CN116234555A

CN116234555A - Modified release formulations of trimetazidine in modified form

Info

Publication number: CN116234555A
Application number: CN202180051890.7A
Authority: CN
Inventors: A·D·莱文; J·帕特尔; G·慕尼; S·赫比格
Original assignee: Ambria Pharmaceutical
Current assignee: Ambria Pharmaceutical
Priority date: 2020-06-30
Filing date: 2021-06-28
Publication date: 2023-06-06
Also published as: KR20230028535A; AU2021299197A1; IL299544A; WO2022005926A1; JP2023531802A; CA3187827A1; EP4171232A1

Abstract

The present invention provides pharmaceutical compositions comprising modified release formulations of trimetazidine (e.g., CV-8972) in modified form. The composition comprises an erodable polymer, such as hydroxypropyl methylcellulose (HPMC), which allows for sustained release of the modified form of trimetazidine and its metabolites in the body. The invention also provides methods of using such compositions in the treatment of conditions including angina and heart failure.

Description

Modified release formulations of trimetazidine in modified form

Cross Reference to Related Applications

The present application claims the benefit and priority of U.S. provisional patent application No. 63/046,115 filed on

month

6 and 30 of 2020, U.S. provisional patent application No. 63/046,117 filed on

month

6 and 30 of 2020, U.S. provisional patent application No. 63/183,294 filed on

month

5 and 3 of 2021, and U.S. provisional patent application No. 63/183,299 filed on

month

5 and 3 of 2021, each of which is incorporated herein by reference.

Technical Field

The present invention relates to pharmaceutical compositions containing modified release formulations of trimetazidine (trimetazidine) in modified form, and the use of such compositions in the treatment of medical conditions, including angina and heart failure.

Background

Heart disease is the leading cause of death worldwide, with 1500 tens of thousands dying from heart disease worldwide in 2015. In many forms of heart disease, reduced cardiac efficiency results from changes in mitochondrial energy metabolism. Mitochondria are subcellular compartments in which metabolites from glucose and fatty acids are oxidized to produce high energy molecules. Increasing fatty acid oxidation in the heart may reduce glucose oxidation and vice versa. Glucose oxidation is a more efficient energy source, but in certain types of heart diseases, such as angina, heart failure, ischemic heart disease, and diabetic cardiomyopathy, fatty acid oxidation predominates in cardiac mitochondria. As a result, the pumping capacity of the heart is reduced.

Disclosure of Invention

CV-8972 (U.S. Pat. No. 10,556,013, the contents of which are incorporated herein by reference in their entirety) -improved forms of trimetazidine-have recently been identified as promising therapeutic candidates for cardiovascular diseases. CV-8972 has the IUPAC name 2- [4- [ (2, 3, 4-trimethoxyphenyl) methyl ] piperazin-1-yl ] ethylpyridine-3-carboxylate and the following structure:

without being limited to any particular theory or mechanism of action, it is believed that when CV-8972 is provided to humans, CV-8972 is in turn broken down into a number of specific biologically active metabolites. CV-8972 was initially decomposed into niacin and a modified form of trimetazidine, which was also identified as CV-8814 in U.S. Pat. No. 10,556,013, having the following structure:

CV-8814 is then converted to trimetazidine in vivo. Notably, both trimetazidine and CV-8814 promote glucose oxidation by blocking 3-keto acyl-CoA thiolase, and thus both are Active Pharmaceutical Ingredients (APIs). Thus, CV-8972 is metabolized in vivo into individual components that exert different biochemical actions to promote glucose oxidation and improve overall mitochondrial respiration in the heart. Because CV-8972 produces different metabolites that act synergistically, CV-8972 is useful as a therapeutic agent in the treatment of heart conditions characterized by elevated fatty acid oxidation. CV-8814 and trimetazidine produced by CV-8972 shift cardiac metabolism from fatty acid oxidation to glucose oxidation to allow the use of more efficient energy sources. Nicotinic acid produced by CV-8972 stimulates the oxidative common metabolic pathways of both glucose and fatty acids, which may also be impaired in patients with heart disease.

The present invention recognizes that CV-8972 rapidly breaks down in vivo into niacin and CV-8814. The present invention also recognizes that a significant amount of niacin in the body may produce certain side effects, such as flushing. The present invention further recognizes that formulations that slow and/or control the breakdown of CV-8972 into niacin and CV-8814 will provide the benefit of reducing or eliminating any niacin side effects (e.g., flushing) while also extending the efficacy of single dose CV-8972, resulting in a reduced frequency of administration.

In this way, the present invention provides a modified release formulation of CV-8972 that promotes the progressive metabolism of CV-8972 in the digestive tract. The modified release formulations of the present invention have improved therapeutic properties because they result in a less acute and more prolonged increase in the pharmacologically active product of CV-8972 in the circulation. Thus, the formulations provided herein greatly increase the utility of this promising new drug candidate.

The compositions of the present invention comprise a mixture comprising a modified form of trimetazidine, such as CV-8972, and an erodable polymer, such as hydroxypropyl methylcellulose (HPMC). When such compositions are orally administered to a subject, the mixture absorbs water in the digestive tract and the polymer gradually breaks down. Thus, two or more hours after administration of the composition, the maximum level of active pharmaceutical ingredient in the subject's plasma is reached and the peak level is about 50% lower than that produced by a conventional formulation containing the same dose of therapeutic agent. Thus, the compositions of the present invention provide for compositions wherein metabolites of CV-8972 or other modified forms of trimetazidine are maintained in vivo above therapeutic thresholds for extended periods of time while alleviating side effects caused by high peak levels. The invention further provides methods of treating a heart condition by providing the compositions described herein.

The pharmaceutical compositions of the invention are useful for treating any condition that can be ameliorated by improving cardiac mitochondrial function. In particular, the compositions are useful for treating cardiovascular conditions such as angina and heart failure. The composition can be readily administered orally, for example as a tablet or capsule. Furthermore, due to the sustained release of the therapeutic agent, the composition need only be taken once or twice a day.

In one aspect, the invention provides a pharmaceutical composition comprising a mixture comprising a modified form of trimetazidine and an erodable polymer that promotes swelling of the mixture in an aqueous environment.

The modified form of trimetazidine can be any compound that is structurally related to trimetazidine, has a similar biochemical function as trimetazidine, or is metabolized in the body to produce trimetazidine. The modified form of trimetazidine can have the structure of one of formulas (IX) and (X):

the erodable polymer may be any biocompatible polymer that breaks down in vivo and promotes swelling of the mixture containing the modified form of trimetazidine. The polymer may be biodegradable. The polymer may be hydrophilic. The polymer may promote the formation of hydrogels. The polymer may be a cellulose derivative. The polymer may be methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethylcellulose or sodium carboxymethylcellulose.

The mixture may contain HPMC in various polymer forms. The different polymeric forms of HPMC may differ in one or more properties. The different polymeric forms of HPMC may differ in one or more of viscosity, degree of methoxy substitution, degree of hydroxypropoxy substitution, and average molecular weight.

Each polymeric form of HPMC may independently have a defined viscosity. For a 2% aqueous solution in polymeric form at 20 ℃ the viscosity can be from about 2cP to about 4cP, from about 4cP to about 6cP, from about 5cP to about 8cP, from about 12cP to about 18cP, from about 40cP to about 60cP, from about 80cP to about 120cP, from about 300cP to about 500cP, from about 1200cP to about 2400cP, from about 2500cP to about 5000cP, from about 9000cP to about 18,000cP, from about 12,000cP to about 24,000cP, from about 75,000cP to about 150,000cP, at least about 2cP, at least about 4cP, at least about 5cP, at least about 12cP, at least about 40cP, at least about 80cP, at least about 300cP, at least about 1200cP, at least about 2500cP, at least about 9000cP, at least about 12,000cP, at least about 75,000cP, less than about 4cP, less than about 6, less than about 8cP, less than about 18cP, less than about 60, less than about 2400,000 cP, less than about 24,000cP, less than about 150,000cP.

Each polymeric form of HPMC may independently have a defined degree of methoxy substitution. The degree of methoxy substitution may be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, or from about 28% to about 32%.

Each polymeric form of HPMC may independently have a defined degree of hydroxypropoxyl substitution. The degree of hydroxypropoxy substitution may be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.

Each polymeric form of HPMC may independently have a defined average molecular weight. The average molecular weight may be about 10kDa, about 13kDa, about 20kDa, about 26kDa, about 41kDa, about 63kDa, about 86kDa, about 110kDa, about 120kDa, about 140kDa, about 180kDa or about 220kDa.

A mixture containing HPMC in multiple polymer forms may contain a limited amount of one polymer form. HPMC may contain about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of a polymeric form.

The mixture may contain a defined amount of the modified form of trimetazidine. The mixture may contain at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight of the modified form of trimetazidine.

The pharmaceutical composition may be formulated for a particular route of administration. The medicament may be formulated for oral, enteral, intravenous or rectal administration.

The pharmaceutical composition may be formulated as a unit dose containing a defined amount of the modified form of trimetazidine. The unit dose may contain modified forms of trimetazidine from about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, about 200mg, about 500mg, about 5mg to about 10mg, about 5mg to about 20mg, about 5mg to about 50mg, about 5mg to about 100mg, about 5mg to about 200mg, about 5mg to about 500mg, about 10mg to about 20mg, about 10mg to about 50mg, about 10mg to about 100mg, about 10mg to about 200mg, about 10mg to about 500mg, about 20mg to about 50mg, about 20mg to about 100mg, about 20mg to about 200mg, about 20mg to about 500mg, about 50mg to about 100mg, about 50mg to about 200mg, about 50mg to about 500mg, about 100mg to about 200mg, about 100mg to about 500mg, or about 200mg to about 500 mg.

The pharmaceutical composition may be formulated such that a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject is reached within a defined time interval after the pharmaceutical composition is provided to the subject.

The metabolite of the modified form of trimetazidine can be any compound that is produced when the modified form of trimetazidine is metabolized in the body. The metabolite of the modified form of trimetazidine may be a compound of formula (IX), trimetazidine, niacin, niacinamide or niacinamide ribose.

The time interval between the time at which the composition is provided to the subject and the time at which the maximum level of trimetazidine or a metabolite of the improved form of trimetazidine in the sample from the subject is reached may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, about 1 hour to about 8 hours, about 2 hours to about 8 hours, about 3 hours to about 8 hours, about 4 hours to about 8 hours, about 1 hour to about 7 hours, about 2 hours to about 7 hours, about 3 hours to about 7 hours, about 4 hours to about 7 hours, about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 5 hours, about 2 hours to about 5 hours, about 5 hours to about 5 hours, or about 5 hours.

The sample in which the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is measured may be any fluid-containing sample from a subject. The sample may be a plasma sample, a blood sample, a serum sample, a saliva sample, a urine sample, a sputum sample, a mucus sample, a stool sample, or a stomach sample.

The pharmaceutical composition may be formulated such that when the composition is provided to a subject, the time interval between a first time point at which a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is reached in a sample from the subject and a second time point at which a half maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is reached in a sample from the subject is defined.

The time interval between the point at which the maximum level of trimetazidine or the metabolite of the improved form of trimetazidine in the sample from the subject is reached and the point at which the half maximum level of trimetazidine or the metabolite of the improved form of trimetazidine in the sample from the subject is reached may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, about 1 hour to about 8 hours, about 2 hours to about 8 hours, about 3 hours to about 8 hours, about 4 hours to about 8 hours, about 1 hour to about 7 hours, about 2 hours to about 7 hours, about 3 hours to about 7 hours, about 4 hours to about 7 hours, about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, about 6 hours to about 4 hours, about 4 hours to about 5 hours, or about 5 hours.

The pharmaceutical composition may be formulated such that when the composition is provided to a subject, the maximum level of trimetazidine in modified form or a metabolite of trimetazidine in modified form in a sample from the subject does not exceed a defined value.

The maximum level of trimetazidine in the modified form or the metabolite of trimetazidine in the modified form in a sample from a subject can be less than about 6 μg/mL, less than about 5 μg/mL, less than about 4 μg/mL, less than about 3 μg/mL, less than about 2 μg/mL, or less than about 1 μg/mL.

In another aspect, the invention provides a pharmaceutical composition comprising a mixture of trimetazidine and hydroxypropyl methylcellulose (HPMC) in a defined weight ratio in modified form.

The mixture may contain a weight ratio of about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 3:2, about 2:1, about 3:1, about 4:1, about 5:1, about 1:100 to about 100:1, about 1:100 to about 50:1, about 1:100 to about 20:1, about 1:100 to about 10:1, about 1:100 to about 5:1, about 1:100 to about 2:1, about 1:50 to about 100:1, about 1:50 to about 50:1, about 1:50 to about 20:1, about 1:50 to about 10:1, about 1:50 to about 5:1, about 1:50 to about 2:1, about 1:20 to about 100:1, about 1:20 to about 50:1, about 1:20 to about 20:1: modified forms of trimetazidine and HPMC from about 1:20 to about 10:1, from about 1:20 to about 5:1, from about 1:20 to about 2:1, from about 1:10 to about 100:1, from about 1:10 to about 50:1, from about 1:10 to about 20:1, from about 1:10 to about 10:1, from about 1:10 to about 5:1, from about 1:10 to about 2:1, from about 1:5 to about 100:1, from about 1:5 to about 50:1, from about 1:5 to about 20:1, from about 1:5 to about 10:1, from about 1:5 to about 5:1, from about 1:5 to about 2:1, from about 1:3 to about 100:1, from about 1:3 to about 50:1, from about 1:3 to about 20:1, from about 1:3 to about 10:1, from about 1:3 to about 5:1, or from about 1:3 to about 2:1.

The modified form of trimetazidine can be any compound structurally related to trimetazidine, such as any of those described above.

Each polymeric form of HPMC may independently have a defined viscosity, degree of methoxy substitution, degree of hydroxypropoxy substitution, or average molecular weight, as any of the values of those parameters above.

The mixture containing HPMC in a plurality of polymeric forms may contain a defined amount of one polymeric form, such as any of the above amounts.

The mixture may contain a defined amount of the modified form of trimetazidine, such as any of the above amounts.

The pharmaceutical composition may be formulated as a unit dose containing a defined amount of the modified form of trimetazidine, such as any of the above amounts.

The pharmaceutical composition may be formulated such that a maximum level of trimetazidine, or a metabolite of the modified form of trimetazidine, in a sample from the subject is reached within a defined time interval after providing the pharmaceutical composition to the subject.

The metabolite of trimetazidine in modified form can be any of the above-mentioned compounds.

The time interval between the time at which the composition is provided to the subject and the time at which the maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is reached in the sample from the subject may be any of the time intervals described above.

The sample in which the modified form of trimetazidine is measured may be any of the samples described above.

The time interval between the point at which the maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is reached in the sample from the subject and the point at which the half maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is reached in the sample from the subject may be any of the time intervals described above.

The maximum level of trimetazidine in the modified form or a metabolite of trimetazidine in the modified form in a sample from a subject can be any of the above values.

In another aspect, the invention provides a method of treating a disease, disorder, condition in a subject by providing to the subject a pharmaceutical composition comprising a mixture comprising a modified form of trimetazidine and an erodable polymer that promotes swelling of the mixture in an aqueous environment.

The erodable polymer may be any biocompatible polymer that promotes swelling of the mixture containing the modified form of trimetazidine. The polymer may be biodegradable. The polymer may be hydrophilic. The polymer may promote the formation of hydrogels. The polymer may be a cellulose derivative. The polymer may be methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethylcellulose or sodium carboxymethylcellulose.

The pharmaceutical composition may be provided to the subject by a particular route of administration. The medicament may be provided to the subject orally, enterally, intravenously or rectally.

The method can produce a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject within a defined time interval after the pharmaceutical composition is provided to the subject.

The method may produce a defined time interval between a first time point at which a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is reached in a sample from the subject and a second time point at which a half maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is reached in a sample from the subject.

The time interval between the point at which the maximum level of trimetazidine or the metabolite of the improved form of trimetazidine in the sample from the subject is reached and the point at which the half maximum level of trimetazidine in the sample from the subject is reached may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, about 1 hour to about 8 hours, about 2 hours to about 8 hours, about 3 hours to about 8 hours, about 4 hours to about 8 hours, about 1 hour to about 7 hours, about 2 hours to about 7 hours, about 3 hours to about 7 hours, about 4 hours to about 7 hours, about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 6 hours to about 1 hour, about 1 hour to about 5 hours, about 5 hours or about 5 hours.

The method can produce in a sample from the subject a maximum level of trimetazidine in a modified form or a metabolite of trimetazidine in a modified form that does not exceed a defined value.

The disease, disorder or condition may be any condition that can be ameliorated by improving cardiac mitochondrial function. The disease, disorder or condition may be a cardiovascular condition. The disease, disorder or condition may be an aneurysm, angina, atherosclerosis, cardiomyopathy, cerebrovascular disease, congenital heart disease, coronary Artery Disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart failure, hypertension (high blood pressure), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.

In another aspect, the invention provides a method of treating a disease, disorder, condition in a subject by providing to the subject a pharmaceutical composition comprising a mixture comprising a modified form of trimetazidine and hydroxypropyl methylcellulose (HPMC), wherein the mixture comprises a defined weight ratio of the modified form of trimetazidine and HPMC.

The mixture may contain a modified form of trimetazidine and HPMC in one of the above ratios.

The disease, disorder or condition may be any condition that can be ameliorated by improving cardiac mitochondrial function, such as any of those described above.

Drawings

FIG. 1 is a schematic representation of the hydrolytic and metabolic pathways of CV-8972.

FIG. 2 is a graph of the water solubility of CV-8972 as a function of pH due to instability via a dynamic process.

FIG. 3 is a process flow diagram for manufacturing a CV-8972 prototype dry compressed MR tablet formulation.

Fig. 4 is a process flow diagram for manufacturing an MR tablet formulation for pilot scale batches of CV-8972 200 and 50mg wet granulation.

FIG. 5 is a graph showing the dissolution profile of 50mg and 200mg 4 hours of modified release hydrogel tablets in 0.1M HCl pH1.0 at 37 ℃.

FIG. 6 is a graph showing the dissolution profile of 50mg and 200mg 8 hours modified release hydrogel tablets in 0.1M HCl pH1.0 at 37 ℃.

FIG. 7 is a graph showing the dissolution profile of 200mg 8 hours modified release hydrogel tablets at 37℃after storage under specified conditions in 0.1M HCl pH 1.0.

Figure 8 is a graph showing plasma levels of CV-8814 in dogs following oral administration of 200mg (free base equivalent) of CV-8972 under fasted conditions.

FIG. 9 is a graph showing simulated combined plasma levels of CV-8814 and trimetazidine predicted in humans after oral administration of 200mg IMB-1018972MR tablets as 8 hour release tablets under MAD administration (QD and BID) and fed conditions.

FIG. 10 is a table of treatment of subjects of FIH study of IMB-1018972.

FIG. 11 is a table of the evaluation given in the single dose MR section of the FIH study for IMB-1018972.

FIG. 12 is a table of the evaluations given in the multi-dose MR section of the FIH study for IMB-1018972.

FIG. 13 is a table of analytical data sets for single dose MR fractions of FIH studies of IMB-1018972.

FIG. 14 is a table of analytical data sets for the multi-dose MR portion of the FIH study of IMB-1018972.

Figure 15 is a summary table of the demographics of the FIH study of IMB-1018972-single dose MR section (safety set).

Fig. 16 is a summary table of the demographic characteristics of the FIH study of IMB-1018972-multi-dose MR section (safety set).

FIG. 17 is a table of exposure levels of FIH studies of IMB-1018972 versus single dose MR fraction (safety margin).

FIG. 18 is a table of exposure levels-multi-dose MR fraction (safety collections) of FIH studies of IMB-1018972.

FIG. 19 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (linear) -single dose MR fraction (PK pool) of FIH studies of IMB-1018972.

FIG. 20 is a graph of the geometric mean IMB-1028814 plasma concentration versus time profile (semi-log scale) -single dose MR fraction (PK pool) of the FIH study of IMB-1018972.

FIG. 21 is a graph of the geometric mean trimetazidine plasma concentration versus time profile (linear) -single dose MR fraction (PK pool) of FIH studies of IMB-1018972.

FIG. 22 is a graph of the geometric mean trimetazidine plasma concentration versus time profile (semilog scale) -single dose MR fraction (PK pool) of the FIH study of IMB-1018972.

FIG. 23 is a graph of the geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (linear) -single dose MR fraction (PK pool) of FIH studies of IMB-1018972.

FIG. 24 is a graph of the geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (semi-log scale) -single dose MR fraction (PK pool) of FIH studies of IMB-1018972.

FIG. 25 is a table of aggregate statistical geometric mean [ range ] of the pharmacokinetic parameters of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine plasma versus single dose MR fraction (PK pool) of FIH study of IMB-1018972.

FIG. 26 is a table of exploratory analysis-single dose MR fractions (PK collections) of food effects of IMB-1028814 and trimetazidine after administration of 200mg of 8 hour MR IMB-1018972 for FIH study of IMB-1018972.

FIG. 27 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 28 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 through day 5 of FIH study of IMB-1018972.

FIG. 29 is a graph of geometric mean trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 through day 5 of FIH study of IMB-1018972.

FIG. 30 is a graph of geometric mean trimetazidine plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 31 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 through day 5 of FIH study of IMB-1018972.

FIG. 32 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 33 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 34 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 35 is a graph of geometric mean trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 36 is a graph of geometric mean trimetazidine plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 37 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 38 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5 of FIH study of IMB-1018972.

FIG. 39 is a table of aggregate statistical geometric mean [ range ] of the pharmacokinetic parameters of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine plasma versus the multi-dose MR fraction (PK pool) of FIH study of IMB-1018972.

FIGS. 40A and 40B are tabular summaries of all TEAE-single dose MR parts (safety collections) of FIH studies of IMB-1018972 by systemic organ category, preferred terminology and treatment.

FIG. 41 is a tabular summary of all TEAE-single dose MR parts (safety collections) of FIH studies of IMB-1018972 by system organ category, preference terminology and treatment.

FIG. 42 is a tabular summary of all TEAE-single dose MR fractions (safety collections) by treatment, relationship and severity of FIH study of IMB-1018972.

FIG. 43 is a tabular summary of all TEAE-multi-dose MR fractions (safety collections) by treatment, relationship and severity of FIH study of IMB-1018972.

Detailed Description

The present invention provides pharmaceutical compositions comprising a mixture of a modified form of trimetazidine, such as CV-8972, and an erodable polymer, such as hydroxypropyl methylcellulose (HPMC). When the composition is in an aqueous environment, such as the Gastrointestinal (GI) tract, the polymer absorbs moisture to promote swelling of the mixture. In addition, the polymer gradually disintegrates in an aqueous environment to achieve a controlled release of the modified form of trimetazidine, which then disintegrates into niacin and CV-8814 in a controlled manner, thereby providing a controlled and modified release of niacin into the body. Thus, when the composition is orally administered to a subject, the level of Active Pharmaceutical Ingredient (API) in the blood exhibits both lower peaks and longer durations above the minimum therapeutic threshold, and side effects from niacin are minimized, as compared to when the same modified form of trimetazidine is provided at the same dose in conventional formulations.

For oral delivery of the modified form of trimetazidine, the modified release formulation of the present invention confers several advantages over existing formulations. First, since the API of the pharmaceutical composition of the present invention in blood is continuously maintained above a threshold value, the pharmaceutical composition of the present invention can be administered less frequently than the existing composition. For example, the oral formulations provided herein containing CV-8972 are suitable for once-daily or twice-daily dosing regimens. Furthermore, because peak levels of API in blood are up to 50% lower than levels achieved with existing compositions, the formulations of the present invention reduce side effects caused by interactions between niacin and API with unintended targets in the body. Finally, the above attributes improve the overall therapeutic efficacy of modified forms of trimetazidine (e.g., CV-8972).

Improved form of trimetazidine

The present invention provides compositions comprising a mixture comprising a modified form of trimetazidine. Trimetazidine has the following structure:

trimetazidine was described as the first cytoprotective anti-ischemic agent developed and has long been used to treat angina pectoris.

Trimetazidine promotes glucose oxidation by inhibiting oxidation of fatty acids. Glucose oxidation and fatty acid oxidation are energy-producing metabolic pathways that compete with each other for substrates. In glucose oxidation, glucose is broken down into pyruvate via glycolysis in the cytosol of the cell. Pyruvic acid then enters the mitochondria, where it is converted to acetyl-CoA (acetyl CoA). In beta oxidation of fatty acids that occurs in mitochondria, two carbon units from long chain fatty acids are in turn converted to acetyl CoA. The remaining steps in energy production from the oxidation of glucose or fatty acids are common to both pathways. Briefly, they involve the breakdown of acetyl CoA into carbon dioxide via the citric acid cycle, concomitant generation of a proton gradient across the inner mitochondrial membrane via a series of oxygen-dependent electron transfer reactions, and the use of potential energy in the proton gradient to drive ATP synthesis. Trimetazidine inhibits oxidation of fatty acids by blocking long-chain 3-keto acyl-CoA thiolases, resulting in cells that rely on glucose oxidation to support energy production.

Forcing cardiac mitochondria to rely on oxidation of glucose rather than fatty acids as an energy source provides therapeutic benefit to many patients suffering from cardiovascular conditions. In certain types of heart disease, the overall efficiency of energy production by the heart's mitochondria is reduced, in part, due to the increased dependence on fatty acid oxidation relative to glucose oxidation. Glucose oxidation is a more efficient energy generation pathway than fatty acid oxidation, such as by consumption of each O ₂ The number of ATP molecules produced by the molecule is measured. Thus, by promoting glucose oxidation (e.g., trimetazidine), overall cardiac efficiency can be increased.

CV-8972 has recently been identified as a derivative of trimetazidine with improved pharmacological properties. CV-8972 has the structure of the IUPAC name 2- [4- [ (2, 3, 4-trimethoxyphenyl) methyl ] piperazin-1-yl ] ethylpyridine-3-carboxylate and the formula (X):

when CV-8972 is administered to a subject, it is initially broken down into niacin and CV-8814, CV-8814 having the IUPAC name 2- [4- [ (2, 3, 4-trimethoxyphenyl) methyl ] piperazin-1-yl ] ethanol and the structure of formula (IX):

CV-8814 is a hydroxyethyl derivative of trimetazidine, and the hydroxyethyl group is subsequently removed in vivo to provide trimetazidine. CV-8972 and its metabolites are described in U.S. Pat. No. 10,556,013, the contents of which are incorporated herein by reference.

The improved therapeutic properties of CV-8972 are due in part to the effects of niacin. Nicotinic acid as a reagent for the synthesis of Nicotinamide Adenine Dinucleotide (NAD) ⁺ ) Nicotinamide adenine dinucleotide is an oxidized form of the necessary coenzyme in the mitochondrial electron transfer reaction. Providing NAD ⁺ The precursor ensures stable mitochondrial redox reactionsOccurs robustly to drive ATP synthesis, whether oxidation of glucose or fatty acids is used to supply the citric acid cycle. Thus, the niacin product of CV-8972 promotes mitochondrial respiration.

CV-8972 is gradually decomposed into CV-8814 and then into trimetazidine, which also contributes to the improved therapeutic properties of CV-8972. Like trimetazidine, CV-8814 inhibits 3-keto acyl-CoA thiolase, and thus CV-8972 delivers two different Active Pharmaceutical Ingredients (APIs). However, CV-8814 does not produce the same undesirable side effects as trimetazidine. Furthermore, due to sequential metabolism of CV-8972, the levels of circulating trimetazidine after administration of CV-8972 are much lower than after administration of comparable doses of trimetazidine itself. Thus, CV-8972 provides more sustained circulating API levels and fewer side effects than pure trimetazidine.

Other modified forms of trimetazidine that can be used in the compositions of the present invention are described, for example, in U.S. patent nos. 4,100,285 and 4,574,156, the contents of each of which are incorporated herein by reference.

Erodable polymer comprising HPMC

The present invention provides compositions comprising a mixture comprising erodable polymers that promote swelling of the mixture in an aqueous environment. Erodable polymers are any polymers that decompose in vivo over physiologically relevant time frames. The erodable polymer may have other characteristics that promote the gradual release of the modified form of trimetazidine from the mixture. For example, but not limited to, the polymer may be one or more of the following: biocompatible, i.e. harmless to living tissue; hydrophilic; hygroscopic; tending to form hydrogels.

Without wishing to be bound by theory, the polymer-containing mixture may promote gradual release by one or more mechanisms. For example, swelling the mixture by absorbing water may promote diffusion of the modified form of trimetazidine from the mixture. Degradation of the polymer may also allow the modified form of trimetazidine to be released from the mixture. Osmotic pressure due to the high concentration gradient of the compound between the inside and outside of the mixture may also contribute to the diffusion of the modified form of trimetazidine from the mixture.

For example, but not limited to, the polymer may be a cellulose derivative, a gelatin derivative (e.g., a crosslinked gelatin derivative), or a polyester derivative.

The derivative of cellulose is a linear beta (1→4) linked D glucose unit comprising a polymer containing substituents on one or more hydroxyl groups of each glucose unit. Substituents may be organic or inorganic and are typically attached via an ester or ether linkage. Cellulose ester derivatives include carboxymethyl cellulose (CMC), such as sodium carboxymethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), and methyl cellulose. Cellulose ether derivatives include cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose sulfate, cellulose triacetate and nitrocellulose. The use of cellulose-based polymers to form biodegradable hydrogels is known in the art and is described, for example, in Sanning et al, "biodegradable cellulose-based hydrogels: design and application (Biodegradable Cellulose-based Hydrogels: design and Applications) "," Materials "(Materials) 2009,2,353-373; doi 10.3390/ma2020353, the contents of which are incorporated herein by reference.

The mixture may contain multiple polymers or multiple polymer forms of the same polymer. For example, HPMC polymer forms may differ in a variety of physical properties, including viscosity, degree of methoxy substitution, degree of hydroxypropoxy substitution, or average molecular weight.

The viscosity of the HMPC polymer form can be determined by testing under standard conditions, including the concentration of HMPC in the solution and the temperature of the solution. For example, but not limited to, HPMC concentration may be 1%, 1.5%, 2%, 2.5%, or 3%. For example, but not limited to, the temperature of the solution may be 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, or 25 ℃.

The polymeric form of the cellulose derivative, such as HPMC, may have a defined viscosity. For example, but not limited to, for a 2% aqueous solution of a polymeric form at 20 ℃, the polymeric form of HPMC may have a viscosity of about 2cP to about 4cP, about 4cP to about 6cP, about 5cP to about 8cP, about 12cP to about 18cP, about 40cP to about 60cP, about 80cP to about 120cP, about 300cP to about 500cP, about 1200cP to about 2400cP, about 2500cP to about 5000cP, about 9000cP to about 18,000cP, about 12,000cP to about 24,000cP, about 75,000cP to about 150,000cP, at least about 2cP, at least about 4cP, at least about 5cP, at least about 12cP, at least about 40cP, at least about 80cP, at least about 300cP, at least about 1200cP, at least about 2500cP, at least about 9000cP, at least about 12,000cP, at least about 75,000cP, less than about 4cP, less than about 6cP, less than about 8cP, less than about 18,000cP, less than about 150,000cP, less than about 18,000cP, less than about 150,000 cP.

Polymeric forms of cellulose derivatives, such as HPMC, may have varying degrees of substitution of the glucose units. The degree of substitution may be expressed as a weight percent of the substituent or as a molar ratio of the substituent to the glucose unit. For cellulose derivatives having two different substituents, such as HPMC, the polymer form may be described by the degree of substitution of each substituent.

Each polymeric form of HPMC may independently have a defined degree of methoxy substitution. For example, but not limited to, the degree of methoxy substitution may be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, or from about 28% to about 32%.

Each polymeric form of HPMC may independently have a defined degree of hydroxypropoxyl substitution. For example, but not limited to, the degree of hydroxypropoxyl substitution may be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.

When multiple forms of polymer such as HPMC are present, one or more of the polymeric forms may be present in a defined amount. For example, but not limited to, a polymer (e.g., HPMC) may contain about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of one polymeric form.

Pharmaceutical composition

The pharmaceutical compositions of the present invention comprise modified release formulations comprising one or more modified forms of trimetazidine. The formulation contains a mixture comprising one or more modified forms of trimetazidine and one or more erodable polymers that promote swelling of the mixture in an aqueous environment. The hygroscopic and erodable nature of the polymer may allow the mixture to form a hydrogel that slowly breaks down in the digestive tract of the subject. Thus, the mixture promotes the stable release of the modified form of trimetazidine and its metabolites into the circulation.

The mixture may contain a modified form of trimetazidine and a polymer in defined weight ratios. Such as but not limited to, the mixture may contain a weight ratio of about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 3:2, about 2:1, about 3:1, about 4:1, about 5:1, about 1:100 to about 100:1, about 1:100 to about 50:1, about 1:100 to about 20:1, about 1:100 to about 10:1, about 1:100 to about 5:1, about 1:100 to about 2:1, about 1:50 to about 100:1, about 1:50 to about 50:1, about 1:50 to about 20:1, about 1:50 to about 10:1, about 1:50 to about 5:1, about 1:50 to about 2:1, about 1:20 to about 100:1, about 1:20 to about 50:1, about 1:20 to about 20:1, about 1:20 to about 10:1: modified forms of trimetazidine and polymers from about 1:20 to about 5:1, from about 1:20 to about 2:1, from about 1:10 to about 100:1, from about 1:10 to about 50:1, from about 1:10 to about 20:1, from about 1:10 to about 10:1, from about 1:10 to about 5:1, from about 1:10 to about 2:1, from about 1:5 to about 100:1, from about 1:5 to about 50:1, from about 1:5 to about 20:1, from about 1:5 to about 10:1, from about 1:5 to about 5:1, from about 1:5 to about 2:1, from about 1:3 to about 100:1, from about 1:3 to about 50:1, from about 1:3 to about 20:1, from about 1:3 to about 10:1, from about 1:3 to about 5:1, or from about 1:3 to about 2:1.

The pharmaceutical composition may be formulated such that it yields defined values for one or more parameters, as described below in relation to the method of the invention. For example, but not limited to, the parameter may be C _{Maximum value} Administration and achievement of C _{Maximum value} Time interval between T _1/2 Or AUC.

The pharmaceutical compositions of the present invention may contain excipients. For example, but not limited to, the composition may contain a sweetener, flavoring agent, coloring agent, or preservative. The composition may contain one or more of mannitol, starch and magnesium stearate.

Therapeutic method

The present invention provides methods of treating a disease, disorder, condition in a subject by providing any of the above compositions. The modified release formulation of the present invention provides for a more stable release of the modified form of trimetazidine than conventional formulations. The excellent release profile may be reflected in one or more of the following parameters.

One parameter that may be used to distinguish the formulations of the present invention from other compositions containing the same dose of the modified form of trimetazidine is C _{Maximum value} I.e., the maximum level of a drug or metabolite of a drug in a sample after administration of one dose of the drug but before administration of a second dose of the drug. The formulations of the present invention can produce such C _{Maximum value} Values lower than C produced by conventional formulations containing the same dose _{Maximum value} Values. In the process of the invention, lower C _{Maximum value} Can be expressed in relative terms, for example, by reference to C produced by administration of another formulation _{Maximum value} A comparison is made, or expressed in absolute terms, for example by comparison with a defined threshold. C (C) _{Maximum value} May be directed to a modified form of trimetazidine or a metabolite of the compound. For example, after application of a composition containing a compound of formula (X), C of the compound of formula (X) can be determined _{Maximum value} Or can determine the C of a compound of formula (IX), trimetazidine or niacin _{Maximum value} 。

For example, but not limited to, the maximum level of trimetazidine or a metabolite of a modified form of trimetazidine in a sample from a subject can be less than about 20 μg/mL, less than about 15 μg/mL, less than about 12 μg/mL, less than about 10 μg/mL, less than about 8 μg/mL, less than about 6 μg/mL, less than about 5 μg/mL, less than about 4 μg/mL, less than about 3 μg/mL, less than about 2 μg/mL, less than about 1 μg/mL, less than about 0.8 μg/mL, less than about 0.6 μg/mL, less than about 0.4 μg/mL, less than about 0.2 μg/mL, or less than about 0.1 μg/mL.

For example, but not limited to, the maximum level of trimetazidine in a sample from a subject or a metabolite of trimetazidine in a modified form can be less than about 10%, less than about 20%, less than about 30%, less than about 40%, less than about 50%, less than about 60%, less than about 70%, less than about 80%, less than about 90% of the maximum level resulting from administration of a different composition containing the same amount of trimetazidine in a modified form.

Another parameter that can be used to distinguish the formulation of the present invention from other compositions containing the same dose of the modified form of trimetazidine is that administration of the composition to a subject results in its C in a sample from the subject from the modified form of trimetazidine or a metabolite of the modified form of trimetazidine _{Maximum value} Time intervals between time points of (a). The modified release formulations of the present invention can produce longer to C than other formulations _{Maximum value} Is a time interval of (a) for a time period of (b). To C _{Maximum value} May be expressed in relative terms, for example by comparison with the time interval of another formulation, or in absolute terms, for example by comparison with a defined period of time.

For example, but not limited to, the time interval between the time at which the composition is provided to the subject and the time at which the maximum level of trimetazidine or the metabolite of the improved form of trimetazidine in the sample from the subject is reached may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, about 1 hour to about 8 hours, about 2 hours to about 8 hours, about 3 hours to about 8 hours, about 4 hours to about 8 hours, about 1 hour to about 7 hours, about 2 hours to about 7 hours, about 3 hours to about 7 hours, about 4 hours to about 7 hours, about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 5 hours, or about 5 hours.

For example, but not limited to, the time interval between the time at which the composition is provided to the subject and the time at which the maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is reached in the sample from the subject may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400% greater than the time interval after administration of another composition containing the same dose of the modified form of trimetazidine.

Another parameter that can be used to distinguish the formulations of the present invention from other compositions containing the same dose of the modified form of trimetazidine is T _1/2 I.e. to achieve a modified form of trimetazidine or a metabolite C of a modified form of trimetazidine _{Maximum value} The time interval between the time point at which the concentration of the compound or metabolite reaches its half maximum. The modified release formulations of the present invention can produce a T that is greater than that produced by other formulations containing the same dose of the modified form of trimetazidine _1/2 T of higher value _1/2 The value, i.e. the longer time interval. T (T) _1/2 Can be expressed in relative terms, e.g., by T with another formulation _1/2 A comparison is made, or expressed in absolute terms, for example, by comparison with a defined period of time.

For example, but not limited to, the time interval between the point at which the maximum level of trimetazidine or the metabolite of the improved form of trimetazidine in the sample from the subject is reached and the point at which the half maximum level of trimetazidine in the sample from the subject is reached may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, from about 1 hour to about 5 hours, from about 5 hours to about 5 hours, or from about 5 hours.

For example, but not limited to, the time interval between the time at which the maximum level of trimetazidine or a metabolite of the improved form of trimetazidine in a sample from a subject is reached and the time at which the half maximum level of trimetazidine in a sample from a subject is reached may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400% greater than the time interval after administration of another composition containing the same dose of improved form of trimetazidine.

Another parameter that can be used to distinguish the formulations of the present invention from other compositions containing the same dose of the modified form of trimetazidine is the area under the curve (AUC), i.e. the constant integral of the concentration of the compound or metabolite as a function of time. The modified release formulations of the invention can yield higher AUC values than those produced by other formulations containing the same dose of the modified form of trimetazidine. AUC may be expressed in relative terms, for example by comparison with the AUC of another formulation, or in absolute terms, for example by comparison with a defined threshold.

For example, but not limited to, the AUC of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400% greater than the AUC after administration of another composition containing the same dose of the modified form of trimetazidine.

The sample in which the modified form of trimetazidine is measured can be any fluid-containing sample from a subject. The sample may be a plasma sample, a blood sample, a serum sample, a saliva sample, a urine sample, a sputum sample, a mucus sample, a stool sample, or a stomach sample.

The composition may be provided to the subject by a particular route of administration. The medicament may be provided to the subject orally, enterally, intravenously or rectally.

The composition may be provided according to a dosing regimen. The dosing regimen may comprise one or more of dose, frequency and duration of dosing.

The doses may be provided at any suitable time interval. For example, but not limited to, the dosage may be provided daily, twice daily, three times daily, four times daily, five times daily, six times daily, eight times daily, 48 hours, 36 hours, 24 hours, 12 hours, 8 hours, 6 hours, 4 hours, 3 hours, two days, three days, four days, five days, weekly, twice weekly, three times weekly, four times weekly, or five times weekly.

The dose may be provided as a single dose, i.e. the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in separate doses, i.e. the dose may be provided as a plurality of tablets, capsules, pills, etc.

Administration may be for a defined period of time. For example, but not limited to, the dose may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, or longer.

Diseases, disorders and conditions

The methods of the invention can be used to treat a disease, disorder, or condition in a subject. The disease, disorder or condition may be any condition that may be ameliorated by improving mitochondrial function of the heart. The disease, disorder or condition may be a cardiovascular condition. The disease, disorder or condition may be an aneurysm, angina, atherosclerosis, cardiomyopathy, cerebrovascular disease, congenital heart disease, coronary Artery Disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, hypertension (hypertension), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.

Angina pectoris (angina) is chest pain or pressure, which is usually caused by insufficient blood flow to the heart muscle. Pain or discomfort is located behind or to the left of the sternum and may radiate to the left arm, neck, jawbone, or back. Several classifications of angina pectoris are known.

Stable angina, also known as exertional angina, is associated with myocardial ischemia. In stable angina, chest discomfort and related symptoms are often triggered by some physical activity (such as running or walking), but when the patient is resting or is sublingually taking nitroglycerin, the symptoms are little or absent. Symptoms usually abate a few minutes after the activity and recur when the activity resumes. Symptoms may also be induced by cold weather, indigestible meal, and emotional stress.

Unstable angina is altered or worsened angina. Unstable angina has at least one of the following characteristics: (1) at rest or with mild exercise, typically lasting more than 10 minutes, (2) severe and new onset, i.e. within 4-6 weeks of before, and (3) in a gradual up mode, i.e. significantly more severe, longer lasting or more frequent than before.

Cardiac syndrome X, also known as microangiogenic angina, is angina-like chest pain in the context of angiographic normal epicardial coronary arteries. The main reasons for this are unknown, but obviously the factors involved are endothelial dysfunction and reduced flow in the slightly resistant vessels of the heart. Microvascular angina may be part of the pathophysiology of ischemic heart disease.

Refractory angina is a chronic condition (duration ≡3 months) in which angina (1) occurs in the context of Coronary Artery Disease (CAD), (2) cannot be controlled by a combination of optimal drug therapy, angioplasty or bypass surgery, and (3) in which reversible myocardial ischemia has been clinically established as the cause of symptoms.

Examples

Example 1

Wet granulated formulations containing 50mg or 200mg free base equivalent CV-8972 were prepared according to the 200mg compositions shown in table 1.

Table 1.

¹ CV-8972 is 3HCl.1H of the free base ₂ O salt (molar weight = 542.86 g/mol); 261.30mg of salt corresponds to 200mg of free base CV-8972

² Administration as free base (molar weight= 415.49 g/mol) -molar weight ratio= 1.3066

³ Adjusting the titers for each API lot

⁴ The total filling weight of the tablet can be changed by +/-5 percent

These wet granulation formulations are based on previous direct compression, by hand loading the mixed powders into individual punches, followed by separate compression. The two formulations were slightly different in composition to allow conversion to wet granulation, but were identical in specification and performance.

Because of the large number of drug Substances (APIs) present in the tablet (about 50%) and their potential impact on the tablet properties, the transition from direct compression to wet granulation is considered prudent in order to provide some better control over flow, hardness and other properties. Formulation design and scale-up experiments confirm that this is a reasonable decision, as mixing, powder flow and API bulk variability have proven problematic in providing suitable direct compression formulations. (additional work is planned to evaluate dry granulation processes for commercial development in order to replace current wet granulation processes, thereby better facilitating scale-up and high-throughput manufacturing).

200mg MR 8 hour release tablets are designed to be taken twice daily (BID) by the patient.

The form of CV-8972 for the formulation had the following structure and properties:

chemical name: 2- {4- [ (2, 3, 4-trimethoxyphenyl) methyl ] piperazin-1-yl } ethylpyridine-3-carboxylic acid ester tri-hydrochloride monohydrate

The molecular formula: c (C) ₂₂ H ₃₂ N ₃ O ₅ Cl ₃ .1H ₂ O

Molecular weight: 542.86 g/mol (3HCl.1H) ₂ O)

Associated molar weight: 524.86 g/mol (3 HCl anhydrous); 415.49 g/mol (free base, anhydrous)

pKa (estimated): 4.85 (nicotinic acid salt); about 5.50 (piperazine); about 7.99 (piperazine)

cLog P (free base): 1.26-1.63

Melting point: DSC measurements from batch 289-MBA-33 (Tox. Batch):

abrupt melting at 221℃preceded by the appearance of a broadband (DSC) starting from 208 DEG C

Losing most of the monohydrate water between 100 and 127 DEG C

Calculated melting point = 218.41 °c

Melting enthalpy = -298J/g

This molecule is a hybrid NCE that undergoes hydrolytic cleavage and metabolism when taken orally to produce CV-8814, niacin, trimetazidine (TMZ), and other potential systemic metabolites.

FIG. 1 is a schematic representation of the hydrolytic and metabolic pathways of CV-8972. It should be noted that there are other potential metabolic pathways that have not yet been evaluated in humans.

CV-8972 is relatively insoluble as a salt in most organic solvents, but is less soluble as the free base. However, when the most basic estimated pKa is about 7.9, the molecule is always present as a charged ion in the physiological pH range of 1-8.

FIG. 2 is a graph of the water solubility of CV-8972 as a function of pH due to instability via a dynamic process. The dramatic drop in solubility between pH 6.1-9.2 indicates that the dissolution kinetics can vary significantly from gastric juice (pH 1-2) to intestinal juice (pH 6.5-8). However, given a saturated alkali solubility of 5-10mg/mL, a dose of 200mg of alkali may dissolve throughout the gastrointestinal tract under sinking conditions.

The pH stability profile of a 1mg/mL solution of CV-8972 at 23℃is summarized and shown in Table 2.

Table 2.

Hydrolysis proceeds via the first step shown in fig. 1, as niacin and CV-8814 are the only decomposition products produced. For a 1mg/mL solution, the optimal pH for solution stability appears to be about pH 5-5.1, with acid-catalyzed hydrolysis increasing below pH 5.0 and base-catalyzed hydrolysis increasing above pH 5.0.

Excipients used in the formulation are standard for erodable hydrogel tablets to produce a modified release product. Since the CV-1018972 salt is very soluble, hypromellose polymers of different molecular weights and degrees of crosslinking are used to hydrate the gel and slowly release the soluble drug. Mannitol is included as a soluble sugar that balances water into the formulation, and magnesium stearate is used as a lubricant. In addition to detailed stability assessment of the drug in the prototype excipient mixture and formulation, extensive drug stability screening has previously been performed using a large number of excipients.

Example 2

Pilot and clinical tablet batches were made manually by direct mixing and compression to support phase 1 SAD/MAD studies at ICU pharmacies. The formulations used in these evaluations are shown in table 3.

Table 3.

¹ CV-8972 is 3HCl.1H of the free base ₂ O salt (molar weight = 542.86 g/mol);

³ Adjusting the titers for each API lot

⁴ The total filling weight of the tablet can be changed by +/-5 percent

The formulations used for the study were directly compressed, the mixed powder was filled into individual punches by hand and pressed alone at CV-8972 equivalent weights of 50mg and 200mg free base according to the compositions shown in Table 3.

The 8 hour MR release tablet was selected for further study and the dose was only 200mg and placebo. The composition is shown in table 4.

Table 4.

¹ Based on 550mg total tablet weight and 100% API purity

² Amounts of CV-8972 and mannitol EZ were adjusted for potency of the API batches used

Pilot-plant demonstration batches were manufactured at a total batch on the order of 5kg to evaluate future GMP batches for scale-up performance and equipment train compatibility.

Fig. 4 is a process flow diagram for manufacturing an MR tablet formulation for pilot scale batches of CV-8972 200 and 50mg wet granulation. Wet granulation was used, with slight variations in composition and scale-up for manufacturing clinical supply batches of about 43,000 tablets per batch or a total batch of about 24kg, as described in table 1.

A summary of wet granulation processes for manufacturing clinical products is provided herein.

Screening the API through a 20 mesh screen.

The API, mannitol and Methocel E5 were dispensed into HPDE wide mouth barrels in four aliquots (including pellet batches).

The dry mix of each sub-batch was charged to a 25L high shear granulator and mixed for 1 minute at impeller speed 150rpm, chopper speed 360 rpm.

405g of purified water USP was sprayed into the mixer via peristaltic pump and granulated using impeller 150 RPM/chopper 1500 RPM.

Granulation was continued until no dry powder remained at impeller 65 RPM/chopper 800RPM and particle formation began.

The wet granules from the high shear granulator were discharged via a CoMill (screen-250; impeller-circular; mill speed 2500 rpm) into a 12L fluid bed dryer drum; drying to maintain sufficient fluidization and target product temperature of NLT 40 ℃ (inlet 60 ℃ C.; 110 Nm) ³ /h volume throughput).

LOD% is determined at a set time based on process experiments during amplification. The target LOD was NMT 2.0% at a target LOD temperature of 85 ℃.

Discharge of dry particles and CoMill (screen-50; impeller-square; 2500 rpm).

Repeating the above steps three times in the case of other sub-batches and combining the particles to determine the final weight; sieving through a 20-mesh sieve; calculation of

The amounts of K100M superfine DC2 and magnesium stearate were sieved and added to the granules as described in steps 15-18.

Mix in 80L bin (bin) at 15rpm for 5 minutes and use 25 tablets, direct compression using pre-calibrated tablet weight and hardness settings.

Theoretical weight=550 mg (API potency to be adjusted by salt factor)

Average weight of 25 tablets = 95-105% of theory

Individual weight range = 90-110% of theory

Tablet hardness=15 kp (target value); NLT 11kp

Samples for assay and bulk tablets were stored in polyethylene bags (Poly Bag) and 20L HDPE drums.

After full quality release and review, package from bulk tablet barrels into patient bottles. Packaged into 60cc HDPE containers with child resistant caps at room temperature and placed under stable storage conditions of 5 ℃, 25 ℃/60% RH or 40 ℃/75% RH using added desiccant.

The following test was applicable to tablet release:

appearance of tablet

Identification, determination, purity, unknown impurities and total impurities with respect to CV-8814

Content uniformity

Dissolution release test

Residual moisture

Tablet hardness

Microbial test

Dissolution profiles of 50mg and 200mg MR tablet batches evaluated in SAD/MAD studies and other pilot runs have been collected in 0.1N HCl. They reach >80% dissolution in 4 hours or 8 hours, depending on the formulation.

Based on these data and the PK profile obtained, experimental dissolution specifications and validated dissolution assays were established, and release and stability samples were evaluated accordingly.

Extensive stability assessment of 200mg 8 hour MR tablets to be used at both 25 ℃/60% RH and 40 ℃/75% RH showed significant consistency in release when stored in containers with or without desiccant.

FIG. 7 is a graph showing the dissolution profile of 200mg 8 hours modified release hydrogel tablets at 37℃after storage under specified conditions in 0.1M HCl pH 1.0. The tablets were stored for 1 week, 2 weeks, 6 weeks, 3 months or 6 months with or without desiccant at 25 ℃/60% RH or 40 ℃/75% RH.

The specifications are designed to control the combination of initial surface burst release and long-term release via matrix erosion to ensure consistent oral delivery. Table 5 shows the proposed dissolution test specifications and the average value ranges obtained in the pilot batch stability study for 6 months.

Table 5.

Furthermore, the dissolution data at t=0 for three clinical batches prepared under cGMP conditions are shown in table 6.

Table 6.

Batch of	1 hour	For 2 hours	4 hours	8 hours	For 10 hours	For 12 hours
							DP-APS19-164	34.8	51.2	71.9	91.7	95.9	98.1
DP-APS19-165	34.5	51.3	73.1	92.8	96.3	98.5
							DP-APS19-166	34.4	51.4	73.1	92.5	95.9	97.6

The overall conclusion from the 200mg 8 hour MR dissolution study is:

release formulations are extremely consistent and robust;

from the point of view of stability, even under acceleration conditions, there is little variability;

formulation performance is reproducible when expanded and run multiple times.

Example 3

As can be seen from the previous examples, CV-8972 is very soluble as a salt and as a free base, with a minimum solubility of about 10mg/mL as the free base and a minimum solubility >100mg/mL as the salt. Thus, a volume of 250mL of neutral pH aqueous solution can dissolve CV-8972 up to 2.5g, which is significantly 5-10 times higher than the potential maximum daily dose of 250-500 mg.

The calculated cLog P for CV-8972 was about 1.5 and in vitro CaCo2 experiments showed that at about 2.9X10 ^-5 Permeability (P) at cm/sec _app ) Far greater than 1 x 10 ^-6 cm/s, with little sign of run-off. In contrast, CV-8814 exhibited similar behavior in the same study.

Thus, CV-8972 may itself be regarded as BCS grade 1, but pre-systemic metabolism of CV-8814 and possibly other metabolites may complicate and affect the actual biopharmaceutical absorption profile found in the human body. CV-8972 in dogs was estimated to have >50% bioavailability when administered as a solution, as compared to IV CV-8814.

Solution stability of CV-8972 was evaluated in a variety of media currently used to simulate dissolution and stability conditions in various parts of the gastrointestinal tract. Since CV-8972 will undergo hydrolysis upon dissolution in the gastrointestinal tract, it would be important to understand these kinetics in the design of immediate release and controlled release formulations. HPLC methods were used to perform these evaluations. A summary of the decomposition kinetics of CV-8972 versus medium at 37℃and 0.2mg/mL is shown in Table 7.

Table 7.

¹ As defined by janttrate and Dressman.

² Sodium bicarbonate solution>1M) neutralized 0.1M HCl solution;

³ a surfactant component sodium taurocholate (NaT); lecithin (Lec); glycerol Monooleate (GMO); sodium oleate (NaO); no enzyme is present.

⁴ K _obs Is the calculated first order rate constant for CV-8972 hydrolysis

Regarding the data in table 7, attention is paid to the following points:

there is a significantly more complex behaviour/interaction between CV-8972 and FaSSGF, faSSIF and FeSSIF components, which cannot all be explained by pH differences.

The presence of surfactants such as bile acids, lecithin or glycerol monooleate appear to "protect" CV-8972 or slow its rate of hydrolysis, possibly via complexation.

While the above may suggest potentially beneficial food effects in vivo, in practice a smaller effect of feeding versus fasting is observed in humans for 200mg, 8 hour MR tablets (see section 5.1.2 below).

In summary, there may be some protection of the components of FaSSGF, faSSIF and FeSSIF, especially when compared to stability in 0.1N HCl or bicarbonate or phosphate buffers at pH 6-8. From the positive side, the fastest decomposition rate still has a T of 1.5 hours _1/2 This should provide sufficient residence time for release and absorption in the upper gastrointestinal tract.

Although stability in 0.1N HCl at 37 ℃ appears to be low, it can be said to provide the most demanding in vitro release and hydrolysis resistance test for dissolution testing. Considering the parent and CV-8814, CV-8972 is considered stable enough to use this condition via pH stabilization and rapid assay. No difference in dissolution rates was found between 0.1N HCl, water and pH 6.8 phosphate buffer. The dissolution in pH 5 acetate buffer, faSSGF, faSSIF and FeSSIF was found to be analytically complex as release by HPLC and analytical measurements were disturbed. Analytical methods will be developed to address this problem while the IVIVC/IVIVIVR data is evolving.

Additional and extensive in vitro stability studies have been conducted across species to assess the effect of gastrointestinal tract, liver tissue and plasma on half-life as measured by in vitro clearance of CV-8972 in various biological media. This suggests that CV-8972 may be relatively unstable in the gastrointestinal tract (according to its design), but may be stable enough in the intestinal brush border and enzymes therein to allow adequate absorption in intact form.

To enable evaluation and selection of MR formulations in humans, dogs were subjected to PK studies under fasted conditions to determine how relevant the in vitro and in vivo release profiles are.

Figure 8 is a graph showing plasma levels of CV-8814 in dogs following oral administration of 200mg (free base equivalent) of CV-8972 under fasted conditions. CV-8972 was provided as an immediate release powder in a capsule, (b) a modified release tablet at a 4 hour release rate, or a modified release tablet at a 8 hour release rate.

Table 8 summarizes the calculated in vitro release rate constants (K _d Hours of ^-1 ) And 90% of the time (T _90％ Hour) and e.g. via Wagner-Nelson technology ² Calculated corresponding in vivo absorption rate constant (K _a Hours of ^-1 ) And time to 90% dose absorption (T _90％ Hours).

Table 8.

Overall, the in vivo data appeared to show about 2-fold faster absorption than predicted from the in vitro data for 4 hours and 8 hours of tablet release. These data may have limited predictive value for humans due to metabolic differences between dogs and humans, but estimation of absorption kinetic parameters is considered useful at this stage of development. This method would be similarly used in humans to deconvolute the absorption PK profile and correlate in vivo and in vitro release rates.

Data recently obtained from humans in SAD/MAD studies, including feeding/fasted, are currently being evaluated; preliminary evaluations showed that the 4 and 8 hour release of 50mg and 200mg tablets performed similarly to that observed in dogs, but required more extensive analysis for effective comparison. Little or no effect of food on human PK appears to be observed, which appears to be a beneficial outcome of the study with respect to patient dosing.

At steady state following 200mg 8 hour MR tablet administration, some information has been made about estimating C _{Minimum of} Relative to C _{Maximum value} Modeling horizontally. For CV-8814, the effect and benefit of BID versus QD dosing was clearly observed for this formulation, showing that BID versus QD dosed C _{Maximum value} /C _{Minimum of} The ratio is reduced by 10 times; for TMZ (about 2-fold reduction ratio) and the combined level (about 3-fold reduction ratio), this is less pronounced. Again, this supports and demonstrates the benefits for BID administration of the formulation.

Further evaluations are being performed to evaluate initial IV/IVC readings in humans, covering both the active substances CV-8814 and Trimetazidine (TMZ).

Table 9 shows predicted C of CV-8814, trimetazidine and both in humans after oral administration of 200mg IMB-1018972MR tablets as 8 hour release tablets under MAD administration (QD and BID) and fed conditions _{Maximum value} 、C _{Minimum of} And C _Maximum- C _{Minimum of} Ratio.

Table 9.

Example 4

Study design

A randomized, double-blind study of phase 1 humans in healthy subjects to study the safety, tolerability, and pharmacokinetics (including food effects) of IMB-1018972.

Purpose(s)

The primary objective was to evaluate the safety and tolerability of Modified Release (MR) formulations of IMB-1018972 in single oral doses and 200mg 8 hour MR formulations of IMB-1018972 in multiple oral doses in healthy subjects.

Secondary purposes include: assessing the Pharmacokinetic (PK) profile of a single oral dose MR formulation of IMB-1018972 and a multiple oral dose 200mg 8 hour MR formulation of IMB-1018972 in a healthy subject; assessing absorption and PK profile of a 200mg 8 hour MR formulation of IMB-1018972 following multiple oral doses taken with food in healthy subjects; and evaluating the safety and tolerability of 200mg 8 hour MR formulation of IMB-1018972 after multiple oral doses taken with food in healthy subjects.

Design and treatment

This is a double blind, randomized study comprising single and multi-dose MR fractions to evaluate the safety, tolerability and PK of single oral doses of MR formulation of trimetazidine, single oral doses of MR formulation of IMB-1018972 and multiple oral doses of 200mg 8 hours MR formulation of IMB-1018972.

Single dose MR portion

In the single dose MR portion, 1 group of 12 healthy subjects (each taking active drug) was included. Subjects received 1 of the 4 MR formulations of single oral doses of IMB-1018972 on

days

1, 4, 7 and 10 under fasted conditions (overnight fasted for at least 10 hours) in the same fixed order for all subjects. The MR formulation of IMB-1018972 to be administered on day 13 under fed conditions was 1 out of the 4 MR formulations administered on

days

1, 4, 7 and 10 under fasted conditions. The formulation selected for day 13 administration was 200mg of the 8 hour MR formulation as determined by the sponsor based on the available safety, tolerability and PK results for the 4 MR formulations.

The following treatments were administered in a single dose MR fraction:

day 1: under fasted conditions, a single oral dose of 50mg 8 hr MR formulation of IMB-1018972 (n=12)

Day 4: under fasted conditions, a single oral dose of 50mg 4 hour MR formulation of IMB-1018972 (n=12)

Day 7: 200mg of 8-hour MR formulation of IMB-1018972 in single oral dose (n=12) under fasted conditions

Day 10: 200mg 4 h MR formulation of IMB-1018972 in single oral dose (n=12) under fasted conditions

Day 13: 200mg of 8-hour MR formulation of IMB-1018972 in single oral dose (n=12) under fed conditions

Multi-dose MR portion

In the multi-dose MR section, 1 group of 12 healthy subjects (all taking active drug) was included. Subjects received multiple oral doses of 200mg of the 8 hour MR formulation of IMB-1018972q12h for 5 consecutive days under fed conditions; on day 5, only a single morning dose was administered.

Study schedule

Screening: between day-35 and day-1 (admission)

Confinement period: single dose MR portion: 1 clinical phase from day-1 (admission) to day 13 about 72 hours (day 16) after study drug administration; multi-dose MR portion: 1 clinical phase from day-1 (admission) to day 5 about 48 hours (day 7) after study drug administration

Follow-up: single dose MR portion: 7 to 14 days (between day 23 and day 30) after the last PK blood sample; multi-dose MR portion: 6 to 8 days after the last PK blood sample (day 14.+ -. 1 day)

A subject

Single dose MR portion: 12 healthy male or female subjects; for this group, all efforts were made to have a 50:50 ratio of male and female subjects, but at least 4 subjects of each sex were dosed

Multi-dose MR portion: 12 healthy male or female subjects; for this group, all efforts were made to have a 50:50 ratio of male and female subjects, but at least 4 subjects of each sex were dosed

Principal criteria for incorporation

Age: screening was 18 to 65 years (including 18 and 65 years)

Body Mass Index (BMI): 18.0kg/m ² To 32.0kg/m ² (comprising 18.0 kg/m) ² And 32.0kg/m ² )

Status: healthy subject

Research medicament

Active pharmaceutical

Pharmaceutical product: IMB-1018972

Activity: fatty acid oxidation inhibitor

Development was used to: ischemic cardiovascular disease

Intensity: 50mg MR formulation and 200mg MR formulation with 4-and 8-hour dissolution profiles (based on free base)

Dosage form: oral MR tablet to be used in MR section

The manufacturer: PRA pharmacy

Lot number: 2479-1810-00441 (bulk drug)

Active pharmaceutical

Pharmaceutical product: universal force (Vastarel) MR (trimetazidine hydrochloride)

Activity: fatty acid oxidation inhibitor

Development was used to: angina pectoris

Intensity: 35mg

Dosage form: oral modified release tablets

The manufacturer: shi Weiya Research pharmaceutical (pakistan) (private) company (server Research & Pharmaceuticals (Pakistan) (pvt.) ltd.)

Lot number: 273782 (pharmaceutical product)

Variable(s)

Safety: adverse events, clinical laboratories, vital signs, 12-lead electrocardiography, continuous cardiac monitoring (telemetry), and physical examination

Pharmacokinetics: plasma concentrations of IMB-1018972, IMB-1028814 and trimetazidine, urine concentrations of IMB-1018972, IMB-1028814 and trimetazidine, single dose MR fraction: c (C) _{Maximum value} 、t _{Maximum value} 、AUC _0-t 、AUC _0-inf 、AUC _{Additional(s)} ％、k _el 、t _1/2 CL/F (IMB-1028814 only) and V _z F (IMB-1028814 only). Day 1 of the multi-dose MR section: c (C) _{Maximum value} 、t _{Maximum value} And AUC _0-т And day 5 of the multi-dose MR section: c (C) _{Maximum value} 、t _{Maximum value} 、C _{Minimum of} 、k _el 、t _1/2 、AUC _0-т 、CL _ss F (IMB-1028814 only), V _z F (IMB-1028814 only) and R _ac Urine PK parameters (estimated using non-compartmental analysis as appropriate): ae _{Urine flow} 、Fe _{Urine flow} And CL _R

Statistical method

Sample size calculation: for this FIH study, no prospective calculation of statistical efficacy was performed. The sample size was chosen to provide information on the safety, tolerability and PK of single dose MR formulation of IMB-1018972 and multi-dose 200mg 8 hour MR formulation of IMB-1018972, and is typical of FIH studies. Any p-value to be calculated according to the statistical analysis plan is explained from the point of view of exploratory features of the study.

Safety parameters: descriptive statistics

PK parameters: descriptive statistics of all relevant PK parameters: n, mean, SD, minimum, median, maximum, geometric mean and coefficient of variation; for C _{Maximum value} And analysis of variance of AUC parameters to determine dose ratio and FE

Results

Subject treatment

One subject of the single dose MR fraction was withdrawn from the study due to an elevated alanine Aminotransferase (ALT) (possibly associated; up to 149IU/L on day 11) with a moderate treatment producing adverse events (TEAE) and received no last single oral dose of 200mg 8 hour MR formulation of IMB-1018972 on day 13 under fed conditions. These discontinued subjects were not replaced. All 88 subjects were included in the PK and safety collections.

Table 10: treatment of a subject

Demographic data

Single dose MR portion

Twelve subjects were included, 6 of which were females and 6 of which were males. The average age was 32 years and the average BMI was 25.8kg/m2. The age of the individual is between 19 and 62 years and the BMI of the individual is between 21.5 and 31.0kg/m 2. Eleven subjects were caucasians and 1 subject was black or african americans.

Multi-dose MR portion

Twelve subjects were included, 6 of which were females and 6 of which were males. The average age was 45 years and the average BMI was 25.1kg/m2. The age of the individual is between 24 and 64 years and the BMI of the individual is between 20.0 and 29.2kg/m 2. Eleven subjects were caucasians and 1 subject was asian.

Safety of

In the single dose MR fraction, healthy male and female subjects were well tolerated with 50mg MR formulation and 200mg MR formulation with dissolution profiles of 4 and 8 hours under fasted conditions and then 200mg 8 hour MR formulation with IMB-1018972 under fed conditions, except for 1 subject with an ALT elevation (up to 149 IU/L) after 2 single doses of 50mg MR formulation and 2 doses of 200mg MR formulation. No flushed TEAE was reported in the single dose MR fraction.

In the multi-dose MR section, healthy male and female subjects were well tolerated for 5 days of treatment with 200mg of 8-hour MR formulation with multiple oral doses of IMB-1018972q12h under fed conditions. 2 postmenopausal female subjects reported a light flush, of which 1 reported a persistent "hot flush" as part of the medical history. No subjects were withdrawn and no dose modification was required due to flushed TEAE.

In general, no mortality was reported during the study. Most reported TEAEs were transient and resolved at the time of the follow-up, with no sequelae. Most TEAEs were mild and no severe TEAE was reported during the study. Moderate TEAE was 5 cases of flushing as described above, 1 case of TEAE in restlessness, back pain, nausea, tonsillitis, post-operative bleeding, ALT elevation and influenza-like disease. Moderate TEAE with elevation of ALT was reported by subjects in the single dose MR fraction. Due to the TEAE, the subject was withdrawn from the study. Researchers believe that elevated TEAE (up to 149IU/L on day 11) may be relevant for the study drug.

In the single dose MR fractions, there was no significant difference between fasted and fed IMB-1018972 administration for the amount and incidence of TEAE.

The TEAE most commonly reported during the study was systemic organ vascular like disorders (mainly flushing TEAE), general disorders and administration site conditions, nervous system disorders, gastrointestinal disorders and musculoskeletal and connective tissue disorders.

The investigator considered that most of the TEAEs reported during the study were not related to the study drug.

No clinical relevance was found in clinical laboratories, vital signs, 12-lead electrocardiography, continuous cardiac monitoring (telemetry) or physical examination.

Pharmacokinetics of

IMB-1018972 was analyzed in the plasma of all blood samples of subjects receiving IMB-1018972 in this study, but IMB-1018972 was only measured in a few plasma samples. Thus, only the concentration of IMB-1018972 is listed in the present clinical study report, and no descriptive statistics or concentration-time profile are provided. In addition, the PK parameters of plasma IMB-1018972 were not calculated. Thus, urine samples were not analyzed for IMB-1018972 concentration.

Because the pharmacodynamic effects of IMB-1028814 and trimetazidine are the same, data for IMB-1028814 and trimetazidine, respectively, and for the sum of IMB-1028814 and trimetazidine concentrations, are provided.

Single dose MR portion

After administration of 50mg and 200mg of a single oral fasted dose of IMB-1018972, t of IMB-1028814 _{Maximum value} The case of the 8-hour MR formulation (2 hours for 50mg and 200mg IMB-1018972) is earlier than the case of the 4-hour MR formulation (5 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972). After a single oral fasted dose of both 50mg and 200mg of IMB-1018972, t of trimetazidine _{Maximum value} In the case of the 8-hour MR formulation (8 hours for 50mg IMB-1018972 and 5 hours for 200mg IMB-1018972) the case of the 4-hour MR formulation (6 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972) was later. After a single oral fasted dose of both 50mg and 200mg of IMB-1018972, IMB-1028814+ trimetazidine t _{Maximum value} The situation was similar for the 8-hour MR formulation (5 hours for 50mg IMB-1018972 and 2.5 hours for 200mg IMB-1018972) and the 4-hour MR formulation (5 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972).

C of IMB-1028814 for 8 hour MR formulation versus 4 hour MR formulation after administration of 50mg and 200mg of a single oral fasted dose of IMB-1018972 _{Maximum value} 35% and 32% lower, respectively, of trimetazidine C _{Maximum value} 20% and 24% lower, respectively, and IMB-1028814 +trimetazidine C _{Maximum value} 21% lower and 34% lower, respectively.

AUC of IMB-1028814 after 8 hours MR formulation after administration of 50mg of a single oral fasted dose of IMB-1018972 compared to after 4 hours MR formulation _0-t 26% lower AUC of trimetazidine _0-t 12% lower and IMB-1028814+ trimetazidine AUC _0-t 18% lower. AUC of IMB-1028814 after an oral fasted dose of 200mg of IMB-1018972 after an 8-hour MR formulation compared to after a 4-hour MR formulation _0-t AUC of trimetazidine at 6% higher _0-t 4% higher, and IMB-1028814+ trimetazidine AUC _0-t The height is 5 percent.

After administration of 50mg MR formulation and 200mg MR formulation with dissolution profiles of 4 and 8 hours under fasted conditions, geometric mean t for IMB-1028814 _1/2 Between 3.35 hours and 4.27 hours, for trimetazidine, the geometric mean t _1/2 Between 8.11 hours and 9.35 hours, and for IMB-1028814 +trimetazidine, the geometric mean t _1/2 Between 6.95 hours and 7.96 hours. Thus, for each analyte, t between 4 fasted treatments _1/2 No difference was observed.

Influence of food

The possible effect of food on the PK of IMB-1028814 and trimetazidine was explored by comparing the administration of 200mg MR formulation of IMB-1018972 administered in a single oral dose to FDA-defined high fat breakfast and 8 hour dissolution profile under fasted conditions.

In both cases, the median IMB-1028814t was reached 3 hours after dosing _{Maximum value} . Under fasted conditions, median trimetazidine t was reached 5 hours post-dose relative to 3 hours post-dose _{Maximum value} 。

Explore food pairs C of IMB-1028814 and trimetazidine _{Maximum value} 、AUC _0-t And AUC _0-inf Is a function of (a) and (b). No food effect was observed on the IMB-1028814 exposure parameter AUC _0-t And AUC _0-inf (both of the estimated values were 1.16, and90% CI in the range of 1.05 to 1.28). However, after FDA defined high fat breakfast, C after single dose of 200mg 8 hours MR IMB-1018972 _{Maximum value} About 42% higher (estimated 1.42;90% CI range 1.24 to 1.63) relative to administration under fasted conditions.

No food-affecting trimetazidine exposure parameter C was observed after single dose administration of 200mg of 8 hours MR IMB-1018972 _{Maximum value} (estimated 1.10;90% CI range 0.99 to 1.21), AUC _0-t (estimated 0.99;90% CI range 0.91 to 1.09) and AUC _0-inf Evidence of (estimates of 0.97;90% CI range of 0.88 to 1.07).

Multi-dose MR portion

Median IMB-1028814t after administration of 200mg of 8 hour MR IMB-1018972 dose _{Maximum value} For trimetazidine, at day 1 and day 5 for 2 hours, median t _{Maximum value} 5.5 hours and 5 hours on day 1 and day 5, respectively.

Based on a visual inspection of the geometric mean plasma concentration-time profile and geometric mean trough concentration, a conclusion can be drawn: by day 5 after 200mg of 8 hour MR IMB-1018972 administered at multiple doses, both IMB-1028814 and trimetazidine concentrations reached steady state.

On day 5, relative to day 1, the geometric mean R of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine _ac 1.22, 2.28 and 1.66 respectively. This indicated minimal accumulation of IMB-1028814 in plasma, moderate accumulation of trimetazidine in plasma, and moderate accumulation of IMB-1028814+ trimetazidine in plasma. The geometric mean half-lives for the 200mg 8 hour MR IMB-1018972 doses were 3.85 hours, 9.52 hours and 8.64 hours for IMB-1028814, trimetazidine and IMB-1028814+ trimetazidine, respectively.

Conclusion(s)

Safety of

Overall, healthy male and female subjects are generally well tolerated by single and multi-dose MR formulations. No clinical relevance was found in clinical laboratories, vital signs, 12-lead ECG, continuous cardiac monitoring (telemetry) or physical examination. Notably, no hemodynamic changes were found after administration of IMB-1018972 as an MR formulation, nor was a change in QTc interval found.

No mortality was reported during the study. Most TEAEs were mild and no severe TEAE was reported during the study. Overall, 12 out of 181 TEAEs total were moderate.

Two subjects withdraw from the study: 1 subject was withdrawn due to moderate SAE (unlikely to be related) of influenza-like disease, and 1 subject was withdrawn due to moderate TEAE (likely to be related) with elevation of ALT.

Overall, there was no apparent dose dependence of the amount and incidence of TEAE.

Administration under fed conditions, no significant difference in the amount and incidence of TEAE between fasted and fed IMB-1018972 administration was observed in the single dose MR fractions.

Pharmacokinetics of

IMB-1018972 could be measured in only a small number of plasma samples taken during the study.

When the results of dose of IMB-1018972 of single and multiple MR formulations under fasted and fed conditions are combined, the system bioavailability of IMB-1018972 initially hydrolyzes to IMB-1028814 and subsequently IMB-1028814 is relatively fast, with the median t for IMB-1028814 _{Maximum value} Between 0.5 and 5 hours after administration, and for trimetazidine, median t _{Maximum value} Between 1.5 and 8 hours after administration. Median t _{Maximum value} Is not increased with the increase of the dose of IMB-1018972

No food-affecting IMB-1028814 exposure parameter AUC was observed after administration of a single dose of 200mg of 8 hours MR IMB-1018972 _0-t And AUC _0-inf Evidence of (c). However, C under fed conditions after administration of a single dose of 200mg 8 hours MR IMB-1018972 relative to administration under fasted conditions _{Maximum value} And about 42% higher.

No food-affecting trimetazidine exposure parameter C was observed after single dose administration of 200mg of 8 hours MR IMB-1018972 _{Maximum value} 、AUC _0-t And AUC _0-inf Evidence of (c).

When single and multiple IMB-1018972 dose results under fasted and fed conditions are combined, the geometric mean t for IMB-1028814 _1/2 Between 2.5 hours and 4.5 hours, and for trimetazidine, the geometric mean t _1/2 Between 6.5 hours and 9.5 hours. Geometric mean t _1/2 Does not increase with increasing dose of IMB-1018972.

Within 48 hours after administration of a single oral dose of IMB-1018972 in the range 50mg to 400mg, an average of 3.99% to 5.74% of the dose was expelled as IMB-1028814 in urine and an average of 23.11% to 32.55% of the dose was expelled as trimetazidine.

Within 48 hours after administration of a single oral dose of 35mg of trimetazidine, an average 54.47% dose was expelled as trimetazidine in urine.

Under fed conditions, no relevant accumulation of IMB-1028814 was observed (Rac 1.22) and medium accumulation of trimetazidine (Rac 2.28) after twice daily dosing for 5 days with 200mg of 8 hours MR IMB-1018972.

Overall (L)

In view of the positive risk/benefit profile and observed PK profile of the IMB-1018972 metabolite IMB-1028814 and trimetazidine in this FIH study, further clinical development of IMB-1018972 was warranted.

Introduction to the invention

IMB-1018972 is an orally administered small molecule that has been developed as a therapeutic agent for ischemic cardiovascular disease and related abnormal cellular energetics. Potential indications include angina, heart failure and peripheral vascular disease. IMB-1018972 is a Novel Chemical Entity (NCE) of a pharmacological moiety fatty acid oxidation (pFAX) inhibitor that functions to protect or enhance energy metabolism in cells exposed to hypoxia or ischemia. Other pFOX inhibitors include ranolazine (Ranexa), perhexiline, and trimetazidine. Glucose oxidation is more efficient at producing adenosine triphosphate per consumption of one oxygen molecule than fatty acid oxidation.

IMB-1018972 undergoes hydrolysis after administration, and the hydrolysis products are inhibitors of niacin (also known as niacin or vitamin B3) and 3-keto acyl CoA thiolase (3-KAT), designated IMB-1028814. In addition to IMB-1018972, IMB-1028814 was also widely studied and characterized in non-clinical studies. IMB-1028814 undergoes further metabolism and 1 metabolite is trimetazidine, a drug marketed in Europe since 1987 for the treatment of angina pectoris.

The main mechanism of action of IMB-1028814 is thought to competitively inhibit 3-KAT, which results in the transition of substrate utilization from fatty acid oxidation to glucose oxidation in the myocardium. Delivery of niacin can be used to additionally enhance cell energetics.

The non-clinical pharmacologic and toxicological data collected when CSP was finalized support clinical studies administered for up to 4 weeks of IMB-1018972 to assess its safety, tolerability, PK and pharmacodynamics in humans.

Trimetazidine administered in this study was a drug for the treatment of angina pectoris marketed in europe since 1978.

Basis of study

Prior to the study described in this CSR, no clinical study with IMB-1018972 was performed. Thus, this first human study (FIH) was conducted to evaluate the safety, tolerability and PK of IMB-1018972 as a Modified Release (MR) formulation.

During the study, a single dose MR moiety was added to evaluate the safety, tolerability and PK profile of a single oral dose of the newly developed MR formulation of IMB-1018972. These involve 4 MR preparations: IMB-1018972 at 50mg and 200mg dose strengths, each formulation had a 4 hour dissolution profile and an 8 hour dissolution profile. The purpose of these MR formulations is twofold: the first aim is to reduce IMB-1018972 and its subsequent metabolite C _{Maximum value} The method comprises the steps of carrying out a first treatment on the surface of the The second objective is to extend the absorption time and maintain the total exposure as measured by AUC. Lower C is expected _{Maximum value} Will improve overall tolerability and extend absorption time, with the retained AUC expected to reduce the variability observed in exposure to IR formulations. Based on availability of 4 MR formulations administered under fasted conditions in a single dose MR fractionSafety, tolerability, and PK results the formulation selected by the sponsor for administration in the single dose MR moiety under fed conditions was 200mg of the 8 hour MR formulation. The MR formulation test is important because the formulation is planned to be used in a phase 2 proof of concept study initiated by the 2020 program.

The last part (multi-dose MR part) was added to evaluate the safety, tolerability and PK profile of a multi-dose (once every 12 hours [ q12h ], 5 consecutive days) MR formulation with 200mg dose intensity and 8 hour dissolution profile (200 mg 8 hour MR formulation) taken with food. The dose and formulation were tested in fasted and fed states in a single dose MR fraction. The dose and formulation are intended for use in a patient population in a later study, and the data collected from the subject cohort in this last section will provide information for this decision.

Purpose of investigation

Main purpose(s)

To evaluate the safety and tolerability of single oral doses of the MR formulation of IMB-1018972 and multiple oral doses of the 200mg 8 hour MR formulation of IMB-1018972 in healthy subjects.

Secondary purpose

To evaluate PK profile of single oral dose MR formulation of IMB-1018972 and multiple oral dose 200mg 8 hour MR formulation of IMB-1018972 in healthy subjects

To assess absorption and PK profile of 200mg 8 hour MR formulation of IMB-1018972 following multiple oral doses taken with food in healthy subjects

To assess the safety and tolerability of 200mg 8 hour MR formulation of IMB-1018972 following multiple oral doses taken with food in healthy subjects

Study plan

Overall study design and planning

Type of study

This is a double blind, randomized study that included single and multi-dose MR fractions to evaluate the safety, tolerability and PK of single oral doses of MR formulation of IMB-1018972 and multiple oral doses of 200mg 8 hour MR formulation of IMB-1018972. The study began with the SAD section.

Single dose MR portion

days

1, 4, 7 and 10 under fasted conditions, as determined by the sponsor based on the available safety, tolerability and PK results of the 4 MR formulations.

The single dose MR portion comprises:

qualification screening period up to 35 days

One study period involving the administration of a single dose of IMB-1018972 on

days

1, 4, 7, 10 and 13

Safety assessment and blood sampling for PK purposes from day 1 before dosing to 48 hours after last drug administration

Discharge 72 hours after the last study drug administration

Follow-up visit 7 to 14 days after the last PK blood sample

Multi-dose MR portion

In the multi-dose MR section, 1 group of 12 healthy subjects (all taking active drug) was included. The subject received multiple oral doses of the MR formulation of IMB-1018972q12h for 5 consecutive days under fed conditions; on day 5, only a single morning dose was administered. The MR formulation of the administered IMB-1018972 was identical to the formulation administered in the single dose MR fraction under both fasted and fed conditions.

The multi-dose MR portion comprises:

qualification screening period up to 35 days

One study period involving the administration of 200mg of 8 hour MR formulation of multiple doses of IMB-1018972 from day 1 to day 5

Discharge 48 hours after last drug administration

Follow-up visit 6 to 8 days after the last PK blood sample

Screening period

Subjects reported to the medical screening facility to be eligible for screening within 5 weeks prior to (first) study drug administration.

Subjects signed a study-specific ICF prior to any study-specific screening procedure. Written informed consent was obtained for all subjects, whether or not they were eligible to participate in the study. The signed ICF is retained and archived at the PRA and a copy is provided to the subject.

Treatment period

The subjects were clinically 1 treatment period. Subjects entered the clinical study center at day-1 afternoon. Day 1 is the (first) day of drug administration.

Subjects in the single dose MR fraction were discharged on day 16 (72 hours after the last study drug administration on day 13) after the completion of the assessment. Subjects in the multi-dose MR fraction were discharged on day 7 (48 hours after the last study drug administration on day 5) after the completion of the assessment.

Follow-up visit

For the single dose MR fractions, follow-up evaluations were performed 7 to 14 days (23 to 30 days) after the last PK blood sample. For the multi-dose MR fractions, follow-up evaluations were performed 6 to 8 days (day 14±1) after the last PK blood sample.

Discussion of study design

Influence of food

In the single dose MR section, 12 healthy subjects (each taking active drug) received 1 of the 4 MR formulations of single oral dose IMB-1018972 in the same fixed order for all subjects under fasted conditions (overnight fasted for at least 10 hours) on

days

1, 4, 7 and 10. On day 13, 1 of these 4 MR formulations was selected for administration to the same subject under fed conditions (high fat breakfast defined by the FDA prior to dosing) to assess the possible effect of food on PK of IMB-1018972. This allows comparison of PK and tolerability of IMB-1018972 in plasma in subjects after administration of the MR formulation under fasted and fed conditions.

In the multi-dose MR section, 12 healthy subjects received multiple oral doses of the MR formulation of IMB-1018972q12h for 5 consecutive days under fed conditions; on day 5, only a single morning dose was administered. The MR formulation of the applied IMB-1018972 was identical to the MR formulation applied in the single dose MR section. The safety, tolerability and PK of the MR formulation of multiple doses taken with food were evaluated.

Others

The planned confinement period, discharge date and follow-up period may be adjusted according to the newly emerging study results. Furthermore, the timing, type, and number of safety and PK assessments may vary over the course of the study.

In vitro studies (cytochrome P450[ CYP ]3A4/GT1A1/CYP2C19/CYP2C 9) did not show interactions with oral contraceptives. Women of child bearing age using appropriate contraceptive methods are included in the study in order to correlate the results of the FIH study with a female target patient population.

The use of healthy subjects allows for a clearer interpretation of the study results than patients, as there are no confounding factors due to disease states and/or concomitant drug changes.

The study was conducted in different subject groups, as the number of doses to be tested and all assessments associated with these courses were considered too extensive to be conducted in a single subject group of repeated participation.

Researchers have taken all of the conventional precautions required for research at an early stage of the development of new drugs.

Selection of study population

The entire study population contained 88 subjects.

In both single-dose and multi-dose MR fractions, a total of 24 healthy male or female subjects (12 in each fraction) were included. All efforts were made to have a 50:50 ratio between male and female subjects, but a minimum of at least 4 subjects of each sex were dosed in each fraction.

Inclusion criteria

Subjects were eligible for inclusion in the study if they met all of the following inclusion criteria:

1. Gender: either male or female.

2. Age: the screening was 18 to 65 years (including 18 and 65 years).

3. Body Mass Index (BMI): 18.0kg/m2 to 32.0kg/m2 (including 18.0kg/m2 and 32.0kg/m 2).

4. Status: healthy subjects.

5. At the time of screening, women may have fertility (but not pregnant or lactating), or lack fertility (surgical sterilization or physiological inability to pregnant, or at least 1 year after menopause [ continuous 12 months amenorrhea duration ]); all women were confirmed to be not pregnant by serum pregnancy tests performed at screening and at each admission.

6. Female subjects with fertility and a fertile male sexual partner must agree to use adequate contraception from the start of screening until 90 days after the follow-up visit. Adequate contraception is defined as the use of hormonal contraceptives or intrauterine devices in combination with at least 1 of the following contraceptive forms: a diaphragm, cervical cap or condom. Depending on the lifestyle of the subject, complete abstinence is also acceptable.

7. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from (first) visit to the clinical study center until 90 days after the follow-up visit. Adequate contraception in a male subject (and its female partner) is defined as the use of hormonal contraceptives or intrauterine devices in combination with at least 1 of the following contraceptive forms: a diaphragm, cervical cap or condom. Depending on the lifestyle of the subject, complete abstinence is also acceptable.

8. All prescribed medications must be discontinued at least 30 days before (first) entering the clinical research center. Hormonal contraceptives are an exception and can be used throughout the study.

9. All over-the-counter drugs, vitamin formulations and other food supplements or herbs (e.g., st. John's word) must be deactivated at least 14 days before (first) entering the clinical research center. Paracetamol is an exception and is allowed to use until it has entered the clinical research center.

10. 48 hours before (each) entering the clinical research center, it is willing to abstain from alcohol, methylxanthine containing beverages or foods (coffee, tea, cola, chocolate, energy drinks), grapefruit (fruit juice) and tobacco products.

11. Good physical and mental health based on medical history, physical examination, clinical laboratory and vital signs, as judged by researchers.

12. No clinically abnormal 12-lead ECG at screening (incomplete right bundle branch block is acceptable): for men and women, PR interval <210ms, QRS duration <120ms, and QTc interval (Fridericia's). Ltoreq.450 ms.

13. Willing and able to sign ICFs.

Exclusion criteria

The subject will be excluded from participation if any of the following exclusion criteria are met:

1. Previously engaged in current research.

Pra or sponsor employee.

3. History of related medications and/or food allergies.

4. Tobacco products were used within 3 months prior to (first) drug administration.

5. History of alcohol abuse or drug abuse (including soft drugs such as cannabis products).

6. Positive drug and alcohol screening (opioid, methadone, cocaine, amphetamine [ including headpill ], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol) at screening and (each) entering the clinical study center.

7. On average, more than 24 units of alcohol are consumed per week (1 unit of alcohol equals about 250mL of beer, 100mL of wine, or 35mL of spirit).

8. Positive selection for hepatitis b surface antigen (HBsAg), anti-Hepatitis C Virus (HCV) antibodies or anti-HIV 1 and 2 antibodies.

9. Drug studies were enrolled 60 days prior to (first) drug administration in the current study. In the current study, more than 4 other drug studies were enrolled within 12 months prior to (first) drug administration.

10. Blood was donated or lost to more than 100mL within 60 days prior to (first) drug administration. In the current study, more than 1.5 liters of blood (for male subjects)/more than 1.0 liters of blood (for female subjects) were donated or lost within 10 months prior to (first) drug administration.

11. Researchers believe that significant and/or acute diseases may affect the safety assessment within 5 days prior to (first) drug administration.

12. Veins which are not suitable for infusion or blood sampling.

Note that subjects should avoid eating any poppy seed-containing food within 48 hours (2 days) prior to going to the clinical study center for screening to avoid false positive drug screening results. Furthermore, they should avoid strenuous exercise within 96 hours (4 days) prior to screening, as this may lead to abnormal clinical laboratory values.

Removing the subject from the assessment

Participation in this study was entirely voluntary. Subjects were given the right to withdraw from the study at any time for any reason.

The investigator had the right to terminate the subject's participation for any of the following reasons: difficulty in obtaining a blood sample, violation of a protocol, severe AE or SAE, or any other reason related to the safety of the subject or the integrity of the study data.

If the subject exits the study, the sponsor should be immediately notified. If there is a medical reason for withdrawal, the subject will continue to receive supervision from the researcher until satisfactory health is restored.

Subjects who did not successfully complete all screening evaluations for any reason to exit or withdraw were considered to be screening failure.

After receiving the subject number, subjects who either withdraw from the study or voluntarily withdraw from the study for any reason (whether related to study drug or not) are considered prematurely terminated subjects. If the subject is withdrawn for reasons related to the study medication, the subject is terminated prematurely at the discretion of the researcher without replacement. If the subject does not complete the study for reasons unrelated to study medication, the subject may be terminated prematurely after the sponsor and PRA agree with each other to exchange.

Decisions regarding replacement of the subject are recorded.

PRA makes all efforts to ensure that early termination subjects receiving study drug complete safety follow-up assessments.

Stopping rules for individual subjects

Dosing of the subjects was stopped at any time during the study if any of the following occurred:

serious adverse effects (i.e., SAE believed to be at least likely to be related to study drug administration).

The overall pattern of clinically significant changes in any safety parameters (e.g., moderate or severe AE in >1 subject), these changes may appear slight for individual events, but appear to the sponsor or researcher to represent a safety issue overall.

Other findings decided by the researcher and/or sponsor's medical inspector that further dosing should be stopped.

Treatment of

Single dose MR portion

The formulation selected for day 13 administration was 200mg of the 8 hour MR formulation, as determined by the sponsor based on the available safety, tolerability and PK results of the 4 MR formulations administered on

days

1, 4, 7 and 10 under fasted conditions.

The following treatments were administered in a single dose MR fraction:

Multi-dose MR portion

Twelve subjects received multiple oral doses of 200mg of the 8-hour MR formulation of IMB-1018972q12h for 5 consecutive days under fed conditions; on day 5, only a single morning dose was administered.

Investigation of drug Properties

Active pharmaceutical

Pharmaceutical product: IMB-1018972

Activity: fatty acid oxidation inhibitor

Development was used to: ischemic cardiovascular disease

Dosage form: oral MR tablet to be used in MR section

The manufacturer: PRA pharmacy

Lot number: 2479-1810-00441 (bulk drug)

Active pharmaceutical

Pharmaceutical product: wanshengli MR (trimetazidine hydrochloride)

Activity: fatty acid oxidation inhibitor

Development was used to: angina pectoris

Intensity: 35mg

Dosage form: oral MR tablet

The manufacturer: shi Weiya research pharmaceutical (Pakistan) (private) Co., ltd

Lot number: 273782 (pharmaceutical product)

Study drug was stored in the lock-up facility of the PRA pharmacy and monitored continuously under the required storage conditions. Study medication is distributed by pharmacists to researchers or authorized designated personnel.

Method of assigning subjects to treatment groups

After informed consent was obtained, subjects were screened according to inclusion and exclusion criteria. Subjects meeting all qualification criteria received subject numbers at the time of inclusion in the study. Based on the randomized codes generated by the biometric department of PRA, they received a subject number prior to administration. Subject numbering ensures identity throughout the study.

Subject numbers 501 to 512 are for single dose MR portions and subject numbers 513 to 524 are for multi-dose MR portions.

Any replacement subject will receive the subject number to be replaced, increased by 200, and be administered the same treatment. Subjects were assigned to study sections and study groups based on their availability. Treatments within the group are assigned according to a randomized code generated by the biometric department of the PRA.

In both MR fractions, all 12 subjects received IMB-1018972.

Subjects who did not successfully complete all screening evaluations for any reason to exit or withdraw were considered to be screening failure. Such subjects, as well as subjects eligible to be included in the study but not receiving study medication, did not receive subject numbers, and only input applicable data into the eCRF.

Selection of dose in study

Based on non-clinical toxicology data, subjects in the present clinical study are considered to be free of unreasonable risk of adverse effects. Based on the level of adverse effects (NOAEL) not observed in 28 day dogs at 200 mg/kg/day (oral), the calculated Human Equivalent Dose (HED) was 108 mg/kg/day. For a 60kg individual, the NOAEL dose will be 6480mg. In the case of 10-fold safety factor application, this would allow a Maximum Recommended Starting Dose (MRSD) of 648 mg/day. 7,8 the initial dose planned in the current phase 1 study was 50mg, corresponding to 60kg subjects of 0.83 mg/kg/day. The starting dose is less than 10% of the MRSD determined from canine NOAEL and less than 1% of canine NOAEL.

The maximum planned dose of 1600mg for healthy volunteers in this study was 25% of the HED NOAEL dose of 6480mg and was only 2.5 times higher than MRSD. The conservative dosing margin is expected to cover potential therapeutic exposure, for example in patients with kidney or liver damage, or in the case of interaction with potential drugs of IMB-1018972. This risk of healthy volunteers was determined to be acceptable at these exposure levels based on the absence of irreversible or significant toxicity and the absence of a sentinel safety biomarker.

The relevant animal study was a 28 day canine study, with NOAEL of IMB-1018972 of 200 mg/kg/day. AUC of IMB-1028814 at this dose, day 26, for male and female _0-8x2 417,733 and 652,849ng h/mL, respectively. AUC of trimetazidine at this dose at day 26 for male and female _0-8x2 15,042 and 13,834ng h/mL respectively.

The sponsor added a queue that tested a single 35mg MR dose of trimetazidine (ten thousand-force). This dose was chosen because it is the most common dose of trimetazidine in the treatment of angina, and therefore is known to have an effective PK profile.

Timing of doses in study

Study drug was administered to subjects in an upright position with 240mL of tap water. Allowing an additional volume of water to be comfortably consumed the capsule/tablet if desired; this additional volume is recorded in the eCRF. For afternoon/evening administration, doses were given at 08:00h to 11:00h and 20:00h to 23:00 h. Each individual subject was dosed at about the same time (+ -15 minutes) per dosing day. The study drug was not chewed.

Administration of study medication is supervised by a researcher or authorized designated personnel. After drug administration, oral and hand examinations were performed.

Administration under fasted conditions

Single dose MR portion

Prior to dosing (

days

1, 4, 7 and 10 in the single dose MR section), subjects fasted overnight at least 10 hours after the light dinner in the evening of the previous day. Following dosing, subjects fasted for 4 hours until lunch. Fluids other than water are not allowed during fasting; however, no water (other than the water taken with the dose) was allowed from 2 hours before administration until 1 hour after administration.

Subjects in the single dose MR fraction were not allowed to lie down within 4 hours after dosing, except when evaluation was required.

Administration under fed conditions

Single dose MR portion

Subjects fasted overnight for at least 10 hours after a fast meal in the evening before dosing on day 13. On day 13, subjects received FDA-defined high fat breakfast, which had to be consumed within 20 minutes. Administration occurs 30 minutes after breakfast begins. Following dosing, subjects fasted for 4 hours until lunch. During fasting, fluids other than water are not allowed. The subject was not allowed to lie down within 4 hours after dosing, except when evaluation was required.

Multi-dose MR portion

Morning dose

The subject fasted overnight for at least 10 hours after a fast meal in the evening before each morning dose. On

days

1 and 5, the subject received a standard breakfast that had to be consumed within 20 minutes. Administration occurs 30 minutes after breakfast begins. Following dosing, subjects fasted for 4 hours until lunch. During fasting, fluids other than water are not allowed. Breakfast is not standardized on days 2 to 4 and is provided up to 1 hour prior to dosing and is eaten up to the end of dosing. Subjects need not be fasted after these days of administration.

Evening dose

From day 1 to day 4, a night snack was provided up to 1 hour prior to dosing and was consumed prior to dosing. Subjects fasted overnight at least 10 hours after eating the fast.

The subject was not allowed to lie down for 4 hours after morning or evening dosing, except when evaluation was required.

Diet during study

A fasted period of at least 4 hours is required before clinical laboratory samples are obtained at all time points.

When not fasted, meals and snacks (such as decaffeinated coffee, herbal tea, fruit and biscuits) were provided according to PRA Standard Operating Procedures (SOP). Providing a light dinner in the evening prior to those days requiring fasting until lunch time (fasting conditions); fast food is provided the evening before the day of fasting is required until the FDA-defined high fat breakfast or breakfast (fed condition).

The FDA-defined high fat breakfast for day 13 of the single dose MR section, 918kcal, comprises:

2 omelets (15 g butter/margarine fried) (about 100 g)

1 part bacon (40 g) (or, for vegetarian, brix cheese 60+)

1 part of fried potato (115 g)

2 pieces of (roasted) (wheat) bread (about 70 g) and 15g margarine

1 cup of whole milk (240 mL)

The aggregate 918kcal (vegetarian version 915 kcal) can be subdivided as follows:

39g protein=156 kcal

59g fat=527 kcal

59g carbohydrate=235 kcal

Blind method

In both MR fractions, all 12 subjects received IMB-1018972.

Since only the subject samples receiving the active drug IMB-1018972 were analyzed, copies of the randomized codes were provided by the pharmacy to the bioanalytical laboratory that analyzed PRA of PK samples.

Other limitations during previous and concomitant therapies and studies

From (first) entering the clinical study center until follow-up, use of all prescribed medications is not allowed. Hormonal contraceptives are allowed throughout the study except for hormonal contraceptives. From the (first) entry into the clinical study center until follow-up, use of all over-the-counter drugs, vitamin formulations, and other food supplements or herbs (e.g., st. John's word) is not allowed. Except for paracetamol: from the beginning of the (first) admission, the researcher may allow a limited amount of paracetamol for the treatment of headache or any other pain. Other drugs for AE treatment could be prescribed only if deemed necessary by the investigator. If a drug is used, the name, dose and dosing regimen of the drug need to be recorded in eCFF.

During the stay in the clinical research center, alcohol, methylxanthine containing beverages or foods (coffee, tea, cola, chocolate, energy drinks), grapefruit (fruit juice) and tobacco products are not allowed to be used.

During the 96 hours (4 days) prior to (each) admission and during the stay at the clinical study center, no vigorous exercise was allowed.

Subjects were not allowed to eat any poppy seed-containing food for 48 hours (2 days) prior to (each) entering the clinical study center, as this may lead to false positive drug screening results.

Female subjects with fertility and with a fertile male sexual partner were required to use adequate contraception from screening until 90 days after follow-up visit (see description below).

If surgical sterilization is not performed, the male subject is required to use adequate contraception (see description below) and no sperm donation occurs for 90 days from the (first) visit to the clinical study center.

Adequate contraception is defined as the use of hormonal contraceptives or intrauterine devices in combination with at least 1 of the following contraceptive forms: a diaphragm, cervical cap or condom. Depending on the lifestyle of the subject, complete abstinence is also acceptable.

During the study, subjects were not allowed to donate blood until a follow-up visit (except for blood sampling for the study plan).

Compliance with treatment

Study medication was administered at the clinical study center. To ensure therapeutic compliance, administration of study medication is supervised by the researcher or authorized designated personnel. Compliance was further confirmed by bioassay evaluation of IMB-1018972, IMB-1028814, and trimetazidine in plasma and urine samples.

The exact time of study drug administration and the number of units administered are recorded in eCRF. Following the procedure of drug accountability as specified in CSP.

Safety and pharmacokinetic measurements and variables

The present study was conducted to evaluate safety, tolerability and PK after a single oral dose of MR formulation of IMB-1018972 and multiple oral doses of 200mg 8 hour MR formulation of IMB-1018972. The study did not include efficacy or pharmacodynamic assessments.

Adverse events

AE were recorded from (first) admission until the end of the follow-up visit. Any clinically significant observation in the results of clinical laboratory, 12-lead ECG, vital signs or physical examination is recorded as AE.

Treatment-producing AE (TEAE) is defined as any event that does not exist prior to (first) administration of the study drug, or that does exist already after exposure to the study drug with worsening severity or frequency.

AE that occurred prior to (first) administration of study drug was considered pre-treatment AE.

At several time points before and after drug administration, subjects were asked a non-guiding question to determine the occurrence of AE. During the study, subjects were asked at regular intervals to follow up on the general status of any AE. In addition, all AEs spontaneously reported during the study were recorded. Details include description of the event, date and time of onset, date and time of end, total duration, severity, relationship to study medication, intervention, severity and outcome. All answers were interpreted by the investigator and recorded in the eCRF. All AEs were classified according to AE "supervisory active medical dictionary (Medical Dictionary for Regulatory Activities) (MedDRA; 22.0 edition).

AE severity is classified as mild, moderate or severe; the relationship between AE and study drug is indicated as none, unlikely, probable (possibly), probable (likely) or definite. Adverse events assessed as possible, probable or definitive are considered relevant to study drug; AE assessed as none or unlikely were considered to be independent of study drug.

The concomitant medication or other therapy required in the case of any AE is recorded. Concomitant medications are classified according to the world health organization drug dictionary (World Health Organization Drug Dictionary) (22.0 edition).

All AEs were followed until they resolved or stabilized.

Clinical laboratory

Blood and urine samples were collected for clinical laboratory assessment according to PRA SOP.

The following parameters were measured:

clinical chemistry (serum quantification): total bilirubin, alkaline phosphatase, gamma glutamyl transferase, aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), lactate dehydrogenase, creatinine, urea, total protein, glucose, inorganic phosphate, sodium, potassium,

Calcium and chloride

Hematology (blood quantification): white blood cells, red blood cells, hemoglobin, hematocrit, platelets, partially autodifferentiated (lymphocytes, monocytes, eosinophils, basophils and neutrophils), mean red blood cell volume, mean red blood cell hemoglobin and mean red blood cell hemoglobin concentration

Coagulation (blood quantification): prothrombin time (reported in seconds and as an internationally normalized ratio), activated partial thromboplastin time and fibrinogen

Urine sample analysis (urine qualitative): haemoglobin, urobilinogen, ketones, glucose and proteins

Serology: HBsAg, anti-HCV and anti-HIV 1 and 2

Drug and alcohol screening: opioids, methadone, cocaine, amphetamines (including headshot), cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants and alcohol

Pregnancy test (female only): beta human chorionic gonadotrophin in serum

Urine for urine sample analysis was obtained from the PK urine collection container at the end of the collection time interval.

In the case of unexplained or unexpected clinical laboratory test values, the test should be repeated as soon as possible and follow-up should be performed until the results have returned to normal range and/or sufficient interpretation of the abnormality is found. The clinical laboratory clearly marks all laboratory test values outside the normal range and the researcher indicates which of these deviations are clinically significant. Clinically significant laboratory result bias is recorded as AE and indicates relationship to treatment.

Vital signs

After the subject had been at rest in the supine position for at least 5 minutes, systolic and diastolic blood pressure and pulse were recorded. These evaluations were performed using automated equipment. Body temperature and respiration rate are then measured.

Electrocardiogram

After the subject has been at least 5 minutes at rest in the supine position, a standard 12-lead ECG is recorded. ECG was recorded using an ECG machine equipped with computer based time interval measurements (with no/minimal interference by procedure). The following ECG parameters were recorded: heart rate, PR interval, QRS duration, QT interval, QTcF interval, and interpretation of the ECG profile by the researcher.

Continuous heart monitoring (remote measurement)

In both single-dose and multi-dose MR fractions, telemetry was not performed.

All relevant or significant arrhythmia events are recorded in the rhythm strip (10 seconds). Clinically significant events of ECG were evaluated by researchers.

Physical examination

Physical examination was performed according to PRA SOP. In addition, weight and height were measured according to prasiop.

Pharmacokinetic measurements

Blood sampling

At time points defined in the evaluation schedule, 3mL of blood samples were collected at each time point for analysis of the plasma samples for IMB-1018972, IMB-1028814 and trimetazidine. Blood samples are obtained via an indwelling intravenous catheter or by direct venipuncture. The exact time of blood sampling was recorded in eCRF.

During the day of telemetry, the subject remained in a calm supine position (no/minimal interference by the procedure) for 10 minutes, followed by each ECG assessment (scheduled to be performed prior to PK sampling) for up to 5 minutes. The start and stop times for (total) 15 minute time periods were recorded.

Details concerning sample collection, sample aliquoting, sample handling, sample storage, and sample transportation can be found in the laboratory Manual (laboratory manual) made by PRA.

Plasma samples (in the future) may also be used for research purposes such as assessing the activity of IMB-1018972 and trimetazidine, identifying exploratory biomarkers of predictable activity, cytochrome P450 profiles, or other exploratory assessments that may be helpful in characterizing the molecular mechanisms of IMB-1018972 and trimetazidine. For this purpose, the sample will be stored for up to 15 years.

Urine collection

Urine was collected for analysis of IMB-1018972, IMB-1028814 and trimetazidine during the time intervals defined in the evaluation schedule. Subjects were instructed to completely empty their bladders prior to study drug administration and at the end of each acquisition time interval. Blank urine was collected within 12 hours prior to study drug administration. The exact time of urine collection and the urine weight throughout the time interval (before and after any urine stabilizing agent, if used) were recorded in eCRF.

Details about sample collection, sample aliquoting, sample handling, sample storage, and sample transportation can be found in the handbook of laboratory made by PRA.

Urine samples can be stored for up to 1 year for further analysis of metabolites in urine in the event that unknown metabolites are found in the plasma.

Genotyping

At time points defined in the evaluation schedule, up to 7mL blood samples were taken for genotyping to better understand the effect of genotyping (e.g., CYP allele) on PK data. For subjects who had been screened prior to IEC approved protocol version 3.0 (day 25 of 3.2019), the blood sample was optional, while for subjects who participated in the study after IEC approved protocol version 3.0 (day 25 of 3.2019), the blood sample was mandatory.

Blood samples were double coded (1 code at PRA and 1 code at sponsor) and samples were saved until 15 years after the end of the study.

Blood samples are collected via an indwelling intravenous catheter or by direct venipuncture. The exact time of blood sampling is recorded in eCRF.

Safety and pharmacokinetic variables

The security variables to be measured include:

·AE

clinical laboratory

Vital signs

12 lead ECG

Continuous heart monitoring (telemetry)

Physical examination

Pharmacokinetic variables

Pharmacokinetic variables were the plasma and urine concentrations of IMB-1018972, IMB-1028814 and trimetazidine and their PK parameters. PK parameters determined or calculated using non-compartmental analysis are given in the table.

Table 11: plasma IMB-1018972, IMB-1028814 and trimetazidine parameters

The sum of the concentrations of IMB-1028814 and trimetazidine and PK parameters was calculated, with a corrected molecular weight of 310kDa for IMB-1028814 and 266kDa for trimetazidine.

The trough plasma levels of IMB-1018972, IMB-1028814 and trimetazidine were also determined (MAD fraction only).

AUC was calculated using the linear ascending/log descending trapezoidal rule, expressed in units of concentration x time.

Table 12: urine IMB-1018972, IMB-1028814 and trimetazidine parameters

Drug concentration measurement

The analysis of IMB1018972, IMB-1028814 and trimetazidine in plasma and urine samples was performed at the bioanalytical laboratory of PRA using a validated liquid chromatography-mass spectrometry/mass spectrometry method. The results from the calibration samples and the quality control samples indicate acceptable performance of these methods throughout the experiment. The data on the performance and stability of the method indicate that the sample results as reported are reliable.

Statistical and analytical planning of safety and pharmacokinetic evolution

Security collection

All subjects who had received at least 1 dose of IMB101897 or trimetazidine.

Pharmacokinetic aggregation

All subjects who had received at least 1 dose of IMB-1018972 or trimetazidine and provided adequate bioassay evaluation results to calculate reliable PK parameter estimates.

Statistical and analytical planning for safety and pharmacokinetic assessment

Details about the creation of the list and summary table and map can be found in the SAP and generated by the biometric department of the PRA. SAP was completed prior to database locking (and blindness breaking of study treatment codes).

All security and PK data are listed. Furthermore, all data are summarized in tabular and/or graphical form and descriptive statistics are given as appropriate.

Evolution of safety and tolerability

Safety and tolerability are assessed by AE, clinical laboratory, vital signs, ECG, continuous cardiac monitoring (telemetry) and physical examination findings, and any other parameters relevant to safety assessment.

Safety results are listed for all individuals and descriptive statistics are calculated, including changes from baseline (as applicable).

Pharmacokinetic assessment

Descriptive statistics (number, arithmetic mean, SD, coefficient of variation, minimum, maximum, median and geometric mean) of the plasma and urine PK parameters of IMB-1028814, trimetazidine and IMB-1028814+ trimetazidine in the PK population were calculated (as applicable).

The effect of food on the relative oral bioavailability of IMB-1018972 after a single oral administration was explored. This occurs in the single dose MR section, where the subject receives the same dose, first under fasted conditions, then under fed conditions. The evaluation is based on C _{Maximum value} 、AUC _0-t And AUC _0-inf 90% ci based on the ratio of geometric mean values of the logarithmic transformation data.

Determination of sample size

For this FIH study, no prospective calculation of statistical efficacy was performed. The sample size was chosen to provide information on safety, tolerability and PK after a single dose MR formulation of IMB-1018972 and a multi-dose 200mg8 hour MR formulation of IMB-1018972, and is a typical sample size for FIH studies. Any p-value to be calculated from SAP is interpreted from the perspective of the exploratory features of the study.

Study subjects

Subject 505 of the single dose MR fraction was withdrawn from the study because of the moderately elevated TEAE (possibly associated; day 11 up to 149 IU/L) and received no last single oral dose of 200mg of 8 hour MR formulation of IMB-1018972 on day 13 under fed conditions. None of these discontinued subjects were replaced. All 88 subjects were included in the PK and safety collections.

Fig. 10 is a treatment table of a subject.

Genotyping

All subjects provided blood samples for genotyping. Blood samples were used to genotype subjects of particular interest for CYP2D6 to better understand the differences in PK data. Any analysis of the relationship between genotyping and PK data will be presented separately from the present CSR.

Measurement of treatment compliance

Study medication was administered at the clinical study center. To ensure therapeutic compliance, administration of study medication is supervised by the researcher or authorized designated personnel. Based on observations during study drug administration, there was no sign of non-compliance. In addition, bioassay evaluation of IMB-1018972, IMB-1028814 and trimetazidine in plasma and urine samples confirmed treatment compliance.

Clinical laboratory assessment

Laboratory value changes over time

Although changes from baseline in several individuals were observed in clinical laboratory values, no clinically significant trend was observed.

Individual subject variation

At various times during the study, most subjects had one or more values outside of the range for clinical laboratory testing. Most of them were mild and the researchers considered no clinical significance. Multiple ALT levels measured for 1 subject were above the normal range and were considered clinically significant abnormalities.

Vital signs, ECG, physical examination findings, and other security-related observations

Vital signs

Although several individual changes from baseline were observed, none of blood pressure, pulse, body temperature, and respiratory rate showed trend or clinically relevant changes during any of the study portions.

Electrocardiogram

During any of the study portions, no clinically significant changes or trends in heart rate, PR interval, QRS duration, QT interval, or QTcF interval were observed. All 12-lead ECG assessments were recorded as normal, or in the case of abnormal recordings, these results were considered not clinically significant.

Continuous heart monitoring (remote measurement)

All telemetry ECG evaluation results obtained in the SAD and MAD sections are recorded as normal, or in the case of abnormal recordings, these results are considered not clinically significant.

Physical examination

All abnormalities observed at the time of screening and all changes observed after screening by physical examination were considered clinically insignificant.

Watch for modified release formulations

Fig. 11 is a table of evaluations given for the single dose MR section, with the following symbols:

a. physical examination: at screening, at day-1 (admission; this is an oriented examination conducted at the discretion of the investigator only) and at follow-up. On other dates, physical examination can be performed according to the instructions only if the researcher is at his discretion.

b. Clinical laboratory tests (including clinical chemistry, hematology, coagulation and urine sample analysis): at screening, on day-1 (admission), 24 hours after each administration and at follow-up.

c.12 lead ECG: PK sampling time points at screening, on day-1 (admission), before each dose and 1, 4, 6, 12, 24 and 48 hours after each dose, and at follow-up.

d. Vital signs (supine position systolic and diastolic blood pressure, pulse, body temperature and respiration rate): at screening, on day-1 (hospital admission), before and 1, 4, 6, 12, 24 and 48 hours after each dose, and at follow-up.

e. Subjects received 1 of the 4 MR formulations of single oral doses of IMB-1018972 on

days

1, 4, 7 and 10 under fasted conditions.

f. Blood sampling of PK for IMB-1018972, IMB-1028814 and trimetazidine in plasma: before each dose and 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 hours after each dose (and 72 hours after day 13 dose).

g. AE were recorded from admission until the end of the follow-up visit.

h. Blood sampling for genotyping is mandatory.

Fig. 12 is a table of evaluations given for the multi-dose MR section, with the following symbols:

b. Clinical laboratory tests (including clinical chemistry, hematology, coagulation and urine sample analysis): at screening, at day-1 (admission), 24 hours after the last dose and at follow-up.

c.12 lead ECG: at screening, at day-1 (admission), before the time points of 1, 4, 6, 12, 24 and 48 hours after the first dose on day 1, and after the last dose on day 5, and at follow-up.

d. Vital signs (supine position systolic and diastolic blood pressure, pulse, body temperature and respiration rate): at screening, at day-1 (admission), prior to the last dose, 1, 4, 6, 12, 24 and 48 hours after the last dose, and at follow-up.

e. Study drug (200 mg 8 hour MR formulation) was administered twice daily for 5 days; on day 5, only a single morning dose was administered. Study drug administration was performed under fed conditions.

f. On day 1, blood samples of PK for IMB-1028814 and trimetazidine were collected before and at 0.5, 1, 2, 4, 5, 6, 8, 10 and 12 hours after dosing. Samples were taken 12 hours prior to night dosing. On day 5, blood samples of PK for IMB-1028814 and trimetazidine were collected before and at 0.5, 1, 2, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 hours after dosing. Pre-morning dosing samples were also taken on

days

2, 3 and 4.

g. AE were recorded from admission until the end of the follow-up visit.

h. Blood sampling for genotyping is mandatory.

FIG. 13 is a table of analytical data sets for single dose MR portions

FIG. 14 is a table of analytical data sets for multi-dose MR portions

Demographics and other baseline characteristics

Single dose MR portion

Twelve subjects were included, 6 of which were females and 6 of which were males. The average age was 32 years and the average BMI was 25.8kg/m2. The age of the individual is between 19 and 62 years and the BMI of the individual is between 21.5 and 31.0kg/m 2. Eleven subjects were caucasians and 1 subject was black or african americans. Eleven subjects were not spanish or latin, while 1 subject was spanish or latin. The summary of the PK set is the same as the summary of the security set.

Fig. 15 is a summary of demographic characteristics-single dose MR section (safety set).

Multi-dose MR portion

Twelve subjects were included, 6 of which were females and 6 of which were males. The average age was 45 years and the average BMI was 25.1kg/m2. The age of the individual is between 24 and 64 years and the BMI of the individual is between 20.0 and 29.2kg/m 2. Eleven subjects were caucasians and 1 subject was asian. None of the 12 subjects were spanish or latin. The summary of the PK set is the same as the summary of the security set.

Fig. 16 is a summary of demographic characteristics—multi-dose MR section (safety set).

Other baseline characteristics

All subjects met inclusion and exclusion criteria. There was no clinical significance found in relation to the medical history or previous medications. Drug and alcohol screening results were negative for all subjects at screening and (each) admission. At the time of screening, the results of the serological parameters were negative for all subjects. Pregnancy test results at screening, (each) admission and follow-up were negative for all women participating in the study.

Degree of exposure

A total of 88 subjects were dosed in the present study: 12 subjects in the single dose MR portion, and 12 subjects in the multi-dose MR portion.

In the single dose MR section, all 12 subjects received 4 single doses of MR formulation of IMB-1018972 under fasted conditions: 50mg of 8-hour MR formulation on day 1, 50mg of 4-hour MR formulation on day 4, 200mg of 8-hour MR formulation on day 7, and 200mg of 4-hour MR formulation on day 10. On day 13, all 11 of the 12 subjects received 200mg of 8 hour MR formulation of IMB-1018972 under fed conditions. Subject 505 was withdrawn from the study because of a moderate TEAE (possibly related; up to 149IU/L on day 11) of elevated ALT and did not receive the last single oral dose of 200mg 8 hour MR formulation of IMB-1018972 on day 13 under fed conditions.

FIG. 17 is a table of exposure levels-single dose MR portion (safety Assembly)

In the multi-dose MR section, from day 1 to day 4, all 12 subjects received multiple oral doses of 200mg of the IMB-1018972q12h MR formulation under fed conditions, followed by a single morning dose on day 5.

FIG. 18 is a table of exposure levels-multi-dose MR portion (safety Assembly)

Single dose MR portion

After administration of 50mg and 200mg of a single oral fasted dose of IMB-1018972, t of IMB-1028814 _{Maximum value} The case of the 8-hour MR formulation (2 hours for 50mg and 200mg IMB-1018972) is earlier than the case of the 4-hour MR formulation (5 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972). After a single oral fasted dose of both 50mg and 200mg of IMB-1018972, t of trimetazidine _{Maximum value} In the case of the 8-hour MR formulation (8 hours for 50mg IMB-1018972 and 5 hours for 200mg IMB-1018972) the case of the 4-hour MR formulation (6 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972) was later. After a single oral fasted dose of both 50mg and 200mg of IMB-1018972, IMB-1028814+ trimetazidine t _{Maximum value} For 8 hours MR formulation (for 50mg IMB1018972 is 5 hours and 2.5 hours for 200mg IMB-1018972) and 4 hours MR formulation (5 hours for 50mg IMB-1018972 and 3 hours for 200mg IMB-1018972) are similar.

C of IMB-1028814 for 8 hour MR formulation versus 4 hour MR formulation after administration of 50mg and 200mg of a single oral fasted dose of IMB-1018972 _{Maximum value} 35% and 32% lower, respectively, of trimetazidine C _{Maximum value} 20% and 24% lower, respectively, and IMB-1028814 +trimetazidine C _{Maximum value} 21% and 34% lower, respectively (table 28).

AUC of IMB-1028814 after 8 hours MR formulation after administration of 50mg of a single oral fasted dose of IMB-1018972 compared to after 4 hours MR formulation _0-t 26% lower, trimetazidine C _{Maximum value} 12% lower and IMB-1028814 +trimetazidine C _{Maximum value} 18% lower. AUC of IMB-1028814 after an oral fasted dose of 200mg of IMB-1018972 after an 8-hour MR formulation compared to after a 4-hour MR formulation _0-t 6% higher, trimetazidine C _{Maximum value} 4% higher, and IMB-1028814 +trimetazidine C _{Maximum value} The height is 5 percent.

Influence of food

Geometric mean IMB-1028814 blood after study drug administration under fed conditionsPulp concentrations initially increased more slowly than after study drug administration under fasted conditions. However, under both conditions, the median t was reached 3 hours after administration _{Maximum value} 。

Trimetazidine plasma concentrations increased more slowly under fed conditions than after study drug administration under fasted conditions. The median t was reached at 5 hours post-dosing relative to 3 hours post-dosing under fasted conditions _{Maximum value} 。

Explore food pairs C of IMB-1028814 and trimetazidine _{Maximum value} 、AUC _0-t And AUC _0-inf Is a function of (a) and (b). No food effect was observed on the IMB-1028814 exposure parameter AUC _0-t And AUC _0-inf Evidence of (both estimates 1.16, and 90% CI in the range 1.05 to 1.28). However, after FDA defined high fat breakfast, C after single dose of 200mg 8 hours MR IMB-1018972 _{Maximum value} About 42% higher (estimated 1.42;90% CI range 1.24 to 1.63) relative to administration under fasted conditions.

FIG. 19 is a graph of geometric mean IMB-1028814 plasma concentration-time profile (linear) -single dose MR fraction (PK pool)

FIG. 20 is a graph of geometric mean IMB-1028814 plasma concentration-time profile (semilog scale) -single dose MR fraction (PK pool)

FIG. 21 is a graph of geometric mean trimetazidine plasma concentration versus time profile (linear) -single dose MR fraction (PK pool)

FIG. 22 is a graph of geometric mean trimetazidine plasma concentration versus time profile (semilog scale) -single dose MR fraction (PK pool)

FIG. 23 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (linear) -single dose MR fraction (PK pool)

FIG. 24 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (semi-log scale) -single dose MR fraction (PK pool)

FIG. 25 is a table of aggregated statistical geometric mean [ range ] of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine plasma pharmacokinetic parameters-single dose MR fraction (PK pool)

FIG. 26 is a table of exploratory analysis of food effects of IMB-1028814 and trimetazidine after 200mg of 8 hour MR IMB-1018972 administration-single dose MR fraction (PK pool)

Multi-dose MR portion

On day 1, all pre-dose samples had lower plasma concentrations of IMB-1028814 and trimetazidine than LLOQ.

Similar to the SAD and MAD fractions, the systemic bioavailability of 200mg 8 hour MR IMB-1018972 dose of IMB-1018972 initially hydrolyzed to IMB-1028814 and subsequently IMB-1028814 was relatively rapid on

days

1 and 5. Median IMB-1028814t _{Maximum value} 2 hours on day 1 and day 5, respectively, and for trimetazidine median t _{Maximum value} 5.5 hours and 5 hours on day 1 and day 5, respectively.

On day 5, the geometric mean values Rac of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine were 1.22, 2.28 and 1.66, respectively, relative to day 1. This indicated minimal accumulation of IMB-1028814 in plasma, moderate accumulation of trimetazidine in plasma, and moderate accumulation of IMB-1028814+ trimetazidine in plasma.

The geometric mean half-lives for the 200mg 8 hour MR IMB-1018972 doses were 3.85 hours, 9.52 hours and 8.64 hours for IMB-1028814, trimetazidine and IMB-1028814+ trimetazidine, respectively.

FIG. 27 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 28 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 29 is a graph of geometric mean trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 30 is a graph of geometric mean trimetazidine plasma concentration versus time profile (semilog scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 31 is a graph of geometric mean IMB-1028814 +trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 32 is a graph of geometric mean IMB-1028814 +trimetazidine plasma concentration-time profile (semi-log scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 33 is a graph of geometric mean IMB-1028814 plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 34 is a graph of geometric mean IMB-1028814 plasma concentration-time profile (semilog scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 35 is a graph of geometric mean trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 36 is a graph of geometric mean trimetazidine plasma concentration versus time profile (semilog scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 37 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration versus time profile (linear) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 38 is a graph of geometric mean IMB-1028814+ trimetazidine plasma concentration-time profile (semilog scale) -multi-dose MR fraction (PK pool) from day 1 to day 5

FIG. 39 is a table of aggregate statistical geometric mean [ range ] of IMB-1028814, trimetazidine and IMB-1028814 +trimetazidine plasma pharmacokinetic parameters-multi-dose MR fraction (PK pool)

Conclusion of pharmacokinetics

When combining single and multiple dose results of IMB-1018972 under fasted and fed conditions (including the results of MR formulations), the system bioavailability of IMB-1018972 initially hydrolyzed to IMB-1028814 and subsequently IMB-1028814 is relatively fast, with the median t for IMB-1028814 _{Maximum value} Between 0.5 and 5 hours after administration, and for trimetazidine, median t _{Maximum value} Between 1.5 and 8 hours after administration. Median t _{Maximum value} Is not increased with the increase of the dose of IMB-1018972.

During the SAD or MAD portions, no subjects reached the predefined stopping criteria for male and female IMB-1028814 plasma exposure of 417,733 and 652,849ng h/mL, respectively.

Systemic exposure to IMB-1028814 and trimetazidine to C after receiving a single oral dose of IMB-1018972 in the range of 50 to 400mg under fasted conditions _{Maximum value} 、AUC _0-t And AUC _0-inf Is dose proportional.

No food-affecting IMB-1028814 exposure parameter AUC was observed after administration of a single dose of 150mg IMB-1018972 _0-t And AUC _0-inf Evidence of (c). However, C after administration of a single dose of 150mg IMB-1018972 under fed conditions relative to administration under fasted conditions _{Maximum value} About 36% lower.

After administration of a single dose of 150mg IMB-1018972, no food effect on trimetazidine exposure parameter C was observed _{Maximum value} 、AUC _0-t And AUC _0-inf Evidence of (c).

No food-affecting trimetazidine was observed after administration of a single dose of 200mg of 8 hours MR IMB-1018972Oxazine exposure parameter C _{Maximum value} 、AUC _0-t And AUC _0-inf Evidence of (c).

When single and multiple IMB-1018972 dose results (including those of MR formulations) under fasted and fed conditions are combined, the geometric mean t for IMB-1028814 _1/2 Between 2.5 hours and 4.5 hours, and for trimetazidine, the geometric mean t _1/2 Between 6.5 hours and 9.5 hours. Geometric mean t _1/2 Is not increased with the increase of the dose of IMB-1018972.

Within 48 hours after administration of a single oral dose of IMB-1018972 in the range 50mg to 400mg, an average of 3.99% to 5.74% of the dose is excreted as IMB-1028814 in urine and an average of 23.11% to 32.55% of the dose is excreted as trimetazidine in urine.

Within 48 hours after administration of a single oral dose of 35mg of trimetazidine, an average 54.47% dose was excreted as trimetazidine in urine. No relevant accumulation of IMB-1028814 was observed after administration of 150mg and 50mg of IMB-1018972 14 days twice daily under fed conditions (R for 150mg and 50mg _ac 1.18 and 1.10, respectively), and the accumulation of trimetazidine is moderate (r for 150mg and 50mg _ac 1.63 and 1.89 respectively). After 200mg of 8 hour MR IMB-1018972 5 days administered twice daily under fed conditions, no associated accumulation of IMB-1028814 was observed (R _ac 1.22), while trimetazidine accumulates to a moderate level (R _ac 2.28).

Summary of adverse events

Single dose MR portion

A total of 37 TEAEs were reported in 10 out of 12 subjects (83.3%) receiving IMB-1018972. There is no report of death. Subject 505 of the single dose MR fraction was withdrawn from the study because of the moderate TEAE of ALT elevation. This TEAE is described below and in more detail in section 12.2.2. Most TEAEs are transient and resolve by the time of follow-up without sequelae. There were still 3 cases of TEAE at the follow-up: aphthous ulcers, hematomas at the catheter site and catheter site related reactions. Thirty-six of the 37 TEAEs were mild, and 1 was moderate. Severe TEAE was not reported. Moderate TEAE was an example of an ALT elevation event (up to 149IU/L on day 11) that researchers thought to be unrelated to study drug. The subject (subject 505) was withdrawn from the study due to the TEAE and did not receive the last single oral dose of 200mg 8 hour MR formulation of IMB-1018972 on day 13 under fed conditions.

Of the 37 TEAEs, 6 were reported by 4 (33.3%) subjects receiving 50mg of 8-hour MR formulation of IMB-1018972 under fasted conditions, 9 were reported by 6 (50%) subjects receiving 50mg of 4-hour MR formulation of IMB-1018972 under fasted conditions, 6 were reported by 5 (41.7%) subjects receiving 200mg of 8-hour MR formulation of IMB-1018972 under fasted conditions, 11 were reported by 8 (66.7%) subjects receiving 200mg of 4-hour MR formulation of IMB-1018972 under fasted conditions, and 5 were reported by 2 (18.2%) subjects receiving 200mg of 8-hour MR formulation of IMB-1018972 under fed conditions. The amount and incidence of TEAE did not have a significant dose or dissolution time dependence. There was also no significant difference between fasted and fed IMB-1018972 administration of 200mg 8 hour MR formulation of IMB-1018972 for the number and incidence of TEAE.

TEAE, which is reported most frequently by SOC (i.e., by. Gtoreq.20% of the subjects), is:

11 cases of TEAE with general disorder and administration site pathology reported by 7 (58.3%) subjects (5 cases of TEAE as catheter site-related response, 2 cases of TEAE as catheter site hematoma, and 1 case each of catheter site pain, debilitation, medical device site dryness, and medical device site stimulation).

8 cases of TEAE with neurological disorder reported by 7 (58.3%) subjects (6 cases of TEAE are headache and 2 cases of TEAE are dizziness).

5 cases of TEAE with gastrointestinal disorder reported by 4 (33.3%) subjects (2 cases of TEAE are abdominal pain, and 1 case each of upper abdominal pain, aphthous ulcers and diarrhea).

Of the 37 TEAEs reported, 7 reported by 4 out of 12 subjects (33.3%) were considered by the investigator to be relevant to the study drug, and 30 reported by 10 out of 12 subjects (83.3%) were considered by the investigator to be irrelevant to the study drug. After 200mg of 8 hour MR formulation of IMB-1018972 under fed conditions, no drug related TEAE was reported. Reported drug-related TEAEs are:

2 (16.7%) subjects had kidney and urinary system disorders with 5 TEAE with frequent urination.

Study with 1 TEAE with ALT elevation.

Nervous system disorders with headache in 1 case TEAE.

Overall tolerance

Healthy male and female subjects were well tolerated for treatment with 50mg MR formulation and 200mg MR formulation with 4 and 8 hour dissolution profiles under fasted conditions and then 200mg 8 hour MR formulation with IMB-1018972 under fed conditions, except for 1 subject who had elevated ALT (up to 149 IU/L) after 2 single doses of 50mg MR formulation and 2 doses of 200mg MR formulation.

Multi-dose MR portion

A total of 40 TEAEs were reported from 12 out of 12 subjects (100%) receiving IMB-1018972. All TEAEs were mild and no mortality report was present. Most TEAEs are transient and resolve by the time of follow-up without sequelae. There are still four cases of TEAE at follow-up: contact dermatitis, erythema, influenza-like diseases, oropharyngeal pain, and medical device site irritation.

TEAE, which is reported most frequently by SOC (i.e., reported by > 30% of the subjects), is:

9 cases of TEAE with neurological disorder reported by 7 (58.3%) subjects (6 cases of TEAE for headache, 2 cases of TEAE for dizziness and 1 case of TEAE for postural dizziness).

9 cases of TEAE with gastrointestinal disorder reported by 5 (41.7%) subjects (2 cases of TEAE are abdominal pain, and 1 case each of diarrhea, dyspepsia, pale stool, flatulence, gingival pain, oral discomfort and dental pain).

4 cases of TEAE with general disorder and administration site pathology reported by 4 (33.3%) subjects (1 case each of catheter site pain, influenza-like disease, medical device site irritation, and thirst).

Musculoskeletal and connective tissue disorders reported by 4 (33.3%) subjects with 4 TEAEs (2 TEAEs are myalgia, and 1 TEAE each of neck pain and limb pain).

Renal and urinary disorders with 4 TEAEs with frequent urination in 4 (33.3%) subjects.

Of the 40 TEAEs reported, 10 TEAEs reported by 7 of the 12 subjects (58.3%) were considered by the investigator to be relevant to the study drug, and 30 TEAEs reported by 9 of the 12 subjects (75%) were considered by the investigator to be irrelevant to the study drug. Drug-related TEAE (i.e., reported by ≡15% of subjects) reported most frequently by SOC is:

Neurological disorders reported by 2 subjects (16.7%) with 2 TEAEs (1 TEAE each in dizziness and headache).

Vascular disorders with 2 TEAEs with flushing reported by 2 (16.7%) subjects.

Overall tolerance

Healthy male and female subjects were well tolerated for five days of treatment with 200mg of 8 hour MR formulation of IMB-1018972q12h at multiple oral doses under fed conditions. Notably, 2 mild flushes were reported by 2 subjects (subjects 513 and 517), who were postmenopausal women and 1 of whom reported a persistent "hot flush" as part of the medical history. No subjects were withdrawn and no dose modification was required due to flushed TEAE.

FIGS. 40A and 40B are table summaries of all TEAE-single dose MR fractions (safety collections) by system organ category, preference terminology and treatment

FIG. 41 is a tabular summary of all TEAE-single dose MR parts (safety collections) by systemic organ category, preference terminology and treatment

FIG. 42 is a tabular summary of all TEAE-single dose MR fractions (safety collections) by treatment, relationship and severity

FIG. 43 is a tabular summary of all TEAE-multi-dose MR fractions (safety collections) by treatment, relationship and severity

Death, other serious adverse events, and other serious adverse events

One subject was withdrawn during the study.

Subject 505 was a 21 year old white man with a BMI of 21.5kg/m2. The subject participated in a single dose MR moiety and was scheduled to receive 50mg of 8-hour MR formulation under fasted conditions on day 1, 50mg of 4-hour MR formulation under fasted conditions on day 4, 200mg of 8-hour MR formulation under fasted conditions on day 7, 200mg of 4-hour MR formulation under fasted conditions on day 10, and 200mg of 8-hour MR formulation of IMB-1018972 under fed conditions on day 13. He did not report a history of the relevant disease and did not receive concomitant medications at baseline. The subject began reporting ALT-elevated TEAE on day 5 (1 day after 50mg 4 hour MR formulation administration on day 4). The TEAE is moderate and the investigator thought to be likely to be involved in studying the drug. The subject still received a dose of 200mg of the 8-hour MR formulation under fasted conditions on day 7 and a dose of 200mg of the 4-hour MR formulation under fasted conditions on day 10. ALT values for the subjects were within the normal range (0-68 IU/L) at screening (29 IU/L), on day-1 (34 IU/L) and on day 2 (31 IU/L). ALT levels increased to a value of 72IU/L above the upper normal limit (68 IU/L) on day 5, to 97IU/L on day 8 and to 149IU/L on day 11, then decreased again to 102IU/L on day 14 and to 84IU/L on day 16. By day 24 follow-up, ALT levels were restored to 42IU/L, which was within the normal range. Also on this day, the TEAE was recorded to resume. High ALT levels of 149IU/L on day 11 were considered clinically significant abnormalities by the investigator, based on whom the investigator decided to withdraw the subject from the study (without receiving additional doses). Throughout this period, AST levels were within normal ranges. Due to the withdrawal, the subject did not receive the last single oral dose of 200mg 8 hour MR formulation of IMB-1018972 planned under fed conditions on day 13. After the 11 th day exit, the subject returned for follow-up on day 24 and was scheduled for safety assessment. The subject also reported mild TEAE on day 1 contact dermatitis (uncorrelated), skin exfoliation from day 3 to day 6 (uncorrelated), and abdominal pain from day 13 to day 14 (uncorrelated).

TEAE, which caused subject 505 to withdraw from the study ALT, was considered by the investigator to be likely to be associated with the study drug because of its time dependence on study drug administration.

Subject 505 of the single dose MR fraction was withdrawn from the study due to the moderate TEAE of ALT elevation. TEAE starts on day 5, i.e. 1 day after 50mg of 4 hour MR formulation was administered on day 4. ALT values for the subjects were within the normal range (0-68 IU/L) at screening (29 IU/L), on day-1 (34 IU/L) and on day 2 (31 IU/L). ALT levels increased to a value of 72IU/L above the upper normal limit (68 IU/L) on day 5, to 97IU/L on day 8 and to 149IU/L on day 11, then decreased again to 102IU/L on day 14 and to 84IU/L on day 16. By day 24 follow-up, ALT levels were restored to 42IU/L, which was within the normal range. Also on this day, the TEAE was recorded to resume. High ALT levels of 149IU/L on day 11 were considered clinically significant abnormalities by the investigator, based on whom the investigator decided to withdraw the subject from the study. Throughout this period, the AST level of subject 505 is within the normal range. No other cases of clinically significant abnormal laboratory parameters were recorded at any time during the study.

Concomitant therapy

Single dose MR portion

Seven subjects received or took concomitant medications in the single dose MR portion. Five female subjects used contraception during the study. In addition, 4 subjects received concomitant medications as follows:

one subject (subject 501) received 1000mg of paracetamol once for headache.

One subject (subject 509) received 1000mg of paracetamol once for intermittent episodes of headache (preferred term: headache).

One subject (subject 510) received twice 500mg of paracetamol and once 1000mg of paracetamol for headache.

One subject (subject 511) received 1000mg of paracetamol once for the cold (preferred term: nasopharyngitis).

These drugs are not believed to have an effect on the results of the study.

Multi-dose MR portion

Five subjects received or took concomitant medications in the multi-dose MR portion. Three female subjects used contraception during the study. In addition, 3 subjects received concomitant medications as follows:

one subject (subject 514) received 1000mg paracetamol twice for headache.

One subject (subject 519) received Ji Nuotong (gelomyrtol) 3 times per day for 2 days and 500mg paracetamol 3 times per day for 2 days for influenza-like symptoms (preferred term: influenza-like disease).

One subject (subject 524) received 500mg of paracetamol once for headache. These drugs are not believed to have an effect on the results of the study.

Discussion and general conclusion

Discussion of Security

In general, healthy male and female subjects are generally well tolerated by single and multi-dose MR formulations. No clinical relevance was found in clinical laboratories, vital signs, 12-lead ECG, continuous cardiac monitoring (telemetry) or physical examination. Notably, no hemodynamic changes were found after administration of IMB-1018972 as an MR formulation, nor was a change in QTc interval found.

Nicotinic acid (niacin) is a direct hydrolysate of IMB-1018972 and accounts for about 30% of the molecular weight of IMB-1018972. In this study, TEAE was reported to be flush, which is characterized in agreement with the flush observed with niacin administration. All events were transient and resolved without intervention. No subjects were withdrawn due to flushed TEAE and no dose change was required.

In the multi-dose MR section, 2 postmenopausal female subjects reported 2 mild flushes, with 1 subject reporting persistent "hot flushes" as part of the medical history. No subjects were withdrawn due to TEAE and no dose change was required. The nature of these TEAEs in MR formulations was sporadic, transient, self-limiting and mild, indicating an acceptable tolerability profile for IMB-1018972 in 200mg 8 hour MR formulations.

One subject of the single dose MR fraction was withdrawn from the study due to the moderate TEAE with elevated ALT. Researchers believe that elevated TEAE of ALT (up to 149IU/L on day 11) may be associated with the study drug and regress without intervention. The most frequently reported TEAEs during the study were SOC vascular disorders (TEAE that is predominantly flushing), general disorders and administration site conditions, nervous system disorders, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. The investigator considered that most of the TEAEs reported during the study were not related to the study drug.

Pharmacokinetics of

200mg of the 8 hour MR IMB-1018972 formulation has been selected as the most suitable for phase 2 proof of concept studies.

Security-conclusion

Overall, healthy male and female subjects are generally well tolerated by single and multi-dose MR formulations. There are no clinically relevant findings in clinical laboratories, vital signs, 12-lead ECG, continuous cardiac monitoring (telemetry) or physical examination. Notably, no hemodynamic changes were found after administration of IMB-1018972 as an IR or MR formulation, nor was a change in QTc interval found.

Pharmacokinetic-conclusion

When combining single and multiple dose results of IMB-1018972 under fasted and fed conditions, the system bioavailability of IMB-1018972 initially hydrolyzed to IMB-1028814 and subsequently IMB-1028814 is relatively fast, with the median t for IMB-1028814 _{Maximum value} Between 0.5 and 5 hours after administration, and for trimetazidine, median t _{Maximum value} Between 1.5 and 8 hours after administration. Median t _{Maximum value} Is not increased with the increase of the dose of IMB-1018972.

When single and multiple IMB-1018972 dose results (including those of MR formulations) under fasted and fed conditions are combined, geometric mean for IMB-1028814t _1/2 Between 2.5 hours and 4.5 hours, and for trimetazidine, the geometric mean t _1/2 Between 6.5 hours and 9.5 hours. Geometric mean t _1/2 Is not increased with the increase of the dose of IMB-1018972.

Overall (L)

Further clinical development of IMB-1018972 was warranted in view of the positive risk/benefit profile and observed PK profile of IMB-1018972 metabolite IMB-1028814 and trimetazidine in this single and multi-dose FIH study.

Incorporated by reference

Throughout this disclosure, other documents, such as patents, patent applications, patent publications, journals, books, papers, web content are referenced and cited. All such documents are hereby incorporated by reference for all purposes.

Equivalents (Eq.)

Various modifications of the invention, as well as many additional embodiments thereof, in addition to those shown and described herein, will become apparent to persons skilled in the art from the entire contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplifications and guidance that can be applied to the practice of the invention in its various embodiments and equivalents thereof.

Claims

1. A pharmaceutical composition comprising a mixture, the mixture comprising:

a compound of formula (X):

and

erodable polymers that promote swelling of the mixture in an aqueous environment.

2. The pharmaceutical composition of claim 1, wherein the polymer is hydroxypropyl methylcellulose (HPMC).

3. The pharmaceutical composition of claim 2, wherein the HPMC comprises a first polymeric form having a first viscosity and a second polymeric form having a second viscosity lower than the first viscosity.

4. The pharmaceutical composition of claim 3, wherein the first viscosity is at least 75,000cp for a 2% aqueous solution of HPMC in the first polymer form at 20 ℃.

5. The pharmaceutical composition of claim 3, wherein the first polymeric form comprises at least 50% by weight of the HPMC.

6. The pharmaceutical composition of claim 3, wherein the first polymeric form comprises HPMC having a methoxy degree of substitution of about 19% to about 24%.

7. The pharmaceutical composition of claim 3, wherein the first polymeric form comprises HPMC having a degree of hydroxypropoxyl substitution of about 7% to about 12%.

8. The pharmaceutical composition according to claim 1, wherein the mixture comprises at least 10% by weight of the compound of formula (X).

9. The pharmaceutical composition of claim 1, wherein the composition is formulated for oral administration.

10. The pharmaceutical composition of claim 9, wherein the composition is a unit dose comprising from about 10mg to about 500mg of the compound of formula (X).

11. A method of treating a disease, disorder, condition in a subject, the method comprising providing to a subject having a disease, disorder, or condition a pharmaceutical composition comprising a mixture comprising:

a compound of formula (X):

and

12. The method of claim 11, wherein the polymer is hydroxypropyl methylcellulose (HPMC).

13. The method of claim 12, wherein the HPMC comprises a first polymeric form having a first viscosity and a second polymeric form having a second viscosity lower than the first viscosity.

14. The method of claim 13, wherein the first viscosity is at least 75,000cp for a 2% aqueous solution of HPMC in the first polymer form at 20 ℃.

15. The method of claim 13, wherein the first polymeric form comprises at least 50% by weight of the HPMC.

16. The method of claim 11, wherein the mixture comprises at least 10% by weight of the compound of formula (X).

17. The method of claim 11, wherein the composition is provided orally to the subject.

18. The method of claim 17, wherein the time interval between the first time point at which the composition is provided to the subject and the second time point at which the maximum level of the metabolite of the compound of formula (X) in the subject's plasma is reached is at least two hours.

19. The method of claim 18, wherein the metabolite of the compound of formula (X) is a compound of formula (IX):

20. the method of claim 11, wherein the disease, disorder, or condition is selected from the group consisting of aneurysms, angina, atherosclerosis, cardiomyopathy, cerebrovascular disease, congenital heart disease, coronary Artery Disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, hypertension (hypertension), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.

21. A pharmaceutical composition comprising a mixture, the mixture comprising:

A compound of formula (X):

and

hydroxypropyl methylcellulose (HPMC),

wherein the mixture comprises the compound of formula (X) and HPMC in a weight ratio of about 1:10 to about 10:1.

22. The pharmaceutical composition of claim 21, wherein the mixture comprises the compound of formula (X) and the polymer in a weight ratio of about 1:5 to about 5:1.

23. The pharmaceutical composition of claim 22, wherein the mixture comprises the compound of formula (X) and the polymer in a weight ratio of about 1:3 to about 2:1.

24. The pharmaceutical composition of claim 23, wherein the composition is a unit dose comprising from about 10mg to about 500mg of the compound of formula (X).

25. The pharmaceutical composition of claim 21, wherein the HPMC comprises a first polymeric form having a first viscosity and a second polymeric form having a second viscosity lower than the first viscosity.

26. The pharmaceutical composition of claim 25, wherein the first viscosity is at least 75,000cp for a 2% aqueous solution of HPMC in the first polymer form at 20 ℃.

27. The pharmaceutical composition of claim 25, wherein the first polymeric form comprises at least 50% by weight of the HPMC.

28. The pharmaceutical composition of claim 25, wherein the first polymeric form comprises HPMC having a methoxy degree of substitution of about 19% to about 24%.

29. The pharmaceutical composition of claim 25, wherein the first polymeric form comprises HPMC having a degree of hydroxypropoxyl substitution of about 7% to about 12%.

30. The pharmaceutical composition of claim 21, wherein the composition is formulated for oral administration.

31. A method of treating a disease, disorder, condition in a subject, the method comprising providing to a subject having a disease, disorder, or condition a pharmaceutical composition comprising a mixture comprising:

a compound of formula (X):

and

hydroxypropyl methylcellulose (HPMC),

32. The method of claim 31, wherein the mixture comprises the compound of formula (X) and the polymer in a weight ratio of about 1:5 to about 5:1.

33. The method of claim 32, wherein the mixture comprises the compound of formula (X) and the polymer in a weight ratio of about 1:3 to about 2:1.

34. The method of claim 31, wherein the HPMC comprises a first polymeric form having a first viscosity and a second polymeric form having a second viscosity lower than the first viscosity.

35. The method of claim 34, wherein the first viscosity is at least 75,000cp for a 2% aqueous solution of HPMC in the first polymer form at 20 ℃.

36. The method of claim 34, wherein the first polymeric form comprises at least 50% by weight of the HPMC.

37. The method of claim 31, wherein the composition is provided orally to the subject.

38. The method of claim 31, wherein the time interval between the first time point at which the composition is provided to the subject and the second time point at which the maximum level of the metabolite of the compound of formula (X) in the subject's plasma is reached is at least two hours.

39. The method of claim 31, wherein the metabolite of the compound of formula (X) is a compound of formula (IX):

40. the method of claim 31, wherein the disease, disorder, or condition is selected from the group consisting of aneurysms, angina, atherosclerosis, cardiomyopathy, cerebrovascular disease, congenital heart disease, coronary artery disease, coronary heart disease, diabetic cardiomyopathy, heart attack, heart failure, hypertension, ischemic heart disease, pericardial disease, peripheral arterial disease, rheumatic heart disease, stroke, transient ischemic attack, valvular heart disease, and valvular heart disease.