Optimal dosing of leriglitazone

Abstract

The present disclosure provides a method for treating a disease or disorder in a patient, comprising administering an optimal dose of leriglitazone or a pharmaceutically acceptable salt thereof, such as leriglitazone HCl, to a patient in need thereof.Leriglitazone is a PPAR-γ agonist used to treat various diseases and disorders, including, but not limited to, liver diseases such as non-alcoholic steatohepatitis, lung diseases such as acute respiratory distress syndrome and acute lung injury, and central nervous system diseases such as X-linked adrenoleukodystrophy, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, and Friedreich's ataxia.

Description

[Technical Field]

[0001] Field of Disclosure The present disclosure provides a method for treating a disease or disorder in a patient, the method comprising administering an optimal dose of leriglitazone or a pharmaceutically acceptable salt thereof, e.g., leriglitazone HCl, to a patient in need thereof. Leriglitazone can be used to treat a variety of diseases and disorders, including, but not limited to, liver diseases such as nonalcoholic steatohepatitis (NASH), lung diseases and disorders such as acute respiratory distress syndrome and acute lung injury, and central nervous system diseases such as X-linked adrenoleukodystrophy (X-ALD), adrenomyeloneuropathy (AMN), cerebral adrenoleukodystrophy (cALD), and Friedreich's ataxia. [Background technology]

[0002] background 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (referred to herein as "leriglitazone" or compound (1)) is a metabolite of pioglitazone that has selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity. See, for example, Sohda et al., Chem. Pharm. Bull. 43(12):2168-2172 (1995); Maeshiba et al., Arzneim.-Forsch / Drug Res. 47(I):29-35 (1997). WO2015 / 150476A1 discloses leriglitazone for use in treating central nervous system diseases. WO2018 / 100557 discloses leriglitazone for the treatment of nonalcoholic fatty liver disease ("NAFLD"), nonalcoholic steatohepatitis ("NASH"), and other diseases and disorders. WO2019 / 234689 discloses an algorithm-based method for administering leriglitazone based on the patient's steady-state plasma level and related pharmacokinetic parameters. There is a need in the art for methods for administering safe and effective doses of leriglitazone and 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride (referred to herein as "leriglitazone HCl"), particularly to pediatric patients. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2018 / 100557 [Patent Document 2] International Publication No. 2019 / 234689 [Non-patent literature]

[0004] [Non-Patent Document 1] Sohda et al., Chem. Pharm. Bull. 43(12):2168-2172 (1995) [Non-patent document 2] Maeshiba et al., Arzneim.-Forsch / Drug Res. 47(I):29-35 (1997) Summary of the Invention [Means for solving the problem]

[0005] Abstract Leriglitazone is orally bioavailable and shows linear pharmacokinetics in humans.However, due to the drug clearance that increases or decreases leriglitazone plasma concentration, and the variation in bioavailability between individual patients due to other factors, such as body weight, age, sex and BMI, it is difficult to administer therapeutically effective amounts of leriglitazone using conventional dosing technology.In addition, patients treated with leriglitazone may suffer from severe diseases, such as X-ALD, AMN, cALD, Friedreich's ataxia, pulmonary inflammation or NASH.Therefore, in order to maximize efficacy and minimize toxic side effects in this group of patients, an appropriate initial dose of leriglitazone or leriglitazone HCl must be administered. In one aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient Compound (1) or a pharmaceutically acceptable salt thereof, wherein an initial dose (mg) of Compound (1) or a pharmaceutically acceptable salt thereof is a compound represented by Formula I:

number

[0006] BW is the patient's weight (kg);

[0007] AGE is the patient's age (years);

[0008] SEX is the patient's sex, male is 1 and female is 2;

[0009] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0010] FOOD is the patient's food status, with 0 for fasting and 1 for fed;

[0011] BW coef is about 0.6 to about 0.9;

[0012] AGE coef is about 0.02 to about 0.2;

[0013] SEX coef is about 0.04 to about 0.25;

[0014] BMI coef is about 0.3 to about 0.8;

[0015] FOOD coef is about 0.02 to about 0.7;

[0016] AUC target (The target area under the concentration-time curve is about 40 to about 240 μg·h / mL of compound (1).) The method is determined according to the following:

[0017] In another embodiment, SF is 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, or 0.9.

[0018] In another embodiment, Compound (1) is administered to a patient and the SF is 0.74.

[0019] In another embodiment, Compound (1) HCl is administered to a patient and the SF is 0.81.

[0020] In another embodiment, the disease or disorder is a CNS disease or disorder, and the AUC target is 170±20% μg·h / mL.

[0021] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is a pediatric patient, i.e., the patient is 17 years of age or younger, and the AUC target is 170±20% μg·h / mL.

[0022] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is an adult patient, i.e., the patient is over 17 years of age, and the AUC target is 170±20% μg·h / mL.

[0023] In another embodiment, the disease or disorder is a pulmonary disease or disorder, and the AUC target is 170±20% μg·h / mL.

[0024] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is a pediatric patient, and the AUC target is 170±20% μg·h / mL.

[0025] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is an adult patient, and the AUC target is 170±20% μg·h / mL.

[0026] In another embodiment, the disease or disorder is a CNS disease or disorder, and the AUC target is 200±20% μg·h / mL.

[0027] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is an adult patient, and the AUC target is 200±20% μg·h / mL.

[0028] In another embodiment, the disease or disorder is a pulmonary disease or disorder, and the AUCtarget is 200±20% μg·h / mL.

[0029] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is an adult patient, and the AUC target is 200±20% μg·h / mL.

[0030] In another embodiment, the disease or disorder is a CNS disease or disorder, and the AUC target is 100–135 μg·h / mL.

[0031] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is a pediatric patient, and the AUC target is 100–135 μg·h / mL.

[0032] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is an adult patient, and the AUC target is 100–135 μg·h / mL.

[0033] In another embodiment, the disease or disorder is a pulmonary disease or disorder, and the AUC target is 100–135 μg·h / mL.

[0034] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is a pediatric patient, and the AUC target is 100–135 μg·h / mL.

[0035] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is an adult patient, and the AUC target is 100–135 μg·h / mL.

[0036] In another embodiment, the disease or disorder is a liver disease or disorder, e.g., NASH or NAFLD, and the AUC target is 50±20% μg·h / mL.

[0037] In another aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising determining the AUC in the patient from about 0.5 to about 12 hours, e.g., about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours, after a dose of Compound (1) or a pharmaceutically acceptable salt thereof;

[0038] (i) administering a higher dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC is less than 149 μg·hr / mL;

[0039] (ii) administering a lower dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC is greater than 221 μg·hr / mL; and

[0040] (iii) if the AUC is between 150 and 220 μg·hr / mL, administering the same dose of compound (1) or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising:

[0041] In another aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising determining the AUC of Compound (1) in the patient from about 0.5 to about 12 hours, e.g., about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours, after administration of a dose of Compound (1) or a pharmaceutically acceptable salt thereof; and

[0042] administering a higher dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) is less than 149 μg·hr / mL;

[0043] (ii) administering a lower dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) exceeds 191 μg·hr / mL; and

[0044] (iii) if the AUC of compound (1) is between 150 and 190 μg·hr / mL, administering the same dose of compound (1) or a pharmaceutically acceptable salt thereof. Including,

[0045] The method is provided wherein the patient is a pediatric patient.

[0046] In another aspect, the disclosure provides a method of treating a liver disease or disorder, e.g., NASH, in a patient in need thereof, comprising determining the AUC of leriglitazone in the patient about 0.5 to about 12 hours, e.g., about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours, after administration of a dose of leriglitazone or leriglitazone HCl; and

[0047] administering a higher dose of leriglitazone or leriglitazone HCl if the AUC of compound (1) is less than 49 μg·h / mL; (ii) administering a lower dose of leriglitazone or leriglitazone HCl if the AUC of leriglitazone exceeds 101 μg·h / mL; and

[0048] (iii) administering the same dose of leriglitazone or leriglitazone HCl if the AUC of leriglitazone is between 50 and 100 μg·h / mL. The present invention provides a method comprising:

[0049] In another aspect, the present disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising:

[0050] (i) administering 10 mL of an oral suspension containing 15 mg of leriglitazone HCl per mL to a patient for 1 to 10 weeks, e.g., 1 to 4 weeks, e.g., 1 to 6 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and

[0051] (ii) administering to the patient after (i) 12 mL of an oral suspension containing 15 mg of leriglitazone HCl per mL. The present invention provides a method comprising:

[0052] In another aspect, the present disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising:

[0053] (i) administering 10 mL of an oral suspension containing 13.66 mg of leriglitazone per mL to a patient for 1 to 10 weeks, e.g., 1 to 4 weeks, e.g., 1 to 6 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and

[0054] (ii) administering to the patient after (i) 12 mL of an oral suspension containing 13.66 mg of leriglitazone per mL. The present invention provides a method comprising:

[0055] In another embodiment, compound (1) or a pharmaceutically acceptable salt thereof is leriglitazone. In another embodiment, compound (1) or a pharmaceutically acceptable salt thereof is leriglitazone HCl.

[0056] In another aspect, the present disclosure provides a method of treating a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, such as non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), a chronic granulomatous disorder, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

[0057] Additional embodiments and advantages of the disclosure will be set forth in part in the description that follows, and in part will arise from the description, or may be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. [Brief explanation of the drawings]

[0058] [Figure 1] FIG. 1 is a line graph showing the ontogenetic profile for CYP2C8 in pediatric subjects.

[0059] [Figure 2] FIG. 2 is a line graph showing the ontogenetic profile for CYP3A4 in pediatric subjects.

[0060] [Figure 3] FIG. 3 is a line graph showing the ontogenetic profile for relative CYP3A4 / CYP2C8 in pediatric subjects.

[0061] [Figure 4] FIG. 4 shows the workflow for the leriglitazone PBPK model.

[0062] [Figure 5] FIG. 5 is a line graph showing the mean total plasma concentration-time profile of leriglitazone for the SAD part under fasting conditions on a semi-logarithmic scale.

[0063] [Figure 6] FIG. 6 is a line graph showing the mean total plasma concentration-time profile of M3 (5-[[4-[2-[5-acetylpyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) of the SAD part under fasting conditions on a semi-logarithmic scale.

[0064] [Figure 7] FIG. 7 compares neuroPK in rat and Phase 1 human data.

[0065] [Figure 8] FIG. 8 is a line graph showing the total plasma concentration-time profile (mean + / - SD) of leriglitazone for the MAD part from days 1 to 13 on a semi-log scale.

[0066] [Figure 9] FIG. 9 is a line graph showing the total plasma concentration-time profile (mean + / - SD) of M3 for the MAD part from days 1 to 13 on a semi-log scale.

[0067] [Figure 10] 10 is a two-line graph showing simulated (line; 10 x 6 virtual individuals) and observed (individual data points; from the Phase 1 SAD part) plasma concentration-time profiles of leriglitazone after a single 90 mg dose (fasted and fed) of leriglitazone HCl. Circles represent observed individual data. Gray lines represent simulated individual study results, and the solid black line is the mean data for the simulated population (n = 60). The dashed gray lines represent the 95th and 5th percentiles of the simulated data.

[0068] [Figure 11] 11 is a two-line graph showing simulated (line; 10 x 6 virtual individuals) and observed (individual data points; from the Phase 1 SAD part) plasma concentration-time profiles of leriglitazone after a single 270 mg dose (fasted and fed) of leriglitazone HCl. Circles represent observed individual data. Gray lines represent simulated individual study results, and the solid black line is the mean data for the simulated population (n = 60). The dashed gray lines represent the 95th and 5th percentiles of the simulated data.

[0069] [Figure 12]12 is a two-line graph showing simulated (line; 10×8 virtual individuals) and observed (data points; from the Phase 1 study MAD part) plasma concentration-time profiles of leriglitazone after multiple daily oral doses of 135 mg and 270 mg fed leriglitazone HCl. Circles represent observed individual data. Gray lines represent simulated individual test results, and the solid black line is the mean data for the simulated population (n=80). The dashed gray lines represent the 95th and 5th percentiles of the simulated data.

[0070] [Figure 13] Figure 13 is a line graph showing the dose-linearity of drug exposure (AUC) in the age range of 6 to 12 years receiving 0.5 to 5 mg / kg.

[0071] [Figure 14] Figure 14 shows six line graphs showing observed leriglitazone total concentrations (black dots) overlaid on PBPK simulations using Upreti ontogeny for the age groups >2 to 6 years. The gray line is the median of the simulation. The gray area is the 95% prediction interval around the simulated concentrations.

[0072] [Figure 15] Figure 15 shows two line graphs showing observed leriglitazone total concentrations (black dots) overlaid on PBPK simulations using Upreti ontogeny for the >6 to 12 year age group. The gray line is the median of the simulation. The gray area is the 95% prediction interval around the simulated concentration.

[0073] [Figure 16] Figure 16 shows two line graphs showing observed leriglitazone total concentrations (black dots) overlaid on PBPK simulations using Upreti ontogeny for the >12 year age group. The gray line is the median of the simulation. The gray area is the 95% prediction interval around the simulated concentration.

[0074] [Figure 17] FIG. 17 is a forest plot showing a comparison of observed AUC versus PBPK model median for each pediatric age group.

[0075] [Figure 18] FIG. 18 is a forest plot showing a comparison of the AUC-body weight correlation of the observations versus the PBPK model for each pediatric age group.

[0076] [Figure 19] FIG. 19 is a forest plot showing a comparison of observed versus PBPK modeled clearance-body weight relationships for each pediatric age group.

[0077] [Figure 20] FIG. 20 is a forest plot showing the effect of covariates on AUC after administration of leriglitazone. DETAILED DESCRIPTION OF THE INVENTION

[0078] Detailed Description I. Administration of Compound (1) or a Pharmaceutically Acceptable Salt Thereof The disclosed method includes administering 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof to a patient in need thereof. 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione is also sometimes referred to as 5-(4-(2-(5-(1-hydroxyethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione, hydroxypioglitazone, hydroxypioglitazone, or M-IV. See, e.g., Sohda et al., Chem. Pharm. Bull. 43(12):2168-2172 (1995) and Maeshiba et al., Arzneim.-Forsch / Drug Res. 47(1):29-35 (1997). In some embodiments, the methods of the present disclosure comprise administering leriglitazone to a patient in need thereof. In some embodiments, the methods of the present disclosure comprise administering leriglitazone HCl to a patient in need thereof.

[0079] 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione has two chiral centers, one of which is the carbon atom at position 5 of the thiazolidine-dione ring, as shown by the arrows, and the other asymmetric atom is at position 1 of the hydroxyethyl group: [ka]

[0080] As used herein, the term "5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione" or "compound (1)" includes all possible stereoisomers, including enantiomers (see compounds (2)-(5) below) and diastereomers, and mixtures thereof, including racemic and diastereomeric mixtures of 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione.

[0081] In one embodiment, the method of the present disclosure comprises administering (R)-5-[[4-[2-[5-(R)-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (compound (2)) or a pharmaceutically acceptable salt thereof to a patient in need thereof. [ka]

[0082] In another embodiment, the method of the present disclosure comprises administering (R)-5-[[4-[2-[5-(S)-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (compound (3)), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [ka]

[0083] In another embodiment, the method of the present disclosure comprises administering (S)-5-[[4-[2-[5-(R)-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (compound (4)), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [ka]

[0084] In another embodiment, the method of the present disclosure comprises administering (S)-5-[[4-[2-[5-(S)-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (compound (5)), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. [ka]

[0085] Compounds (2)-(5) have been prepared and isolated (see WO2015 / 150476A1), but their absolute (R / S) stereochemistry has not yet been determined. The retention times of each enantiomer have been measured by chiral HPLC.

[0086] Reference to compounds (1)-(5) of the present disclosure refers to these compounds primarily in their isotopic form. 1 H form, i.e., not more than 1% of the total number of hydrogen atoms per mole of compound 2 It is intended to be referred to as having hydrogen atoms in the form of the H isotope (deuterium). In one embodiment, no more than 0.015% of the total number of hydrogen atoms per mole of compound (which is the natural abundance of deuterium) is 2 It is in the form of the H isotope (deuterium).

[0087] In one embodiment, the patient is administered a mixture comprising non-equimolar amounts of each of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the patient is administered a mixture comprising 20%±10% w / w amounts of each of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, the patient is administered a mixture comprising 25%±5% w / w amounts of each of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, the patient is administered a mixture comprising each of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof, wherein the mixture comprises an enantiomeric excess of one or more of Compound (2), Compound (3), Compound (4), and Compound (5).

[0091] In another embodiment, the patient is administered a mixture comprising equimolar amounts of each of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof, i.e., 25% w / w amount of each compound or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the patient is administered a mixture comprising non-equimolar amounts of Compound (2), or a pharmaceutically acceptable salt thereof; Compound (3), or a pharmaceutically acceptable salt thereof; Compound (4), or a pharmaceutically acceptable salt thereof; and Compound (5), or a pharmaceutically acceptable salt thereof, wherein the mixture is optically active.

[0093] In another embodiment, the mixture comprises: (a) compound (2) or a pharmaceutically acceptable salt thereof, and compound (3) or a pharmaceutically acceptable salt thereof; (b) compound (4) or a pharmaceutically acceptable salt thereof, and compound (5) or a pharmaceutically acceptable salt thereof; (c) compound (2) or a pharmaceutically acceptable salt thereof, and compound (4) or a pharmaceutically acceptable salt thereof; and (d) Compound (3) or a pharmaceutically acceptable salt thereof, and compound (5) or a pharmaceutically acceptable salt thereof, wherein each compound or pharmaceutically acceptable salt thereof is independently present in an equimolar or non-equimolar amount.

[0094] In another embodiment, the patient is administered mixture (c) or mixture (d), which mixtures are as defined above.

[0095] In another embodiment, the patient is (a) as active agents, compound (2) or a pharmaceutically acceptable salt thereof, and compound (3) or a pharmaceutically acceptable salt thereof; (b) as active agents, compound (4) or a pharmaceutically acceptable salt thereof, and compound (5) or a pharmaceutically acceptable salt thereof; (c) as active agents, compound (2) or a pharmaceutically acceptable salt thereof, and compound (4) or a pharmaceutically acceptable salt thereof; and (d) as an active agent, compound (3) or a pharmaceutically acceptable salt thereof, and compound (5) or a pharmaceutically acceptable salt thereof. The patient is administered a mixture consisting essentially of:

[0096] In another embodiment of the mixtures (a)-(d) mentioned above, the two compounds mentioned in each mixture are present in equimolar amounts. The mixtures may also contain small amounts (e.g., less than 10 wt.%, less than 3 wt.%, less than 1 wt.%, and less than 0.1 wt.%) of other stereoisomers of formula (1). The mixtures may also be enantiomerically enriched with respect to one or more of compounds (2), (3), (4), and (5).

[0097] In another embodiment of the present disclosure, a pharmaceutically acceptable salt of Compound (1) is administered to a patient. Suitable pharmaceutically acceptable salts include, for example, salts of the following acids: formic acid, acetic acid, propionic acid, benzoic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, maleic acid, malic acid, tartaric acid, citric acid, nitric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isocitric acid, xinafoic acid, tartaric acid, trifluoroacetic acid, pamoic acid, anthranilic acid, mesylic acid, 1,5-naphthalenedisulfonic acid, oxalacetic acid, oleic acid, Pharmaceutically acceptable acid addition salts of Compound (1) include those prepared from stearic acid, salicylic acid, p-hydroxybenzoic acid, nicotinic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, phosphoric acid, phosphonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, sulfuric acid, cyclohexylaminosulfonic acid, algenic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid. In certain embodiments, pharmaceutically acceptable acid addition salts of Compound (1) include those prepared from hydrochloric acid and hydrobromic acid. In one embodiment, a pharmaceutically acceptable salt of Compound (1) is a hydrochloric acid salt, such as 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride.

[0098] Leriglitazone can be prepared by any suitable method known in the art, for example, the methods described in WO2015 / 150476A1 and WO2018 / 116281A1. Leriglitazone is also commercially available, for example, from Santa Cruz Biotechnology and Toronto Research Chemicals (Toronto, Ontario, Canada).

[0099] II. Methods and Uses of the Disclosure In one embodiment, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (Compound (1)) or a pharmaceutically acceptable salt thereof, wherein an initial dose (mg) of Compound (1) or a pharmaceutically acceptable salt thereof is a compound of Formula I:

number

[0100] SF is the salinity factor, SF is 0.7–0.9;

[0101] BW is the patient's weight (kg);

[0102] AGE is the patient's age (years);

[0103] SEX is the patient's sex, male is 1 and female is 2;

[0104] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0105] FOOD is the patient's food status, with 0 for fasting and 1 for fed;

[0106] BW coef is about 0.6 to about 0.9;

[0107] AGE coef is about 0.02 to about 0.2;

[0108] SEX coef is about 0.04 to about 0.25;

[0109] BMI coef is about 0.3 to about 0.8;

[0110] FOOD coef is about 0.02 to about 0.7;

[0111] AUC target is about 40 to about 240 μg·h / mL of compound (1). The method is determined according to the following:

[0112] Equation I was derived from a population pharmacokinetic model developed by analyzing the combined concentration-time data from three clinical studies in patients receiving Compound (1). See Example 2. In this model, the key pharmacokinetic parameters, clearance (CL) and bioavailability (F), were found to be significantly related to the covariates weight, age, sex, BMI, and dietary status. The overall pharmacokinetic relationship between dose, CL, F, and AUC can be expressed as AUC = F × Dose / CL, which can be rearranged to Dose = AUC × CL / F to calculate the dose required to achieve a desired target AUC, taking into account the patient's individual CL and F. Equation I includes the calculation of a patient's CL (numerator) and F (denominator) as a function of the patient's individual covariates derived from the population pharmacokinetic model.

[0113] In another embodiment, the disclosure provides Compound (1), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a patient, wherein the initial dose (mg) of Compound (1), or a pharmaceutically acceptable salt thereof, is determined according to Formula I.

[0114] In another embodiment, BW coef is approximately 0.6 to 0.9.

[0115] In another embodiment, the AGE coef is approximately 0.02 to 0.2.

[0116] In another embodiment, SEX coef is approximately 0.04 to 0.25.

[0117] In another embodiment, the BMI coef is approximately 0.3 to 0.8.

[0118] In another embodiment, FOOD coef is approximately 0.02 to 0.7.

[0119] In another embodiment, the AUC target is approximately 40 to 240 μg·h / mL of compound (1).

[0120] In another embodiment, BW coef is 0.6 to 0.9.

[0121] In another embodiment, the AGE coef is 0.02 to 0.2.

[0122] In another embodiment, SEX coef is 0.04 to 0.25.

[0123] In another embodiment, the BMI coef is 0.3 to 0.8.

[0124] In another embodiment, FOOD coef is 0.02 to 0.7.

[0125] In another embodiment, the AUC target is 40 to 240 μg·h / mL of compound (1).

[0126] In another embodiment, BW coef is 0.75.

[0127] In another embodiment, the AGE coef is 0.131.

[0128] In another embodiment, SEX coef is 0.147.

[0129] In another embodiment, the BMI coef is 0.541.

[0130] In another embodiment, FOOD coef =0.0477.

[0131] In another embodiment, SF is 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, or 0.9.

[0132] In another embodiment, Compound (1), e.g., leriglitazone, is administered and the SF is 0.74.

[0133] In another embodiment, Compound (1) HCl, e.g., leriglitazone HCl, is administered and the SF is 0.81.

[0134] In another embodiment, the AUC target is 50±20% μg.hr / mL, 60±20% μg.hr / mL, 70±20% μg.hr / mL, 80±20% μg.hr / mL, 90±20% μg.hr / mL, 100±20% μg.hr / mL, 110±20% μg.hr / mL, 120±20% μg.hr / mL, 130±20% μg.hr / mL, 140±20% μg.hr / mL, 150±20% μg.hr / mL, 160±20% μg.hr / mL, 170±20% μg.hr / mL, 180±20% μg.hr / mL, 190±20% μg.hr / mL, or 200±20% μg.hr / mL, as appropriate, depending on the disease or disorder being treated and the age of the patient.

[0135] In another embodiment, the AUC targetis 50±10% μg.hr / mL, 60±10% μg.hr / mL, 70±10% μg.hr / mL, 80±10% μg.hr / mL, 90±10% μg.hr / mL, 100±10% μg.hr / mL, 110±10% μg.hr / mL, 120±10% μg.hr / mL, 130±10% μg.hr / mL, 140±10% μg.hr / mL, 150±10% μg.hr / mL, 160±10% μg.hr / mL, 170±10% μg.hr / mL, 180±10% μg.hr / mL, 190±10% μg.hr / mL, or 200±10% μg.hr / mL, as appropriate, depending on the disease or disorder being treated and the age of the patient.

[0136] In another embodiment, the AUC target is 40 μg.hr / mL, 50 μg.hr / mL, 60 μg.hr / mL, 70 μg.hr / mL, 80 μg.hr / mL, 90 μg.hr / mL, 100 μg.hr / mL, 110 μg.hr / mL, 120 μg.hr / mL, 130 μg.hr / mL, 140 μg.hr / mL, 150 μg.hr / mL, 160 μg.hr / mL, 170 μg.hr / mL, 180 μg.hr / mL, 190 μg.hr / mL, 200 μg.hr / mL, 210 μg.hr / mL, 220 μg.hr / mL, 230 μg.hr / mL, or 240 μg.hr / mL, as appropriate, depending on the disease or disorder being treated and the age of the patient.

[0137] In another embodiment, the disease or disorder is a CNS disease or disorder.

[0138] In another embodiment, the disease or disorder is a pulmonary disease or disorder.

[0139] In another embodiment, the disease or disorder is a liver disease or disorder.

[0140] In another embodiment, the patient is a pediatric patient.

[0141] In another embodiment, the patient is an adult patient.

[0142] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is a pediatric patient, and the AUC target is 170±20% μg·h / mL.

[0143] In another embodiment, the disease or disorder is a CNS disease or disorder, the patient is an adult patient, and the AUC target is 200±20% μg·h / mL.

[0144] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is a pediatric patient, and the AUC target is 170±20% μg·h / mL.

[0145] In another embodiment, the disease or disorder is a pulmonary disease or disorder, the patient is an adult patient, and the AUC target is 200±20% μg·h / mL.

[0146] In another embodiment, the disease or disorder is a CNS disease or disorder, and the AUC target is 100±20% μg·h / mL.

[0147] In another embodiment, the disease or disorder is a pulmonary disease or disorder, and the AUC target is 100±20% μg·h / mL.

[0148] In another embodiment, the disease or disorder is a liver disease or disorder, and the AUC target is 50±20% μg·h / mL.

[0149] In another embodiment, the amount (mg) of Compound (1) or a pharmaceutically acceptable salt thereof administered to a patient as an initial dose is administered to the patient in subsequent doses for up to 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks, or longer.

[0150] In another embodiment, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising determining the AUC of Compound (1) in the patient about 0.5 to about 12 hours, e.g., about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours, after administration of a dose of Compound (1) or a pharmaceutically acceptable salt thereof;

[0151] (i) administering a higher dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) is less than 149 μg·hr / mL;

[0152] (ii) administering a lower dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) exceeds 221 μg·hr / mL; and

[0153] (iii) if the AUC of compound (1) is between 150 and 220 μg·hr / mL, administering the same dose of compound (1) or a pharmaceutically acceptable salt thereof. The present invention provides a method comprising:

[0154] In another embodiment, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising determining the AUC of Compound (1) in the patient about 0.5 to about 12 hours, e.g., about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours, after administration of a dose of Compound (1) or a pharmaceutically acceptable salt thereof; and (i) administering a higher dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) is less than 149 μg·hr / mL; (ii) administering a lower dose of compound (1) or a pharmaceutically acceptable salt thereof if the AUC of compound (1) exceeds 191 μg·hr / mL; and (iii) if the AUC of compound (1) is between 150 and 190 μg·hr / mL, administering the same dose of compound (1) or a pharmaceutically acceptable salt thereof. Including, The method is provided wherein the patient is a pediatric patient.

[0155] In another embodiment, the disclosure provides Compound (1), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a patient, comprising determining the AUC of Compound (1) in the patient after a dose of Compound (1), or a pharmaceutically acceptable salt thereof; (i) if the AUC of compound (1) is less than 149 μg·hr / mL, a higher dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; (ii) if the AUC of compound (1) exceeds 221 μg·hr / mL, a lower dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; and (iii) if the AUC of compound (1) is between 150 and 220 μg·hr / mL, the same dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; The present invention provides Compound (1), or a pharmaceutically acceptable salt thereof, wherein the patient is a pediatric patient.

[0156] In another embodiment, the disclosure provides Compound (1), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a patient, comprising determining the AUC of Compound (1) in the patient after a dose of Compound (1), or a pharmaceutically acceptable salt thereof; (i) if the AUC of compound (1) is less than 149 μg·hr / mL, a higher dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; (ii) if the AUC of compound (1) exceeds 191 μg·hr / mL, a lower dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; and (iii) if the AUC of compound (1) is between 150 and 190 μg·hr / mL, the same dose of compound (1) or a pharmaceutically acceptable salt thereof is administered to the patient; The present invention provides Compound (1), or a pharmaceutically acceptable salt thereof, wherein the patient is a pediatric patient.

[0157] In another embodiment, the present disclosure provides a method of treating a disease or disorder in a patient (e.g., a pediatric or adult patient) in need thereof, comprising: (i) administering 10 mL of an oral suspension containing 15 mg of leriglitazone HCl per mL to a patient for 1 to 10 weeks, e.g., 1 to 4 weeks, e.g., 1 to 6 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and (ii) administering to the patient after (i) 12 mL of an oral suspension containing 15 mg of leriglitazone HCl per mL. The present invention provides a method comprising:

[0158] In another embodiment, the present disclosure provides a method of treating a disease or disorder in a patient, e.g., a pediatric or adult patient, in need thereof, comprising:

[0159] (i) administering 10 mL of an oral suspension containing 13.66 mg of leriglitazone per mL to a patient for 1 to 10 weeks, e.g., 1 to 4 weeks, e.g., 1 to 6 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and

[0160] (ii) administering to the patient after (i) 12 mL of an oral suspension containing 13.66 mg of leriglitazone per mL. The present invention provides a method comprising:

[0161] In another embodiment, the disclosure provides compound (1), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a patient, e.g., a pediatric or adult patient, in need thereof, comprising: (i) 10 mL of an oral suspension containing about 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof, preferably leriglitazone HCl, per mL is administered to a patient for 1 to 10 weeks, for example, 1 to 4 weeks, for example, 1 to 6 weeks, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and (ii) 12 mL of an oral suspension containing about 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof, preferably leriglitazone HCl, per mL is administered to the patient after (i); Compound (1) or a pharmaceutically acceptable salt thereof is provided.

[0162] In another aspect, the disclosure provides a method of treating a disease or disorder in a patient, e.g., a pediatric or adult patient, in need thereof, comprising:

[0163] (i) administering 10 mL of an oral suspension containing about 13.66 mg of leriglitazone per mL to a patient for 1 to 10 weeks, e.g., 1 to 4 weeks, e.g., 1 to 6 weeks, e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks; and

[0164] (ii) administering to the patient after (i) 12 mL of an oral suspension containing approximately 13.66 mg of leriglitazone per mL. The present invention provides a method comprising:

[0165] In another embodiment, compound (1) or a pharmaceutically acceptable salt thereof is 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride, which is referred to herein as "leriglitazone HCl" or "MIN-102."

[0166] In another embodiment, leriglitazone HCl is administered to the patient as an oral suspension containing about 15 mg of leriglitazone HCl per mL.

[0167] In another embodiment, leriglitazone HCl is administered to the patient as a tablet, capsule, or other solid form containing about 30 mg leriglitazone HCl, about 60 mg leriglitazone HCl, or about 90 mg leriglitazone HCl.

[0168] III. Diseases and Disorders The methods and uses of the present disclosure involve administering compound (1) or a pharmaceutically acceptable salt thereof, such as leriglitazone or leriglitazone HCl, to a patient in need thereof to treat various diseases or disorders.

[0169] In one embodiment, the disease or disorder is regulated by peroxisome proliferator-activated receptor gamma (PPAR-γ), which regulates, among other things, fatty acid storage and glucose metabolism and has been implicated in the pathology of numerous diseases and disorders.

[0170] In another embodiment, the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease such as non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), a chronic granulomatous disorder, polycystic ovary syndrome, thyroid carcinoma, thyroid autoimmune disorder, pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, or a lung disease or disorder such as an inflammatory respiratory disease, a viral-induced inflammatory lung condition or disease, acute inflammation of the lung, or an interstitial lung disease.

[0171] In another embodiment, the disease or disorder is a central nervous system disease or disorder.

[0172] In another embodiment, the disease or disorder is selected from the group consisting of a neurodegenerative disease, a cerebrovascular disease, a stroke, epilepsy, a viral disease, a neuroinflammatory disease, a brain tumor, an organic acidemia, a fatty acid disorder, and a genetic mitochondrial disorder.

[0173] In another embodiment, the disease or disorder is a neurodegenerative disease.

[0174] In another embodiment, the disease or disorder is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, and motor neuron disease.

[0175] In another embodiment, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, ALS, degenerative ataxia, multiple system atrophy, NBIA (neurodegenerative and brain iron accumulation disorder), neuromyopathy, and motor neuron disease.

[0176] In another embodiment, the disease or disorder is metachromatic leukodystrophy.

[0177] In another embodiment, the disease or disorder is cerebral adrenoleukodystrophy.

[0178] In another embodiment, the disease or disorder is adrenomyeloneuropathy.

[0179] In another embodiment, the disease or disorder is X-linked adrenoleukodystrophy.

[0180] In another embodiment, the disease or disorder is a degenerative ataxia. In another embodiment, the degenerative ataxia is Friedreich's ataxia.

[0181] In another embodiment, the disease or disorder is a motor neuron disease.

[0182] In another embodiment, the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenomyeloneuropathy (AMN).

[0183] In another embodiment, the disease or disorder is a central nervous system disorder. In another embodiment, the central nervous system disorder is a cerebrovascular disease selected from the group consisting of global or focal ischemia, intracerebral hemorrhage, stroke, and vascular dementia. In another embodiment, the central nervous system disorder is a viral disease selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, poliomyelitis, herpes simplex, and varicella-zoster.

[0184] In another embodiment, the disease or disorder is a rare metabolic disease, e.g., a metabolic disease that affects fewer than 200,000 people in the United States or 5 or fewer per 10,000 people in the European Union. In another embodiment, the rare metabolic disease is selected from the group consisting of organic acidemias, fatty acid disorders, and inherited mitochondrial disorders.

[0185] In another embodiment, the disease or disorder is a mitochondrial disease.

[0186] Mitochondria are tiny subunits present inside every cell in the human body except red blood cells. Their primary role is to convert food and oxygen entering the cell into energy useful to the cell. Pyruvate uptake across the inner mitochondrial membrane is a central branch point in cellular energy metabolism due to its ability to balance glycolysis and oxidative phosphorylation and to counterbalance catabolic and anabolic metabolism (see, e.g., Divakaruni et al., PNAS 110(14):5422-5427 (2013)). The mitochondrial pyruvate carrier (MPC) is an inner membrane transporter that facilitates pyruvate uptake from the cytoplasm into mitochondria. It is a central regulator of mitochondrial substrate utilization, and limiting mitochondrial pyruvate uptake can enhance the use of fatty acids and a range of amino acids to promote cellular energy and biosynthesis (see, e.g., Divakaruni et al., J. Cell Biol. (2017)).

[0187] MPC contains two proteins, MPC1 and MPC2, which form a complex carrier in the inner mitochondrial membrane. MPC transports pyruvate into the mitochondrial matrix, which is necessary for pyruvate metabolism and is important in metabolic pathways (see, e.g., McCommis et al., Biochem. J. 466: 443-454 (2015)).

[0188] Mitochondrial diseases are a group of disorders each associated with mitochondrial dysfunction. Mitochondrial diseases are chronic, hereditary, and often congenital disorders that occur when mitochondria are unable to produce enough energy for the body to function properly. Mitochondrial diseases can be present at birth, but can also occur at any age. These diseases can affect cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears, and / or pancreas. Mitochondrial dysfunction can occur not only when mitochondria do not function, but can also be caused by other diseases or conditions. Mitochondrial diseases refer to a heterogeneous group of disorders, including primary and secondary mitochondrial disorders (see, for example, Niyazov et al., Mol. Syndromol. 7:122-137 (2016)). Primary mitochondrial disorders can result from germline mutations in mitochondrial DNA (mtDNA) and / or nuclear DNA (nDNA) genes that either directly encode OXPHOS (oxidative phosphorylation) proteins or affect OXPHOS function by affecting the production of the complex machinery required to drive the OXPHOS process. In contrast, secondary mitochondrial disorders occur in many pathological processes that do not involve OXPHOS, including congenital diseases caused by germline mutations in non-OXPHOS genes. Secondary mitochondrial disorders can also be acquired following adverse environmental effects that can cause oxidative stress. Many conditions can lead to secondary mitochondrial dysfunction, including autism, Parkinson's disease, Alzheimer's disease, muscular dystrophy, Lou Gehrig's disease, diabetes, and cancer.

[0189] In another embodiment, the mitochondrial disease is Rett syndrome, Alpers disease; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh syndrome; Leigh-like syndrome; Maternally inherited Leigh syndrome (MILS); Mitochondrial depletion syndrome (MDS); Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalomyopathy; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); Myoclonic epilepsy with ragged fibers (MERRF); Mitochondrial neuropathies. Gastrointestinal encephalopathy syndrome (MNGIE); Neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; Chronic progressive external ophthalmoplegia (CPEO); Dominant optic atrophy (DOA); Autosomal dominant optic atrophy (ADOA); Mitochondrial myopathy; Cardiomyopathy; Mitochondrial encephalopathy; Myoclonic epilepsy; Maternally inherited diabetes and deafness (MIDD); Ataxia neuropathy spectrum; 3-methylglutaconic aciduria; Sensorineural hearing loss; Neuroradiological findings of Leigh-like syndrome (MEGDEL); SURF1 (Complex IV) COX-deficient Leigh syndrome due to Sureit protein deficiency); oxidative phosphorylation disorders; Barth syndrome; fatal infantile cardiomyopathy (LIC); pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutations; isolated or mixed OXPHOS deficiencies due to currently unresolved genetic defects involving disturbances in pyruvate oxidation and ATP+PCr production rates; POLG2 mutations; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatinine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; lactic acidosis; leukoencephalopathy with brainstem involvement and elevated lactate (LBSL); Luft disease; carnitine palmitoyltransferase (CPT I or CPT II) deficiency; short-chain acyl-CoA dehydrogenase deficiency (SCAD); short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD); medium-chain acyl-CoA dehydrogenase deficiency (MCAD); multiple acyl-CoA dehydrogenase deficiency (MADD); long-chain acyl-CoA dehydrogenase deficiency (LCAD); very long-chain acyl-CoA dehydrogenase deficiency (VLCAD);A primary mitochondrial disorder selected from the group consisting of trifunctional protein (TFP) deficiency; and glutaric aciduria type II.

[0190] In another embodiment, the mitochondrial disease is selected from the group consisting of Rett syndrome; dominant optic atrophy (DOA); autosomal dominant optic atrophy (ADOA); complex I deficiency; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged fibers (MERRF); mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE); neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; and chronic progressive external ophthalmoplegia (CPEO).

[0191] In another embodiment, the mitochondrial disease is Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); myotonic dystrophy (BMD); congenital myopathies; glycogen storage disorders; spinal and bulbar muscular atrophy (SBMA); argininosuccinic aciduria; autism spectrum disorder (ASD); autoimmune diseases of the skin (e.g., pemphigus vulgaris and lupus); methylmalonic and propionic aciduria; disorders of purine and / or pyrimidine synthesis; facio-scapular syndrome. and secondary mitochondrial disorders selected from the group consisting of: femoral muscular dystrophy (FSHD); congenital muscular dystrophies; collagen VI muscular dystrophies (e.g., Ullrich congenital muscular dystrophy, Bethlem myopathy, distal oculopharyngeal and Emery-Dreyfus); DiGeorge syndrome; and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathies, Charcot-Marie-Tooth (CMT) neuropathy and drug-induced peripheral neuropathy).

[0192] In another embodiment, the disease or disorder is a liver disease or disorder.

[0193] In another embodiment, the disease or disorder is non-alcoholic steatohepatitis (NASH).

[0194] In another embodiment, the disease or disorder is a pulmonary disease or disorder.

[0195] In another embodiment, the disease or disorder is an inflammatory lung condition, or the disease caused by a viral infection is hyperinflammation.

[0196] In another embodiment, the inflammatory pulmonary condition or disease caused by a viral infection is systemic inflammatory response syndrome (SIRS).

[0197] In another embodiment, the inflammatory pulmonary condition or disease caused by a viral infection is acute respiratory distress syndrome (ARDS) or acute lung injury (ALI).

[0198] In another embodiment, the inflammatory lung condition or disease caused by a viral infection is pneumonia.

[0199] In another embodiment, the inflammatory pulmonary condition or disease caused by a viral infection is a hyperinflammatory syndrome. In another embodiment, the hyperinflammatory syndrome is hypercytokinemia or a "cytokine storm." In another embodiment, the hypercytokinemia is accompanied by multiple organ failure. In another embodiment, the hyperinflammatory syndrome is hemophagocytic lymphohistiocytosis.

[0200] In another embodiment, viral infection is caused by double-stranded and single-stranded DNA viruses.Exemplary DNA viruses include but are not limited to chickenpox, human cytomegalovirus, herpes simplex virus type 1, adenovirus, papillomavirus, varicella-zoster, cytomegalovirus, Epstein-Barr, smallpox, cowpox, vaccinia virus and parvovirus.

[0201] In another embodiment, the viral infection is caused by an RNA virus. Exemplary RNA viruses include, but are not limited to, coronavirus, respiratory syncytial virus, parainfluenza-3 virus, bovine viral diarrhea virus, Venezuelan equine encephalomyelitis virus, dengue virus, yellow fever virus, coxsackie B3 virus, encephalomyocarditis virus, influenza A virus, Zika virus, Ebola virus, Junin virus, Lassa fever virus, chikungunya virus, reovirus, rotavirus, enterovirus, rhinovirus, hepatovirus, cardiovirus, aphthovirus, poliovirus, parechovirus, erbovirus, kobuvirus, teschovirus, coxsackie, rubella virus, hepatitis C virus, influenza virus A, influenza virus B, influenza virus C, isavirus, thogotovirus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, canine distemper virus, rabies virus, vesicular stomatitis, Marburg virus, hepatitis E virus, lentivirus (HIV), and hantavirus.

[0202] In another embodiment, the viral infection is caused by a reverse transcribing virus, such as HIV, caulimovirus, cocoa staghorn virus (CSSV), and hepatitis B virus.

[0203] In another embodiment, the viral infection is caused by a coronavirus.

[0204] In another embodiment, the coronavirus is an animal coronavirus.

[0205] In another embodiment, the coronavirus is a human coronavirus.

[0206] In another embodiment, the human coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2, or a mutant strain of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

[0207] In another embodiment, the human coronavirus is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

[0208] In another embodiment, the human coronavirus is a mutant strain of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, or SARS-CoV-2.

[0209] In another embodiment, the human coronavirus is HCoV-229E.

[0210] In another embodiment, the human coronavirus is a mutant strain of HCoV-229E.

[0211] In another embodiment, the human coronavirus is HCoV-OC43.

[0212] In another embodiment, the human coronavirus is a mutant strain of HCoV-OC43.

[0213] In another embodiment, the human coronavirus is HCoV-NL63.

[0214] In another embodiment, the human coronavirus is a mutant strain of HCoV-NL63.

[0215] In another embodiment, the human coronavirus is HCoV-HKU1.

[0216] In another embodiment, the human coronavirus is a mutant strain of HCoV-HKU1.

[0217] In another embodiment, the human coronavirus is SARS-CoV.

[0218] In another embodiment, the human coronavirus is a mutant strain of SARS-CoV.

[0219] In another embodiment, the human coronavirus is MERS-CoV.

[0220] In another embodiment, the human coronavirus is a mutant strain of MERS-CoV.

[0221] In another embodiment, the human coronavirus is SARS-CoV-2.

[0222] In another embodiment, the human coronavirus is a mutant strain of SARS-CoV-2.

[0223] In another embodiment, the disease or disorder is acute inflammation of the lung caused by a bacterial infection, a parasitic infection, any of the viral infections mentioned above, Moldoveanu et al., J Inflamm Res 2:1-11 (2009), or any other cause. Rezoagli et al., Ann Transl Med 5(14):282 doi: 10.21037 / atm.2017.06.62 (2017).

[0224] In another embodiment, the acute inflammation of the lung is pneumonia.

[0225] In another embodiment, the acute inflammation of the lung is ARDS. In another embodiment, the ARDS is not caused by a viral infection.

[0226] In another embodiment, the disease or disorder is an interstitial lung disease (ILD).

[0227] In another embodiment, the ILD is caused by a drug / chemical, eg, chemotherapy, environmental exposure; an autoimmune disease; or any other, eg, idiopathic, cause.

[0228] In another embodiment, the ILD is selected from the group consisting of acute interstitial pneumonia, allergic bronchopulmonary aspergillosis, asbestosis, beryllium disease, autoimmune pulmonary alveolar proteinosis, Blau syndrome, bronchiolitis obliterans, bronchiolitis obliterans organizing pneumonia, chronic granulomatous disease, coal workers' pneumoconiosis, CREST syndrome, idiopathic organizing pneumonia, cystic fibrosis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, diffuse panbronchiolitis, mediastinal fibrosis, Froster-Hall syndrome, and others. These include: Schitz syndrome, idiopathic acute eosinophilic pneumonia, idiopathic pulmonary fibrosis (IPF), idiopathic pulmonary hemosiderosis, Kabuki syndrome, kaolin pneumoconiosis, Kartagener syndrome, pulmonary coloboma, Manouvrier syndrome, meconium aspiration syndrome, nontuberculous mycobacterial lung disease, pleuropulmonary parenchymal fibroelastosis, alveolar microlithiasis, recurrent respiratory papillomatosis, respiratory distress syndrome, silicosis, tracheobronchomalacia, Wolf-Hirschorn syndrome, or Young syndrome.

[0229] In another embodiment, the ILD is idiopathic pulmonary fibrosis (IPF).

[0230] IV. Pharmaceutical Compositions and Pharmaceutical Uses Pharmaceutical compositions comprising Compound (1) or a pharmaceutically acceptable salt thereof, such as leriglitazone, and a pharmaceutically acceptable excipient can be administered by any suitable route of administration, including, for example, any of the following delivery routes: oral, buccal, topical, epicutaneous, subcutaneous, transdermal, intramuscular, parenteral, ocular, rectal, vaginal, inhalation, buccal, sublingual, and intranasal.

[0231] The present disclosure also provides the use of Compound (1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder in a patient in need thereof.

[0232] In one embodiment, Compound (1) or a pharmaceutically acceptable salt thereof is administered orally. The oral form of the pharmaceutical composition can be solid or liquid. Suitable oral dosage forms include tablets, capsules, pills, granules, suspensions, emulsions, syrups, or liquids. The pharmaceutical composition may be in a solid form, for example, selected from tablets, capsules, pills, or granules. In one embodiment, the oral form is a tablet. In another embodiment, the oral form is an oral solution or suspension. These are advantageous when patients have difficulty swallowing, for example, as a result of disease, or in the case of elderly and pediatric use. Sublingual formulations are also advantageous.

[0233] The amount that is "effective" will vary from patient to patient, depending on the individual's age and general condition, the specific active agent(s), and the like. Thus, it is not always possible to identify an exact "effective amount." However, an appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Thus, the dosage of the active agent will depend on the nature and severity of the condition, the patient's age and condition, and other factors known to those of ordinary skill in the art. Typical daily dosages are 0.1 mg to 200 mg, e.g., 20 mg to 200 mg; for example, for adults, 10 mg to 100 mg may be administered as a single dose without further administration or in multiple doses, e.g., 1 to 3 times daily. The compounds described herein may also be administered in a daily dose of 80 mg to 600 mg. In one embodiment, the daily dose for an adult is 50 mg to 300 mg. In one embodiment, the daily dose for an adult is about 90 mg, about 120 mg, about 150 mg, about 180 mg, or about 210 mg. The daily dose for children is 0.1 mg to 200 mg, hi another embodiment, the daily dose for children is 10 mg to 100 mg.

[0234] Pharmaceutical compositions can contain conventional excipients known in the art and can be prepared by conventional methods.Specific compound or compound mixture can be selected for specific delivery route.Some compound or compound mixture can also be suitable based on their use for treating NAFLD and NASH, X-ALD, AMN, cALD or other diseases or disorders.

[0235] Oral dosage forms can be prepared by combining Compound (I) or a pharmaceutically acceptable salt thereof in an intimate mixture with at least one excipient according to conventional pharmaceutical compounding techniques.Excipients can be in a variety of forms depending on the desired composition form for administration.For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starch, sugar, microcrystalline cellulose, kaolin, diluents, granulating agents, lubricants, binders, stabilizers, and disintegrants.

[0236] Due to their ease of administration, tablets, caplets (coated oral tablets), and capsules (e.g., hard gelatin, HPMC, or starch capsules) represent embodiments of solid oral dosage units, in which solid pharmaceutical excipients are used. If desired, tablets or caplets can be coated by standard aqueous or non-aqueous techniques. These dosage forms can be prepared by any of the methods of pharmacy. Generally, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing one or more compounds with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0237] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing one or more compounds (1) or pharmaceutically acceptable salts thereof in a free-flowing form, e.g., powder or granules, optionally mixed with one or more excipients, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0238] The pharmaceutical composition may further comprise one or more other therapeutic agents. The combination treatments may be administered simultaneously, sequentially, or separately, by the same or different routes, or before, during, and after a surgical or interventional procedure.

[0239] In one embodiment, the present disclosure provides a pharmaceutical composition comprising leriglitazone HCl as an oral aqueous suspension.

[0240] In another embodiment, the present disclosure provides a pharmaceutical composition comprising leriglitazone HCl, polysorbate 80, sodium carboxymethylcellulose and water.

[0241] In another embodiment, the present disclosure provides a pharmaceutical composition comprising leriglitazone HCl, colloidal microcrystalline cellulose and carboxymethylcellulose sodium.

[0242] Pharmaceutical compositions of the present disclosure containing Compound (1) HCl may also contain, if necessary, sweeteners such as sorbitol powder, sodium saccharin, preservatives such as sodium benzoate, flavorings, pH adjusters such as sodium citrate and citric acid monohydrate.

[0243] Leriglitazone or a pharmaceutically acceptable salt thereof may be administered to patients who are taking other medications, such as anti-inflammatory and analgesic agents, antidiabetic agents (e.g., metformin), dopamine agonists (e.g., levodopa), MAO-B inhibitors, catechol O-methyltransferase (COMT) inhibitors, anticholinergics, other anti-Parkinson's drugs (e.g., amantadine), anti-NMDA receptor (e.g., memantine), cholinesterase inhibitors, ACE inhibitors, glutamate antagonists (e.g., riluzole), antioxidants, and the like. , immunomodulatory agents (e.g., fingolimod, anti-CD52, CD25, and CD20 monoclonal antibodies, interferon-beta-1a, natalizumab, laquinimod, dimethyl fumarate), chemotherapeutic agents, enzyme-replacement therapeutic agents, substrate-reducing therapeutic agents, corticosteroids, antiproliferative agents (e.g., methotrexate), anticonvulsants, anticoagulants, antihypertensive agents, neuroprotective agents, and NRf2 activators can also be used in accordance with the present disclosure. Leriglitazone or a pharmaceutically acceptable salt thereof may also be used when the patient is undergoing gene therapy, bone marrow transplant, deep brain stimulation, or radiation therapy.

[0244] The one or more therapeutic agents may include sulfonylureas (e.g., glimepiride, glipizide, glyburide), glinidine (also known as meglitinides), thiazolidinediones (e.g., pioglitazone, rosiglitazone, lobeglitazone), dipeptidyl peptidase 4 (DPP4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, omarigliptin), sodium / glucose cotransporter 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin), glucagon-like peptide-1 (GLP1) receptor agonists (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide), glucagon-like peptide-1 (GLP-1), and insulin (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1) and oral insulin preparations).

[0245] In some embodiments, leriglitazone or a pharmaceutically acceptable salt thereof is administered to patients with inflammatory lung conditions or diseases caused by viral infection, acute lung inflammation, or ILD in combination with one or more optional therapeutic agents.Optional therapeutic agents include hydroxychloroquine, chloroquine, antiviral agents such as remdesivir and favipiravir, IL6 inhibitors such as Kevzara and Actemra (Roche), corticoids, anti-cytokine inhibitors such as anakinra, JAK inhibitors, antibiotics, and antifungal agents.

[0246] Non-limiting exemplary antiviral agents include oseltamivir, ganciclovir, lopinavir / ritonavir (Kaletra®), and remdesivir. Antiviral agents also include reverse transcriptase inhibitors (RTIs). In one embodiment, the RTI is a nucleoside reverse transcriptase inhibitor (NRTI). Non-limiting exemplary NRTIs include abacavir (ZIAGEN™), abacavir / lamivudine (Epzicom), abacavir / lamivudine / zidovudine (TRIZIVIR™), adefovir, alovudine, amdoxovir, apricitabine, ATRIPLA®, BARACLUDE®, BIKTARVY®, censavudine, COVIRACIL™, DAPD / DXG, D-D4FC, dexelbucitabine, didanosine (VIDEX™), didanosine extended-release (Videx EC), dOTC, EFdA, emtricitabine (EMTRIVA™), emtricitabine / tenofovir alafenamide (DESCOVY®), emtricitabine / tenofovir disoproxil fumarate (TRUVADA®), elvucitabine, fosalvudine, lamivudine / zidovudine (COMBIVIR™), EVIPLERA™, GENVOYA®, HIVID™, KIVEXA™, lamivudine In another embodiment, the RTI is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Non-limiting exemplary NNRTIs include delavirdine, efavirenz, etravirine, nevirapine, and rilvipirine. Antiviral agents also include protease inhibitors.Non-limiting exemplary protease inhibitors include amprenavir, fosamprenavir, indinavir, nelfinavir, saquinavir, atazanavir, darunavir, and tipranavir.

[0247] In one embodiment, the one or more optional therapeutic agents are merimepodib, tocilizumab (Actemra®), favipiravir (Avigan®), tocilizumab / favipiravir, leronlimab (PRO 140), remdesivir, ruxolitinib (Kevzara®), sarilumab, chloroquine phosphate (Aralen®, Resochin®), chloroquine hydrochloride, azithromycin (Zithromax®), hydroxychloroquine sulfate / azithromycin, lopinavir / ritonavir (Kaletra®), eculizumab (Soliris®), human monoclonal antibody targeting SARS-CoV-2, APN01, Dano Previr (Ganovo®), TJM2 (TJ003234), selinexor (XPOVIO®), remestemcel-L (RYONCIL™), LAM-002 (apilimod), lintatolimod (Ampligen®), DAS181, CM4620-IE, CAP-1002, SAB-185, ENU200, camostat mesylate, IFX-1, namilumab (IZN-101), GIAPREZA™ (angiotensin II), MN- 166 (ibudilast), Rebif® (interferon beta-1a), ivermectin (Stromectol®, Mectizan®), NVX-CoV2373, Thiolano®, plitidepsin (Aplidin®), opaganib (Yeliva®), RHB-107, opaganib / RHB-107, EIDD-2801, dimcirumab, TAK-888, ARMS-1, GENOSYL® (nitric oxide) gas, INOpulse®, BPI-002, rhu-pGSN, galidesivir (BCX4430), BXT-10, L-glutamine oral powder (Endari®), Sylvant (siltuximab), Linebacker, Equivir, HTCC (N-(2-hydroxypropyl)-3-trimethylammonium 47 chitosan chloride), darunavir (Prezista®), darunavir / cobicistat (Prezcobix™),INOmax® (nitric oxide), WP1122, OYA1, Arbidol (umifenovir), Remescor®, MAN-01, STI-4920 (CMAB020), TZLS-501, IFN-alpha 2b, niclosamide, KL4, or WP1122.

[0248] Leriglitazone or a pharmaceutically acceptable salt thereof and one or more optional therapeutic agents may be administered in combination under one or more of the following conditions: different cycles, different durations, different concentrations, different routes of administration, etc.

[0249] V. Definition Various examples and embodiments of the inventive subject matter disclosed herein are possible and will become apparent to those of ordinary skill in the art given the benefit of this disclosure. In this disclosure, references to "some embodiments," "certain embodiments," "certain exemplary embodiments," "particular embodiments," and similar phrases each mean that the embodiments are non-limiting examples of the inventive subject matter, and that alternative embodiments exist that are not excluded.

[0250] The articles "a," "an," and "the" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" refers to one element or to more than one element.

[0251] As used herein, the term "about" includes the stated value ±10%. Thus, "about 10" means 9 to 11.

[0252] The word "comprising" is used consistent with its open-ended meaning, meaning that a given product or process may, if desired, have additional features or elements beyond those explicitly recited. Whenever an embodiment is described using the word "comprising," it is understood that otherwise similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also contemplated as being within the scope of this disclosure.

[0253] The term "ameliorate" in the context of the present disclosure is understood to mean any improvement to the condition of the patient being treated.

[0254] The term "bid administration" or "BID" refers to administration of a therapeutic agent twice daily.

[0255] The term "SAD" refers to a single oral administration of a therapeutic agent.

[0256] An "effective" or "therapeutically effective" amount of a drug or pharmaceutical active agent refers to a non-toxic but sufficient amount of the drug or pharmaceutical agent to produce the desired effect. The amount that is "effective" varies from patient to patient, depending on the individual's age and general condition, the specific active agent(s), etc. Therefore, it is not always possible to specify an exact "effective amount." However, the appropriate "effective" amount in any individual case can be determined by one skilled in the art using routine experimentation.

[0257] In the context of this specification, the term "treatment" or "treating" and similar terms means improving or eliminating a disease or one or more symptoms associated with said disease. "Treatment" also encompasses improving or eliminating the physiological sequelae of a disease.

[0258] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids.

[0259] The terms "prevention" or "preventing" refer to a reduction in the risk of acquiring or developing a given disease or disorder, or a reduction or inhibition of the recurrence of the disease or disorder.

[0260] As used herein, the phrase "PK variability" or "pharmacokinetic variability" refers to the inter-individual variability in the pharmacokinetic parameters of a drug, resulting in different plasma concentration-time profiles following administration of the same dose to different patients.

[0261] As used herein, the term "steady state" refers to the pharmacokinetic situation when the rate of drug administration equals the rate of drug elimination.

[0262] As used herein, the term "AUC" refers to the area under the plasma (or blood) concentration-time curve of leriglitazone, which represents exposure to the compound within a relevant time interval.

[0263] As used herein, the term "AUC at steady state" or "AUC ss " refers to the AUC within the dosing interval at steady state.

[0264] As used herein, the term "steady-state trough" or "C min ss " refers to the minimum steady-state plasma drug concentration during the dosing interval.

[0265] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0266] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are bonded.

[0267] The terms "enantiomer" and "enantiomeric" refer to a molecule that is not superimposable on its mirror image and is therefore optically active, where an enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[0268] The term "racemic" refers to a mixture of equal parts of enantiomers, which mixture is optically inactive.

[0269] The term "absolute configuration" refers to the arrangement in space of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0270] Stereochemical terminology and conventions used herein, unless otherwise indicated, are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0271] The term "enantiomeric excess" or "ee" refers to a measure of how much more of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is |RS| * 100, where R and S are the mole or weight fractions of each of the enantiomers in the mixture, and R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess can be calculated by ([α] obs / [α] max ) * [α] is defined as 100 obs is the optical rotation of the mixture of enantiomers, and [α] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or polarimetric analysis.

[0272] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance in which all of its molecules (within the limits of detection) have the same sense of chirality.

[0273] The terms "enantiomerically enriched" or "enantiomerically enriched" refer to a sample of a chiral substance whose enantiomer ratio is greater than 50:50. An enantiomerically enriched compound may be enantiomerically pure.

[0274] The term "primary mitochondrial disorder" or "PMD" refers to mitochondrial diseases that can arise from germline mutations in mitochondrial DNA (mtDNA) and / or nuclear DNA (nDNA) genes that encode electron transport chain (ETC) proteins and, therefore, the generation of adenosine triphosphate (ATP), the main cellular energy carrier.

[0275] The term "secondary mitochondrial disorder" or "SMD" refers to mitochondrial diseases with many pathological processes that do not involve oxidative phosphorylation (OXPHOS), including congenital diseases caused by germline mutations in non-OXPHOS genes. SMD can also be acquired following adverse environmental effects that can cause oxidative stress.

[0276] The term "initial dose" refers to the first dose of a drug administered to a patient.

[0277] The term "subsequent dose" refers to any dose of a drug administered to a patient after the initial dose.

[0278] The term "pediatric patient," as used herein, refers to a patient who is 17 years of age or younger. In some embodiments, a pediatric patient is between 2 months and 17 years of age. In some embodiments, a pediatric patient is between 6 months and 17 years of age.

[0279] The term "adult patient," as used herein, refers to a patient over the age of 17. [Example]

[0280] The methods and uses of treatment or prevention described herein will now be further described in detail with reference to the following examples.These examples are provided for illustrative purposes only, and the embodiments described herein are not to be construed as being limited to these examples in any way.Rather, the embodiments should be construed as embracing any and all variations that become apparent as a result of the teachings provided herein.Formula I (see above) was created based on Example 2.

[0281] Example 1 Physiologically Based Pharmacokinetic (PBPK) Modeling to Guide Leriglitazone HCl Starting Dose in Pediatric Patients Phase 1 study Study Design: A phase 1, randomized, double-blind, placebo-controlled, single-center clinical study was conducted with leriglitazone HCl in 33 healthy male volunteers (HV) (19-54 years old, 63.2-95.7 kg) divided into two parts: a single ascending dose (SAD) at three dose levels (30, 90, and 270 mg) in fasted conditions, followed by two dose levels (90 and 270 mg) in fed conditions; an 8-day multiple ascending dose (MAD) at two dose levels (135 and 270 mg) using a double-blind parallel-group design, and a separate cohort of subjects in an open-label parallel-group design at two dose levels (135 and 270 mg), including cerebrospinal fluid (CSF) collection on day 8. In the fasting condition, a fasting period of at least 4 hours was required before plasma samples were obtained. The food effect (FE) was assessed by comparing fasted and fed conditions (medication administered after a high-fat breakfast according to the FDA definition with a calculated caloric content of 918 kcal). In the fed part of the MAD, medication was administered before a regular breakfast. Leriglitazone HCl was supplied by ChemConnection, and a 6 mg / ml oral suspension of leriglitazone (20% w / v kleptose, 2% ethanol in 100 mM phosphate buffer, pH 7.8) was used in the study.

[0282] Safety: Safety and tolerability assessments consisting of adverse events (AEs), clinical tests, vital signs, 12-lead electrocardiogram (ECG), and physical examination.

[0283] Blood, urine, and CSF sample collection: For SAD, blood samples were collected at the following time points: pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours post-dose. Urine was collected pre-dose (within 12 hours prior to dosing) and at collection intervals of 0-6, 6-12, 12-24, 24-36, and 36-48 hours post-dose. For the MAD, blood samples were collected pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-dose on day 1, pre-dose and 4 hours post-dose on days 2-7, and pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours post-dose on day 8. CSF was collected on day -1 and 4 hours post-dose on day 8.

[0284] Pharmacokinetic parameter calculation: PK parameters (C max , T max , t 1 / 2 , AUC 0-t , CL / F, Vz / F, AUC 0-τ , R AUC , R.C. max ) was estimated using non-compartmental analysis (NCA) (Phoenix WinNonlin® version 6.3).

[0285] Statistical Analysis: Descriptive statistics for all relevant PK parameters: n, mean, minimum, median, maximum, geometric mean, and coefficient of variation (CV%); C to determine dose proportionality and food effect (FE). max and analysis of AUC variation.

[0286] Brain distribution The ratio of unbound leriglitazone concentration in brain to unbound concentration in plasma (Kpu,u; Cb,u / Cp,u) was calculated as the unbound CSF C max Unbound plasma C max Calculated by dividing by . Unbound C max The unbound fraction in plasma (fu,p) was calculated to obtain the values ​​previously reported. Rodriguez-Pascau, L. et al., Sci. Transl. Med. 13, eabc0555 (2021).

[0287] PBPK model development A PBPK model for leriglitazone HCl was developed using Simcyp Population-Based Simulator version 17 release 1.

[0288] All input parameters for the PBPK model of leriglitazone are listed in Table 1. [Table 1]

[0289] A first-order absorption model with inputs based on clinical data was used to describe the absorption kinetics of the drug. Dose-dependent k values ​​were estimated from the Phase 1 SAD data, and the C of leriglitazone was max and a less than dose-proportional increase in C max The MechPeff model, which relies on the physicochemical properties of the drug (logP), predicted an Fa value of 0.99, consistent with the in vitro passive permeability data, and was set to 1.0 in the final model. [Table 2]

[0290] The Vss estimated from the phase 1 SAD data using NCA (Phoenix WinNonlin version 8.0) was 0.29 L / kg (Table 2). Method 3 was used because the predicted Vss (=0.39 L / kg) was closest to the estimated Vss in the PBPK model. A global scalar of 0.7 was applied to fit the estimate. The full PBPK model was applied in all simulations of the drug's plasma concentration-time profile to recover the shape of the concentration-time profile.

[0291] Biliary clearance of leriglitazone was found to be relatively small in sandwich-cultured hepatocytes, with a CLint of 0.0005 μL / min / mg protein (0.358 μL / min / million hepatocytes). After scale-up, the biliary clearance component accounted for 19.5% of the total clearance.

[0292] CYP2C8 and CYP3A4 were identified as the main contributing enzymes to leriglitazone metabolism in vitro, with CYP2C8 largely responsible for the formation of the main metabolite M3. The kinetic parameters of human CYP2C8- and CYP3A4-mediated metabolism of leriglitazone were investigated in vitro using recombinant CYP3A4 and CYP2C8 enzymes (ADMESCOPE, Finland). The fitted Km and Vmax values ​​for CYP2C8 were 34.0 μM and 2.27 pmol / min / pmol CYP based on M3 formation, and 13.7 μM and 1.60 pmol / min / pmol CYP based on leriglitazone depletion. Elimination of leriglitazone was very slow, especially at high initial concentrations, and the fit accuracy was not as good as that based on M3 formation. Metabolism of leriglitazone by recombinant CYP3A4 was not saturated at the initial concentrations used. Therefore, the kinetic parameters Km and Vmax could not be fitted. Based on these results, the contribution of CYP2C8 remains more significant (approximately 70% metabolic fraction) over the therapeutic range, i.e., up to 30 μM initial incubation concentration.

[0293] Individual PK data and M3 plasma concentration data for leriglitazone revealed that up to 51% of leriglitazone was converted to M3 (maximum M3:leriglitazone AUC ratio = 0.51), and metabolism of leriglitazone was divided into CYP2C8 (63.7%), CYP3A4 (30%), and undefined metabolites (6%). Alternative clearance pathways, namely biliary (f eBIL = 19.5%) and renal clearance (f = 5%), the simulated metabolic fraction f mCYP2C8 and f mCYP3A4 were 45% and 24%, respectively, and undefined metabolites 6%. Intrinsic clearance values ​​for CYP2C8 and CYP3A4 were calculated based on the estimated fm values ​​and the mean CL / F value of 0.93 L / h reported from the phase 1 study (MAD part day 8).

[0294] Predictions of plasma concentration-time profiles and clearance were performed in Simcyp Simulator using the default Sim-Healthy volunteer population. The parameter values ​​have been previously described. (Howgate, EM, et al., Xenobiotica Fate Foreign Compd. Biol. Syst. 36, 473-497 (2006); Inoue, S. et al., Xenobiotica Fate Foreign Compd. Biol. Syst. 36, 499-513 (2006).) The study design used to simulate the plasma concentration-time profiles of a single dose of leriglitazone in fasting and fed subjects was based on the Phase 1 SAD results. Concentration-time profiles were simulated over a 144-hour duration using 10 virtual trials of six subjects (all male) aged 21 to 50 years receiving a single oral dose of 30, 90, or 270 mg under fasting conditions and a single oral dose of 90 or 270 mg under fed conditions. Visual inspection of predicted concentration-time profiles was performed to evaluate key PK parameters (AUC, C max and T max ) were compared with those observed in the phase 1 study (Table 8).

[0295] PBPK model validation The PBPK model was validated by comparing predicted concentration-time profiles with observed Phase 1 MAD data. The study design used for the simulation was based on multiple doses of 135 mg or 270 mg in healthy subjects in a fed state. Using 10 virtual trials of eight healthy subjects (all male) aged 19-54 years receiving daily doses of 135 mg or 270 mg orally over eight days, concentration-time profiles were simulated over a 192-hour duration under fed conditions. The 90 mg dose (= 0.89 h) -1 ) were used in the 135 mg simulations. Models were considered acceptable if the ratio of predicted:observed parameters was between 0.8 and 1.25 times.

[0296] Application of PBPK model for estimation of pediatric starting dose The Simcyp Pediatric Simulator was used to model the pharmacokinetic behavior of leriglitazone in neonates, infants, children, and adolescents. The default Simcyp ontogenetic functions for CYP3A4 and CYP2C8, as well as literature functions (Upreti, VV & Wahlstrom, JL, J. Clin. Pharmacol. 56, 266-283 (2016)), were applied in separate simulations to address uncertainties in the CYP ontogenetic functions (Figures 1, 2, and 3). The developed fasting-state PBPK model was predictively applied to estimate the appropriate starting dose for pediatric clinical evaluation by matching the target systemic exposure of 160 μg·h / mL. max To address the issue of potential nonlinearity in the max Based on the range of values, the adult drug model developed at the 30 mg or 90 mg dose level was used directly.

[0297] The pediatric population was divided into the following age bands: 0-1 year, 1-1.5 years, 1.5-2 years, >2 years to 6 years, >6 years to 12 years, and >12 years to <18 years. Multiple-dose simulations under fasting conditions were performed to derive pediatric doses by applying the default Simcyp and Upreti CYP ontogeny functions. The starting dose for pediatric clinical evaluation was planned based on body weight (BW). Allometric scaling was also applied to adjust the dose based on body size.

[0298] Concentration-time profiles were simulated under fasting conditions using 10 virtual trials of 10 pediatric subjects (50% female) in the age groups 0-1 year, 1-1.5 years, 1.5-2 years, 2-<6 years, 6-<12 years, and 12-<18 years) receiving each daily dose of leriglitazone orally for 8 days. The default Simcyp and Upreti CYP ontogeny functions assume the same relationship between enzyme activity and age in both males and females. Therefore, simulation results do not differ significantly between simulations assuming 100% male versus 50% male subjects.

[0299] PBPK validation in pediatric patients A phase 2, open-label clinical study in cALD with five recruited male pediatric patients aged 5-12 years will be conducted to evaluate the effect of leriglitazone treatment on disease progression before human stem cell transplantation.

[0300] Observed leriglitazone plasma concentrations from five patients: one in the 2–5 age group, three in the 6–11 age group, and one compassionate use patient aged >12 years were used for preliminary validation of the pediatric PBPK model (Table 3). [Table 3]

[0301] Following the first dose of leriglitazone HCl, blood samples were collected pre-dose, 2, 6, 12, and 24 hours post-dose, and after 4 and 12 weeks of treatment, pre-dose, and 2 hours post-dose. Plasma concentrations observed after single or repeated doses were overlaid onto PBPK simulations using Upreti ontogeny for the corresponding age groups. Visual inspection was performed to ensure values ​​fell within the 95% confidence intervals of the predicted concentration-time profiles.

[0302] result safety All treatment-emergent adverse events (TEAEs) were mild in severity and resolved without sequelae by follow-up. No serious AEs were reported. Overall, the percentage of subjects reporting TEAEs was similar after placebo and leriglitazone HCl administration (Table 4). [Table 4] * These subjects received an unplanned combination of placebo and active medication. AE: adverse event; E: number of occurrences of AE; N: number of exposed subjects; n: number of subjects experiencing AE; SOC: system organ class; TEAE: treatment-emergent AE; %: number of subjects (n) as a percentage of the number of subjects per treatment (N).

[0303] Thus, single and multiple doses of leriglitazone HCl appear to be safe and well tolerated in healthy male subjects. No clinically meaningful changes from baseline were observed in clinical laboratory assessments, vital signs, ECG, and physical examination.

[0304] Pharmacokinetics of leriglitazone in healthy volunteers The PK parameters of leriglitazone obtained in the SAD are shown in Table 5. [Table 5] *All concentrations are reported as total concentrations

[0305] Under fasting conditions, leriglitazone was rapidly absorbed in all subjects at all doses tested (30, 90, and 270 mg), with measurable concentrations of both leriglitazone and M3 in plasma at the first post-dose sample collection time point (0.25 hours). max ) to reach the max ) ranged between 0.25 and 2.5 hours. After reaching a maximum, the concentrations of leriglitazone and M3 showed a steady decline. The half-lives were approximately 23 to 24 hours for leriglitazone and 22 to 23 hours for M3. In general, the AUC increased proportionally with dose. The combined individual leriglitazone and M3 plasma concentration-time profiles showed little inter-subject variability within the same dose level (Figures 5 and 6). The effect of food on leriglitazone absorption was also evaluated. Under fed conditions, administration of leriglitazone resulted in a clear delay in leriglitazone uptake at all tested doses (90 and 270 mg). The T of leriglitazone and M3 max is lower than in the fasting state max Although values ​​were observed at 3 to 6 hours, the AUC did not differ substantially from that in the fasted state. max decreases, and T max was prolonged, but total exposure was unaffected.

[0306] Approximately 6.8% of the leriglitazone dose was excreted in urine over the 48-hour collection period, mostly conjugated as leriglitazone (6.5%) and M3 (0.3%). Only limited amounts were excreted as free leriglitazone (<0.4%) or M3 (<0.01%). Meals did not alter the amounts of leriglitazone and M3 excreted in urine.

[0307] The PK parameters obtained in the MAD are shown in Table 6. [Table 6] * All concentrations are reported as total concentrations

[0308] The plasma concentration-time profiles for leriglitazone and M3 following an initial dose of 135 or 270 mg in fed conditions were similar to the profiles obtained in SAD. Steady state was reached after 5 days. On day 8, the concentration versus time profiles showed increased concentrations (Figures 8 and 9). Both leriglitazone and M3 significantly increased the RC for leriglitazone (both dose levels). max The RAUC ranged from 1.63 (M3 after the 270 mg dose) to 1.81 (leriglitazone after the 270 mg dose).

[0309] At 4 hours post-dose on Day 8, the total CSF concentrations of leriglitazone and M3 were 188 and 13 ng / mL for the 135 mg dose and 332 and 22 ng / mL for the 270 mg dose, respectively (Table 6). Thus, doubling the leriglitazone dose nearly doubled the CSF concentrations of leriglitazone (1.8-fold) and M3 (1.7-fold). Total leriglitazone concentrations in the CSF represented 2.2-2.5% of the total plasma concentration, whereas M3 only represented 0.4%. Brain penetration of leriglitazone was good, whereas that of M3 was limited.

[0310] Brain penetration of leriglitazone in rats and humans In a single-dose neuropharmacological study in rats, at an effective dose of 17 mg / kg, the unbound brain concentration of leriglitazone was 175 ng / ml, similar to the measured CSF concentration of 274 ng / ml (Figure 7). Given that the validity of CSF as a surrogate marker for unbound brain concentration has been demonstrated in rats, CSF levels of leriglitazone were measured in the Phase 1 study and confirmed to be similar to those in rodents. The unbound brain-to-plasma ratio (Kpu,u) of leriglitazone, as a measure of brain distribution of free drug, was 0.55 in humans and 0.25 in rats (Table 7). [Table 7]

[0311] These results indicate that the drug exhibits favorable brain penetration, which is due to the high passive permeability of the drug and, consequently, the limited role of major brain efflux transporters such as P-gp and / or BCRP in brain penetration. These data also support the subsequent use of PBPK models to predict pediatric starting doses and design PK sampling schemes based on matching the target systemic exposure in adults.

[0312] Development and validation of a PBPK model for leriglitazone A PBPK model for leriglitazone was developed using Simcyp software (Figure 4, Table 1). The model incorporates CYP3A4- and CYP2C8-mediated metabolism, as well as biliary clearance, derived from in vitro data, and estimates fm CYP3A4 , fm CYP2C8 and f eBIL were 24%, 45%, and 19.5%, respectively.

[0313] During model development, the SAD data were used as the model training dataset, and the MAD data were used as the model validation dataset. Application of the developed model recovered systemic exposure following single dose administration of 90 to 270 mg in either the fed or fasted state in HV. A comparison of the simulated and observed plasma concentration-time profiles for leriglitazone following a single oral dose of 90 or 270 mg in fasted and fed conditions is shown in Figures 10 and 11. The concentration-time profile for a single oral dose of 30 mg in fasted conditions was also simulated (data not shown). The model adequately recovered the clinical data, as the majority of observed individual data points were within the 5% to 95% percentiles, and at least one study recovered the observed mean data up to 120 hours after dosing. The simulated AUC and C maxThe values ​​were within 0.80 to 1.15 times the observed values ​​(Table 8). [Table 8]

[0314] As model validation, subsequent simulations also recovered systemic exposure following multiple dose administration of 135 mg to 270 mg in HV in the fed state. The model adequately recovered the clinical data, as the majority of observed data points were within the 5% to 95% percentiles, and at least one trial recovered the observed mean data (Figure 12). Simulated steady-state AUC and C max The values ​​were within 1.04 to 1.14 times the observed values ​​(Table 9). [Table 9]

[0315] Application of PBPK model for estimating pediatric starting dose A predictive PBPK model was applied to estimate an appropriate starting dose for pediatric clinical evaluation by matching a target systemic exposure of 160 μg·h / mL based on preclinical pharmacology and safety evaluations combined with Phase 1 data. This target systemic exposure is equivalent to a 150 mg QD adult dose based on linear extrapolation from data obtained with a 135 mg QD dose. Default Simcyp and Upreti ontogeny functions for CYP3A4 and CYP2C8 were applied to separate simulations.

[0316] Pediatric doses were derived using a multiple-dose simulation (fasting) over 8 days to match the target systemic exposure in adult patients receiving 150 mg. When the default Simcyp ontogenetic function was applied, the predicted doses were 1.9, 1.9, 2.0, 2.2, 2.2, and 2.1 mg / kg QD for the age groups 0 to 1 year, 1 to 1.5 years, 1.5 to 2 years, 2 to <6 years, 6 to <12 years, and 12 to <18 years, respectively; when the Upreti ontogenetic function was applied, the doses were 2.4, 2.3, 2.3, 2.4, 2.3, and 2.1 mg / kg QD (Table 10). [Table 10] * Pediatric dose = Adult dose × (BWp / BWa) 0.75

[0317] Validation of PBPK models with pediatric patient data An open-label clinical study in cALD is underway to evaluate the effect of leriglitazone treatment on the progression of early cerebral lesions in male pediatric patients aged 2 to 12 years. The target exposure for this clinical study was set at 170 μg·h / mL, slightly above the originally proposed exposure of 160 μg·h / mL, based on preclinical pharmacology and safety evaluations combined with phase 1 data. Therefore, because simulated drug exposure is dose-proportional within various pediatric age groups, the pediatric starting dose for this clinical study was linearly extrapolated from that derived from the pediatric PBPK model for a systemic exposure of 160 μg·h / mL (Figure 13).

[0318] Data from five cALD patients aged 5-12 years were used to validate the pediatric starting dose estimates with actual pediatric patient data (Table 3). Plasma concentrations observed after a single dose (baseline) or multiple doses (visit 2) were overlaid onto PBPK simulations using Upreti ontogeny for the corresponding age groups. The observed data points are successfully contained within the 95% confidence intervals (Figures 14, 15, and 16).

[0319] To further explore the PBPK model, individual Bayesian predictions of CL / F and AUC (derived as F × DOSE / CL) at steady state were obtained from observed concentration measurements in five pediatric patients using a leriglitazone population PK (popPK) model developed in adults and compared with corresponding parameters from the PBPK model across the age range of interest (see Supplementary Material for a brief description of the model). The Bayesian prediction parameters compare favorably with the PBPK simulations (Figures 17, 18, and 19).

[0320] conclusion A PBPK model was constructed to predict exposure and estimate starting doses across all pediatric age groups and validated by confirming that the predicted PK profiles were highly similar to the Phase 1 profiles. From the adult PBPK model, a pediatric PBPK model was developed using an extensive library of pediatric demographics, developmental physiology, and biochemistry. Johnson, TN et al., Drug Metab. Dispos. Biol. Fate Chem. 44, 1090-1098 (2016). The predictive value of the pediatric Simcyp model was evaluated for a number of drugs in neonates, infants, children, and adolescents. Johnson, TN et al., Paediatr. Anaesth. 21, 291-301 (2011). Neither PPARγ nor biliary clearance ontogeny functions were applied in pediatrics because of rapid maturation and the likelihood that adult activity is reached very quickly. Johnson, TN et al., Drug Metab. Dispos. Biol. Fate Chem. 44, 1090-1098 (2016); Beck, F. et al. Proc. Biol. Sci. 247, 83-87 (1992). In contrast, the metabolic rate f used to develop the adult model mCYP2C8 and f mCYP3A4These values ​​are important because these are the key enzymes responsible for leriglitazone metabolism. Human clinical drug-drug interaction (DDI) data are not yet available to quantitatively estimate the total fraction metabolized by each enzyme (fm), and fm CYP2C8 and fm CYP3A4The values ​​are based on the AUC-M3 to AUC-leriglitazone ratio and on in vitro studies using recombinant enzymes, which may present some limitations in the model. Kinetic parameters could not be calculated due to the lack of saturation of recombinant CYP3A4, but both approaches converged to similar fm values ​​and are acceptable as initial fm estimates for populations where differences in CYP ontogeny are not relevant. The fm values ​​used to develop the leriglitazone model in adults are important given the large differences in how the primary enzymes CYP2C8 and CYP3A4 evolve with age. For both the Simcyp default (Johnson, TN et al., Drug Metab. Dispos. Biol. Fate Chem. 44, 1090-1098 (2016)) and literature CYP ontogeny (Upreti, VV et al., J. Clin. Pharmacol. 56, 266-283 (2016)) profiles, the two enzymes are either fully developed (Simcyp) or parallel developed (Upreti) in pediatric subjects over 2 years of age, whereas their activities differ significantly in those under 2 years of age, suggesting that misassignment may be more important. Indeed, application of the Simcyp default ontogeny resulted in slightly lower predicted pediatric doses, particularly in those under 2 years of age, due to the assumption of lower CYP2C8 and CYP3A4 activity (Figures 1, 2, and 3). In contrast, application of allometric scaling resulted in overprediction of doses, evident in all age groups under 6 years of age. Therefore, the pediatric starting dose for the clinical study was selected based on the Upreti ontogeny theory, because it takes into account higher CYP activity and is a more conservative approach. Preliminary validation of this pediatric PBPK model was enabled by comparing simulations with data from five pediatric cALD patients, with very encouraging results. In addition, the Bayesian prediction parameters for five pediatric cALD patients using the popPK model favorably compared PBPK simulations and served as validation of the PBPK model for pediatric use.

[0321] This study demonstrates that leriglitazone, unlike other PPARγ agonists, exhibits PK appropriate for achieving CNS target exposure, making it a promising candidate for use in neurodegenerative and neuroinflammatory indications. The PBPK model will help gain understanding of the processes affecting leriglitazone PK, inform pediatric clinical development and starting doses, and support regulatory submissions and labeling, including DDIs.

[0322] Example 2 Population Pharmacokinetic Modeling of Leriglitazone HCl in Healthy Volunteers and Patients with Neurodegenerative Disorders Clinical studies included: MT-1-01 (healthy volunteers), MT-2-01 (adult males with adrenomyeloneuropathy (AMN)), and MT-2-03 (males and females aged 12 years or older with Friedreich's ataxia).

[0323] data A total of 2140 valid plasma concentration measurements from 130 individuals were used for analysis. Full PK profiles were available only from MT-1-01. In MT-2-03, only pre-dose (trough) concentrations were collected at multiple visits, while in MT-2-01, sparse post-dose samples were also collected. Less than 1% of all samples were below the limit of quantification.

[0324] method The following key steps were taken in the analysis:

[0325] 1. Exploratory graphical analysis of concentration-time and covariate data.

[0326] 2. Structural model development using only data from healthy volunteers (MT-1-01) and including important structural covariates (diet, weight).

[0327] 3. Re-estimation of parameters for the complete analysis dataset (MT-1-01, MT-2-01, MT-2-03). Completion of the base model.

[0328] 4. Stepwise automated covariate modeling (SCM) using the base model.

[0329] 5. Refine the final model to include significant covariates.

[0330] 6. Check the final model for suitability (visual prediction check).

[0331] 7. Simulation.

[0332] NONMEM v7.5 was used for population modeling. The RxODE package (v0.9.2) in R (v4.0.2) was used for simulations.

[0333] For covariate model development, a fixed allometric exponent of 0.75 was used for clearance and intercompartmental flow (Q), while a power exponent of 1.0 was used for the relationship between volume and body weight.

[0334] Stepwise automated covariate modeling (SCM) was applied to the base model of the full analysis dataset using a forward addition / backward elimination procedure as implemented in PsN, Karlsson and Savic, Clin Pharmacol Ther 82:17-20 (2008). To improve the computational time of SCM, PsN applies a Taylor transformation to generate a linear form of the model, to which the covariate function is then applied. Anderson et al., Annu Rev Pharmacol Toxicol 48:303-332 (2008). The final model from the SCM procedure was then converted back to its original, untransformed form.

[0335] The following covariates were tested in the model for their association with CL and relative bioavailability (F): BMI height age Ethnicity (Hispanic / Latin American yes / no) sex Laboratory variables: aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, albumin, creatine clearance (Cockcroft-Gault)

[0336] Initially, only covariate values ​​at baseline were tested. In case of significance and inclusion in the model, the model was re-run using time-varying covariate values.

[0337] For continuous covariates, linear or power functions were tested, as shown in the following equations:

number

[0338] where Pi is the parameter estimate for the i-th patient with a value of the covariate (COVARi) centered or median-scaled around the typical median of the covariate (MEDCOVAR), and θ is the slope (power exponent) of the parameter-covariate relationship.

[0339] Dichotomous categorical covariates were included as follows: P i =P TV ×(1+θ×CATCOVAR)

[0340] where θ is the coefficient of the parameter-covariate relationship. CATCOVAR takes a value of 0 or 1 for the state (absence / presence) of the covariate value in a particular individual.

[0341] Forward covariate selection was performed using a p-value of p<0.05 (χ2p=0.05, ν=1=3.84) as the inclusion criterion, followed by backward deletion using a p-value of p<0.01 (χ2p=0.01, ν=1=6.63) as the inclusion criterion.

[0342] The coefficient values ​​for AGE, SEX, BW, BMI, and FOOD in Formula I are model parameters that quantify and explain the variability of leriglitazone exposure in patients. They are estimated by fitting the model to clinical data using nonlinear mixed-effects modeling. See, for example, Mould and Upton, CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e6; doi:10.1038 / psp.2012.4; Mould and Upton, CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e38; doi:10.1038 / psp.2013.14; Mould and Upton, CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e88; doi:10.1038 / psp.2013.71.

[0343] result modeling A two-compartment model with first-order absorption and linear elimination provided a good fit to the available data. The typical absorption rate was fast (5.2 h) when leriglitazone was taken without food. -1 ), however, was reduced by 82.9% when taken with food. Furthermore, food reduced bioavailability by 4.8%. Body weight was included in the model as a covariate for clearance, intercompartmental flow, and volume terms by allometric scaling with a fixed power exponent.

[0344] Furthermore, significant covariates were identified in an automated covariate search, which included a stepwise forward search (significance criterion p<0.05) followed by a subsequent backward elimination step with more stringent criteria (p<0.01). Age was significantly associated with clearance (lower the younger the patient), as was gender (14.7% lower CL in women). Body mass index (BMI) was significantly correlated with (relative) bioavailability (higher values ​​with higher BMI). Figure 20 illustrates the effect of covariates on AUC. (MIN-102 refers to leriglitazone.)

[0345] simulation Simulations were performed comparing the concentration-time profiles predicted by the popPK model with predictions obtained from a previously developed physiologically based PK (PBPK) model (see Example 1). Both models produced comparable results.

[0346] In addition, the model was used to simulate concentration-time profiles in children between 5 and 12 years of age, and the predictions obtained closely matched actual observations obtained in the ongoing pediatric study MT-2-02 of patients affected by cerebral adrenoleukodystrophy (cALD).

[0347] conclusion The pharmacokinetics of leriglitazone were generally well-behaved, exhibiting rapid absorption (in the fasted state), low variability, dose-proportional exposure, and no nonlinearity in elimination over time. These favorable characteristics allowed the data to be described by a relatively simple two-compartment population PK model. No differences in PK were noted between patients (Friedreich's ataxia or AMN) and healthy volunteers, and estimation of model parameters in the combined data set was straightforward. The single most important factor affecting the shape of the PK profile (but not the AUC) was food. Taking leriglitazone in the fed state reduced the absorption rate by 82.9%, resulting in a lower and slower Cmax. However, the impact on bioavailability (and therefore the AUC) was minimal (<5%); therefore, specific dosing recommendations regarding the food state are not necessary.

[0348] Body weight was incorporated into the model as a factor influencing the clearance terms (CL and Q) and the volume terms (V1 and V2) according to the principle of allometric scaling. It is now well-recognized in clinical pharmacology that these parameters are typically scaled by body size, and allometric power exponents of 0.75 and 1.0 have been established for clearance and volume, respectively. Using these theoretical power exponents as fixed rather than estimated values ​​is particularly useful when using models for extrapolation to smaller individuals, i.e., children, who were not part of the analysis dataset. Patients in the active treatment group gained weight, but using actual weight rather than baseline weight at each visit did not provide any advantage in model fit. Weight gain is a known side effect of leriglitazone due to fluid retention in tissues, i.e., edema, and this change has little relevance to leriglitazone clearance unless it affects cardiac output or metabolic capacity in the liver.

[0349] Additional covariates were evaluated only for CL and F, in part because interindividual variability in central volume could not be adequately estimated, and also because the key PK parameter for clinical decision-making is the AUC, which is determined by CL and F. Automated covariate exploration revealed significant associations between F and BMI (higher F is associated with higher BMI), CL and age (younger patients have lower CL), and CL and sex (females have lower CL).

[0350] It should be noted that F is not a "clean" parameter; in the absence of venous data, its absolute value cannot be determined; only its variability relative to a typical value of 1 can be determined. Furthermore, bioavailability is a composite parameter that represents not only the fraction of drug absorbed from the intestine but also the fraction not eliminated during the first pass through the liver. Therefore, the relationship with BMI cannot be attributed to a specific physiological process and should be viewed as an empirical finding. For all practical purposes regarding dosing, it is the combination of CL and F (i.e., "oral" clearance or CL / F) that determines steady-state exposure.

[0351] The effect of age on CL, although significant, is somewhat limited and, considering the curvature of the power function, is more relevant at younger ages than at older ages. In the illustrated forest plot, the AUC can be 16% higher in 12-year-old children compared with a 38-year-old representative patient, with all other covariates, including weight and BMI, remaining equal. Simulations comparing model predictions with actual observations in children younger than 12 years (MT-2-02) showed that the effect of age may be less pronounced in children younger than 12 years. However, at this stage, comparisons were only performed in four patients between the ages of 5 and 12 years. Once all MT-2-02 PK data are available, model updates may clarify the actual relevance of this covariate. VI. Terminology [Table 11-1] [Table 11-2]

[0352] VII. Specific Embodiments The present disclosure also provides the following specific embodiments.

[0353] Embodiment 1. A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (leriglitazone) or a pharmaceutically acceptable salt thereof, wherein the initial dose (mg) of leriglitazone or a pharmaceutically acceptable salt thereof is a compound represented by Formula I:

number

[0354] SF is the salinity factor, SF is 0.7–0.9;

[0355] BW is the patient's weight (kg);

[0356] AGE is the patient's age (years);

[0357] SEX is the patient's sex, male is 1 and female is 2;

[0358] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0359] FOOD is the patient's dietary status, with fasting being 0 and feeding being 1;

[0360] BW coef is about 0.6 to about 0.9;

[0361] AGE coefis about 0.02 to about 0.2;

[0362] SEX coef is about 0.04 to about 0.25;

[0363] BMI coef is about 0.3 to about 0.8;

[0364] FOOD coef is about 0.02 to about 0.7;

[0365] AUC target is about 40 to about 265 μg / mL of leriglitazone) Determined in accordance with the method.

[0366] Embodiment 2. BW coef 2. The method of embodiment 1, wherein the ρ is 0.75.

[0367] Embodiment 3. AGE coef 3. The method of claim 1 or 2, wherein

[0368] Embodiment 4. SEX coef 4. The method of any one of embodiments 1 to 3, wherein is 0.147.

[0369] Embodiment 5. BMI coef 5. The method of any one of embodiments 1 to 4, wherein is 0.541.

[0370] Embodiment 6. FOOD coef 6. The method of any one of embodiments 1 to 5, wherein:

[0371] Embodiment 7. The method of any one of embodiments 1-6, wherein the disease or disorder is a CNS disease or disorder.

[0372] Embodiment 8 The method of any one of embodiments 1-6, wherein the disease or disorder is a pulmonary disease or disorder.

[0373] Embodiment 9. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the serotonin concentration is 100 to 135 μg.hr / mL.

[0374] Embodiment 10. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the serotonin concentration is 150±20% μg.hr / mL.

[0375] Embodiment 11. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the IL-10 concentration is 170±20% μg.hr / mL.

[0376] Embodiment 12. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the IL-10 is 190±20% μg.hr / mL.

[0377] Embodiment 13. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the serotonin concentration is 200±20% μg.hr / mL.

[0378] Embodiment 14. Target AUC target 9. The method of any one of embodiments 1 to 8, wherein the serotonin concentration is 220±20% μg.hr / mL.

[0379] Embodiment 15. The method of any one of embodiments 1 to 6, wherein the disease or disorder is a liver disease or disorder.

[0380] Embodiment 16. AUC target 16. The method of embodiment 15, wherein the saturation is 50±20% μg·hr / mL.

[0381] Embodiment 17. The method of any one of embodiments 1 to 11, wherein the patient is a pediatric patient.

[0382] Embodiment 18 The method of any one of embodiments 1-16, wherein the patient is an adult patient.

[0383] Embodiment 19 The method of any one of embodiments 1-18, wherein leriglitazone is administered.

[0384] Embodiment 20 The method of embodiments 1-18, wherein leriglitazone HCl is administered.

[0385] Embodiment 21. Leriglitazone or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a patient in need thereof, wherein the initial dose (mg) of leriglitazone or a pharmaceutically acceptable salt thereof is a compound represented by Formula I:

number

[0386] SF is the salinity factor, SF is 0.7–0.9;

[0387] BW is the patient's weight (kg);

[0388] AGE is the patient's age (years);

[0389] SEX is the patient's sex, male is 1 and female is 2;

[0390] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0391] FOOD is the patient's dietary status, with fasting being 0 and feeding being 1;

[0392] BW coef is about 0.6 to about 0.9;

[0393] AGE coef is about 0.02 to about 0.2;

[0394] SEX coef is about 0.04 to about 0.25;

[0395] BMI coef is about 0.3 to about 0.8;

[0396] FOOD coef is about 0.02 to about 0.7;

[0397] AUC target is about 40 to about 265 μg / mL of leriglitazone) Leriglitazone or a pharmaceutically acceptable salt thereof, as determined according to

[0398] Embodiment 22. BW coef 22. Leriglitazone or a pharmaceutically acceptable salt thereof according to embodiment 21, wherein

[0399] Embodiment 23. AGE coef 23. Leriglitazone or a pharmaceutically acceptable salt thereof according to embodiment 21 or 22, wherein

[0400] 24. SEX coef 24. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21-23, wherein R is 0.147.

[0401] Embodiment 25. BMI coef 25. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21-24, wherein R is 0.541.

[0402] Embodiment 26. FOOD coef =0.0477.

[0403] Embodiment 27. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 26, wherein the disease or disorder is a CNS disease or disorder.

[0404] Embodiment 28. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 26, wherein the disease or disorder is a pulmonary disease or disorder.

[0405] Embodiment 29. Target AUC target 29. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 28, wherein the IL-14 is 100 to 135 μg.hr / mL.

[0406] Embodiment 30. Target AUC target 9. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8, wherein the IL-10 is 150±20% μg.hr / mL.

[0407] Embodiment 31. Target AUC target 29. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 28, wherein the IL-10 is 170±20% μg.hr / mL.

[0408] Embodiment 32. Target AUC target 29. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 28, wherein the IL-10 is 190±20% μg.hr / mL.

[0409] Embodiment 33. Target AUC target 29. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 28, wherein the IL-10 is 200±20% μg.hr / mL.

[0410] Embodiment 34. Target AUC target 29. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 28, wherein the IL-10 is 220±20% μg.hr / mL.

[0411] Embodiment 35. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 26, wherein the disease or disorder is a liver disease or disorder.

[0412] Embodiment 36. AUCtarget is 50±20% μg·hr / mL.

[0413] Embodiment 37. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 31, wherein the patient is a pediatric patient.

[0414] Embodiment 38. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 36, wherein the patient is an adult patient.

[0415] Embodiment 39 Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 38, wherein SF is 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, or 0.9.

[0416] Embodiment 40. The method of any one of embodiments 1 to 18, wherein SF is 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, or 0.9.

[0417] Embodiment 41. A method of treating a disease or disorder in a patient in need thereof, comprising administering 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (leriglitazone) or 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione hydrochloride (leriglitazone HCl) to the patient, wherein the initial dose (mg) of leriglitazone or leriglitazone HCl is a compound of Formula I:

number

[0418] SF is the salt factor, SF is 0.74 when leriglitazone is administered and 0.81 when leriglitazone HCl is administered;

[0419] BW is the patient's weight (kg);

[0420] AGE is the patient's age (years);

[0421] SEX is the patient's sex, male is 1 and female is 2;

[0422] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0423] FOOD is the patient's dietary status, with fasting being 0 and feeding being 1;

[0424] BW coef is about 0.6 to about 0.9;

[0425] AGE coef is about 0.02 to about 0.2;

[0426] SEX coef is about 0.04 to about 0.25;

[0427] BMI coef is about 0.3 to about 0.8;

[0428] FOOD coef is about 0.02 to about 0.7;

[0429] AUC target is about 40 to about 265 μg / mL of leriglitazone) Determined in accordance with the method.

[0430] Embodiment 42. BW coef42. The method of embodiment 41, wherein the ρ is 0.75.

[0431] Embodiment 43. AGE coef 43. The method of embodiment 41 or 42, wherein R is 0.131.

[0432] Embodiment 44. SEX coef 44. The method of any one of embodiments 41 to 43, wherein is 0.147.

[0433] Embodiment 45. BMI coef 45. The method of any one of embodiments 41 to 44, wherein is 0.541.

[0434] Embodiment 46. FOOD coef 46. ​​The method of any one of embodiments 41 to 45, wherein:

[0435] Embodiment 47 The method of any one of embodiments 41 to 46, wherein the disease or disorder is a CNS disease or disorder.

[0436] Embodiment 48 The method of any one of embodiments 41-46, wherein the disease or disorder is a pulmonary disease or disorder.

[0437] Embodiment 49. Target AUC target The method of any one of embodiments 41 to 48, wherein the serotonin concentration is 100 to 135 μg.hr / mL.

[0438] Embodiment 50. Target AUC target The method of any one of embodiments 41 to 48, wherein the serotonin concentration is 150±20% μg.hr / mL.

[0439] Embodiment 51. Target AUC target The method of any one of embodiments 41 to 48, wherein the IL-10 is 170±20% μg.hr / mL.

[0440] Embodiment 52. Target AUC targetThe method of any one of embodiments 41 to 48, wherein the IL-10 is 190±20% μg.hr / mL.

[0441] Embodiment 53. Target AUC target The method of any one of embodiments 41 to 48, wherein the serotonin concentration is 200±20% μg.hr / mL.

[0442] Embodiment 54. Target AUC target The method of any one of embodiments 41 to 48, wherein the serotonin concentration is 220±20% μg.hr / mL.

[0443] Embodiment 55 The method of any one of embodiments 41-46, wherein the disease or disorder is a liver disease or disorder.

[0444] Embodiment 56. AUC target 56. The method of embodiment 55, wherein the saturation is 50±20% μg·hr / mL.

[0445] Embodiment 57 The method of any one of embodiments 41-51, wherein the patient is a pediatric patient.

[0446] Embodiment 58 The method of any one of embodiments 41 to 56, wherein the patient is an adult patient.

[0447] Embodiment 59 The method of any one of embodiments 41-58, wherein leriglitazone is administered.

[0448] Embodiment 60 The method of embodiments 41-59, wherein leriglitazone HCl is administered.

[0449] Embodiment 61. Leriglitazone or leriglitazone HCl for use in treating a disease or disorder in a patient in need thereof, wherein the initial dose (mg) of leriglitazone or leriglitazone HCl is a compound represented by Formula I:

number

[0450] SF is the salt factor, SF is 0.74 when leriglitazone is administered and 0.81 when leriglitazone HCl is administered;

[0451] BW is the patient's weight (kg);

[0452] AGE is the patient's age (years);

[0453] SEX is the patient's sex, male is 1 and female is 2;

[0454] BMI is the body mass index (kg / m) derived from the patient's BW and height. 2 ) and;

[0455] FOOD is the patient's dietary status, with fasting being 0 and feeding being 1;

[0456] BW coef is about 0.6 to about 0.9;

[0457] AGE coef is about 0.02 to about 0.2;

[0458] SEX coef is about 0.04 to about 0.25;

[0459] BMI coef is about 0.3 to about 0.8;

[0460] FOOD coef is about 0.02 to about 0.7;

[0461] AUC target is about 40 to about 265 μg / mL of leriglitazone) Leriglitazone or leriglitazone HCl, as determined according to

[0462] Embodiment 62. BW coefLeriglitazone or leriglitazone HCl according to embodiment 61, wherein

[0463] Embodiment 63. AGE coef Leriglitazone or leriglitazone HCl according to embodiment 61 or 62, wherein

[0464] 64. SEX coef 64. Leriglitazone or leriglitazone HCl according to any one of embodiments 61-63, wherein R is 0.147.

[0465] Embodiment 65. BMI coef 65. Leriglitazone or leriglitazone HCl according to any one of embodiments 61-64, wherein R is 0.541.

[0466] Embodiment 66. FOOD coef = 0.0477.

[0467] Embodiment 67. Leriglitazone or leriglitazone HCl according to any one of embodiments 61 to 66, wherein the disease or disorder is a CNS disease or disorder.

[0468] Embodiment 68. Leriglitazone or leriglitazone HCl according to any one of embodiments 61 to 66, wherein the disease or disorder is a pulmonary disease or disorder.

[0469] Embodiment 69. Target AUC target is between 100 and 135 μg.h / mL.

[0470] Embodiment 70. Target AUC target is 150±20% μg.hr / mL.

[0471] Embodiment 71. Target AUC target Leriglitazone or leriglitazone HCl according to any one of embodiments 61-68, wherein the IL-10 is 170±20% μg.hr / mL.

[0472] Embodiment 72. Target AUC target Leriglitazone or leriglitazone HCl according to any one of embodiments 61-68, wherein the IL-10 is 190±20% μg.hr / mL.

[0473] Embodiment 73. Target AUC target is 200±20% μg.hr / mL.

[0474] Embodiment 74. Target AUC target is 220±20% μg.hr / mL.

[0475] Embodiment 75. Leriglitazone or leriglitazone HCl according to any one of embodiments 61 to 66, wherein the disease or disorder is a liver disease or disorder.

[0476] Embodiment 76. AUC target is 50±20% μg·h / mL.

[0477] Embodiment 77. Leriglitazone or leriglitazone HCl according to any one of embodiments 21 to 31, wherein the patient is a pediatric patient.

[0478] Embodiment 78. Leriglitazone or leriglitazone HCl according to any one of embodiments 1 to 36, wherein the patient is an adult patient.

[0479] Embodiment 79. Leriglitazone or leriglitazone HCl according to any one of embodiments 21 to 38, wherein leriglitazone is administered.

[0480] Embodiment 80 Leriglitazone or leriglitazone HCl according to embodiments 21-38, wherein leriglitazone HCl is administered. VIII. References

[0481] 1. Rodriguez-Pascau, L. et al., Sci. Transl. Med. 13, eabc0555 (2021).

[0482] 2. Johnson, TN & Ke, AB, J. Clin. Pharmacol. 61 Suppl 1, S83-S93 (2021).

[0483] 3. Leong, R. et al., Clin. Pharmacol. Ther. 91, 926-931 (2012).

[0484] 4. Zhao, P. et al., Clin. Pharmacol. Ther. 89, 259-267 (2011).

[0485] 5. Upreti, VV & Wahlstrom, JL, J. Clin. Pharmacol. 56, 266-283 (2016).

[0486] 6. Howgate, EM, et al., Xenobiotica Fate Foreign Compd. Biol. Syst. 36, 473-497 (2006).

[0487] 7. Inoue, S. et al., Xenobiotica Fate Foreign Compd. Biol. Syst. 36, 499-513 (2006).

[0488] 8. Kusminski, CM et al., Diabetologia 50, 634-642 (2007).

[0489] 9. Miyazaki, Y. et al., J. Clin. Endocrinol. Metab. 89, 4312-4319 (2004).

[0490] 10. Qiu, D. & Li, X.-N., Int. J. Clin. Pharmacol. Ther. 53, 746-752 (2015).

[0491] 11. Dupuis, L. et al., PloS One 7, e37885 (2012).

[0492] 12. Kernan, WN et al., N. Engl. J. Med. 374, 1321-1331 (2016).

[0493] 13. Viscoli, CM et al., J. Clin. Endocrinol. Metab. 102, 914-922 (2016).

[0494] 14. Eckland, DA & Danhof, M., Exp. Clin. Endocrinol. Amp Diabetes 108, 234-242 (2000).

[0495] 15. Boris, M. et al., J. Neuroinflammation 4, 3 (2007).

[0496] 16. Capano, L. et al., Mol. Autism 9, 59 (2018).

[0497] 17. Ibanez, L. et al., J. Adolesc. Health Off. Publ. Soc. Adolesc. Med. 61, 446-453 (2017).

[0498] 18. Stabile, G. et al., J. Pediatr. Adolesc. Gynecol. 27, 177-182 (2014).

[0499] 19. Tafuri, KS et al., J. Clin. Res. Pediatr. Endocrinol. 5, 236-239 (2013).

[0500] 20. Christensen, ML et al., J. Clin. Pharmacol. 45, 1137-1144 (2005).

[0501] 21. Johnson, TN et al., Drug Metab. Dispos. Biol. Fate Chem. 44, 1090-1098 (2016).

[0502] 22. Johnson, TN & Rostami-Hodjegan, A., Paediatr. Anaesth. 21, 291-301 (2011).

[0503] 23. Beck, F. et al., Proc. Biol. Sci. 247, 83-87 (1992)

[0504] Now that the present disclosure has been fully described, it will be understood by those skilled in the art that the present disclosure can be practiced within a wide equivalent range of conditions, processes and other parameters without affecting the scope of the invention or any embodiment thereof.

[0505] Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0506] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (leriglitazone) or a pharmaceutically acceptable salt thereof, preferably the HCl salt, for use in treating a disease or disorder in a patient in need thereof, wherein the initial dose (mg) of leriglitazone or a pharmaceutically acceptable salt thereof is a compound represented by Formula I: [Equation 8] (In the formula, SF is 0.7 to 0.9; BW is the patient's weight (kg); AGE is the patient's age (in years); SEX is the sex of the patient, male is 1 and female is 2; BMI is the body mass index (kg / m) derived from the patient's BW and height. ２ ) and FOOD is the patient's eating state, fasting is 0 and fed is 1; BW ｃｏｅｆ is from about 0.6 to about 0.9; AGE ｃｏｅｆ is from about 0.02 to about 0.2; SEX ｃｏｅｆ is from about 0.04 to about 0.25; BMI ｃｏｅｆ is about 0.3 to about 0.8; FOOD ｃｏｅｆ is from about 0.02 to about 0.7; AUC ｔａｒｇｅｔ is about 40 to about 240 μg·hr / mL of leriglitazone Leriglitazone or a pharmaceutically acceptable salt thereof, as determined according to

2. BW ｃｏｅｆ 2. The method of claim 1, wherein Leriglitazone or a pharmaceutically acceptable salt thereof is 0.

75.

3. AGE ｃｏｅｆ 3. The method of claim 1, wherein Leriglitazone or a pharmaceutically acceptable salt thereof is 0.

131.

4. SEX ｃｏｅｆ 4. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R is 0.

147.

5. BMI ｃｏｅｆ 5. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R is 0.

541.

6. FOOD ｃｏｅｆ 6. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein:

7. the disease or disorder is a CNS disease or disorder or a pulmonary disease or disorder, and the AUC ｔａｒｇｅｔ 7. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the leriglitazone or pharmaceutically acceptable salt thereof has a vasoconstriction coefficient of 170±20% μg·hr / mL.

8. 8. The method of claim 7, wherein the patient is a pediatric patient.

9. the disease or disorder is a CNS disease or disorder or a pulmonary disease or disorder, the patient is an adult patient, and the AUC ｔａｒｇｅｔ 7. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the leriglitazone or pharmaceutically acceptable salt thereof has a vasoconstriction coefficient of 200±20% μg·hr / mL.

10. the disease or disorder is a liver disease or disorder, and the AUC ｔａｒｇｅｔ 7. The leriglitazone or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the leriglitazone or pharmaceutically acceptable salt thereof has a vasoconstriction coefficient of 50±20% μg·hr / mL.

11. 11. The method of claim 1, wherein the amount (mg) of leriglitazone or a pharmaceutically acceptable salt thereof administered to the patient as the initial dose is administered to the patient in subsequent doses for up to six weeks.

12. leriglitazone or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a patient in need thereof, wherein the AUC of leriglitazone is determined in said patient after a dose of leriglitazone or a pharmaceutically acceptable salt thereof; (i) if the AUC is less than 149 μg-hr / mL, a higher dose of leriglitazone or a pharmaceutically acceptable salt thereof is administered to the patient; (ii) if the AUC exceeds 191 μg-hr / mL, a lower dose of leriglitazone or a pharmaceutically acceptable salt thereof is administered to the patient; and (iii) if the AUC is between 150 and 190 μg hr / mL, the same dose of leriglitazone or a pharmaceutically acceptable salt thereof is administered to the patient; Leriglitazone or a pharmaceutically acceptable salt thereof, wherein the patient is a pediatric patient.

13. 1. Leriglitazone or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a patient in need thereof, (i) administering to said patient 10 mL of an oral suspension containing about 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof, preferably leriglitazone HCl per mL for 1 to 10 weeks; and (ii) 12 mL of an oral suspension containing about 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof, preferably leriglitazone HCl per mL, is administered to the patient after (i).

14. 14. The compound according to any one of claims 1 to 6 or 11 to 13, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disorder, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

15. 15. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 14, wherein the disease or disorder is a central nervous system disease or disorder.

16. 16. The leriglitazone or pharmaceutically acceptable salt thereof of any one of claims 7, 8, 9 or 15, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, stroke, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemias, fatty acid disorders, and genetic mitochondrial disorders.

17. 17. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 16, wherein the central nervous system disease or disorder is a neurodegenerative disease.

18. 18. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 17, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, amyotrophic lateral sclerosis (ALS), degenerative ataxia, multiple system atrophy, neurodegenerative and brain iron accumulation disorder (NBIA), neuromyopathy, and motor neuron disease.

19. 19. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 18, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

20. 20. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 19, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

21. 19. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 18, wherein the degenerative ataxia is Friedreich's ataxia.

22. 19. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 18, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barré syndrome, and adrenomyeloneuropathy (AMN).

23. 17. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 16, wherein the central nervous system disorder is a cerebrovascular disease selected from the group consisting of global or focal cerebral ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

24. 17. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 16, wherein the central nervous system disorder is a viral disease selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, poliomyelitis, herpes simplex, and varicella zoster.

25. 17. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 16, wherein the central nervous system disease or disorder is a rare metabolic disease selected from the group consisting of organic acidemias, fatty acid disorders, and inherited mitochondrial disorders.

26. 15. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 14, wherein the disease or disorder is a mitochondrial disease.

27. The mitochondrial diseases include Rett syndrome, Alpers disease; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh syndrome; Leigh-like syndrome; Maternally inherited Leigh syndrome (MILS); Mitochondrial depletion syndrome (MDS); Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalomyopathy; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); Myoclonic epilepsy with ragged fibers (MERRF); Mitochondrial neurogastrointestinal encephalopathy. Neuropathic syndrome (MNGIE); Neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; Chronic progressive external ophthalmoplegia (CPEO); Dominant optic atrophy (DOA); Autosomal dominant optic atrophy (ADOA); Mitochondrial myopathy; Cardiomyopathy; Mitochondrial encephalopathy; Myoclonic epilepsy; Maternally inherited diabetes and deafness (MIDD); Ataxia neuropathy spectrum; 3-methylglutaconic aciduria; Sensorineural hearing loss; Neuroradiological findings of Leigh-like syndrome (MEGDEL); SURF1 (Complex IV) COX-deficient Leigh syndrome due to surface protein deficiency; oxidative phosphorylation disorders; Barth syndrome; fatal infantile cardiomyopathy (LIC); pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutations; isolated or combined OXPHOS deficiency due to currently unresolved genetic defects involving disturbances in pyruvate oxidation and ATP+PCr production rates; POLG2 mutations; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatinine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; lactic acidosis; leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL); Luft disease; carnitine palmitoyltransferase (CPT I or CPT II) Deficiency; Short-chain acyl-CoA dehydrogenase deficiency (SCAD); Short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD); Medium-chain acyl-CoA dehydrogenase deficiency (MCAD); Multiple acyl-CoA dehydrogenase deficiency (MADD); Long-chain acyl-CoA dehydrogenase deficiency (LCAD); Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD);27. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 26, which is a primary mitochondrial disorder selected from the group consisting of trifunctional protein (TFP) deficiency; and glutaric aciduria type II.

28. 28. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 27, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome; dominant optic atrophy (DOA); autosomal dominant optic atrophy (ADOA); Complex I deficiency; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged fibers (MERRF); mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE); neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; and chronic progressive external ophthalmoplegia (CPEO).

29. The mitochondrial disease is selected from the group consisting of Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); myotonic dystrophy (BMD); congenital myopathies; glycogen storage disorders; spinal-bulbar muscular atrophy (SBMA); argininosuccinic aciduria; autism spectrum disorder (ASD); autoimmune diseases of the skin (e.g., pemphigus vulgaris and lupus); methylmalonic and propionic aciduria; disorders of purine and / or pyrimidine synthesis; facioscapulohumeral muscular dystrophy (FSHD); 28. The compound of claim 27, wherein the secondary mitochondrial disorder is selected from the group consisting of congenital muscular dystrophies; collagen VI muscular dystrophies (e.g., Ullrich congenital muscular dystrophy, Bethlem myopathy, distal oculopharyngeal and Emery-Dreyfus); DiGeorge syndrome; and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathies, Charcot-Marie-Tooth (CMT) neuropathy and drug-induced peripheral neuropathy).

30. 15. The leriglitazone or pharmaceutically acceptable salt thereof of claim 7, 8, 9, or 14, wherein the pulmonary disease or disorder is an inflammatory pulmonary condition or disease caused by a viral infection, acute inflammation of the lung, or an interstitial lung disease.

31. 31. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 30, for the treatment of an inflammatory pulmonary condition or disease caused by a viral infection in a patient in need thereof.

32. 32. The leriglitazone or a pharmaceutically acceptable salt thereof of claim 31 , wherein the viral infection is a human coronavirus infection, an influenza virus infection, or an HIV virus infection.

33. 33. The leriglitazone or a pharmaceutically acceptable salt thereof of claim 32, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant strain thereof.

34. 34. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 33, wherein the human coronavirus is SARS CoV-2.

35. 35. The leriglitazone or a pharmaceutically acceptable salt thereof of claim 34, wherein the human coronavirus is a mutant strain of SARS CoV 2.

36. 36. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 35, wherein the inflammatory pulmonary condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

37. 37. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 36, wherein the inflammatory pulmonary condition or disease caused by the viral infection is acute respiratory distress syndrome.

38. 31. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 30 for the treatment of acute pulmonary inflammation in a patient in need thereof.

39. 39. The method of claim 38, wherein the acute inflammation of the lung is caused by a bacterial infection.

40. 39. The leriglitazone or a pharmaceutically acceptable salt thereof of claim 38, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

41. 31. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 30 for the treatment of interstitial lung disease in a patient in need thereof.

42. 42. The leriglitazone or a pharmaceutically acceptable salt thereof of claim 41, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

43. 15. Leriglitazone or a pharmaceutically acceptable salt thereof according to claim 10 or 14, wherein the liver disease or disorder is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD).

44. 1. A method of treating a disease or disorder in a patient in need thereof, comprising the step of administering to said patient 5-[[4-[2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (leriglitazone) or a pharmaceutically acceptable salt thereof, wherein an initial dose (mg) of leriglitazone or a pharmaceutically acceptable salt thereof is a compound of Formula I: [Equation 9] (In the formula, SF is 0.7 to 0.9; BW is the patient's weight (kg); AGE is the patient's age (in years); SEX is the sex of the patient, male is 1 and female is 2; BMI is the body mass index (kg / m) derived from the patient's BW and height. ２ ) and FOOD is the patient's eating state, fasting is 0 and fed is 1; BW ｃｏｅｆ is from about 0.6 to about 0.9; AGE ｃｏｅｆ is from about 0.02 to about 0.2; SEX ｃｏｅｆ is from about 0.04 to about 0.25; BMI ｃｏｅｆ is about 0.3 to about 0.8; FOOD ｃｏｅｆ is from about 0.02 to about 0.7; AUC ｔａｒｇｅｔ is about 40 to about 240 μg·hr / mL of leriglitazone Determined in accordance with the method.

45. BW ｃｏｅｆ 45. The method of claim 44, wherein is 0.

75.

46. AGE ｃｏｅｆ 46. ​​The method of claim 44 or 45, wherein is 0.

131.

47. SEX ｃｏｅｆ 47. The method of any one of claims 44 to 46, wherein is 0.

147.

48. BMI ｃｏｅｆ The method of any one of claims 44 to 47, wherein is 0.

541.

49. FOOD ｃｏｅｆ 49. The method of any one of claims 44 to 48, wherein = 0.0477.

50. the disease or disorder is a CNS disease or disorder or a pulmonary disease or disorder, and the AUC ｔａｒｇｅｔ The method of any one of claims 44 to 49, wherein the IL-10 concentration is 170±20% μg h / mL.

51. 51. The method of claim 50, wherein the patient is a pediatric patient.

52. the disease or disorder is a CNS disease or disorder or a pulmonary disease or disorder, the patient is an adult patient, and the AUC ｔａｒｇｅｔ The method of any one of claims 44 to 49, wherein the IL-10 concentration is 200±20% μg h / mL.

53. the disease or disorder is a liver disease or disorder, and the AUC ｔａｒｇｅｔ The method of any one of claims 44 to 49, wherein the IL-10 concentration is 50±20% μg h / mL.

54. 54. The method of any one of claims 44 to 53, wherein the amount (mg) of leriglitazone or a pharmaceutically acceptable salt thereof administered to the patient as the initial dose is administered to the patient in subsequent doses for up to 6 weeks.

55. A method of treating a disease or disorder in a patient in need thereof, comprising determining the AUC of leriglitazone in the patient after a dose of leriglitazone or a pharmaceutically acceptable salt thereof; and (i) administering a higher dose of leriglitazone or a pharmaceutically acceptable salt thereof if the AUC is less than 149 μg-hr / mL; (ii) administering a lower dose of leriglitazone or a pharmaceutically acceptable salt thereof if the AUC is greater than 191 μg-hr / mL; and (iii) if the AUC is between 150 and 190 μg·hr / mL, administering the same dose of leriglitazone or a pharmaceutically acceptable salt thereof. Including, The method, wherein the patient is a pediatric patient.

56. 1. A method of treating a disease or disorder in a patient in need thereof, comprising: (i) administering to the patient 10 mL of an oral suspension containing about 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof per mL for 1 to 10 weeks; and (ii) administering to said patient after (i) 12 mL of an oral suspension containing 15 mg of leriglitazone or a pharmaceutically acceptable salt thereof per mL. A method comprising:

57. 57. The method of any one of claims 44-49 or 53-56, wherein the disease or disorder is a central nervous system disease or disorder, a mitochondrial disease, a liver disease or disorder, a chronic granulomatous disorder, polycystic ovary syndrome, thyroid cancer, a thyroid autoimmune disorder, a pituitary adenoma, atherosclerosis, hypertension, a skin disease, an inflammatory and autoimmune disease, an inflammatory respiratory disease, or a lung disease or disorder.

58. 58. The method of claim 57, wherein the disease or disorder is a central nervous system disease or disorder.

59. 59. The method of any one of claims 50, 51, 52 or 58, wherein the central nervous system disease or disorder is selected from the group consisting of neurodegenerative diseases, cerebrovascular diseases, stroke, epilepsy, viral diseases, neuroinflammatory diseases, brain tumors, organic acidemias, fatty acid disorders, and genetic mitochondrial disorders.

60. 60. The method of claim 59, wherein the central nervous system disease or disorder is a neurodegenerative disease.

61. 61. The method of claim 60, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, Parkinson's disease, multiple sclerosis, neuromyelitis optica, leukodystrophy, ALS, degenerative ataxia, multiple system atrophy, NBIA (neurodegenerative and brain iron accumulation disorder), neuromyopathy, and motor neuron disease.

62. 62. The method of claim 61, wherein the leukodystrophy is X-linked adrenoleukodystrophy, adrenomyeloneuropathy, cerebral adrenoleukodystrophy, or metachromatic leukodystrophy.

63. 63. The method of claim 62, wherein the leukodystrophy is cerebral adrenoleukodystrophy.

64. 62. The method of claim 61, wherein the degenerative ataxia is Friedreich's ataxia.

65. 62. The method of claim 61, wherein the motor neuron disease is selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillain-Barre syndrome, and adrenomyeloneuropathy (AMN).

66. 60. The method of claim 59, wherein the central nervous system disorder is a cerebrovascular disease selected from the group consisting of global or focal ischemia, intracerebral hemorrhage, stroke, and vascular dementia.

67. 60. The method of claim 59, wherein the central nervous system disorder is a viral disease selected from the group consisting of meningitis, encephalitis, rabies, measles, mumps, poliomyelitis, herpes simplex, and varicella zoster.

68. 60. The method of claim 59, wherein the central nervous system disease or disorder is a rare metabolic disease selected from the group consisting of organic acidemias, fatty acid disorders, and inherited mitochondrial disorders.

69. 58. The method of claim 57, wherein the disease or disorder is a mitochondrial disease.

70. The mitochondrial diseases include Rett syndrome, Alpers disease; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh syndrome; Leigh-like syndrome; Maternally inherited Leigh syndrome (MILS); Mitochondrial depletion syndrome (MDS); Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalomyopathy; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); Myoclonic epilepsy with ragged fibers (MERRF); Mitochondrial neurogastrointestinal encephalopathy. Neuropathic syndrome (MNGIE); Neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; Chronic progressive external ophthalmoplegia (CPEO); Dominant optic atrophy (DOA); Autosomal dominant optic atrophy (ADOA); Mitochondrial myopathy; Cardiomyopathy; Mitochondrial encephalopathy; Myoclonic epilepsy; Maternally inherited diabetes and deafness (MIDD); Ataxia neuropathy spectrum; 3-methylglutaconic aciduria; Sensorineural hearing loss; Neuroradiological findings of Leigh-like syndrome (MEGDEL); SURF1 (Complex IV) COX-deficient Leigh syndrome due to surface protein deficiency; oxidative phosphorylation disorders; Barth syndrome; fatal infantile cardiomyopathy (LIC); pyruvate carboxylase deficiency; pyruvate dehydrogenase deficiency; POLG mutations; isolated or combined OXPHOS deficiency due to currently unresolved genetic defects involving disturbances in pyruvate oxidation and ATP+PCr production rates; POLG2 mutations; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatinine deficiency syndrome; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; lactic acidosis; leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL); Luft disease; carnitine palmitoyltransferase (CPT I or CPT II) Deficiency; Short-chain acyl-CoA dehydrogenase deficiency (SCAD); Short-chain 3-hydroxyacetyl-CoA dehydrogenase deficiency (SCHAD); Medium-chain acyl-CoA dehydrogenase deficiency (MCAD); Multiple acyl-CoA dehydrogenase deficiency (MADD); Long-chain acyl-CoA dehydrogenase deficiency (LCAD); Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD);70. The method of claim 69, wherein the primary mitochondrial disorder is selected from the group consisting of trifunctional protein (TFP) deficiency; and glutaric aciduria type II.

71. 71. The method of claim 70, wherein the mitochondrial disease is selected from the group consisting of Rett syndrome; dominant optic atrophy (DOA); autosomal dominant optic atrophy (ADOA); Complex I deficiency; Leber's hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh's syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy with ragged fibers (MERRF); mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE); neuropathy, ataxia and retinitis pigmentosa (NARP); Pearson syndrome; and chronic progressive external ophthalmoplegia (CPEO).

72. The mitochondrial disease is selected from the group consisting of Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); myotonic dystrophy (BMD); congenital myopathies; glycogen storage disorders; spinal-bulbar muscular atrophy (SBMA); argininosuccinic aciduria; autism spectrum disorder (ASD); autoimmune diseases of the skin (e.g., pemphigus vulgaris and lupus); methylmalonic and propionic aciduria; disorders of purine and / or pyrimidine synthesis; facioscapulohumeral muscular dystrophy.

71. The method of claim 70, wherein the secondary mitochondrial disorder is selected from the group consisting of: FSHD; congenital muscular dystrophies; collagen VI muscular dystrophies (e.g., Ullrich congenital muscular dystrophy, Bethlem myopathy, distal oculopharyngeal and Emery-Dreyfus); DiGeorge syndrome; and neuromuscular disorders (e.g., limb-girdle muscular dystrophy, inflammatory myopathies, Charcot-Marie-Tooth (CMT) neuropathy and drug-induced peripheral neuropathy).

73. 58. The method of any one of claims 50, 51, 52, or 57, wherein the lung disease or disorder is an inflammatory lung condition or disease caused by a viral infection, acute inflammation of the lung, or an interstitial lung disease.

74. 74. The method of claim 73 for treating an inflammatory pulmonary condition or disease caused by a viral infection in a patient in need thereof.

75. 75. The method of claim 74, wherein the viral infection is a human coronavirus infection, an influenza virus infection, or an HIV virus infection.

76. 76. The method of claim 75, wherein the human coronavirus is HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, or SARS CoV-2, or a mutant strain thereof.

77. 77. The method of claim 76, wherein the human coronavirus is SARS CoV-2.

78. 78. The method of claim 77, wherein the human coronavirus is a mutant strain of SARS CoV 2.

79. 79. The method of any one of claims 74 to 78, wherein the inflammatory pulmonary condition or disease caused by the viral infection is hypercytokinemia, hemophagocytic lymphohistiocytosis, pneumonia, acute respiratory distress syndrome, or systemic inflammatory response syndrome.

80. 80. The method of claim 79, wherein the inflammatory pulmonary condition or disease caused by the viral infection is acute respiratory distress syndrome.

81. 74. The method of claim 73 for treating acute inflammation of the lung in a patient in need thereof.

82. 82. The method of claim 81, wherein the acute inflammation of the lung is caused by a bacterial infection.

83. 84. The method of claim 83, wherein the acute inflammation of the lung is pneumonia or acute respiratory distress syndrome.

84. 74. The method of claim 73 for treating interstitial lung disease in a patient in need thereof.

85. 84. The method of claim 83, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

86. 58. The method of claim 53 or 57, wherein the liver disease or disorder is nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).

87. 44. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein said leriglitazone or a pharmaceutically acceptable salt thereof is leriglitazone HCl.

88. 44. Leriglitazone or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 or 14 to 43, wherein the leriglitazone or a pharmaceutically acceptable salt thereof is leriglitazone HCl and has an SF of 0.

81.

89. 87. The method of any one of claims 44 to 86, wherein leriglitazone HCl is administered to the patient.

90. 90. The method of any one of claims 44-54, 57-86, or 89, wherein SF is 0.81.

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