. The ASD should be completed as consistently as possible at approximately the same time of day.

[0436] The ASD questionnaire consists of nine items (headache; joint pain; sweating; fatigue; leg weakness; swelling; numbness or tingling; sleep difficulties; and problems with short-term memory), each ranked from 0 to 10 in intensity. The total ASD score is calculated by adding the intensities of the individual symptoms for each of the following: headache; joint pain; sweating; fatigue; leg weakness; swelling; and numbness or tingling. Therefore, the total ASD score can range from 0 to 70. All individual item scores (including sleep difficulties and short-term memory problems) are collected and analyzed within the individual item scores. Acromegaly Quality of Life Questionnaire

[0437] The AcroQoL questionnaire assesses health-related quality of life in individuals with acromegaly. The questionnaire consists of 22 questions across two domains: body appearance (8 questions) and mental state (14 questions). The mental state domain is divided into two subscales: appearance (7 questions) and the impact of the disease on personal relationships (7 questions). Each question is answered on a scale of 1 to 5 (always, most of the time, sometimes, rarely, or never). Higher scores indicate a better quality of life. EQ-5D-5L

[0438] The EQ-5D-5L (5 severity levels of EQ-5D), developed by EuroQoL, is a standardized tool that is completed by individuals and used as a measure of health outcomes applicable to a wide range of health conditions. It includes 5 health dimensions: mobility, self-care ability, ability to perform daily activities, pain and discomfort, and anxiety and depression.

[0439] Based on qualitative and quantitative research conducted by the EuroQoL Group, each domain has five options (levels): "No problem," "Minor problem," "Moderate problem," "Severe problem," and "Unable / Extreme problem." Responses to all five dimensions can be converted into a single aggregate index, i.e., utility (range: 0 to 1), using a set of values. Higher index values ​​represent better health. Overall impression of improvement and severity.

[0440] The PGI-I is a 7-point scale designed to measure changes in symptoms over a specific time period compared to baseline. Treatment response to the PGI-I ranges from 1 ("significant improvement") to 7 ("very poor"). Lower scores indicate improvement. The PGI-S is also assessed on a 7-point Likert scale, ranging from 1 ("normal, not necessarily sick") to 7 ("most severe illness"). Higher scores indicate more severe illness.

[0441] The examples and embodiments described herein are for illustrative purposes only, and all modifications or alterations suggested by those skilled in the art are included within the spirit and scope of this application and the scope of the appended claims. [Simplified Explanation of the Diagram]

[0049] Figure 1. Illustration of the dose-proportioning observed in humans given HMG capsule formulations or SDD tablet formulations containing compound A-HCl.

[0050] Figure 2. Illustration of the performance of HMG capsule formulation and SDD tablet formulation of compound A-HCl in dogs with or without pentagastrin pretreatment.

[0051] Figure 3. Illustration of hormone levels observed in the primary analysis population of the Acrobat Edge clinical trial.

[0052] Figure 4. Illustration of evidence of dose response observed in the Acrobat Edge and Evolve clinical trials.

[0053] Figure 5. Illustration of the estimated glutar plasma paltusotine concentration required for therapeutic effect and the prediction of dose-proportioning effect for SDD tablet formulation.

[0054] Figure 6. Illustration of the predicted glutar plasma patostine concentration in acromegaly patients taking 60 mg SDD PPI tablets (fasting for 1 hour after administration) compared to the predicted glutar plasma patostine concentration in acromegaly patients who did not take PPIs and in acromegaly patients who took 40 mg HMG capsule formulation (fasting for 2 hours after administration).

[0055] Figure 7a shows interim results from the Acrobat Advance study of a subset of patients receiving paltostine monotherapy.

[0056] Figure 7b. Illustration of interim results from the Acrobat Advance study, which included a subset of patients previously enrolled in the Evolve study.

[0057] Figure 8a. Illustration of interim results of the Acrobat Advance study for all patients included in the study.

[0058] Figure 8b. Illustration of interim results of the Acrobat Advance study of a subset of patients treated with paltostine and cabergoline.

Claims

1. Use of a pharmaceutical composition comprising 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzonitrile (compound A) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating acromegaly in humans; wherein compound A or a pharmaceutically acceptable salt thereof is administered orally to the human once daily; wherein the dosage of the pharmaceutically acceptable salt thereof is about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, or about 80 mg / day; wherein compound A or a pharmaceutically acceptable salt thereof is administered once daily at least 60 minutes before a meal; or wherein treatment of acromegaly with compound A or a pharmaceutically acceptable salt thereof comprises reducing serum insulin-like growth factor-1 (IGF-1) concentration, reducing serum growth hormone (GH) concentration, or both in the human. Lowering IGF-1 concentration includes bringing human serum IGF-1 concentration to normal levels, where normal serum IGF-1 concentration in humans is less than 1 times the upper limit of normal (ULN).

2. As claimed in claim 1, wherein the dosage of compound A or a pharmaceutically acceptable salt thereof is approximately 40 mg / day.

3. As claimed in claim 1, wherein the dosage of compound A or a pharmaceutically acceptable salt thereof is approximately 60 mg / day.

4. As claimed in claim 1, wherein the dosage of compound A or a pharmaceutically acceptable salt thereof is approximately 80 mg / day.

5. The use of any of claims 1 to 4, wherein the human is unresponsive to treatment with a somatostatin analogue, tolerates the treatment, or loses response to the treatment, wherein the somatostatin analogue is octreotide, lanreotide, or pasireotide.

6. The use of any one of claims 1 to 4, wherein the human with acromegaly responds to and tolerates treatment with a somatostatin analogue, wherein the somatostatin analogue is octreotide, lanreotide, or pasireotide.

7. For any of claims 1 to 4, wherein compound A or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets, wherein each tablet comprises: a spray-dried solid dispersion of compound A monohydrochloride; one or more additional pharmaceutically acceptable ingredients; and, where appropriate, one or more film coating agents.

8. As claimed in claim 7, wherein the spray-dried solid dispersion comprises: (a) a monohydrochloride of compound A; and (b) a pharmaceutically acceptable polymer; wherein the monohydrochloride of compound A is dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer; wherein the amount of 3-[4-(4-amino-hexahydropyridin-1-yl)-3-(3,5-difluoro-phenyl)-quinoline-6-yl]-2-hydroxybenzonitrile monohydrochloride is based on compound A; and, where appropriate, less than about 5% by weight of one or more film coating agents.

9. For the purpose of any of the requests 1 to 4, wherein: Compound A or its pharmaceutically acceptable salts are administered once daily on an empty stomach.

10. For any of the uses described in claims 1 to 4, wherein compound A or a pharmaceutically acceptable salt thereof is administered once daily at least 180 minutes after a meal.

11. As claimed in any of claims 1 to 4, wherein compound A or a pharmaceutically acceptable salt thereof is administered once daily before bedtime.

12. As claimed in any of claims 1 to 4, wherein compound A is administered once daily on an empty stomach at least 30 minutes before a meal, with a glass of water.

13. As claimed in claim 7, wherein compound A or a pharmaceutically acceptable salt thereof is administered once daily before bedtime.

14. As claimed in claim 7, wherein compound A or its pharmaceutically acceptable salt is administered once daily on an empty stomach.

15. As claimed in claim 8, wherein compound A or a pharmaceutically acceptable salt thereof is administered once daily before bedtime.

16. As claimed in claim 8, wherein compound A or its pharmaceutically acceptable salt is administered once daily on an empty stomach.

17. For the purpose of any of the requests 1 to 4, wherein: If compound A or a pharmaceutically acceptable salt thereof is co-administered with a drug that alters the pH of the upper gastrointestinal (GI) tract, the daily dose of compound A or a pharmaceutically acceptable salt or solvate thereof shall be increased, wherein the drug that alters the pH of the upper gastrointestinal (GI) tract includes a proton pump inhibitor, a histamine H2-receptor antagonist, or an antacid.

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