WO2025249555A1

WO2025249555A1 - Method for treating or preventing hypertrophic cardiomyopathy

Info

Publication number: WO2025249555A1
Application number: PCT/JP2025/019665
Authority: WO
Inventors: Hironobu TADAKI; Sumiaki FUKUDA; Takeshi WAKASHIMA; Tetsuya HONDO
Original assignee: Japan Tobacco Inc
Current assignee: Japan Tobacco Inc
Priority date: 2024-05-31
Filing date: 2025-05-30
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30

Abstract

One aim of the present invention is to treat or prevent hypertrophic cardiomyopathy. Provided are: a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy comprising a compound inhibiting SGLT1 or a pharmaceutically acceptable salt thereof; and a method of treating or preventing hypertrophic cardiomyopathy, comprising administering a compound inhibiting SGLT1 or a pharmaceutically acceptable salt thereof.

Description

METHOD FOR TREATING OR PREVENTING HYPERTROPHIC CARDIOMYOPATHY

The present invention relates to a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising a compound inhibiting SGLT (Na⁺-glucose cotransporter) 1 or a pharmaceutically acceptable salt thereof, and a method of treating or preventing hypertrophic cardiomyopathy, comprising administering a compound inhibiting SGLT1 or a pharmaceutically acceptable salt thereof.

Hypertrophic cardiomyopathy (HCM) is one of the genetic heart diseases reported in the population globally and is characterized by left ventricular (LV) hypertrophy in the absence of another cardiac, systemic or metabolic disease. In up to 60% of adolescents and adults with HCM, the disease is an autosomal dominant trait caused by mutations in cardiac sarcomere protein genes, such as MYH7, MYBPC3, TNNI3 TNNT2 and other genes (NPL 1, 2). Hypertrophic cardiomyopathy is relatively common with a prevalence of 1:200 to 1:500 in the general population, while symptomatic hypertrophy has been estimated at <1:3000 adults in the United States based on the medical claims data.

HCM is typically divided into two broad categories: non-obstructive HCM (nHCM) and obstructive HCM (oHCM). Non-obstructive HCM is characterized by no significant left ventricular outflow tract obstruction (LVOTO). Obstructive HCM is characterized by LVOTO. Mid-ventricular obstructive HCM, apical HCM, and/or dilated phase of HCM are known as rare forms of HCM. Mid-ventricular obstructive HCM is also called mid-cavity obstructive HCM.

Among referral-based patients with HCM, 30% to 40% will experience unfavorable events, including: (1) sudden death, and (2) atrial fibrillation with a risk of thromboembolic stroke. The pharmacological treatment options for HCM include β-blockers, calcium channel blockers or other agents which have been historically used for the symptomatic relief of HCM. However, their use is mostly empiric and there are no convincing data to suggest that these agents alter the natural history of HCM.

Recently, mavacamten, a cardiac myosin inhibitor, was approved for the treatment of obstructive HCM to improve functional capacity and symptoms. However, mavacamten has a major side effect of increased risk of heart failure due to its mechanism of action (MOA). Therefore, there is a pressing need to develop drugs that can further improve the symptoms and slow down the disease progression in HCM patients.

[PTL 1] WO 2013/031922
[PTL 2] WO 2019/168096
[PTL 3] WO 2019/194207

[NPL 1] 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)
[NPL 2] 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy

FIG. 1 shows the effect of Comp. 1 on the slope of end-diastolic pressure-volume (EDPVR β) relationship in mice with hypertrophic cardiomyopathy. WT: Vehicle-treated wild-type mice, Vehicle: Vehicle-treated HCM mice, Mavacamten 2.5 mg/kg: mavacamten-treated HCM mice, Comp. 1 3 and 6 mg/kg: Comp. 1-treated HCM mice. Mean ± SD (n = 6 - 8). ††: p < 0.01 vs. WT (Aspin-Welch’s t test). §: p < 0.05 vs. Vehicle (Student’s ttest). *: p < 0.05 vs. Vehicle (Dunnett's test).

FIG. 2 shows the planned clinical study schema of test example 2.

FIG. 3 shows the schedule of the Comp. 1 Phase I study procedures (Screening Visit through Day 8).

FIG. 4 shows the schedule of the Comp. 1 Phase I study procedures (Day 9 through Follow-up Visit).

FIG. 5 shows the Bristol Stool Chart.

FIG. 6 shows the EQ-5D-5L questionnaire.

FIG. 7 shows the FACIT-D questionnaire.

Certain embodiments are illustrated as follows.

Item 1
A method of treating or preventing hypertrophic cardiomyopathy, comprising administering to a subject a therapeutically effective amount of a compound of Formula [I]:
or a pharmaceutically acceptable salt thereof,
wherein R¹ is hydrogen or halogen;
R² is C_1-6alkyl or halo-C_1-6 alkyl;
R³ is
(1) halo-C_1-6alkyl,
(2) pyridyl substituted with R^3A, or
(3) pyrazinyl, pyrimidinyl, or pyridazinyl, which may be optionally substituted with R^3B;
R^3A is cyano, halogen, or halo-C_1-3 alkyl;
R^3B is halogen, hydroxy, C_1-3 alkyl, halo-C_1-3 alkyl, C_1-3alkoxy, or -N(R⁴)(R⁵); and
R⁴ and R⁵are each independently hydrogen or C_1-3 alkyl.

Item 2
A method of treating or preventing hypertrophic cardiomyopathy, comprising administering to a subject a therapeutically effective amount of any one of the compounds of Formulae [II] to [VI]:
or a pharmaceutically acceptable salt thereof.

Item 3
The method according to Item 1 or 2, wherein the compound of Formula [I] or a pharmaceutically acceptable salt thereof is a compound of Formula [II]:
or a pharmaceutically acceptable salt thereof.

Item 4
The method according to any one of Items 1 to 3, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.

Item 5
The method according to any one of Items 1 to 3, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.

Item 6
The method according to any one of Items 1 to 5, wherein the subject is a human.

Item 7
The method according to any one of Items 1 to 6, wherein any one of the compounds of Formulae [I] to [VI] is administered before bedtime.

Item 8
A method of administering before bedtime to a subject a compound of Formula [I] according to Item 1 or a pharmaceutically acceptable salt thereof.

Item 9
A method of administering before bedtime to a subject a compound of any one of the compounds of Formulae [II] to [VI] according to Item 2.

Item 10
The method according to Item 8, wherein the compound of Formula [I] or a pharmaceutically acceptable salt thereof is a compound of Formula [II] according to Item 3.

Item 11
The method according to any one of Items 8 to 10, wherein any one of the compounds of Formulae [I] to [VI] or a pharmaceutically acceptable salt thereof is used in a method of treating or preventing hypertrophic cardiomyopathy.

Item 12
The method according to Item 11, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.

Item 13
The method according to Item 11, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.

Item 14
The method according to any one of Items 8 to 13, wherein the subject is a human.

In some embodiments of the methods detailed herein, the compound is the free form of a compound of Formula [I], [II], [III], [IV], [V] or [VI].

In one embodiment of the methods detailed herein, the compound is a pharmaceutically acceptable salt of a compound of Formula [I], [II], [III], [IV], [V] or [VI].

In some embodiments of the methods detailed herein, administration to the subject occurs once daily at bedtime. In some embodiments of the methods detailed herein, administration to the subject occurs at approximately the same time each night before bedtime for a treatment period. The treatment period may be days, weeks, months, years or for the duration of the subject’s lifetime.

A double wave line of the following:
in a partial structure herein is a binding site of the structure.

The term "halogen" used herein includes, for example, fluorine, chlorine, bromine, and iodine.

The term "C_1-3 alkyl" used herein means a straight- or branched-chain saturated hydrocarbon group having 1 to 3 carbon atoms. The term "C_1-3 alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

The term "C_1-6 alkyl" used herein means a straight- or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. The term "C_1-6 alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.

The term "halo-C_1-3 alkyl" used herein means the above mentioned "C_1-3 alkyl" that is substituted with 1 to 5 halogen atoms independently selected from the group of the above mentioned "halogen". The term "halo-C_1-3 alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.

The term "fluoro-C_1-3 alkyl" used herein means the above mentioned "C_1-3 alkyl" that is substituted with 1 to 5 fluorine atoms. The term "fluoro-C_1-3 alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.

The term "halo-C_1-6 alkyl" used herein means the above mentioned "C_1-6 alkyl" that is substituted with 1 to 5 halogen atoms independently selected from the group of the above mentioned "halogen". The term "halo-C_1-6 alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

The term "fluoro-C_1-6 alkyl" used herein means the above mentioned "C_1-6 alkyl" that is substituted with 1 to 5 fluorine atoms. The term "fluoro-C_1-6 alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

The term "C_1-3 alkoxy" used herein means a group wherein the above mentioned "C_1-3 alkyl" binds to an oxygen atom. The term "C_1-3 alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy.

The term "pyridyl" used herein means any one of the following formulae.

The term "pyrazinyl" used herein means the following formula.

The term "pyrimidinyl" used herein means any one of the following formulae.

The term "pyridazinyl" used herein means any one of the following formulae.

The term "substitute" used herein includes any chemically acceptable substitution. For example, the term "pyridyl substituted with R^3A" used herein means any one of the following formulae.

Each substituent of a compound of Formula [I] includes embodiments illustrated as below for each substituent, and a compound of Formula [I] includes any combinations of these embodiments for each substituent.

In one embodiment, R¹ is halogen. In another embodiment, R¹ is fluorine.

In one embodiment, R² is C_1-6 alkyl or fluoro-C_1-6 alkyl. In another embodiment, R² is C_1-6 alkyl. In still another embodiment, R² is fluoro-C_1-3 alkyl.

In one embodiment, R³ is
(1) halo-C_1-6 alkyl,
(2) pyridyl substituted with R^3A, or
(3) pyrazinyl or pyrimidinyl, which may be optionally substituted with R^3B.

In another embodiment, R³ is selected from the group consisting of halo-C_1-6 alkyl and groups of Formulae [H1] to [H14].

In still another embodiment, R³ is halo-C_1-6 alkyl, or a group of Formula [H2] or [H8].

In one embodiment, R^3A is halogen or halo-C_1-3 alkyl. In another embodiment, R^3A is fluorine or fluoro-C_1-3 alkyl.

In one embodiment, R^3B is halogen or halo-C_1-3 alkyl. In another embodiment, R^3B is fluoro-C_1-3 alkyl.

In one embodiment, R⁴ and R⁵ are each independently C_1-3 alkyl.

In one embodiment, a compound of Formula [I] is a compound of Formula [II] or [III].

In another embodiment, a compound of Formula [I] is a compound of Formula [II]. In still another embodiment, a compound of Formula [I] is a compound of Formula [III] monohydrate, i.e., a compound of Formula [VI].

The term "pharmaceutically acceptable salt" includes any salts known in the art that are not associated with excessive toxicity. Such a pharmaceutically acceptable salt includes, specifically, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described in, for example, the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002); and (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007).

A compound of Formula [I] may be reacted with an inorganic acid, organic acid, inorganic base, or organic base according to methods known per se to give each corresponding pharmaceutically acceptable salt thereof.

Such a salt with inorganic acid includes a salt with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Such a salt preferably includes a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

Such a salt with organic acid includes a salt with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphor acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid, hexylresorcinol acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, and glutamic acid. Such a salt preferably includes a salt with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.

Such a salt with inorganic base includes a salt with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium. Such a salt preferably includes a salt with sodium, potassium, calcium, magnesium, and zinc.

Such a salt with organic base includes a salt with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, and lysine. Such a salt preferably includes a salt with tris(hydroxymethyl)methylamine, N-methylglucamine, and lysine.

A compound inhibiting SGLT1 or a pharmaceutically acceptable salt thereof (hereinafter also referred to as an SGLT1 inhibitor) may be any substance that inhibits SGLT1, and includes small molecules, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. SGLT1 inhibitory activity may be measured by methods known to those of ordinary skill in the art and may be calculated based on the intracellular uptake of the labeled form of α-methyl-D-glucopyranoside (¹⁴C-AMG) transported by SGLT1, for example, according to the evaluation method described in any of Patent Literatures 1 to 3.

In one embodiment, the SGLT1 inhibitor is a compound of Formula [I]:
or a pharmaceutically acceptable salt thereof,
wherein each symbol has the same meaning as defined above. Compounds encompassed by Formula (I) can be prepared by methods known to those skilled in the art and may be prepared, for example, by any of the methods described in Patent Literatures 1-3. Moreover, the SGLT1 inhibitory activities of the compounds encompassed by Formula [I] have been confirmed by these literatures.

In one embodiment, the SGLT1 inhibitor is a compound of Formula [I]. In some embodiments, the compound of Formula [I] may be administered in free form.

As used herein, an SGLT1 inhibitor may be used in combination with other drugs, such as a compound inhibiting SGLT2 or a pharmaceutically acceptable salt thereof (hereinafter also referred to as an SGLT2 inhibitor) to treat and/or prevent hypertrophic cardiomyopathy. An SGLT2 inhibitor herein may be any substance that inhibits SGLT2, and includes small molecules, nucleic acids, polypeptides, proteins, antibodies, vaccines, etc. In one embodiment, an SGLT2 inhibitor is a substance with a function to inhibit reuptake of glucose from the urine to increase the excretion amount of sugar in the urine so that the blood glucose level may be reduced.

An SGLT1 inhibitor, e.g., a compound of Formula [I] or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor may exist in their solvate forms. The term "solvate" means a compound where a solvent molecule is coordinated with, for example, a compound of Formula [I] or a pharmaceutically acceptable salt thereof. The solvate may be a pharmaceutically acceptable solvate; and includes, for example, a hydrate, an ethanolate, and a dimethylsulfoxide solvate of a compound of Formula [I] or a pharmaceutically acceptable salt thereof. The solvate specifically includes a hemihydrate, monohydrate, dihydrate, and monoethanolate of a compound of Formula [I]; and a monohydrate of sodium salt of a compound of Formula [I] and a 2/3 ethanolate of dihydrochloride salt thereof. These solvates may be obtained according to any of the known methods. For example, a compound of Formula [III] may exist as its monohydrate as seen in the following Formula [VI].

A compound of Formula [I] may be labelled with an isotope such as ²H(D), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁸O, ¹⁸F, ³⁵S, and ¹²³I. For example, in the case where a compound of Formula [I] has a methyl group, the methyl group may be replaced with a -CD₃ group. The compound thus obtained is also encompassed in the present invention. A compound of Formula [I] that is labeled with an isotope atom may be useful for medicines, in vitroand/or in vivo assays, and/or pharmacokinetic studies.

A compound of Formula [I] or a pharmaceutically acceptable salt thereof is preferably a compound of Formula [I] or a pharmaceutically acceptable salt thereof that is substantively purified, and more preferably a compound of Formula [I] or a pharmaceutically acceptable salt thereof that is purified into a purity of 80% or more.

Inhibiting SGLT1 means that the function of SGLT1 is inhibited so as to disappear or reduce its activity. Preferably, inhibiting SGLT1 means inhibiting human SGLT1. The inhibition of the function of SGLT1, or the disappearance or reduction of its activity is preferably carried out in human clinical indications. In one embodiment, inhibiting SGLT1 may suppress the increase in left ventricular end-diastolic posterior wall thickness (LVPW) and/or slope of end-diastolic pressure-volume relationship (EDPVR β), resulting in a preventive or therapeutic effect on hypertrophic cardiomyopathy. In another aspect, inhibiting SGLT1 may lower LVPW and/or may lower EDPVR β, resulting in a preventive or therapeutic effect on hypertrophic cardiomyopathy.

An HCM drug means a drug that is effective in treating or is being investigated as effective in treating hypertrophic cardiomyopathy. The HCM drug as used herein includes oHCM and nHCM drugs. The oHCM drug as used herein includes, for example, Mavacamten, Aficamten, Sotagliflozin, MYK-224, EDG-7500, and HRS-1893. The nHCM drug as used herein includes, for example, Mavacamten, Aficamten, Sotagliflozin, Ninerafaxstat, Entresto, and TN-201.

A β blocker means a drug that prevents or decreases the stimulation of the adrenergic receptors. A β blocker may be effective in treating one or more conditions related to the heart and/or vascular systems. The β blocker as used herein includes Propranolol, Metoprolol, Carvedilol, and Sotalol.

A calcium antagonist means a drug that blocks or inhibits calcium channels. The calcium antagonist as used herein includes Verapamil, Diltiazem, Nifedipine, and Amlodipine.

Inhibiting SGLT2 means that the function of SGLT2 is inhibited so as to disappear or reduce its activity. Preferably, inhibiting SGLT2 means inhibiting human SGLT2. The inhibition of the function of SGLT2, or the disappearance or reduction of its activity is preferably carried out in human clinical indications.

The SGLT2 inhibitor herein includes, for example, glycosides and salts thereof and solvates thereof. The glycosides herein are those compounds wherein sugars or sugar derivatives glycosidically bind to aglycone moieties (e.g., through a C-glycosidic bond or O-glycosidic bond) and the sugars or sugar derivatives are those having the following structure:
wherein Y is O or S and a glycosidic bond is formed on the carbon atom at the 1-position.

The SGLT2 inhibitor herein includes, for example, the following compounds in Table 1 and Table 2. For the convenience, trivial names are used herein.

In one embodiment, an SGLT1 inhibitor may be used in treatment and/or prevention of hypertrophic cardiomyopathy by administration thereof to a subject in combination with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor.

In another embodiment, provided is a medicament for use in the treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor, which comprises administration of the SGLT1 inhibitor in combination with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor.

In another embodiment, provided is a medicament for use in treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor, which comprises administration of the medicament to a subject undergoing treatment with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor.

The phrase "used in combination (or combination use)" used herein means, for example, administering an SGLT1 inhibitor and one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor, in any order to a subject. Each drug has each particular mode of action, and combination use of these drugs may provide an additive or synergistic therapeutic or preventive effect. In one embodiment, combination use where multiple drugs with different modes of action are used may reduce the dosage amount of each drug compared to the case where each drug is used alone and may reduce side effects specific to each drug. In one embodiment, an SGLT1 inhibitor and one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor, may be administered to a subject concurrently, sequentially, or with a certain interval, e.g., within 30 minutes, within one hour, within two hours, and within four hours, together or separately in any order. The one drug may be administered while a therapeutically effective amount of the active ingredient comprised in the other drug administered first exists in the body of a subject when said one drug is administered to the subject. In another embodiment, an SGLT1 inhibitor may be administered to a subject in a single combined formulation wherein the SGLT1 inhibitor is comprised in combination with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor. The ratios of these drugs to be administered or blended may be optionally selected depending on subjects to be administered, administration routes, subject diseases, symptoms, severity of diseases, and combinations thereof. For example, when the subjects to be administered are a human, 0.01 to 1000 parts by weight of one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor may be used for one part by weight of an SGLT1 inhibitor.

In one embodiment, combination use of an SGLT1 inhibitor with an SGLT2 inhibitor includes use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with glycoside or a salt thereof or a solvate thereof.

In another embodiment, combination use of an SGLT1 inhibitor with an SGLT2 inhibitor includes use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with glycoside or a salt thereof or a solvate thereof.

In one embodiment, combination use of an SGLT1 inhibitor with an SGLT2 inhibitor includes, for example:
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with dapagliflozin,
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with ipragliflozin,
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with tofogliflozin,
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with empagliflozin,
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with canagliflozin, and
use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof in combination with luseogliflozin.

In another embodiment, combination use of an SGLT1 inhibitor with an SGLT2 inhibitor includes:
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with dapagliflozin,
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with ipragliflozin,
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with tofogliflozin,
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with empagliflozin,
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with canagliflozin, and
use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof in combination with luseogliflozin.

The "combination use (or used in combination)" used herein includes a combination use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof and dapagliflozin.

The "combination use (or used in combination)" used herein includes a combination use of a compound of Formula [I] or a pharmaceutically acceptable salt thereof and empagliflozin.

The "combination use (or used in combination)" used herein includes a combination use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof and dapagliflozin.

The "combination use (or used in combination)" used herein includes a combination use of a compound of Formula [II] or a pharmaceutically acceptable salt thereof and empagliflozin.

In some embodiments, a compound of Formula [I] may be used in combination with a different compound of Formula [I]. In some embodiments, one or more compounds of Formula [I] may be used in combination with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor. In some embodiments, two different compounds of Formula [I] may be used in combination. In some embodiments, two different compounds of Formula [I] may be used in combination with one or more of: an HCM drug, a β blocker, a calcium antagonist, and a SGLT2 inhibitor.

The "combination use (or used in combination)" used herein includes a combination use of: (i) a compound of Formula [I], such as a compound of any one of Formula [II], [III], [IV], [V] and [VI], or a pharmaceutically acceptable salt thereof, and (ii) a compound selected from the group consisting of Mavacamten, Aficamten, Sotagliflozin, MYK-224, EDG-7500, HRS-1893, Ninerafaxstat, Entresto, TN-201, Propranolol, Metoprolol, Carvedilol, Sotalol, Verapamil, Diltiazem, Nifedipine, Amlodipine, Dapagliflozin, Ipragliflozin, Tofogliflozin, Empagliflozin, Canagliflozin, Luseogliflozin, and any combination of the foregoing.

Administering a drug to a subject who is subject to treatment with another drug is one embodiment of combination use; for example, when a drug is administered to a subject, the combination use includes administration of the drug to the subject while a therapeutically effective amount of an active ingredient included in another drug that has been administered is present in the body of the subject.

A therapeutically effective amount of an SGLT1 inhibitor used herein may vary depending on subjects to be administered, administration routes, intended diseases, symptoms, severity of diseases, and combination thereof. When a human is orally administered an SGLT1 inhibitor, the lower limit of the therapeutically effective amount includes, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and the upper limit of the therapeutically effective amount includes, for example, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day. In some embodiments, the therapeutically effective amount includes about 1 mg to about 40 mg per day, about 5 mg to about 20 mg per day, about 10 mg to about 20 mg per day, or about 10 mg per day. In some embodiments, the therapeutically effective amount includes about 1 mg to about 40 mg per day. In some embodiments, the therapeutically effective amount includes about 5 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount includes about 10 mg to about 20 mg per day. In some embodiments, the therapeutically effective amount includes about 10 mg per day.

The frequency of administration for an SGLT1 inhibitor, and pharmaceutical compositions herein includes once, twice, thrice, or more per day. Preferably, the frequency of administration is once per day. More preferably, the frequency of administration is once per day before bedtime.

The term "treatment" used herein includes the amelioration of conditions, prevention of aggravation, maintenance of remission, and prevention of relapse. For example, the treatment of hypertrophic cardiomyopathy includes recovery and amelioration of cardiac hypertrophy and function, specifically includes decrease in left ventricular end-diastolic posterior wall thickness (LVPW), and /or slope of end-diastolic pressure-volume relationship (EDPVR β).

The term "prevention" used herein includes suppressing the onset of conditions. For example, the prevention of hypertrophic cardiomyopathy includes maintenance of cardiac hypertrophy and function, specifically, suppression of elevated LVPW and/or EDPVR β.

In one embodiment, HCM patients include patients with any mutations in MYH7, MYBPC3, TNNI3 and/or TNNT2.

New York Heart Association (NYHA) functional classification is a classification of patients whose physical activity is limited as a result of reduced cardiac function and is categorized according to the severity of their symptoms into the following four classes of severity.
Class I: Patients having cardiac disease but no limitation in physical activity. Ordinary physical activity does not cause excessive fatigue, palpitations, or shortness of breath.
Class II: Patients having mild limitation in physical activity. Patients areasymptomatic at rest, but ordinary physical activity causes excessive fatigue, palpitations, or shortness of breath.
Class III: Patients are highly restricted in physical activity. Patients are asymptomatic at rest, but less than ordinary physical activity causes fatigue, palpitations, or shortness of breath.
Class IV: Any physical activity is limited due to cardiac disease. Symptoms occur even at rest and exacerbated by slight exertion.

In one embodiment, HCM patients include those classified by NYHA functional classification.

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a self-administered questionnaire that assesses physical functioning, clinical symptoms, self efficacy, quality of life, and social functioning of patients with cardiovascular disease, assessing health conditions and quality of life associated with health of patients. The higher the score, the fewer clinical symptoms and physical limitations.

In one embodiment, HCM patients include those scored on the KCCQ.

The term “before bedtime” used herein includes the period of time from about 30 minutes to about 5 hours before a subject falls asleep. In some embodiments, the term includes the period of time from about 1 to about 5 hours, about 1 to about 4 hours, about 1 to about 3 hours, about 1 to about 2 hours, about 2 to about 5 hours, about 2 to about 4 hours, about 2 to about 3 hours, about 3 hours to about 5 hours, about 3 hours to about 4 hours, or about 4 hours to about 5 hours before a subject falls asleep. Before bedtime may also indicate a period of time after the start of an evening meal, such as about 1 to about 5 hours, or about 2 to about 4 hours, or about 3 to about 4 hours or any one of about 2, 2.5, 3, 3.5, 4.0, 4.5 hours after the start of a dinner.

In one embodiment, administering before bedtime indicates administering in the evening before bedtime. In one embodiment, administering before bedtime indicates administering in the morning before bedtime.

In one embodiment, administering before bedtime indicates administering on an empty stomach before bedtime.

"Hypertrophic cardiomyopathy" as used herein, consists of oHCM, nHCM, mid-ventricular obstructive HCM, apical HCM, and dilated phase of HCM. "oHCM" is often also referred to as obstructive hypertrophic cardiomyopathy. "nHCM" is often also referred to as non-obstructive hypertrophic cardiomyopathy.

Left ventricular ejection fraction (LVEF) is the ratio of stroke volume (blood volume pumped by the heart with each heartbeat) divided by the left ventricular end-diastolic volume. Left ventricular ejection fraction can be obtained, for example, using an ultrasonograph.

EDPVR shows the relationship between end-diastolic volume and end-diastolic pressure, which can be approximated by an exponential curve. It is indicated that the higher the EDPVR β is, which is a slope of the curve, the more difficulty the heart has in dilatation. That is, EDPVR β is one of the indicators of left ventricular diastolic function.

EDPVR can be obtained using, for example, a pressure-volume measuring catheter system.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject with a higher EDPVR β than a normal range, comprising an SGLT1 inhibitor. In one embodiment, the normal range of EDPVR β is determined to 0.05 to 0.35 according to Single beat method.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising an SGLT1 inhibitor. In one embodiment, the normal range of LVPW is determined to 0.5 to 0.8 according to M-mode method.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising an SGLT1 inhibitor. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with Class II, III, or IV in the category of NYHA functional classification, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising an SGLT1 inhibitor. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with Class II, III, or IV in the category of NYHA functional classification, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising a compound of Formula [I] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with Class II, III, or IV in the category of NYHA functional classification, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising a compound of Formula [II] or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising an SGLT1 inhibitor and an HCM drug. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject withClass II, III, or IV in the category of NYHA functional classification, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising an SGLT1 inhibitor and an HCM drug. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising an SGLT1 inhibitor and an HCM drug.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising an SGLT1 inhibitor and a β blocker. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject withClass II, III, or IV in the category of NYHA functional classification, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising an SGLT1 inhibitor and a β blocker. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising an SGLT1 inhibitor and a β blocker.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising an SGLT1 inhibitor and a calcium antagonist. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject withClass II, III, or IV in the category of NYHA functional classification, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising an SGLT1 inhibitor and a calcium antagonist. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising an SGLT1 inhibitor and a calcium antagonist.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of hypertrophic cardiomyopathy, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for having no effect on LVEF in a subject, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of HCM, comprising an SGLT1 inhibitor. In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor. In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of oHCM, comprising an SGLT1 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for treatment or prevention of nHCM, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for reducing EDPVR β in a subject whose EDPVR β is higher than a normal range, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for reducing LVPW in a subject with a higher LVPW than a normal range, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for improving the category of NYHA functional classification in a subject, comprising an SGLT1 inhibitor and an SGLT2 inhibitor. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject withClass II, III, or IV in the category of NYHA functional classification, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

In one embodiment, the present invention provides a pharmaceutical composition for improving the score of KCCQ in a subject, comprising an SGLT1 inhibitor and an SGLT2 inhibitor. In another embodiment, the present invention provides a pharmaceutical composition for treating hypertrophic cardiomyopathy in a subject with a score 75 or less of KCCQ, comprising an SGLT1 inhibitor and an SGLT2 inhibitor.

A pharmaceutical composition herein may be prepared from a therapeutically effective amount of SGLT1 inhibitor and at least one or more pharmaceutically acceptable carriers, and one or more of an HCM drug, a β blocker, a calcium antagonist, and an SGLT2 inhibitor if needed, optionally followed by mixing, according to methods known in the art of medicinal preparations. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, copolyvidone, light anhydrous silicic acid, croscarmellose sodium, hydroxypropylcellulose, magnesium stearate and OPADRY II Complete Film Coating System 85F48011 White. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, D-mannitol, crystalline cellulose, light anhydrous silicic acid, hydroxypropylcellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, magnesium stearate and OPADRY II Complete Film Coating System 85F48011 White. In some preferable embodiments, the pharmaceutical composition comprises 10 mg SGLT1 inhibitor, 50 mg copolyvidone, 60 mg light anhydrous silicic acid, 10 mg croscarmellose sodium, 22.5 mg hydroxypropylcellulose, 1 mg magnesium stearate and 4.6 mg OPADRY II Complete Film Coating System 85F48011 White. In some preferable embodiments, the pharmaceutical composition comprises 10 mg SGLT1 inhibitor, 56.2 mg D-mannitol, 13.6 mg crystalline cellulose, 0.5 mg light anhydrous silicic acid, 2.5 mg hydroxypropylcellulose, 10 mg croscarmellose sodium, 6 mg low-substituted hydroxypropylcellulose, 1.2 mg magnesium stearate and 3 mg OPADRY II Complete Film Coating System 85F48011 White. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and an HCM drug. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and a β blocker. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and a calcium antagonist. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and two of an HCM drug, a β blocker, a calcium antagonist, and an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of SGLT1 inhibitor, at least one or more pharmaceutically acceptable carriers, and three of an HCM drug, a β blocker, a calcium antagonist, and an SGLT2 inhibitor. The amount of SGLT1 inhibitor in the pharmaceutical composition varies depending on a factor such as dosage forms and dosage amounts and ranges, for example, from 0.1 to 100% by weight of the total amount of the composition.

A dosage form of pharmaceutical composition herein includes oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions; and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

The term "pharmaceutically acceptable carrier" includes various organic or inorganic carrier substances which are conventionally used for a component of a formulation. Such substances include, for example, excipients, disintegrants, binders, fluidizers, and lubricants for solid preparations; solvents, solubilization agents, suspending agents, tonicity agents, buffering agents, and soothing agents for liquid preparations; and bases, emulsifying agents, wetting agents, stabilizers, stabilizing agents, dispersing agents, plasticizing agents, pH adjusters, absorption promoters, gelators, antiseptic agents, bulking agents, solubilizers, solubilization agents, and suspending agents for semisolid preparations. Additives such as preserving agents, antioxidant agents, coloring agents, and sweetening agents may be further added, if needed.

Such an "excipient" includes, for example, lactose, white soft sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethylstarch, low-substitiuted hydroxypropylcellulose, and gum arabic.

Such a "disintegrant" includes, for example, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethyl cellulose, and crystalline cellulose.

Such a "binder" includes, for example, hydroxypropylcellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, white soft sugar, dextrin, starch, gelatin, carmellose sodium, and gum arabic.

Such a "fluidizer" includes, for example, light anhydrous silicic acid and magnesium stearate.

Such a "lubricant" includes, for example, magnesium stearate, calcium stearate, and talc.

Such a "solvent" includes, for example, purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.

Such a "solubilization agent" includes, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.

Such a "suspending agent" includes, for example, benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate.

Such a "tonicity agent" includes, for example, glucose, D-sorbitol, sodium chloride, and D-mannitol.

Such a "buffering agent" includes, for example, disodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

Such a "soothing agent" includes, for example, benzyl alcohol.

Such a "base" includes, for example, water, oils from animals or vegetables such as olive oil, corn oil, arachis oil, sesame oil, and castor oil, lower alcohols such as ethanol, propanol, propylene glycol, 1,3-butylene glycol, and phenol, higher fatty acids and esters thereof, waxes, higher alcohol, polyhydric alcohol, hydrocarbons such as white petrolatum, liquid paraffin, and paraffin, hydrophilic petrolatum, purified lanolin, absorption ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives such as methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, synthetic polymers such as carboxyvinyl polymer, sodium polyacrylate, polyvinylalcohol, and polyvinylpyrrolidone, propylene glycol, macrogol such as Macrogol 200 to 600, and a combination of two or more of them.

Such a "preserving agent" includes, for example, ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

Such an "anti-oxidant agent" includes, for example, sodium sulfite and ascorbic acid.

Such a "coloring agent" includes, for example, food colors (e.g., Food Red No. 2 or No. 3, Food Yellow No. 4, or No. 5) and β-carotene.

Such a "sweetening agent" includes, for example, saccharin sodium, dipotassium glycyrrhizinate, and aspartame.

A pharmaceutical composition herein may be administered orally or parenterally (e.g., topically, rectally, intravenously, intramuscularly, and subcutaneously) to humans as well as mammals other than humans such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, and monkeys. Dosage amounts vary depending on subjects to be administered, diseases, conditions, dosage forms, and administration routes. For example, a daily dose for oral administration to an adult patient typically ranges from about 0.01 mg to about 1 g of the active ingredient. The dose can be administered at one time or in divided doses. In one embodiment, an SGLT1 inhibitor and other drugs may be formulated into separate pharmaceutical compositions, which may be used in combination and may be administered to a subject in any order and at any time intervalin different administration routes. In another embodiment, a dosage amount of each drug in combination use may be reduced compared to administration of each drug alone, and the daily dose for oral administration to an adult patient (body weight 60 kg) ranges from about 0.01 mg to about 1000 mg.

In one embodiment, a kit such as kits for administration, treatment, and/or prevention, a package such as packaged goods, or a set and/or case of drugs which comprises an SGLT1 inhibitor, and optionally, an HCM drug, a β blocker, a calcium antagonist, and/or an SGLT2 inhibitor, and a written matter concerning these drugs indicating that these drugs may or should be used for treatment and/or prevention of intended diseases may be provided. In some embodiments, the kit comprises an SGLT1 inhibitor and an HCM drug. In some embodiments, the kit comprises an SGLT1 inhibitor and a β blocker. In some embodiments, the kit comprises an SGLT1 inhibitor and a calcium antagonist. In some embodiments, the kit comprises an SGLT1 inhibitor and an SGLT2 inhibitor. The kit, package, and set of drugs may comprise one or more containers filled with an SGLT1 inhibitor, and optionally an HCM drug, a β blocker, a calcium antagonist, and/or an SGLT2 inhibitor, and/or other drugs or medicines (or ingredients). Examples of the kit, package, and set of drugs herein include commercial kits, commercial packages, and commercial medicine set for appropriate use in treatment and/or prevention of intended diseases. The written matter comprised in the kit, package, and set of drugs includes a cautionary note or package insert in the form designated by the government organization that regulates manufacturing, use, or sales of pharmaceutical or biological products which ensures an approval by the government organization on manufacturing, use, or sales of products associated with administration to humans. The kit, package, and set of drugs may include packaged products as well as structures configured for appropriate administration steps and configured so as to be able to achieve more preferable medical treatment and/or prevention including treatment and/or prevention of intended diseases.

In some embodiments of the methods, pharmaceutical compositions and kits, the compound is a compound of Formula [II], [III], [IV], [V] or [VI]. In some embodiments of the methods, pharmaceutical compositions and kits, the compound is the free form of a compound of Formula [I], [II], [III], [IV], [V] or [VI]. In some embodiments of the methods, pharmaceutical compositions and kits, the compound is a compound in Table 3, or a pharmaceutically acceptable salt thereof.

The compounds of Examples 1 to 40 (hereinafter referred to as Compounds 1 to 40) were obtained according to the preparation methods described in Patent Literatures 2 and 3. The physical properties and SGLT1 inhibitory activity data of each compound are as described in these literatures.

Test Example 1
Assessment of diastolic function in mice with hypertrophic cardiomyopathy
Myh6 R403Q mutant 129/SvEv mice were established at the Jackson Laboratory Japan, Inc., and the Myh6 R403Q mutant 129/SvEv mice were genotypically selected at the testing facility. The male mice at 9 weeks old were used as mice with hypertrophic cardiomyopathy for this study.

Myh6 gene is the homolog of human MYH7 gene.

Vehicle (CRF-1 powdered diet), Compound 1 (dose levels: approximately 3 mg/kg or 6 mg/kg per day) or mavacamten (dose level: approximately 2.5 mg/kg per day) was administered daily orally to mice with HCM as diet admixture from 9 weeks of age for 8-11 weeks. Compound 1 is also referred to herein as “Comp. 1” and the compound of Formula [II]. As wild-type group, the vehicle was administered daily orally to 129/SvEv male mice as diet admixture from 9 weeks of age. The diet admixture was prepared from a diet (CRF-1 powder, Oriental Yeast Co., ltd.).

Heart rate (HR) and systolic blood pressure (SBP) under awake condition were measured by a tail-cuff method on Days 55 and 56 of administration. Echocardiography was performed on Day 57 of administration. The hemodynamic parameters including the left ventricular end-diastolic pressure and the left ventricular end-diastolic volume were measured under anesthesia and mechanical ventilation from Days 63 to 78 of administration.

An ultrasonograph (Aplio 300, Toshiba Medical Systems Corporation) was used to measure the left ventricular ejection fraction, the left ventricular end-diastolic diameter, the left ventricular end-systolic diameter and the left ventricular end-diastolic posterior wall thickness. A non-invasive automated blood pressure measuring device (BP-98A, Softron Co.,Ltd.) was used to measure the systolic blood pressure and the heart rate. After eight weeks of administration, ADVantage P-V catheter (Model FTH-1212B-3518, Transonic Scisense Inc.) was inserted into the left ventricle from the apex to measure the left ventricular pressure and volume. EDPVR β was calculated from the end-diastolic pressure-volume relationship at baseline and during the transient inferior vena cava occlusion.

For statistical analysis, Student’s t test or Aspin-Welch’s t test was conducted between the wild-type group and the vehicle-treated group of mice with HCM. Student’s t test was conducted between the vehicle-treated group of mice with HCM and the mavacamten-treated group. Dunnett's test was conducted between the vehicle-treated group of mice with HCM and the Compound 1-treated group. The significance level was two-sided 5% or two-sided 1%.

It was confirmed that mice with HCM demonstrated increases in the left ventricular ejection fraction (LVEF), the left ventricular end-diastolic posterior wall thickness (LVPW) and the slope of end-diastolic pressure-volume relationship (EDPVR β), an index of diastolic function (Table 4, FIG. 1). These parameters indicate clinical pathophysiology of LV hypercontractility, concentric hypertrophy and diastolic dysfunction. Compound 1 decreased LVPW and EDPVR βin a dose-related manner without any effect on the LVEF, indicating that Compound 1 improved concentric hypertrophy and diastolic function (Table 4, FIG. 1). Compound 1 is expected to be effective to treat or prevent hypertrophic cardiomyopathy. Mavacamten also improved concentric hypertrophy and diastolic function with a decrease trend in the LVEF (Table 4, FIG. 1).

Applicant determined that a 6 mg/kg dose of Compound 1 in a mouse approximately corresponds to a 10 mg dose of Compound 1 in a human subject.

In one embodiment, a 2.5 mg/kg dose of mavacamten in a mouse approximately corresponds to a 15 mg dose of mavacamten in a human subject.

Table 4. Effect of Comp. 1 on Echocardiography, Hemodynamic Parameters, Heart Rate and Systolic Blood Pressure in Mice with Hypertrophic Cardiomyopathy

Test Example 2
Phase I protocol and result regarding dosing regimen of Compound 1

This clinical trial was conducted according to the following protocol. The most frequently reported TEAEs in Comp. 1-administered subjects were diarrhoea as shown in for example Table 11. Among the Comp.1 dose groups, diarrhoea was least frequent in the Comp.1 10 mg evening dose group as shown in for example Table 11. Two TEAEs of diarrhoea reported in the Comp.1 20 mg morning dose group were judged as severe as shown in for example Table 8.

INVESTIGATIONAL PLAN
Number of Sites and Subjects
This study will be conducted at a single site in the United States.

Approximately 60 healthy subjects will be enrolled and randomly assigned to one of the following 5 groups in a 1:1:1:1:1 ratio (approximately 12 subjects per group).
Group 1: Placebo group
Group 2: Comp. 1 10 mg morning dose group
Group 3: Comp. 1 10 mg evening dose group
Group 4: Comp. 1 20 mg morning dose group
Group 5: Comp. 1 20 mg evening dose group

To ensure an adequate number of completers in each group, replacement subjects may be enrolled in the study, as appropriate, at the Sponsor’s discretion. Each replacement subject will be assigned to the same group as the subject being replaced.

Study Design
This is a randomized, double-blind, placebo-controlled, parallel group study to investigate the safety, tolerability and PK of Comp. 1 when administered once daily (either in the morning before breakfast or in the evening before bedtime) for 21 days in healthy subjects.

Eligible subjects will be admitted to the clinical site on Day -4. Approximately 60 subjects will be randomly assigned into 5 groups in a 1:1:1:1:1 ratio (approximately 12 subjects per group).

To maintain the blind, subjects will receive study drug (Comp. 1 and/or placebo, 2 tablets for each dose) twice daily; in the morning 30 minutes before the start of breakfast (following an overnight fast of at least 10 hours) and in the evening before bedtime (3.5 hours after the start of a dinner) for 21 days from Day 1 through Day 21, as follows:
Group 1: Placebo in the morning and Placebo in the evening
Group 2: Comp. 1 10 mg in the morning and Placebo in the evening
Group 3: Placebo in the morning and Comp. 1 10 mg in the evening
Group 4: Comp. 1 20 mg in the morning and Placebo in the evening
Group 5: Placebo in the morning and Comp. 1 20 mg in the evening

Subjects will be discharged from the clinical site on Day 25 and will return to the clinical site on Day 42±3 for a Follow-up Visit.

Selection of Study Population
Written informed consent must be obtained prior to performing any study-related procedures. A copy of the informed consent will be provided to the subject.

Inclusion Criteria
To qualify for the study, subjects must satisfy the following criteria:

Exclusion Criteria
The following criteria will exclude a subject from participating in the study:

Removal of Subjects from the Study
A subject may be prematurely discontinued from the study/study drug administration under the following conditions:

Subjects who prematurely discontinue the study after receiving study drug on Day 1, Hour 0 should complete an Early Termination Visit within 24 hours after study discontinuation, and a Follow-up Visit, at approximately 21 days after the last study drug administration. Required assessments for these visits are listed in FIG. 4.

For all subjects who prematurely discontinue the study after receiving study drug on Day 1, Hour 0, every effort should be made to collect 1 blood sample for PK assessments as close as possible to the time when the early withdrawal decision is made. At any time during the study, if an AE raises the question for a subject’s potential discontinuation of the study/study drug administration, the Investigator, the Medical Monitor or the Sponsor can request a review of an individual subject’s data as soon as possible.

When a subject discontinues the study/study drug administration, the Investigator/clinical site must notify the Sponsor as soon as possible, but no later than 24 hours of clinical site awareness.

Study Procedures
Informed Consent
Written informed consent must be obtained prior to performing any study-related procedures. A copy of the informed consent will be provided to the subject.

Screening Visit
Day -32 to Day -5
At the Screening Visit, subjects should arrive to the clinical site in the fasted state (overnight fast for at least 10 hours prior to blood and urine sample collection). If a subject arrives for the visit nothaving fasted, all study procedures except the blood/urine collection activities may be performed. The blood/urine collection will be rescheduled on a subsequent day within the Screening Visit window and the subject will be reminded to fast for at least 10 hours.

Please refer to FIG. 3 for the list of screening procedures to be performed. Repeat screening laboratory tests (except for drugs of abuse and alcohol, and viral serology), vital signs and 12-lead ECG assessments are permitted, if considered appropriate by the Investigator, except as stated otherwise. If the repeat test results are outside the normal reference ranges or not clinically acceptable to the Investigator, the subject should be excluded from the study. Study restrictions must be followed.

Admission Period
Day -4 to Day 25
On the morning of Day -4, subjects will be admitted to the clinical site in the fasted state (overnight fast for at least 10 hours prior to blood and urine sample collection) and will remain in the clinical site until Day 25. Please refer to FIG. 3 and FIG. 4 for the list of procedures to be performed during the Admission Period.

During the Admission Period, subjects should fast overnight prior to blood and urine sample collection (except for the non-fasting PK measurements). Study restrictions must be followed.

Subjects who prematurely discontinue the study after receiving study drug on Day 1, Hour 0 should complete an Early Termination Visit within 24 hours after study discontinuation.

Follow-up Visit
Day 42±3
At the Follow-up Visit, subjects should arrive to the clinical site in the fasted state (overnight fast for at least 10 hours prior to blood and urine sample collection). If a subject arrives for the visit not having fasted, all study procedures except the blood/urine collection activities may be performed. The blood/urine collection will be rescheduled on a subsequent day within the Follow-up Visit window and the subject will be reminded to fast for at least 10 hours. Study restrictions must be followed.

Subjects who prematurely discontinue the study after receiving study drug on Day 1, Hour 0 should complete a Follow-up Visit, at approximately 21 days after the last study drug administration.

Study Diet and Restrictions
Study Diet
A standard diet will be provided to subjects while in-house. The standard diet will total approximately 2500 kcal/day and will be comprised of approximately 55% carbohydrates, 30% fat and 15% protein. This diet should not include citrus drinks (especially grapefruit juice), grapefruit, grapefruit products, sour oranges, caffeinated products or alcohol.

Subjects should consume each meal completely and within 30 minutes. The start/end time and the percent consumed for each meal will be recorded in the CRF.

Diarrhea and other GI symptoms may occur due to the pharmacological action of Comp. 1 (i.e., inhibition of glucose absorption from intestine). Refer to the below for suggested measures that may be taken for clinically significant GI events caused by Comp. 1.

Treatment of Clinically Significant Gastrointestinal Treatment-Emergent Adverse Events Caused by Comp. 1
Diarrhea and other GI symptoms may occur due to the pharmacological action of Comp. 1. In single dose and repeated dose toxicity studies in rats and dogs, GI events (e.g., diarrhea, soft feces) were observed. Based on the clinical data from the completed clinical studies, Comp. 1 at single doses ≧120 mg and multiple doses ≧20 mg in healthy subjects, and multiple doses ≧10 mg in subjects with T2DM led to moderate AEs of loose stools and diarrhea. To date, no severe GI AEs have been reported in clinical studies with Comp. 1. The nonclinical data indicated that in addition to diarrhea, Comp. 1 may cause electrolyte imbalances, however, this has not been observed in completed clinical studies with healthy subjects or subjects with T2DM to date.

Following suggested measures may be taken at the discretion of the Investigator for clinically significant GI events caused by Comp. 1:

Following suggested measures may be taken at the discretion of the Investigator for severe GI events caused by Comp. 1:

If the suggested measures do not adequately treat the GI events, subjects may be treated per standard of care in case of emergency.
Study Restrictions
Alcohol, Diet and Exercise Restrictions:
Previous and Concomitant Therapy Restrictions:

Pharmacokinetic Procedures

Blood Samples for Pharmacokinetic Assessments
Blood samples for the quantification of Comp. 1 in plasma will be obtained according to the schedules summarized in FIG. 3 and FIG. 4.

Actual dosing time and sample collection time will be collected for PK data analysis. Refer to the laboratory manual for specific instructions for the collection and processing of blood samples for PK assessments.

Analysis of Comp. 1 in Plasma
Comp. 1 concentrations in plasma will be analyzed using a validated high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.

Analysis of Comp. 1 concentrations in plasma will be performed under unblinded condition to facilitate the analysis of only Comp. 1-treated subjects. Placebo samples may be analyzed, if needed.

Previous and Concomitant Medications/Procedures
Information pertaining to all medication use (including prescription or OTC medications, supplements, vitamins and minerals) and procedures will be collected and recorded in the CRF for the period of 14 days prior to Day -4 and throughout the study. The clinical site should make every effort to contact the Medical Monitor if a subject requires concomitant therapy.

Medical History
A complete medical history will be performed at the Screening Visit and on Day -4 and will include evaluations of the past or present conditions. Pre-existing and/or concomitant medical conditions detected prior to study drug administration on Day 1, e.g., clinically significant abnormalities in ECG, physical examination, vital signs and laboratory test results, as well as any clinically significant events that occur prior to the first dose are considered to be medical history. A history of vaccination will be collected for the period of 3 months prior to Day -4 and recorded in the CRF.

Appropriate medical conditions which are ongoing at the time of admission should be followed up for resolution until the last visit day (i.e., Follow-up Visit on Day 42±3 for subjects completing the study, or Follow-up Visit at approximately 21 days after the last study drug administration for subjects who prematurely discontinued the study) and updated in the CRF.

Physical Examination
The physical examinations will be performed by a physician or qualified designee according to the schedule summarized in FIG. 3 and FIG. 4 and will include examination of the following body systems: general appearance, skin (including hair and nails), HEENT (head, ears, eyes, nose, throat), neck/thyroid, chest/lungs, cardiovascular, gastrointestinal, neurological, psychiatric/emotional, lymphatic and musculoskeletal systems.

Height and Weight Measurements and Body Mass Index Calculation
The height and weight measurements will be performed according to the schedule summarized in FIG. 3 and FIG. 4. Subjects will remove their shoes and wear light clothing to be consistent between measurements of height and/or weight. The BMI will be calculated at Screening Visit using the following equation: BMI = (weight (kg)/[height (m)]²).

The weight in kilograms will be documented to one decimal place and the height in centimeters will be rounded to the nearest whole number. Additional weights may be obtained, if deemed necessary by the Investigator.

Vital Signs
Vital sign assessments including blood pressure, heart rate, respiratory rate and body temperature (°C), will be performed according to the schedule summarized in FIG. 3 and FIG. 4. Subjects will remain supine for at least 5 minutes in preparation for blood pressure and heart rate assessments. Additional vital signs may be assessed, if deemed necessary by the Investigator.

12-lead ECGs
12-lead ECG recordings and conduction intervals including interval from beginning of the QRS complex in the frontal plane to the next QRS complex (RR), Onset of P wave to beginning of QRS complex (PR), QRS complex, time from start of Q wave to the end of T wave (QT) and Fridericia-corrected QT interval (QTcF) will be obtained according to the schedule summarized in FIG. 3 and FIG. 4. Subjects will minimize all unnecessary activities and remain supine for 5 minutes in preparation for each 12-lead ECG assessment. Additional 12-lead ECG recordings may be obtained, if deemed necessary by the Investigator.

Hematology
Blood samples to assess complete blood count including erythrocytes, hematocrit, hemoglobin, platelets, leukocytes and differential (percent and absolute [neutrophil, eosinophil, basophil, lymphocyte, monocyte]) will be obtained under the fasted condition according to the schedule summarized in FIG. 3 and FIG. 4. Additional hematology tests may be performed, if deemed necessary by the Investigator.

Serum Biochemistry
Blood samples to assess alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin (total and direct), blood urea nitrogen, calcium, carbon dioxide, chloride, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, creatine kinase, creatinine, gamma-glutamyl transferase, globulin, glucose, high-sensitivity C-reactive protein, lactate dehydrogenase, phosphorus, potassium, total protein, sodium, triglycerides and uric acid (urate) will be obtained under the fasted condition according to the schedule summarized in FIG. 3 and FIG. 4. Additional serum biochemistry tests may be performed, if deemed necessary by the Investigator.

Coagulation
Blood samples to assess prothrombin time and activated partial thromboplastin time will be obtained according to the schedules summarized in FIG. 3 and FIG. 4. International normalized ratio will also be calculated. Additional coagulation tests may be performed, if deemed necessary by the Investigator.

Urinalysis
Urine samples to assess bilirubin, occult blood, glucose, ketones, leukocyte esterase, nitrite, pH, protein, specific gravity and urobilinogen will be obtained under the fasted condition according to the schedule summarized in FIG. 3 and FIG. 4. If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for erythrocytes, leukocytes, bacteria, casts and epithelial cells) will be performed. Additional urinalysis may be performed, if deemed necessary by the Investigator.

Viral Serology
Blood samples to assess HBsAg, HCV antibodies and HIV antibodies will be obtained at the Screening Visit.

Serum Pregnancy Test
Blood samples to assess pregnancy status by βhCG levels will be collected from all female subjects at the Screening Visit and on Day -4.

Follicle-stimulating Hormone (FSH)
Blood samples to assess the menopausal status will be collected at the Screening Visit from all female subjects who report a history compatible with menopause without an alternative cause (e.g., the FSH test is not required for female subjects who are surgically sterile).

Drugs of Abuse and Alcohol Screen
Urine samples to assess amphetamine, methylenedioxymethamphetamine, barbiturates, benzodiazepine, cannabinoids, cocaine metabolites, opiates, ethanol, oxycodone and methadone will be obtained at the Screening Visit and on Day -4. Additional tests are not permitted, if any of the results are positive, unless a laboratory error has been identified.

Bristol Stool Chart
At the Screening Visit, a member of the site staff will assess subject’s general stool pattern based on the subject’s recollection and review of the BSC definitions (FIG. 5). Subjects will be trained by a member of the site staff at the Screening Visit on how to perform the assessment and document the stool type, date and time on the BSC source document, which will be provided to each subject for completion during the 3 days prior to Day -4; subjects will record the assessments in the source document. On Day -4, the completed BSC source document will be returned to the site for confirmation of the subject’s eligibility.

During the Admission Period (Day -4, Hour -96±3 to Day 25, Hour 96), every time a subject has a bowel movement, a member of the site staff will assist the subject in characterizing the stool using the BSC including documentation of the date and time.

All stool information collected using the BSC during the Admission Period will be recorded in the CRF.

EQ-5D-5L
The EQ-5D-5L questionnaire must be completed by subjects according to the schedule summarized in FIG. 3 and FIG. 4. A copy of the questionnaire is provided in FIG. 6.

FACIT-D Diarrhea Subscale
The FACIT-D (Version 4) diarrhea subscale questionnaire must be completed by subjects according to the schedule summarized in FIG. 3 and FIG. 4. A copy of the questionnaire is provided in FIG. 7.

Clinical Institutions and Laboratories
This study will be conducted by:
PPD Development, L.P. Phase I Clinic

Clinical laboratory tests (e.g., hematology, serum biochemistry, coagulation and urinalysis), drugs of abuse and alcohol, FSH, βhCG and viral serology assessments will be performed by:
PPD Austin Central Laboratory

Comp. 1 plasma concentrations will be quantified by:
Frontage Laboratories, Inc.

Additional laboratory facilities may be added as necessary.

Adverse Events
Safety Definitions
The Sponsor complies with the following International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) AE definitions:

Adverse Event: Any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

Adverse Drug Reaction (ADR): Any noxious and unintended responses to a medicinal product, related to any dose administered. The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an AE is at least reasonably possible, i.e., the relationship cannot be ruled out.

Unexpected Adverse Drug Reaction: An adverse drug reaction not listed in the IB or not listed at the specificity or severity that has been observed.

Adverse Events Related to Physical Examinations, Vital Signs, Laboratory Tests and 12-lead ECG Parameters: Newly detected abnormalities during the AE assessment period compared to those identified before the AE assessment period. Abnormalities detected prior to the AE assessment period worsening in severity during the AE assessment period, judged as clinically significant by the Investigator.

The Investigator should consider the following criteria for the judgement of clinical significance:

If a newly detected abnormality or worsening of an existing abnormality is related to a clinical symptom, sign or disease that has already been recorded as an AE, it should NOT be recorded as an individual AE.

Medical History: Pre-existing/concomitant medical conditions (including clinically significant abnormalities related to ECGs, physical examinations, vital signs and laboratory tests) detected prior to the first dose of study drug administration on Day 1.

Any clinically-significant abnormality, as described above, meeting any of the SAE criteria should be reported according to SAE reporting requirements, in addition to being recorded as an AE in the CRF.

Serious Adverse Event: Any untoward medical occurrence (adverse event) that:

Assessing Adverse Events
When completing appropriate forms for reporting the AE, the Investigator will assess the AE as follows:

Reported Term for Adverse Event:
Individual signs or symptoms should be recorded as AEs, in the absence of a diagnosis. If a diagnosis is available based on the signs or symptoms, the diagnosis should be recorded as the AE term.
Seriousness of Adverse Event:

Severity of Adverse Event:
The severity of an AE should be graded as one of the following three grades: mild, moderate or severe. To determine the severity of AEs, if applicable, the Investigator should also refer to the Common Terminology Criteria for Adverse Events (CTCAE)(Common terminology criteria for adverse events (CTCAE). Version 5.0. National Cancer Institute, National Institutes of Health. Nov 27, 2017) and translate Grade 1, Grade 2, Grade 3 or higher grades into mild, moderate and severe, respectively. The Investigator should determine the severity by taking into account the general status of the subject, baseline values, outcome, as well as the severity grade. An AE of Grade 4 or Grade 5 should be assessed whether or not it meets the criteria for an SAE.

If the severity of an AE increases to a more severe level, the AE with the increased severity should be recorded separately.

Definitions of severity:

Causality of Adverse Event:
The Investigator’s causality assessment determines whether there is a reasonable possibility that the study drug caused or contributed to an AE. Generally, the facts (evidence) or arguments to suggest causal relationship should be documented. Factors to be taken into consideration when assessing causality include subject’s underlying and pre-existing conditions, prior/concomitant medications, timing of onset relative to study drug (i.e., Comp. 1 and/or placebo) administration, the known PK characteristics of study drug, the currently-known safety profile of study drug, known class effects of similar mechanism of action drugs, the de-challenge/re-challenge response (if available) and any other information that is considered relevant by the Investigator. The Investigator will report the causality as “not related” or “related”.

Action Taken with Regard to Study Drug:
If two or more AEs occurred around the same time, leading to a change in the study drug administration, the AE that caused the change should be identified.

Changes in the study drug administration in response to individual AEs should fall under one of the following categories:

Other Action Taken:
If an AE is the reason for initiation of a medication/procedure, the AE number should be recorded on the concomitant medications/procedures page in the CRF.

Outcome of Adverse Event:
One outcome should be recorded for each AE and it should be classified as follows:

Start Date and Time, and End Date and Time of Adverse Event:
The start date and time of each AE during the AE assessment period should be recorded. The end date and time of each AE should be recorded in the following manner:

Reporting Adverse Events
Adverse Events Reporting
Adverse events occurring (initial occurrence or a worsening of a pre-existing condition) after the first dose of study drug administration on Day 1 and up to the last visit day (i.e., Follow-up Visit on Day 42±3 for subjects completing the study, or Follow-up Visit at approximately 21 days after the last study drug administration for subjects who prematurely discontinued the study) will be reported and recorded in the CRFs. Medical conditions identified up to the first dose of study drug administration, including the ones detected as part of the screening procedures, should be documented as medical history.

When a subject discontinues the study/study drug administration due to a non-serious AE, whether or not related to study drug, the Investigator must notify the Sponsor within 24 hours of the clinical site being informed of the discontinuation.

If an AE continues (e.g., the AE does not have an end date/time) past the last visit day (i.e., Follow-up Visit on Day 42±3 for subjects completing the study, or Follow-up Visit at approximately 21 days after the last study drug administration for subjects who prematurely discontinued the study), the Investigator must continue to follow the subject until the AE has recovered/resolved.

The follow-up may be terminated in the following cases:

Serious Adverse Event Reporting
Reporting by Investigator
Detailed instructions regarding SAE reporting will be provided in appropriate documents not part of this protocol. A brief, non-all-inclusive summary is provided below.

Any SAE experienced by a subject after the first dose of study drug administration on Day 1 and up to the last visit day (i.e., Follow-up Visit on Day 42±3 for subjects completing the study, or Follow-up Visit at approximately 21 days after the last study drug administration for subjects who prematurely discontinued the study) will be reported to the Sponsor, the Medical Monitor and PPD PVG Safety. Additionally, SAEs that occur after this period will also be reported to the Sponsor and PPD PVG Safety, if the Investigator considers the SAE related to study drug.

Serious AEs (both initial reports and follow-up information) must be reported to the Sponsor, the Medical Monitor and PPD PVG Safety within 24 hours of the Investigator’s (clinical site’s) awareness or notification of the event.

Notes: To report the SAE, the clinical site must complete the SAE Form for the study. This form is not part of the CRF and will be provided separately to the Investigator. Initial and follow-up SAE reports will be sent to the Sponsor, the Medical Monitor and PPD PVG Safety via fax or e-mail within 24 hours of the Investigator’s (clinical site’s) awareness. In case that the SAE notification cannot be sent by fax or e-mail, the SAE reporting should not be delayed and the clinical site may call and provide the available SAE information to the Sponsor, the Medical Monitor or PPD PVG Safety within 24 hours of the Investigator’s (clinical site’s) awareness. A follow-up written SAE Form should be faxed or e-mailed to the Sponsor, the Medical Monitor and PPD PVG Safety as soon as possible.

The Investigator should make every effort to provide complete information on the SAE Form. At a minimum, the SAE report must contain the subject’s identifiers, event term as known, SAE criterion and the Investigator’s causality assessment, even if the Investigator has minimal information. The SAE report should be amended, if the Investigator changes his/her opinion of causality, based on the follow-up information.

Personal information that could potentially identify the subject MUST NOT be included in any document sent to the Sponsor or designees (PPD PVG Safety, the Medical Monitor) as per ICH GCP Principles 2.11 and other applicable laws and legislations.

The Investigator must continue to follow the subject until the SAE has subsided, the condition becomes chronic in nature, stabilizes (in case of persistent impairment) or the subject dies. Within 24 hours of receipt of follow-up information, the Investigator must complete the SAE Form and submit any supporting documentation, as necessary (e.g., laboratory test reports, patient discharge summary or autopsy reports) to the Sponsor, the Medical Monitor and PPD PVG Safety via fax or e-mail.

Serious Adverse Event Safety Contact Information:
PPD PVG Safety PPD, Inc.
The Investigator is also required to submit SAE reports to the Institutional Review Board (IRB) in accordance with applicable requirements. The Investigator will receive all Suspected Unexpected Serious Adverse Reaction (SUSAR) reports for onward submission to their local IRB, as required.

Reporting by the Sponsor
The Sponsor or designee will report SUSARs to the appropriate Regulatory Authorities.

Exposure in Utero Reporting:
If a female subject or a female partner of a male subject participating in the study becomes pregnant after the subject receives the first dose of study drug and up to 30 days after the last dose of study drug administration, the Investigator should report the pregnancy to the Sponsor, the Medical Monitor and PPD PVG Safety within 24 hours of being notified. To report the pregnancy, the clinical site must complete the Exposure in Utero Form, which is provided separately to the Investigator.

The female subject or the female partner of a male subject should be followed by the Investigator until completion of the pregnancy if the subject received investigational product (i.e., Comp. 1). If the pregnancy ends for any reason before the anticipated date, the Investigator should notify the Sponsor, the Medical Monitor and PPD PVG Safety. At the completion of the pregnancy, the Investigator should document the outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., spontaneous abortion, stillbirth, neonatal death or congenital anomaly), the Investigator should follow the procedures for reporting an SAE as described above.

Overdose Reporting:
An overdose is a significant variation from the recommended/scheduled dosage for a product. For the purposes of this study, overdose is defined as any confirmed use of the study drug more than indicated by the protocol. Information on overdose is collected via a separate form provided to the Investigator. If a subject experiences an overdose during the course of the study, the Investigator or qualified designee must report it to the Sponsor, the Medical Monitor and PPD PVG Safety, as soon as possible after he/she first becomes aware of it. If any overdose leads to an AE or SAE, the AE should be documented/recorded as per AE requirements and the SAE should be reported to the Sponsor, the Medical Monitor and PPD PVG Safety as described above.

Identification of Treatments
Method of Assigning Subjects to Treatment Groups
At screening, potential study subjects will be assigned a screening number. When a subject is rescreened during the study, the subject must be re-consented and assigned a new screening number prior to performing any study related procedures.

Following confirmation of eligibility, upon enrollment into the study on Day 1, subjects will be assigned a four-digit subject number 00XX, where XX represents a consecutively assigned number beginning with 01. The subject number will correspond to a randomly assigned treatment.

To ensure an adequate number of completers, replacement subjects may be enrolled in the study, as appropriate at the Sponsor’s discretion. Each replacement subject will be assigned to the same group as the subject being replaced. The replacement subject will be assigned a four-digit subject number 10XX, where XX represents the same number as the subject being replaced (e.g., the replacement subject for 0001 becomes 1001).

Identity of Investigational Products
Each Comp. 1 Tablet contains 10 mg Comp. 1 and the following inactive ingredients: 50 mg copolyvidone, 60 mg light anhydrous silicic acid, 10 mg croscarmellose sodium, 22.5 mg hydroxypropylcellulose, 1 mg magnesium stearate and 4.6 mg OPADRY II Complete Film Coating System 85F48011 White.

Placebo Tablets matching the Comp. 1 Tablets contain the following inactive ingredients: copolyvidone, light anhydrous silicic acid, croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, low substituted hydroxypropylcellulose, magnesium stearate and OPADRY II Complete Film Coating System 85F48011 White.

OPADRY II Complete Film Coating System 85F48011 White contains 40% of partially hydrolyzed polyvinyl alcohol, 25% of titanium dioxide, 20.2% of macrogol 4000 and 14.8% talc.

Comp. 1 Tablets and Placebo Tablets are white, round, convex, film-coated tablets identical in appearance.

Storage and Handling Procedures
Comp. 1 Tablets, 10 mg and Placebo Tablets should be stored between 20 - 25 °C in a secure location with restricted access.

Clinical Supplies Packaging
A sufficient quantity of Comp. 1 Tablets, 10 mg and Placebo Tablets will be supplied by the Sponsor or designee, to the site.

Bulk Comp. 1 Tablets, 10 mg and Placebo Tablets are packaged in clear glass bottles (30 tablets/bottle) with a low-density polyethylene cushioning material and two alumina/silica desiccant packs (each 1 gram). The bottles are capped with white polypropylene screw caps fitted with a polypropylene/polyethylene liner. Each bottle will be labeled with appropriately text as specified by regulatory requirements.

Glass bottles and closures will be provided by the Sponsor or designee, to the pharmacy for subject-specific packaging. The packaged tablets will be labeled with appropriate text as specified by regulatory requirements.

Study drug should be packaged for subject administration on the day of dosing, however, if this is not feasible, the weekday dose may be packaged up to 24 hours prior to dosing. Weekend dosing may be packaged up to 72 hours in advance of dosing.

Administration of Study Drug
All study drug will be administered orally in a double-blind manner.

To maintain the blind, subjects will receive study drug (Comp. 1 and/or placebo, 2 tablets for each dose) twice daily; in the morning 30 minutes before the start of breakfast (following an overnight fast of at least 10 hours) and in the evening before bedtime (3.5 hours after the start of a dinner) for 21 days from Day 1 through Day 21, as follows:

Each dose of study drug will be administered with 240 mL of potable water, which will be followed by a hand check, if applicable and a mouth check. Subjects having difficulty swallowing the required number of tablets with 240 mL of water may receive additional, documented amount of water sufficient to complete drug administration. Only authorized members of the staff at the clinical site will administer the study drugs. Dosing times may be staggered between subjects for practical reasons. The time of dosing will be recorded for each subject.

The planned allocation and number of tablets for each dose are provided below:

Management of Clinical Supplies
The Investigator at the clinical site will have responsibility for control and proper administration of all study drugs (including any investigational product or reference product) in accordance with this protocol. The Investigator is responsible for ensuring that all study drugs will be stored at recommended storage temperatures and conditions, in a secured area, free of environmental extremes, with restricted access. The Investigator also agrees that all study drugs will be dispensed only to study subjects who have provided written informed consent and have met all entry criteria.

Randomization
Approximately 60 eligible healthy male and female subjects will be randomized in this study in 5 planned groups. In each group, 12 subjects will be randomized on Day 1 to receive Comp. 1 and/or placebo.

To ensure an adequate number of completers in each group, replacement subjects may be enrolled, as appropriate, at the Sponsor’s discretion. Each replacement subject will be assigned the same treatment as the subject being replaced.

The randomization code will be prepared by a member of the Sponsor or designee using an in-house program written in SAS (R), a computer software package. The Sponsor or designee will provide the randomization code to the pharmacy at the clinical site, as well as to select laboratories.

Blinding
To maintain the blind, all randomized subjects will receive study drug (Comp. 1 and/or placebo) twice daily in a double-blind manner; in the morning 30 minutes before the start of breakfast (following an overnight fast of at least 10 hours) and in the evening before bedtime (3.5 hours after the start of a dinner) for 21 days from Day 1 through Day 21.

Comp. 1 Tablets and Placebo Tablets will be supplied as unbranded tablets, which are identical in appearance.

The unblinded pharmacist at the clinical site will be responsible for dispensing the study drug. The treatment assigned to each subject will not be disclosed to the Investigator, the clinical site staff or the subject. The treatment codes will be controlled by the clinical site’s pharmacy and an unblinded statistician in the Sponsor or designee.

The laboratory performing Comp. 1 plasma concentration assessments will be unblinded to facilitate analysis of all samples from the Comp. 1-administered subjects and appropriate samples from subjects in the placebo group.

To maintain the blind during the study and prior to database lock, all drug concentration data from the bioanalytical laboratories, which will be provided only to the Sponsor, will contain mock subject numbers and nominal time points.

Breaking the Blind
The randomization codes may be broken for a particular subject only in the event of a serious adverse experience or medical emergency, which the Investigator feels cannot be adequately treated without knowing the identity of study drug. Every effort must be made to contact the Sponsor prior to breaking the code. If the situation is an emergency, the Investigator may break the blind by revealing the treatment assignment for the specific subject only and must contact the Sponsor as soon as possible thereafter.

Statistical Methods
This section provides an abbreviated statistical analysis plan (SAP) for safety and PK parameters. A formal SAP will be developed at a later time and finalized prior to database lock. Statistical issues not addressed in this section may be addressed in the formal SAP. Any deviations from the SAP will be discussed in the clinical study report.

Subject Population for Analysis
Randomized Population: All subjects who randomized to receive Comp. 1 and/or placebo on Day 1.

Safety Population: All subjects who receive at least one dose of study drug (i.e., Comp. 1 or placebo), including those who do not complete the study.

Pharmacokinetic Population: All subjects who have evaluable PK data collected after taking at least one dose of Comp. 1. Subjects will be excluded or partially excluded from the statistical analysis of PK parameters if they significantly violated the inclusion/exclusion criteria or had protocol deviation(s) that affect the PK data.

Sample Size
Approximately 60 eligible healthy subjects will be randomized into the study. The sample size is not statistically determined.

Interim Analysis
No interim analysis is planned for this study.

Safety Analysis
All safety data analysis will be performed on the safety population unless otherwise stated.

The safety evaluations will include AEs, vital signs, 12-lead ECGs, clinical safety laboratory tests (e.g., hematology, serum biochemistry, coagulation and urinalysis) and BSC findings.

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by system organ class and preferred term.

For continuous parameters, the observed values and change from baseline data will be summarized using descriptive statistics. Counts and percentages will be provided for categorical parameters. Out of range and PCS values for vital signs, ECGs and laboratory test data will be flagged in data listings and will be summarized as appropriate. All safety data will be presented in the data listings.

For the BSC findings, total number of stools, number and percent of stools for each stool type and number and percent of combined Type 6/7 stools will be summarized by group and appropriate periods to be fully specified in the SAP. Average number and types of stools over appropriate periods will be calculated. The observed and change from baseline of the average number and types of stools will be summarized descriptively. Additional analysis for the BSC findings may be performed as appropriate.

Pharmacokinetic Analysis
Pharmacokinetic analysis will be performed on the PK population unless otherwise stated.

The concentration of Comp. 1 in plasma will be summarized in terms of the number of subjects, arithmetic mean, standard deviation, CV, median, minimum and maximum by group and nominal time point. The relationship between dose level, dose regimen and trough concentrations of Comp. 1 may also be assessed.

Exploratory Quality of Life Analysis
The quality of life (QoL) analysis will be performed on the safety population unless otherwise stated.

Frequency counts and percentages for the responses of the 5 individual dimensions in EQ-5D-5L will be presented by group and scheduled time point as appropriate. The observed values and change from baseline of the EQ Visual Analogue Scale (VAS) scores will be summarized with descriptive statistics.

Frequency counts and percentages for the responses to each question in FACIT-D diarrhea subscale will be presented by group and scheduled time point as appropriate. FACIT-D diarrhea subscale scores will be calculated according to the FACIT-D scoring guidelines, which will be provided in the SAP. The observed values and change from baseline of the FACIT-D diarrhea subscale scores will be summarized with descriptive statistics.

Additional QoL analysis may be performed as appropriate.

Quality Control and Quality Assurance
This study will be conducted in compliance with the protocol, GCP as defined in the US 21 Code of Federal Regulations (CFR) Parts 50, 56 and 312, the Sponsor policies and procedures and all applicable state regulations.

The following steps will be taken to ensure the accuracy, consistency, completeness and reliability of the data:
a) Routine clinical site monitoring implementing risk based quality management;
b) Case report form review against source documents;
c) Data management quality control checks;
d) Statistical quality control checks;
e) Continuous data acquisition and cleaning; and
f) Quality control of final report.

A representative from the Sponsor and/or authorized representatives may conduct periodic audits of the clinical sites and study processes, including, but not limited to, the clinical database and the final report. The study may also be subject to inspection by regulatory authorities. The Investigator hereby agrees to allow access to required subject records and other documentation and facilities related to the review and conduct of the study.

Brief Summary of Adverse Events
No deaths or SAEs were reported in the study. Study discontinuations due to AEs occurred in the Placebo, Comp. 1 10 mg morning dose and Comp. 1 20 mg evening dose groups (1 subject in each of these 3 treatment groups).

Among Comp. 1 dose groups, 37/48 (77.1%) subjects reported 79 TEAEs, 2/48 (4.2%) subjects reported 2 severe TEAEs and 35/48 (72.9%) subjects reported 60 TEAEs considered related to study drug. In the Placebo group, 6/12 (50%) subjects experienced 9 TEAEs, 4 of which were considered related to study drug.

Overall summary of TEAEs is provided in Table 5.
Table 5. Overall Summary of Treatment-Emergent Adverse Events - Safety Population

Display of Adverse Events
Treatment-emergent AEs were generally similar across Comp. 1 dose groups. However, the fewest number of TEAEs were reported in the Comp. 1 10 mg evening dose group; with equivalent number observed in the Placebo group (6 subjects [50.0%] and 9 TEAEs in both).

Total 35 (72.9%) subjects who received Comp. 1 experienced 60 ADRs.

Treatment-emergent AEs are summarized by SOC and PT in Table 6. Adverse drug reactions are summarized by SOC and PT in Table 7. Treatment-emergent AEs are summarized by SOC, PT and maximum severity in Table 8 and by SOC, PT and relationship in Table 9. Adverse drug reactions are summarized by SOC and PT and maximum severity in Table 10.

Treatment-emergent AEs are summarized in descending order of total frequency by PT in Table 11 and ADRs are summarized in descending order of total frequency by PT in Table 12.

Table 6. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term - Safety Population

Table 7. Treatment-Emergent Adverse Drug Reactions by System Organ Class and Preferred Term - Safety Population

Table 8. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and Maximum Severity - Safety Population

Table 9. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term and Relationship - Safety Population

Table 10. Adverse Drug Reactions by System Organ Class, Preferred Term and Maximum Severity - Safety Population

Table 11. Treatment-Emergent Adverse Events in Descending Order of Total Frequency by Preferred Term - Safety Population

Table 12. Adverse Drug Reactions in Descending Order of Total Frequency by Preferred Term - Safety Population

Analysis of Adverse Events
The most frequently reported TEAEs in Comp. 1-administered subjects were diarrhoea (35/48 [72.9%] subjects), followed by flatulence (9/48 [18.8%] subjects). Diarrhoea was reported in 2/12 (16.7%) subjects in the Placebo group, 9/12 (75.0%) subjects in the Comp. 1 10 mg morning dose group, 5/12 (41.7%) subjects in the Comp. 1 10 mg evening dose group, 10/12 (83.3%) subjects in the Comp. 1 20 mg morning dose group and 11/12 (91.7%) subjects in the Comp. 1 20 mg evening dose group. Flatulence was reported in 4/12 (33.3%) subjects in the Comp. 1 10 mg morning dose group, 2/12 (16.7%) subjects in the Comp. 1 10 mg evening dose group, 2/12 (16.7%) subjects in the Comp. 1 20 mg morning dose group and 1/12 (8.3%) subjects in the Comp. 1 20 mg evening dose group, whereas it was not reported in any subject in the Placebo group. All other TEAEs occurred in less than 10% of Comp. 1-administered subjects.

Most of the TEAEs were assessed as mild in severity. Moderate TEAEs were reported in 7/48 (14.6%) subjects in the Comp. 1 dose groups and none in the Placebo group. Moderate TEAEs were reported in 2/12 (16.7%) subjects each in the Comp. 1 10 mg evening dose and 20 mg morning dose groups, and 3/12 (25.0%) subjects in the 20 mg evening dose group. Severe TEAEs of diarrhoea were reported in 2/12 (16.7%) subjects in the Comp. 1 20 mg morning dose group; no other severe TEAEs were reported. All TEAEs were recovered by the end of the study, except for 1 TEAE of diarrhoea in the Comp. 1 20 mg morning dose group and 1 TEAE of nasal congestion in the Comp. 1 20 mg evening dose group. Most of the TEAEs did not require any treatment.

The majority of TEAEs of gastrointestinal disorders were considered related to study drug. All ADRs reported in this study were gastrointestinal disorders, except for 1 TEAE of thirst reported in the Comp. 1 20 mg evening dose group. Overall, ADRs were reported in 35/48 (72.9%) subjects in the Comp. 1 dose groups. The most frequently reported ADRs were diarrhoea, followed by flatulence; all TEAEs of diarrhoea and flatulence reported in the study were reported as ADRs.

Bristol Stool Chart Findings
No apparent changes from baseline in the average number of stools per day by period in the Placebo group and Comp. 1 10 mg morning or evening dose groups were noted, and no apparent differences in the average number of stools per day by period between the Placebo group and Comp. 1 10 mg morning or evening dose groups were noted throughout the study. In both Comp. 1 20 mg morning and evening dose groups, a clear increase from baseline and increase compared to the Placebo group in the average number of stools per day by period were noted. In both Comp. 1 10 mg and 20 mg dose groups, the average number of stools per day by period were slightly lower, when administered in the evening compared to when administered in the morning. Similar trends were shown in the average number of stools by day.

In the Placebo group, Type 6/7 stools per the BSC classification were rarely reported throughout the study. The average number of Type 6/7 stools per day by period slightly increased from baseline and compared to the Placebo group in the Comp. 1 10 mg morning and evening dose groups, and it clearly increased from baseline and compared to the Placebo group in the Comp. 1 20 mg morning and evening dose groups. In both Comp. 1 10 mg and 20 mg dose groups, the average number of Type 6/7 stools per day by period was slightly lower, when administered in the evening compared to when administered in the morning. Similar trends were shown in the average number of Type 6/7 stools by day.

Summary of the number and percentage of each stool type by day is presented in Table 13. Descriptive statistics for average number of stools per day and change from baseline are provided in Table 14 and by period in Table 15. A summary of the total number of stools and stool Type 6/7 by day is presented in Table 16. Descriptive statistics for average number of Type 6/7 stools per day and change from baseline are provided in Table 17 and by period in Table 18.

Table 13. Summary of Number and Percentage of Each Stool Type by Day -Safety Population

Table 14. Descriptive Statistics for Average Number of Stools and Change from Baseline by Day - Safety Population

Table
15. Descriptive Statistics for Average Number of Stools per Day by Period -
Safety Population

Table 16. Summary of Total Number of Stools and Stool Type 6/7 by Day - Safety Population

Table 17. Descriptive Statistics for Average Number of Type 6/7 Stools and Change from Baseline by Day - Safety Population

Table
18. Descriptive Statistics for Average Number of Type 6/7 Stools per Day by
Period - Safety Population

Formulation Examples
Formulation Examples of a compound of Formula [I] include, for example, the following formulations, but are not intended to be limited thereto.
Formulation Example 1 (Preparation of a capsule)
(1) Compound 1 30 mg
(2) Microcrystalline cellulose 10 mg
(3) Lactose 19 mg
(4) Magnesium stearate 1 mg
Ingredients (1), (2), (3), and (4) are mixed to be filled in a gelatin capsule.

Formulation Example 2 (Preparation of a tablet)
(1) Compound 1 10 g
(2) Lactose 50 g
(3) Cornstarch 15 g
(4) Carmellose calcium 44 g
(5) Magnesium stearate 1 g

The total amount of Ingredients (1), (2), and (3) and 30 g of Ingredient (4) are combined with water, dried in vacuo, and then granulated. The resulted granules are mixed with 14 g of Ingredient (4) and 1 g of Ingredient (5), and tableted with a tableting machine. In this manner, 1000 tablets comprising 10 mg of Compound 1 for each tablet are obtained.

A compound inhibiting SGLT1, or a pharmaceutically acceptable salt thereof, is expected to be useful for treatment or prevention of hypertrophic cardiomyopathy.

All publications, patent applications, patents and other references mentioned herein are hereby expressly incorporated herein by reference in their entireties, to the same extent as if each were incorporated by reference individually.

Claims

A method of treating or preventing hypertrophic cardiomyopathy, comprising administering to a subject a therapeutically effective amount of a compound of Formula [I]:
or a pharmaceutically acceptable salt thereof,
wherein R¹ is hydrogen or halogen;
R² is C_1-6alkyl or halo-C_1-6 alkyl;
R³ is
(1) halo-C_1-6alkyl,
(2) pyridyl substituted with R^3A, or
(3) pyrazinyl, pyrimidinyl, or pyridazinyl, which may be optionally substituted with R^3B;
R^3A is cyano, halogen, or halo-C_1-3 alkyl;
R^3B is halogen, hydroxy, C_1-3 alkyl, halo-C_1-3 alkyl, C_1-3alkoxy, or -N(R⁴)(R⁵); and
R⁴ and R⁵are each independently hydrogen or C_1-3 alkyl.
A method of treating or preventing hypertrophic cardiomyopathy, comprising administering to a subject a therapeutically effective amount of any one of the compounds of Formulae [II] to [VI]:
or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the compound of Formula [I], or a pharmaceutically acceptable salt thereof, is a compound of Formula [II]:
or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 1, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 1, wherein the subject is a human.
The method of claim 1, wherein the compound of Formula [I], or a pharmaceutically acceptable salt thereof, is administered before bedtime.
The method of claim 2, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 2, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 2, wherein the subject is a human.
The method of claim 2, wherein the any one of the compounds of Formulae [II] to [VI], or a pharmaceutically acceptable salt thereof, is administered before bedtime.
The method of claim 3, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 3, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 3, wherein the subject is a human.
The method of claim 3, wherein the compound of Formula [II], or a pharmaceutically acceptable salt thereof, is administered before bedtime.
A method of administering before bedtime to a subject a compound of Formula [I]:
or a pharmaceutically acceptable salt thereof,
wherein R¹ is hydrogen or halogen;
R² is C_1-6alkyl or halo-C_1-6 alkyl;
R³ is
(1) halo-C_1-6alkyl,
(2) pyridyl substituted with R^3A, or
(3) pyrazinyl, pyrimidinyl, or pyridazinyl, which may be optionally substituted with R^3B;
R^3A is cyano, halogen, or halo-C_1-3 alkyl;
R^3B is halogen, hydroxy, C_1-3 alkyl, halo-C_1-3 alkyl, C_1-3alkoxy, or -N(R⁴)(R⁵); and
R⁴ and R⁵are each independently hydrogen or C_1-3 alkyl.
A method of administering before bedtime to a subject any one of the compounds of Formulae [II] to [VI]:
or a pharmaceutically acceptable salt thereof.
The method of claim 16, wherein the compound of Formula [I], or a pharmaceutically acceptable salt thereof, is a compound of Formula [II]:
or a pharmaceutically acceptable salt thereof.
The method of claim 16, wherein the compound of Formula [I], or a pharmaceutically acceptable salt thereof, is used in a method of treating or preventing hypertrophic cardiomyopathy.
The method of claim 19, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 19, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 16, wherein the subject is a human.
The method of claim 17, wherein the any one of the compounds of Formulae [II] to [VI], or a pharmaceutically acceptable salt thereof, is used in a method of treating or preventing hypertrophic cardiomyopathy.
The method of claim 23, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 23, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 17, wherein the subject is a human.
The method of claim 18, wherein the compound of Formula [II], or a pharmaceutically acceptable salt thereof, is used in a method of treating or preventing hypertrophic cardiomyopathy.
The method of claim 27, wherein the hypertrophic cardiomyopathy is non-obstructive hypertrophic cardiomyopathy.
The method of claim 27, wherein the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy.
The method of claim 18, wherein the subject is a human.