Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to methods of treating cardiovascular conditions and methods of increasing the efficiency of cardiac metabolism.
• Heart disease is the leading cause of death worldwide, accounting for 15 million deaths across the globe in 2015.
• coronary artery disease CAD
• the most common cardiovascular disease blood flow to the heart muscle is reduced due to accumulation of plaque in the arteries of the heart.
• CAD coronary artery disease
• Heart failure is a chronic, progressive condition in which the heart is unable to pump enough blood to meet the body’s needs.
• Conditions that can lead to heart failure include diseases of the heart muscle such as hypertrophic cardiomyopathy in which the muscular wall between the two bottom chambers of the heart becomes abnormally thick, thus obstructing blood flow out of the heart.
• Conditions such as diabetes or pre-diabetes increase the risk of coronary artery disease (CAD), heart failure, and cardiomyopathy.
• CAD coronary artery disease
• ischemic heart disease In heart failure, ischemic heart disease, and diabetic heart disease, decreased cardiac efficiency stems from changes in mitochondrial energy metabolism. Mitochondria are sub- cellular compartments in which metabolites derived from glucose and fatty acids are oxidized to produce high-energy molecules. Increasing fatty acid oxidation in the heart decreases glucose oxidation, and vice versa. Glucose oxidation is a more efficient source of energy, but in certain types of heart disease, such as heart failure, ischemic heart disease, and diabetic cardiomyopathies, fatty acid oxidation predominates in cardiac mitochondria. As a result, the pumping capacity of the heart is reduced.
• the invention relates to methods of treating cardiovascular conditions and methods of increasing the efficiency of cardiac metabolism.
• the invention leverages unexpected findings for the use of compositions containing a compound that improves cardiac mitochondrial function to treat cardiac conditions.
• the compositions contain a compound that is metabolized in the body into multiple products that improve cardiac mitochondrial metabolism by independent but cooperative mechanisms.
• One set of metabolic products which may include trimetazidine and its derivatives, shifts cardiac metabolism from fatty acid oxidation to glucose oxidation.
• Metabolic products in another set serve as precursors for synthesis of nicotinamide adenine dinucleotide (NAD + ) and thus facilitate mitochondrial respiration.
• the compositions may be delivered orally, obviating the need for specialized equipment or personnel. The methods are useful for treating a wide variety of cardiovascular conditions as described herein.
• the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be trimetazidine, etomoxir, oxfenicine, perhexiline, a PPAR agonist, a malonyl CoA decarboxylase inhibitor, or di chloroacetate.
• the NAD + precursor molecule may be nicotinic acid, nicotinamide, nicotinamide mononucleotide (NMN), or nicotinamide riboside.
• the compound of formula (VII) or (VIII) may be PEGylated with an ethylene glycol moiety.
• the ethylene glycol moiety may be attached to one or more of A, L, and C. L may be or include an ethylene glycol moiety.
• the compound may have multiple ethylene glycol moieties, such as one, two three, four, five, or more ethylene glycol moieties.
• the ethylene glycol moiety may form a covalent linkage between the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and the NAD + precursor molecule.
• the ethylene glycol moiety may be separate from a covalent linkage between the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and the NAD + precursor molecule.
• the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be a PEGylated form of trimetazidine.
• the compound of formula (VII) or the compound of formula (VIII) may include nicotinic acid that is covalently linked to a PEGylated form of trimetazidine.
• the nicotinic acid may be covalently linked via the PEGylated moiety, i.e., via an ethylene glycol linkage.
• the nicotinic acid may be covalently linked via the trimetazidine moiety.
• the compound of formula (VII) or the compound of formula (VIII) may have a structure represented by formula (X):
• the compounds and compositions may be provided in a dosage form and the dose may be provided by any suitable route or mode of administration.
• the dose may be provided orally, intravenously, enterally, parenterally, dermally, buccally, topically, transdermally, by injection, subcutaneously, nasally, pulmonarily, or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
• an implantable medical device e.g., stent or drug-eluting stent or balloon equivalents.
• the composition may be provided in one dose per day.
• the composition may be provided in multiple doses per day.
• the composition may be provided in two, three, four, five, six, eight, or more doses per day.
• the dose may contain from about 10 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 800 mg, from about 10 mg to about 600 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 200 mg, from about 25 mg to about 2000 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 600 mg, from about 25 mg to about 400 mg, from about 25 mg to about 300 mg, about 25 mg to about 200 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 600 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, about 50 mg to about 200 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, about 100 mg to about 200 mg, from
• the dose or doses may be provided for a defined period.
• One or more doses may be provided daily for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks or more.
• the invention provides a method of treating cardiac steatosis or a disorder associated with cardiac steatosis in a subject.
• the method includes providing to a subject having, or at risk of developing, cardiac steatosis or a disorder associated with cardiac steatosis a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the invention provides a method of reducing myocardial triglycerides in a subject by providing to a subject having, or at risk of developing, myocardial disease a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the cardiovascular condition may include acute coronary syndrome; aneurysm; angina; atherosclerosis; cardiac adiposity or steatosis including conditions such as aortic stenosis, HIV/ART-associated myocardial steatosis, hypertensive heart disease, pulmonary arterial hypertension, coronary microvascular dysfunction and generalized lipodystrophy; cardiac ischemia-reperfusion injury; cardiomyopathy (inherited or acquired, including obstructive hypertrophic, non-obstructive hypertrophic, dilated, and restrictive forms); cardioprotection (including during cardiac surgery with cardiopulmonary bypass); cerebral vascular disease; chronic coronary syndromes; congenital heart disease; coronary artery disease; coronary heart disease; coronary microvascular dysfunction; diabetic cardiomyopathy (including asymptomatic pre-overt heart failure); heart attack; heart disease; heart failure (all stages and with reduced, mildly reduced or preserved ejection fraction); heart failure after cardiac transplantation in diabetics; hypertension; hypertensive heart disease;
• Aortic stenosis is discussed in Mahmod M, Bull S, Suttie JJ, Pal N, Holloway C, Dass S, Myerson SG, Schneider JE, De Silva R, Petrou M, Sayeed R, Westaby S, Clelland C, Francis JM, Ashrafian H, Karamitsos TD, Neubauer S. Myocardial steatosis and left ventricular contractile dysfunction in patients with severe aortic stenosis. Circ Cardiovasc Imaging. 2013 Sep;6(5):808-16. doi: 10.1161/circimaging.l 13.000559. Epub 2013 Jul 5. PMID: 23833283, the entirety of the contents of which are incorporated by reference herein.
• HIV/ART-associated myocardial steatosis is discussed in Neilan TG, Nguyen KL, Zaha VG, Chew KW, Morrison L, Ntusi NAB, Toribio M, Awadalla M, Drobni ZD, Nelson MD, Burdo TH, Van Schalkwyk M, Sax PE, Skiest DJ, Tashima K, Landovitz RJ, Daar E, Wurcel AG, Robbins GK, Bolan RK, Fitch KV, Currier JS, Bloomfield GS, Desvigne-Nickens P, Douglas PS, Hoffmann U, Grinspoon SK, Ribaudo H, Dawson R, Goetz MB, Jain MK, Warner A, Szczepaniak LS, Zanni MV.
• Hypertensive heart disease is discussed in Sai E, Shimada K, Yokoyama T, Hiki M, Sato S, Hamasaki N, Maruyama M, Morimoto R, Miyazaki T, Fujimoto S, Tamura Y, Aoki S, Watada H, Kawamori R, Daida H. Myocardial triglyceride content in patients with left ventricular hypertrophy: comparison between hypertensive heart disease and hypertrophic cardiomyopathy. Heart Vessels. 2017 Feb;32(2): 166-174. doi: 10.1007/s00380-016-0844-8. Epub 2016 May 3. PMID: 27142065, the entirety of the contents of which are incorporated by reference herein.
• Pulmonary arterial hypertension is discussed in Brittain EL, Talati M, Fessel JP, Zhu H, Penner N, Calcutt MW, West JD, Funke M, Lewis GD, Gerszten RE, Hamid R, Pugh ME, Austin ED, Newman JH, Hemnes AR. Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension. Circulation. 2016 May 17; 133(20): 1936-44. doi: 10.1161/circulationaha.l 15.019351. Epub 2016 Mar 22. PMID: 27006481; PMCID: PMC4870107, the entirety of the contents of which are incorporated by reference herein.
• Coronary microvascular dysfunction is discussed in Wei J, Nelson MD, Szczepaniak EW, Smith L, Mehta PK, Thomson LE, Berman DS, Li D, Bairey Merz CN, Szczepaniak LS.
• Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women.
• PMID 26519031
• PMCID PMC4865076, the entirety of the contents of which are incorporated by reference herein.
• the invention provides a method of reducing lipotoxicity in a subject, including cardiac lipotoxicity, by providing to a subject having, or at risk of developing, lipotoxicity a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the invention provides a method of treating diabetic cardiomyopathy in a subject by providing to a subject having, or at risk of developing, diabetic cardiomyopathy a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the invention provides a method of inducing weight loss in a subject by providing to a subject a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the invention provides a method of preventing or treating cardiac dysfunction (subclinical or symptomatic) and/or improving cardiac energetics in a subject by providing to a subject having an elevated level of HbAlc (i.e. diabetic or pre-diabetic) at least one dose per day of a composition of a compound having a structure represented by formula (X).
• the elevated level of HbAlc may be greater than 6.0%, 6.5% or 7%.
• the dose of the compound of formula (X) may be at least one dose provided orally.
• the compound of formula (X) may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg. Preferably, the dose may be about 200 mg.
• the composition may be a modified-release
• FIG. 1 shows a schematic of the study design for testing the safety and efficacy of IMB- 1018972.
• FIG. 2 is a table of the disposition of subjects of an FIH study of IMB-1018972.
• FIG. 3 is a Schedule of Assessments for SAD part Group A5 of an FIH study of IMB- 1018972.
• FIG.4 is a table of assessments given for the SAD part (and integrated FE arm) Groups
• FIG. 5 is a table of assessments given for the MAD part of an FIH study of IMB- 1018972.
• FIG. 6 is a table of analysis data sets for the SAD Part (and integrated FE Arm) per dose level and total for IMB-1018972 of an FIH study of IMB-1018972.
• FIG. 7 is a table of analysis data sets for the MAD Part per dose level and total for IMB- 1018972 of an FIH study of IMB-1018972.
• FIG. 8 is a table of a summary of demographic characteristics - SAD Part (and Integrated FE Arm) (Safety Set of an FIH study of IMB-1018972.
• FIG. 9 is a table of a summary of demographic characteristics - MAD Part (Safety Set) of an FIH study of IMB-1018972.
• FIG. 10 is a table of the Extent of Exposure - SAD Part (and Integrated FE Arm) (Safety Set) of an FIH study of IMB-1018972.
• FIG. 11 is a table of the Extent of Exposure - MAD Part of an FIH study of IMB- 1018972.
• FIG. 12 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Linear) - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 13 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi -Logarithmic) - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 14 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 15 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi -Logarithmic) - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 16 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic) - SAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 17 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic) - SAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 18 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 19 is a table of Exploratory Analysis of Dose Proportionality for IMB-1028814 and Trimetazidine over the Dose Range of 50 mg to 400 mg IMB-1018972 under Faster Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 20 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 Cmax over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 21 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 AUCo-t over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 22 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 AUCo-inf over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 23 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine Cmax over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 24 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine AUCo-t over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 25 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine AUCo-inf over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 26 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 27 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi -Logarithmic Scale) - FE Arm of SAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 28 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 29 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi -Logarithmic Scale) - FE Arm of SAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 30 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 31 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - FE Arm of SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 32 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-128814 + Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - FE Arm of SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 33 is a table of Exploratory Analysis of Food Effect for IMB-1028814 and Trimetazidine following Administration of 150 mg IMB-1018972 - FE Arm of SAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 34 is a table of Summary Statistics (Arithmetic Mean [SD]) of Urine Pharmacokinetic Parameters for IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine - SAD Part (PK Set) of an FIH study of IMB-1018972.
• SD Arimetic Mean [SD]
• FIG. 35 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time
• FIG. 36 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FH4 study of IMB-1018972.
• FIG. 37 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 38 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 39 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 40 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 41 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 42 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 43 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Linear) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 44 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FIH study of IMB- 1018972.
• FIG. 45 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Linear) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 46 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 47 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - MAD Part (PK Set) of an FIH study of IMB-1018972.
• FIG. 48A and FIG. 48B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - SAD Part (and integrated FE Arm) (Safety Set) with the following notifications: of an FIH study of IMB-1018972.
• FIG. 49A and FIG. 49B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - MAD Part (Safety Set) of an FIH study of IMB-1018972.
• FIG. 50 is a table Summary of All TEAEs by Treatment, Relationship, and Severity- SAD Part (and Integrated FE Arm) (Safety Set) of an FIH study of IMB-1018972.
• FIG. 51 is a table Summary of All TEAEs by Treatment, Relationship, and Severity - MAD Part (Safety Set) of an FIH study of IMB-1018972.
• FIG. 52 is baseline characteristics of randomized participants for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 53 is baseline characteristics of completers for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes, including baseline cardiac imaging findings in those treated for 4 weeks.
• FIG. 54 is adverse effects as of the data cut-off date of September 20, 2021 for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 55 are graphs of resting myocardial PCr/ATP combined, 4- and 8-week cohorts for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 56 are graphs of myocardial triglyceride (MTG) combined 4- and 8-week cohorts for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 57 are graphs of body weight combined 4- and 8-week cohorts for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 58 is correlation analysis data with plots of change in PCr/ATP and baseline HbAlc and baseline fasting glucose for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 59 is correlation analysis data with plots of change in PCr/ATP and change in myocardial triglycerides and baseline myocardial triglycerides for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 60 is correlation analysis data with plots of change in body weight and baseline HbAlc and change in PCr/ATP for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 61 is correlation analysis data with plots of change in myocardial triglycerides and baseline myocardial triglycerides and baseline HbAlc for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 62 is correlation analysis data with plots of change in body weight and change in myocardial triglycerides for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 63 is correlation analysis data and plots for change in PCr/ATP with change in myocardial triglycerides, absolute and % change for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 64 is correlation analysis with plots of change in PCr/ATP with change in myocardial triglycerides, absolute and percent change following removal of an outlier for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• FIG. 65 is correlation analysis data with plots of baseline myocardial triglycerides with HbAlc (%) and other pertinent plots for comparison for Example 3 pharmacodynamic study to evaluate the impact of formula (X) on myocardial energetics and metabolism in Type 2 diabetes.
• the invention provides methods for administering compositions containing a compound that improves cardiac mitochondrial function to treat cardiac conditions.
• the methods include providing such a composition to subject one or more times per day. Because the compositions may be formulated for oral administration, the methods are simple and may be performed by a patient without direct medical supervision. The methods may be used to treat cardiovascular conditions as described herein.
• Glucose oxidation is a more efficient pathway for energy production, as measured by the number of ATP molecules produced per O2 molecule consumed (P/O ⁇ 2.58), than is fatty acid oxidation (P/O —2.3) and that of the ketone body P-hydroxybutyrate (P/O ⁇ 2.5). The importance of this is highlighted by the observation that the heart utilizes more oxygen/gram of tissue than any other organ.
• Glucose oxidation also consumes less NAD + than oxidation of a long-chain fatty acid, palmitate (10 and 31, respectively), hence a shift towards glucose oxidation is expected to increase the cardiomyocyte NAD + pool and NAD + /NADH ratio, and this can be further potentiated by concomitant use of an NAD + precursor such as nicotinic acid.
• NAD + precursor such as nicotinic acid.
• Cardiac NAD + and the NAD + /NADH ratio are reduced in pathologies such as heart failure, cardiac pressure overload and in diabetic cardiomyopathy. However, other metabolic changes contribute to decreased cardiac efficiency in patients with heart disease.
• mitochondrial oxidative metabolism can be impaired in heart failure, and energy production is decreased in ischemic heart disease due to a limited supply of oxygen at rest or under conditions of increased myocardial oxygen demand, such as exercise inducing ischemia.
• stimulation of myocardial glucose oxidation will improve post-ischemic recovery and cardiac efficiency following a period of ischemia and reperfusion.
• the failing heart is characterized by increased glycolysis uncoupled from glucose oxidation, reducing energy production (2 compared with 31 ATP molecules per glucose molecule if the pyruvate from glycolysis is oxidized) and generating lactate leading to intracellular H + accumulation impairing cellular function and intracellular Ca 2+ homeostasis.
• Increased reliance of the myocardium on fatty acids decreases cardiac efficiency via other mechanisms including activation of mitochondrial uncoupling proteins (uncoupling ATP generation from oxidative metabolism) and through futile cycling of fatty acid intermediates resulting in ATP consumption for non-contractile purposes.
• Glucose oxidation and fatty acid oxidation are energy-producing metabolic pathways that compete with each other for substrates.
• glucose oxidation glucose is broken down to pyruvate via glycolysis in the cytosol of the cell. Pyruvate then enters the mitochondria, where it is converted to acetyl coenzyme A (acetyl-CoA).
• acetyl-CoA acetyl coenzyme A
• beta-oxidation of fatty acids which occurs in the mitochondria, two-carbon units from long-chain fatty acids are sequentially converted to acetyl-CoA.
• Acetyl-CoA is oxidized to carbon dioxide (CO2) via the citric acid cycle, which results in the conversion of nicotinamide adenine dinucleotide (NAD + ) to its reduced form, NADH.
• NADH nicotinamide adenine dinucleotide
• NADH drives the mitochondrial electron transport chain.
• the electron transport chain comprises a series of four mitochondrial membrane-bound complexes that transfer electrons via redox reactions. In doing so, the complexes pump protons across the membrane to create a proton gradient.
• the redox reactions of the electron transport chain require molecular oxygen (O2).
• O2 molecular oxygen
• the methods of the invention improve cardiac efficiency by using multiple mechanisms to alter mitochondrial metabolism.
• the methods entail providing compounds that are metabolized in the body into multiple products that have different effects.
• a first metabolic product or set of metabolic products shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, and a second product or set of products modulates the NAD + /NADH redox couple and promotes mitochondrial respiration.
• administering such compounds triggers a change in the pathway used to produce energy and concomitantly improves overall mitochondrial oxidative function. Consequently, the methods of the invention are more effective at restoring cardiac capacity in patients with heart disease than are other methods that target a single metabolic deficiency. Moreover, such methods avoid the use of risky surgical procedures that can lead to serious complications.
• methods of the invention include providing a composition containing a compound that improves cardiac mitochondrial function to a subject.
• the dose may be provided by any suitable route or mode of administration.
• the dose may be provided orally, intravenously, enterally, parenterally, dermally, buccally, topically, transdermally, by injection, subcutaneously, nasally, pulmonarily, or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
• an implantable medical device e.g., stent or drug-eluting stent or balloon equivalents.
• Doses may be provided at any suitable interval.
• doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week.
• the dose may contain a defined amount of the compound that improves cardiac mitochondrial function.
• the dose may contain from about 10 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 800 mg, from about 10 mg to about 600 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 200 mg, from about 25 mg to about 2000 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 600 mg, from about 25 mg to about 400 mg, from about 25 mg to about 300 mg, about 25 mg to about 200 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 800 mg, from about 50 mg to about 600 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, about 50 mg to about 200 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about
• the dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc.
• the dose may be provided in a divided dosage, i.e., the dose may be provided as multiple tablets, capsules, pills, etc.
• the dosing may continue for a defined period.
• doses may be provided for at least one week, at least two weeks, at least three weeks, at least four weeks, at least six weeks, at least eight weeks, at least ten weeks, at least twelve weeks or more.
• the subject may be a human.
• the subject may be a human that has a cardiovascular condition, such as one of those described below.
• the subject may be a human that is at risk of developing a cardiovascular condition, such as one of those described above.
• a subject may be at risk of developing a condition if the subject does not meet established criteria for diagnosis of the condition but has one or more symptoms, markers, or other factors that indicate the subject is likely to meet the diagnostic criteria for the condition in the future.
• the subject may be a pediatric, a newborn, a neonate, an infant, a child, an adolescent, a pre-teen, a teenager, an adult, or an elderly subject.
• the subject may be in critical care, intensive care, neonatal intensive care, pediatric intensive care, coronary care, cardiothoracic care, surgical intensive care, medical intensive care, long-term intensive care, an operating room, an ambulance, a field hospital, or an out-of-hospital field setting such as an outpatient or community setting.
• Certain embodiments of the invention include providing to a subject a composition containing a compound represented by formula (VII) or (VIII):
• A may be covalently linked to C or to L, and L may be covalently linked to C.
• the compound of formula (VII) may include nicotinic acid that is covalently linked to a PEGylated form of trimetazidine.
• the nicotinic acid may be covalently linked via a PEGylated moiety, i.e., via an ethylene glycol linkage.
• the nicotinic acid may be covalently linked via the trimetazidine moiety.
• the compound of formula (VII) or the compound of formula (VIII) may have a structure represented by formula (X):
• Component A may be any suitable compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation. Such compounds can be classified based on their mechanism of action. See Fillmore, N., et al., Mitochondrial fatty acid oxidation alterations in heart failure, ischemic heart disease and diabetic cardiomyopathy, Brit. J. Pharmacol. 171 :2080-2090 (2014), the contents of which are incorporated herein by reference.
• One class of glucose-shifting compounds includes compounds that inhibit fatty acid oxidation directly.
• Compounds in this class include inhibitors of malonyl CoA decarboxylase (MCD), carnitine palmitoyl transferase 1 (CPT-1), or mitochondrial fatty acid oxidation.
• Mitochondrial fatty acid oxidation inhibitors include trimetazidine and other compounds described in International Patent Publication No. WO 2002/064576, the contents of which are incorporated herein by reference. Trimetazidine binds to distinct sites on the inner and outer mitochondrial membranes and affects both ion permeability and metabolic function of mitochondria.
• MCD inhibitors include CBM-301106, CBM-300864, CBM-301940, 5-(l,l,l,3,3,3-hexafluoro-2- hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides, methyl 5-(N-(4-(l, 1,1, 3,3,3- hexafluoro-2-hydroxypropan-2-yl)phenyl)morpholine-4-carboxamido)pentanoate, and other compounds described in Chung, J.F., et al., Discovery of Potent and Orally Available Malonyl- CoA Decarboxylase Inhibitors as Cardioprotective Agents, J. Med. Chem.
• CPT-1 inhibitors include oxfenicine, perhexiline, etomoxir, and other compounds described in International Patent Publication Nos. WO 2015/018660; WO 2008/109991; WO 2009/015485; and WO 2009/156479; and U.S. Patent Publication No. 2011/0212072, the contents of each of which are incorporated herein by reference.
• glucose-shifting compounds includes compounds that stimulate glucose oxidation directly. Examples of such compounds are described in U.S. Patent Publication No. 2003/0191182; International Patent Publication No. WO 2006/117686; U.S. Patent No. 8,202,901, the contents of each of which are incorporated herein by reference.
• glucose-shifting compounds includes compounds that decrease the level of circulating fatty acids that supply the heart.
• examples of such compounds include agonists of PPARa and PPARy, including fibrate drugs, such as clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate, and thiazolidinediones, GW-9662, and other compounds described in U.S. Patent No. 9,096,538, the contents of which are incorporated herein by reference.
• Component L may be any suitable linker.
• the linker can be cleaved in vivo to release components A and B.
• the linker may be an alkoxy group.
• the linker may be polyethylene glycol of any length.
• linkers include 1,3-propanediol, diazo linkers, phosphoramidite linkers, disulfide linkers, cleavable peptides, iminodiacetic acid linkers, thioether linkers, and other linkers described in Leriche, G., et al., Cleavable linkers in chemical biology, Bioorg. Med. Chem. 20:571-582 (2012); International Patent Publication No. WO 1995000165; and U.S. Patent No. 8,461,117, the contents of each of which are incorporated herein by reference.
• Component C may be any molecule that can serve as a precursor to NAD + in vivo.
• NAD + is an important oxidizing agent that acts as a coenzyme in multiple reactions of the citric acid cycle as well as glycolysis and in the conversion of pyruvate to acetyl-CoA by pyruvate dehydrogenase (PDH). In these reactions, NAD + is reduced to NADH. Conversely, NADH is oxidized back to NAD + when it donates electrons to mitochondrial electron transport chain.
• NAD + can be synthesized de novo from tryptophan, but not in quantities sufficient to meet the continual cellular demands for NAD + .
• NAD + is also synthesized via a salvage pathway, which uses precursors that must be supplied from the diet.
• precursors used by the salvage pathway for NAD + synthesis are nicotinic acid (via the Preiss- Handler pathway), nicotinamide, and nicotinamide riboside, the latter two generating nicotinamide mononucleotide (NMN).
• NAD + precursor such as nicotinic acid, nicotinamide, NMN, or nicotinamide riboside
• the compound facilitates NAD + synthesis, stabilization and/or expansion of the intracellular NAD + pool and, reflecting the role of NAD+ as the main hydride acceptor in intermediary metabolism, support of cellular energy producing metabolic pathways in both cytosol and mitochondria.
• This approach will also support signaling pathways which utilize NAD+ as a co-substrate, e.g. ADP -ribose transferases and the sirtuins (NAD + -dependent protein deacetylases), regulating DNA repair and post-translational protein modifications.
• NAD + redox imbalance has been implicated in the pathogenesis of a range of cardiovascular, metabolic, senescent and degenerative conditions, including diabetic cardiomyopathy and heart failure.
• NAD + precursor in compounds of the invention allows the compounds to stimulate energy production in cardiac mitochondria in multiple ways.
• Component A shifts cardiac metabolism from fatty acid oxidation to glucose oxidation, which is inherently more efficient.
• the NAD + precursor provides an essential coenzyme that cycles between oxidized and reduced forms to promote respiration.
• NAD + drives reactions of the citric acid cycle.
• NADH promotes electron transport to create a proton gradient that enables ATP synthesis. Consequently, the chemical potential resulting from oxidation of acetyl CoA is efficiently converted to ATP that can be used for various cellular functions.
• the NAD + precursor molecule may be covalently attached to the compound in any suitable manner. For example, it may linked to A or L, and it may be attached directly or via another linker. Preferably, it is attached via a linker that can be cleaved in vivo.
• the NAD + precursor molecule may be attached via a 1,3-propanediol linkage.
• the compound may be covalently attached to one or more molecules of polyethylene glycol (PEG), i.e., the compound may be PEGylated.
• PEG polyethylene glycol
• the ethylene glycol moiety may serve as a linker, as described above in relation to Component L, or it may be attached to only one component, e.g., Component A, L, or C, of the compound.
• the ethylene glycol moiety may be separate from a covalent linkage between the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and the NAD + precursor molecule.
• the compound may contain a PEG polymer of any size.
• the PEG polymer may have from 1-500 (CH2CH2O) units.
• the PEG polymer may have any suitable geometry, such as a straight chain, branched chain, star configuration, or comb configuration.
• the compound may be PEGylated at any site.
• the compound may be PEGylated on component A, component L (if present), or the NAD + precursor.
• the compound may be PEGylated at multiple sites.
• the various PEG polymers may be of the same or different size and of the same or different configuration.
• the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may be PEGylated with an ethylene glycol moiety.
• the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation may have multiple ethylene glycol moieties, such as one, two three, four, five, or more ethylene glycol moieties.
• the ethylene glycol moiety may form a covalent linkage between the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and the NAD + precursor molecule.
• the ethylene glycol moiety may be separate from a covalent linkage between the compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation and the NAD + precursor molecule.
• the compound of formula (VII) may include nicotinic acid that is covalently linked to a PEGylated form of trimetazidine.
• the nicotinic acid may be covalently linked via a PEGylated moiety, i.e., via an ethylene glycol linkage.
• the nicotinic acid may be covalently linked via the trimetazidine moiety.
• the compounds may include one or more atoms that are enriched for an isotope.
• the compounds may have one or more hydrogen atoms replaced with deuterium or tritium. Isotopic substitution or enrichment may occur at carbon, sulfur, or phosphorus, or other atoms.
• the compounds may be isotopically substituted or enriched for a given atom at one or more positions within the compound, or the compounds may be isotopically substituted or enriched at all instances of a given atom within the compound.
• methods of the invention include providing pharmaceutical compositions containing one or more of the compounds described above.
• a pharmaceutical composition containing a compound may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
• granulating and disintegrating agents for example corn starch, or alginic acid
• binding agents for example starch, gelatin or acacia
• lubricating agents for example magnesium stearate, stearic acid or talc.
• Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
• an oil medium for example peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
• suspending agents for example sodium carboxymethylcellulose, methylcellulose
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example ethyl, or n-propyl p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
• flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
• sweetening agents such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions use in methods of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
• Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the compounds of the invention are useful for improving cardiac efficiency.
• cardiac efficiency A variety of definitions of cardiac efficiency exist in the medical literature. See, e.g.. Schipke, J.D. Cardiac efficiency, Basic Res. Cardiol. 89:207-40 (1994); and Gibbs, C.L. and Barclay, C.J. Cardiac efficiency, Cardiovasc. Res. 30:627-634 (1995), incorporated herein by reference.
• One definition of cardiac mechanical efficiency is the ratio of external cardiac power to cardiac energy expenditure by the left ventricle. See Lopaschuk G.D., et al., Myocardial Fatty Acid Metabolism in Health and Disease, Phys. Rev. 90:207-258 (2010), incorporated herein by reference.
• Another definition is the ratio between stroke work and oxygen consumption, which ranges from 20-25% in the normal human heart. Visser, F., Measuring cardiac efficiency: is it useful? Hear Metab. 39:3-4 (2008), incorporated herein by reference. Another definition is the ratio of the stroke volume to mean arterial blood pressure. Any suitable definition of cardiac efficiency may be used to measure the effects of compounds of the invention.
• the method of the invention is useful for treating cardiac steatosis or a disorder associated with cardiac steatosis.
• Cardiac steatosis is ectopic deposition and abnormal retention of lipids within the heart. It is visualized histologically as fatty acid droplets within the sarcolemma and can be quantified using non-invasive imaging of myocardial triglyceride (MTG) using 'H-magnetic resonance spectroscopy (MRS), as discussed in Szczepaniak LS, Victor RG, Orci L, Unger RH. Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res.
• Cardiac steatosis is commonly associated with diabetes and/or obesity where it is thought to reflect excessive free fatty acid delivery to the heart. This process of excessive ectopic lipid deposition (steatosis) may also affect other non-adipose organs (e.g. liver, contributing to non-alcoholic fatty liver disease or hepatic steatosis, pancreas) as well as the epicardium and pericardium.
• non-adipose organs e.g. liver, contributing to non-alcoholic fatty liver disease or hepatic steatosis, pancreas
• Cardiac Steatosis reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat.
• cardiomyocyte lipid accumulation (including triglyceride and ceramide) is an early and progressive pathological event in the context of a diabetic milieu and worsening of donor cardiac function at 48 weeks post-transplant, as discussed in Marfella R, Amarelli C, Cacciatore F, Balestrieri ML, Mansueto G, D'Onofrio N, Esposito S, Mattucci I, Saempero G, De Feo M, D'Amico M, Golino P, Maiello C, Paolisso G, Napoli C.
• the method of the invention provides a robust and rapid impact on myocardial steatosis, i.e. reducing myocardial lipid overload, to support better function of the obese and/or diabetic myocardium.
• the method includes providing to a subject having, or at risk of developing, cardiac steatosis or a disorder associated with cardiac steatosis a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• the methods of the invention are useful for reducing myocardial triglycerides in a subject.
• the method includes providing to a subject having, or at risk of developing, myocardial a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• Intracellular triglycerides can be metabolized to toxic by-products (e.g. diacylglycerol and ceramides) in a process termed liptoxicity.
• Cardiac lipotoxicity not only involves an excessive accumulation of intra-myocellular triglycerides (TGs) in the heart but also changes in lipid classes, as well as in their fatty acid profile.
• the method includes providing to a subject having, or at risk of developing, lipotoxicity a composition of a compound having a structure represented by formula (X).
• the composition may be provided orally.
• the composition may be provided in at least one dose per day or may be provided in multiple doses per day at a suitable interval.
• the composition may be provided in at least one dose daily for at least two weeks.
• the dose of the compound of formula (X) may be from about 25 mg to about 1000 mg, from about 50 mg to about 600 mg, and from about 100 mg to about 400 mg.
• the dose may be about 200 mg.
• the composition may be a modified-release formulation.
• formula (X) Even short-term administration of formula (X) is associated with meaningful and rapid systemic metabolic effects. See example 3. The majority of subjects in the study lost weight with greater weight loss in those with higher baseline HbAlc. A significant reduction in mean fasting glucose in the cohorts was also achieved.
• Methods of the invention are useful for treating cardiac dysfunction.
• Baseline HbAlc and reduction of HbAlc using the methods of this invention are positively associated with an increase in PCr/ATP.
• the method includes providing to a subject having an elevated level of HbAlc at least one dose per day of a compound having a structure represented by formula (X).
• a cutoff baseline HbAlc of greater than 6.0%, 6.5% or 7% may be used as a predictor of PCr/ATP response.
• the primary objective is to assess the safety and tolerability of single and multiple ascending oral doses of IMB-1018972, and single oral doses of trimetazidine.
• Secondary objectives include: To assess the pharmacokinetic (PK) profile of single and multiple ascending oral doses of IMB-1018972, and single oral doses of trimetazidine; To assess the effect of food on the absorption and the PK profile of IMB-1018972 following a single oral dose of IMB-1018972 in healthy subjects; To evaluate the effect of food on the safety and tolerability of IMB-1018972 following a single oral dose of IMB-1018972 in healthy subjects;
• PK pharmacokinetic
• Subjects assigned to Group A4 also participated in the FE arm and received the same single dose of IMB-1018972 or placebo under fed conditions (Food and Drug Administration [FDA]-defined high-fat breakfast after an overnight fast of at least 10 hours) in a second period at least 1 week after drug administration under fasted conditions in the SAD part.
• FDA Food and Drug Administration
• IMB-1018972 dose-escalation was based on the available safety, tolerability, and PK results of at least 5 dosed subjects in the preceding group.
• a dose-escalation meeting was held between the Investigator and the Sponsor.
• a dose-escalation report (DER) was provided by the Investigator to the Independent Ethics Committee (IEC) following completion of each dose level. Escalation to the next higher dose only proceeded when none of the stopping criteria had been reached and if the available safety, tolerability, and PK results (results up to 48 hours postdose) of at least 5 dosed subjects in the preceding group were acceptable to the Investigator and the Sponsor and after a statement of no objection of the DER from the IEC.
• IMB-1018972 dose escalation was based on the available safety, tolerability, and PK results of at least 8 dosed subjects in the preceding group.
• a dose-escalation meeting was held between the Investigator and the Sponsor. Further, a DER was provided by the Investigator to the IEC following completion of each dose level. Escalation to the next higher dose only proceed when none of the stopping criteria had been reached and if the available safety, tolerability, and PK results (results up to 48 hours after the final morning dose on Day 14) of at least 8 dosed subjects in the preceding group were acceptable to the Investigator and the Sponsor and after a statement of no objection of the DER from the IEC.
• Confinement period SAD part: 1 period in the clinic from Day -1 (admission) to approximately 48 hours after study drug administration (Day 3); an exception was Group A4 also participating in the FE arm in which subjects were in the clinic for 2 periods, each being from Day -1 (admission) to approximately 48 hours after study drug administration (Day 3)
• MAD part 1 period in the clinic from Day -1 (admission) to approximately 48 hours after the last study drug administration on Day 14 (Day 16);
• SAD part 7 to 14 days after the last PK blood sample (between Day 10 and Day 17);
• FE arm 7 to 14 days after the last PK blood sample in the second period (between Day 10 and Day 17);
• MAD part 7 to 14 days after the last PK blood sample (between Day 23 and Day 30);
• SAD part 40 healthy male or female subjects (this included 8 subjects also participating in the FE arm); from Group A4 onwards, all efforts were made to have a ratio of 50:50 for male and female subjects per group, but at minimum at least 3 subjects of each gender were dosed per group
• MAD part 24 healthy male or female subjects; for each group, all efforts were made to have a ratio of 50:50 for male and female subjects, but at minimum at least 4 subjects of each gender were dosed per group
• Age 18 years to 65 years, inclusive, at screening
• Drug product IMB-1018972
• Activity Fatty acid oxidation inhibitor
• Dosage form Oral IR capsule(s) to be used in the SAD and MAD parts
• Vastarel MR trimetazidine dihydrochloride
• Sample size calculation For this FIH study, no prospective calculations of statistical power were made. The sample size was selected to provide information on safety, tolerability, and PK following single and multiple doses of IMB-1018972, single doses of trimetazidine, and is typical for a FIH study. Any p-values to be calculated according to the statistical analysis plan were interpreted in the perspective of the exploratory character of this study.
• PK parameters Descriptive statistics for all relevant PK parameters: n, mean, SD, minimum, median, maximum, geometric mean, and coefficient of variation; analysis of variance on Cmax and AUC parameters to determine dose proportionality and FE
• the predefined target exposure level was approximately 3 to 4 ‘trimetazidine equivalents’, ie, the ratio of the combined exposure of the active metabolites of IMB-1018972 to the single oral doses of 35 mg MR trimetazidine as seen in published literature.
• TEAEs were transient and resolved without sequelae by follow-up.
• Most TEAEs were of mild severity and no severe TEAEs were reported during the study.
• TEAEs of moderate severity were the 5 TEAEs of flushing mentioned above and 1 TEAE each of restlessness, back pain, nausea, tonsillitis, post procedural hemorrhage, ALT increased, and influenza like illness.
• the moderate TEAE of influenza like illness was considered to be an SAE and was reported by a subject in the SAD part who had received a single dose of 150 mg IMB-1018972 under fasted conditions in the SAD part. The subject was withdrawn from the study as a result of this SAE. The SAE was considered by the Investigator unlikely to be related to the study drug.
• TEAEs The most frequently reported TEAEs during the study were of the system organ class vascular disorders (mainly TEAEs of flushing), general disorders and administration site conditions, nervous system disorders, gastrointestinal disorders, and musculoskeletal and connective tissue disorders.
• the geometric mean Cmax increased with dose and ranged between 104 ng/mL and 870 ng/mL for IMB-1028814, between 36.9 ng/mL and 274 ng/mL for trimetazidine, and between 516 nmol/L and 3,839 nmol/L (molar units to account for differences in molecular weight) for IMB-1028814 + trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB- 1018972 under fasted conditions.
• the geometric mean AUCo-t increased with dose and ranged between 290 ng.h/mL and 2,795 ng.h/mL for IMB-1028814, between 424 ng.h/mL and 3,305 ng.h/mL for trimetazidine, and between 2,970 nmol.h/L and 22,365 nmol.h/L for IMB- 1028814 + trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB-1018972 under fasted conditions.
• the geometric mean ti/2 of IMB-1028814 was relatively short, ranging between 2.6 hours and 3 hours over the IMB-1018972 single-dose range under fasted conditions.
• geometric mean ti/2 was longer, ranging between 6.76 hours and 8 hours over the IMB-1018972 single-dose range under fasted conditions.
• Geometric mean ti/2 of IMB-1028814 and trimetazidine did not increase with increasing IMB-1018972 dose indicating that the PK of the 2 moieties was linear.
• trimetazidine tmax was 5 hours, and geometric mean values were 68.6 ng/mL for Cmax, 912 ng.h/mL for AUCo-t, and 929 ng.h/mL for AUCo-inf.
• the geometric mean tl/2 of trimetazidine was 7.49 hours.
• Median IMB-1028814 tmax in plasma was reached at 2 hours postdose under fed conditions relative to 1 hour postdose under fasted conditions.
• Median trimetazidine tmax in plasma was reached at 4 hours postdose under fed conditions relative to 1.5 hours postdose under fasted conditions.
• Cmax was approximately 36% lower following administration of a single dose of 150 mg IMB-1018972 after an FDA-defined high-fat breakfast relative to administration under fasted conditions (estimate of 0.64; 90% CI ranging from 0.39 to 1.04).
• trimetazidine exposure parameters Cmax estimate of 0.91; 90% CI ranging from 0.85 to 0.98
• AUCO-t and AUCO-inf both with an estimate of 1.04 and 90% CI ranging from 0.98 to 1.10 following administration of a single dose of 150 mg IMB-1018972.
• the arithmetic mean percent of the dose excreted in urine ranged between 3.99% and 5.74% for IMB-1028814, and between 23.11% and 32.55% for trimetazidine within 48 hours after a single oral IMB-1018972 dose over the studied dose range of 50 mg to 400 mg.
• an arithmetic mean of 54.47% was excreted in urine as trimetazidine.
• the geometric mean renal clearance (CLR) ranged between 3.76 L/h and 5.37 L/h for IMB-1028814, and between 18.1 L/h and 20.8 L/h for trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB-1018972.
• Geometric mean CLR for trimetazidine was 20.4 L/h following administration of a single oral dose of 35 mg trimetazidine.
• the renal clearance of trimetazidine is greater than the glomerular filtration rate (125 mL/min or 7.5 L/h), indicating that trimetazidine undergoes net tubular secretion.
• median tmax ranged between 0.5 hours and 1 hours postdose for IMB-1028814 on Day 1, and was 3 hours postdose for trimetazidine on Day 1. On Day 14, median tmax was 0.5 hours postdose for IMB-1028814 and 2 hours postdose for trimetazidine.
• Cmax and AUC0-T were higher after 150 mg fed than after 50 mg fed for IMB-1028814 (297% and 336% higher for Cmax and AUCO-T, respectively), trimetazidine (154% and 163% higher for Cmax and AUCO-T respectively), and IMB-1028814 + trimetazidine (257% and 239% higher for Cmax and AUCO-T, respectively).
• geometric mean Cmax was 97% higher on Day 1 after 150 mg fed in the MAD part than after a single dose of 150 mg fed in the SAD part for IMB-1028814.
• geometric mean Cmax was 32% lower on Day 1 after 150 mg fed in the MAD part than after a single dose of 150 mg fed in the SAD part.
• Cmax and AUCO-T were higher after 150 mg fed than after 50 mg fed for IMB-1028814 (377% and 367% higher for Cmax and AUCO-T, respectively), trimetazidine (127% and 126% higher for Cmax and AUCO-T, respectively), and IMB-1028814 + trimetazidine (286% and 211% higher for Cmax and AUCO-T, respectively).
• geometric mean AUCO-T values of IMB- 1028814, trimetazidine, and IMB-1028814 + trimetazidine were higher on Day 14 relative to Day 1.
• Geometric mean Rac for IMB-1028814 was 1.18 and 1.10 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating minimal accumulation of IMB-1028814 in plasma.
• Geometric mean Rac for trimetazidine was 1.63 and 1.89 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating modest accumulation of trimetazidine in plasma.
• Geometric mean Rac for IMB-1028814 + trimetazidine was 1.39 and 1.52 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating modest accumulation of IMB-1028814 + trimetazidine in plasma.
• the geometric mean tl/2 of 4.48 hours after 150 mg fed was longer than that of 2.79 hours after 50 mg fed.
• the geometric mean tl/2 of 9.36 hours after 150 mg fed was similar to that of 9.32 hours after 50 mg fed.
• the geometric mean ti/2 of 8.90 hours for IMB-1028814 after 150 mg fed was similar to that of 9.08 hours after 50 mg fed.
• the predefined target exposure level was approximately 3 to 4 ‘trimetazidine equivalents’, ie, the ratio of the combined exposure of the active metabolites of IMB-1018972 to the single oral doses of 35 mg MR trimetazidine as seen in published literature.
• IMB-1018972 could be measured in only few plasma samples taken during this study.
• the geometric mean tl/2 ranged between 2.5 hours and 4.5 hours for IMB- 1028814, and between 6.5 hours and 9.5 hours for trimetazidine. Geometric mean ti/2 did not increase with increasing IMB-1018972 dose.
• IMB-1018972 metabolites IMB-1028814 and trimetazidine in this single-dose and multiple-dose FIH study, further clinical development of IMB-1018972 is warranted.
• IMB-1018972 is an orally administered small molecule that is being developed as a treatment for ischemic cardiovascular disease and the associated abnormal cellular energetics. Potential indications include angina pectoris, heart failure, and peripheral vascular disease.
• IMB- 1018972 is a new chemical entity (NCE) of the drug class partial fatty acid oxidation (pFOX) inhibitors that acts to preserve or enhance energy metabolism in cells exposed to hypoxia or ischemia.
• Other pFOX inhibitors include ranolazine (Ranexa), perhexiline, and trimetazidine.
• Glucose oxidation is a more efficient producer of adenosine triphosphate per oxygen molecule consumed compared to fatty acid oxidation.
• IMB-1018972 undergoes hydrolysis after administration, and the hydrolysis products are nicotinic acid (also known as niacin or vitamin B3) and an inhibitor of 3-ketoacyl CoA thiolase (3-KAT) named IMB-1028814.
• nicotinic acid also known as niacin or vitamin B3
• 3-ketoacyl CoA thiolase 3-KAT
• IMB-1028814 has been studied and characterized extensively in nonclinical studies. IMB-1028814 undergoes further metabolism and 1 metabolite is trimetazidine, a drug marketed in Europe since 1987 for the treatment of angina pectoris.
• IMB-1028814 The primary mechanism of action of IMB-1028814 is thought to be competitive inhibition of 3-KAT that results in the shift of substrate utilization in the myocardium from fatty acid oxidation to glucose oxidation.
• the delivery of nicotinic acid may serve to additionally enhance cellular energetics.
• Trimetazidine administered in this study is a drug marketed in Europe since 1978 for the treatment of angina pectoris.
• trimetazidine (Vastarel)
• the primary rationale for adding this group was to study the PK profile of commercially available trimetazidine with the same analytical assays utilized in the current study, which would enable a direct comparison of the PK profiles of trimetazidine generated from Vastarel and that generated from the metabolism of IMB-1028814.
• the analytical assays include detection of trimetazidine in blood and urine, which is the primary route of elimination.
• Each subject participated in only 1 group during the study Subjects assigned to Group A4 also participated in the FE arm and received the same single dose of IMB-1018972 or placebo under fed conditions (Food and Drug Administration [FDA]-defined high-fat breakfast after an overnight fast of at least 10 hours) in a second period at least 1 week after drug administration under fasted conditions in the SAD part.
• FDA Food and Drug Administration
• the SAD part consisted of:
• Study drug administration was under fed conditions as determined based on the results of Group A4 in the FE arm.
• the MAD part consisted of:
• Subjects were in the clinic for 1 treatment period (2 treatment periods for subjects of Group A4 also participating in the FE arm). The subjects were admitted to the clinical research center in the afternoon of Day -1. Day 1 was the day of (the first) drug administration.
• Subjects of the SAD part were discharged on Day 3 (48 hours after study drug administration) after completion of the assessments; discharge was on Day 3 of each period for subjects of Group A4 also participating in the FE arm.
• Subjects of the MAD part were discharged on Day 16 (48 hours after the last study drug administration on Day 14) after completion of the assessments.
• the follow-up assessments were performed 7 to 14 days after the last PK blood sample (between Day 10 and Day 17).
• the follow-up assessments were performed 7 to 14 days after the last PK blood sample in the second period (between Day 10 and Day 17).
• the follow-up assessments were performed 7 to 14 days after the last PK blood sample (between Day 23 and Day 30). Discussion of Study Design
• a dose-escalation meeting was held between the Investigator and the Sponsor. Further, a dose-escalation report (DER) was provided by the Investigator to the IEC following completion of each dose level. Escalation to the next higher dose only proceeded when none of the stopping criteria had been reached and if the available safety, tolerability, and PK results of the preceding group were acceptable to the Investigator and the Sponsor and after a statement of no objection of the DER from the IEC.
• the safety, tolerability, and PK results had to be available up to 48 hours postdose for the SAD part and up to 48 hours after the final morning dose on Day 14 for the MAD part. In addition, these results had to be available from at least 5 dosed subjects of the preceding group in the SAD part and at least 8 dosed subjects of the preceding group in the MAD part
• the planned dose levels to be administered could be changed based on the safety, tolerability, and plasma PK results of the previous group(s).
• the increase from one dose level to the next dose level could not be more than 3 -fold.
• a drug-related serious adverse reaction ie, a serious adverse event [SAE] considered at least possibly related to the study drug administration
• Drug-related severe adverse reactions ie, severe adverse events [AEs] considered at least possibly related to the study drug administration
• IMB-1018972 is in the early stage of clinical development, with the SAD part of the study being the first time the compound was administered to man.
• the subjects participating at the lowest dose level of the SAD part subjects of Group Al, were dosed according to a sentinel dosing design to ensure optimal safety. This means that initially, 2 subjects were dosed.
• One of these subjects received the active medication IMB-1018972, and the other subject received placebo.
• the subjects were closely observed by the Investigator for the first 24 hours following drug administration. The general tolerability of the study drug was monitored during this time, and the electrocardiogram (ECG) and vital signs recordings were reviewed. Any reported AEs were also considered in the Investigator’s evaluation.
• ECG electrocardiogram
• Subjects from Group A4 of the SAD part were assigned to the integrated FE arm. After administration of the drug to fasting subjects in the SAD part, the FE arm used the same subjects and experimental procedures. An exception was that subjects consumed an FDA-defined high-fat breakfast prior to dosing to evaluate the possible effect of food on the PK of IMB-1018972. This allowed for a within-subject comparison of the PK of IMB-1018972 in plasma and tolerability after administration in fasted and fed conditions.
• the MAD part could start after the results from the FE arm were available.
• the first group of the MAD part could start when a DER, summarizing safety and available PK data of previous SAD groups, concluded that a single dose with an exposure at/above the expected steady-state exposure in the first MAD group was well tolerated.
• the highest multiple-dose group planned could not exceed the highest planned single dose of 1600 mg/day or the highest tolerated dose in the SAD part. This was predicted to sufficiently cover doses in future dose-finding studies in patients.
• the planned confinement period, day of discharge, and follow-up period could be adapted depending on emerging study results. Also, the timing, type, and number of safety and PK assessments could be changed during the study.
• the overall study population consisted of 88 subjects.
• Gender male or female.
• Age 18 years to 65 years, inclusive, at screening.
• Body mass index (BMI) 18.0 kg/m2 to 32.0 kg/m2, inclusive.
• females could be of childbearing potential (but not pregnant or lactating), or of nonchildbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months]); nonpregnancy was confirmed for all females by a serum pregnancy test conducted at screening and each admission.
• Adequate contraception was defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the subject, was also acceptable.
• Adequate contraception for the male subject (and his female partner) was defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the subject, was also acceptable.
• Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol) at screening and (each) admission to the clinical research center.
• HBV hepatitis B surface antigen
• HCV anti-hepatitis C virus
• the Investigator had the right to terminate participation of a subject for any of the following reasons: difficulties in obtaining blood samples, violation of the protocol, severe AEs or SAEs, or for any other reason relating to the subject's safety or the integrity of the study data.
• PRA made every effort to ensure that early-termination subjects who had received study drug completed the safety follow-up assessments.
• Dosage form Oral IR capsule(s) to be used in the SAD and MAD parts
• Vastarel MR trimetazidine dihydrochloride
• the study drug was stored in the pharmacy at PRA in a locked facility under the required storage conditions with continuous monitoring.
• the study drug was dispensed by the pharmacist to the Investigator or authorized designee.
• the total number of IMB-1018972 capsules given per dose level in the SAD part (and integrated FE arm) and MAD part is given in Table 2.
• the number of placebo capsules that was administered to a placebo subject in a specific group was the same as the number of IMB-1018972 capsules that was given to an IMB-1018972 subject in that group.
• subjects were screened according to the inclusion and exclusion criteria. Subjects who met all eligibility criteria received a subject number upon inclusion in the study. They received the subject number just prior to dosing according to the randomization code generated by the Biostatistics Department of PRA. The subject number ensured identification throughout the study.
• Subject numbers were 101 to 140 for the SAD part, 201 to 224 for the MAD part. Any additional subjects to be included in the SAD part were to be numbered starting from subject number 141 and any additional subjects in the MAD part were to be numbered starting from subject number 225. Any replacement subject was to receive the number of the subject to be replaced, increased by 200, and was to be administered the same treatment(s). Subjects were assigned to a study part and group based on their availability. Treatments within a group were assigned according to the randomization code generated by the Biostatistics Department of PRA.
• each SAD group except for Group A5, 6 subjects were randomly assigned to receive IMB-1018972 and 2 subjects were randomly assigned to receive placebo. In Group A5, all 8 subjects received trimetazidine. In each MAD group, 9 subjects were randomly assigned to receive IMB-1018972 and 3 subjects were randomly assigned to receive placebo.
• the calculated human equivalent dose is 108 mg/kg/day.
• the NOAEL dose would be 6480 mg.
• MRSD maximum recommended starting dose
• the planned starting dose in the current Phase 1 study was 50 mg, equivalent to 0.83 mg/kg/day for a 60-kg subject. This starting dose is less than 10% of the MRSD determined from the dog NOAEL and less than 1% of the dog NOAEL.
• the maximum planned dose in this study of 1600 mg in healthy volunteers was 25% of the HED NOAEL dose of 6480 mg and only 2.5 fold higher than the MRSD.
• the conservative dosing margin was expected to cover potential supratherapeutic exposures, for instance in patients with renal or hepatic impairment, or in case of potential drug interactions with IMB- 1018972. This risk for healthy volunteers at these exposure levels was determined to be acceptable based on the absence of irreversible or significant toxicities without sentinel safety biomarkers.
• the relevant animal study was the 28-day dog study where the NOAEL for IMB- 1018972 was 200 mg/kg/day.
• the AUCo-s x2 for IMB-1028814 on Day 26 at this dose was 417,733 and 652,849 ng.h/mL for males and females, respectively.
• the AUCo-s x 2 for trimetazidine on Day 26 at this dose was 15,042, and 13,834 ng.h/mL for males and females, respectively.
• trimetazidine Vastarel
• This dose was selected as it is the most commonly used dose of trimetazidine in treating angina and it was therefore known that it has an efficacious PK profile.
• the study drug was administered with 240 mL of tap water to the subject in the upright position. If needed, an additional volume of water was allowed to consume the capsules/tablets comfortably; this additional volume was documented in the eCRF.
• the dose was given between 08:00 h and 11 :00 h, and between 20:00 h and 23 :00 h for the aftemoon/evening dose. Dosing for each individual subject was at around the same time ( ⁇ 15 min) on each dosing day. The study drug was not chewed.
• Subjects of Group A4 also participating in the FE arm were not allowed to lie down for 4 hours after dosing, except when required for assessments that needed to be performed.
• a fasting period of at least 4 hours was required before obtaining clinical laboratory samples at all time points.
• meals and snacks (such as decaffeinated coffee, herbal tea, fruit, and biscuits) were provided according to PRA standard operating procedures (SOPs).
• SOPs PRA standard operating procedures
• a light supper was provided on the evening before those days where fasting was required until lunch time (fasted conditions); a snack was provided on the evening before those days where fasting was required until the FDA-defined high-fat breakfast or breakfast (fed conditions).
• 918 kcal consisted of: • 2 fried eggs (in 15 g butter/margarine) (approximately 100 g)
• Strenuous exercise was not allowed within 96 hours (4 days) prior to (each) admission and during the stay(s) in the clinical research center.
• Subjects were not allowed to consume any foods containing poppy seeds within 48 hours (2 days) prior to (each) admission to the clinical research center as this could cause a false positive drug screen result.
• Adequate contraception was defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the subject, was also acceptable.
• Study drug was administered in the clinical research center. To ensure treatment compliance, administration of the study drug was supervised by the Investigator or authorized designee. Compliance was further confirmed by bioanalytical assessment of IMB-1018972, IMB-1028814, and trimetazidine in plasma and urine samples.
• the present study was performed to assess safety, tolerability, and PK following single and multiple doses of single and multiple oral doses of IMB-1018972, single oral doses of trimetazidine. This study did not comprise efficacy or pharmacodynamic assessments.
• AEs were recorded from (first) admission until completion of the follow-up visit. Any clinically significant observations in results of clinical laboratory, 12-lead ECGs, vital signs, or physical examinations were recorded as AEs.
• a treatment-emergent AE was defined as any event not present prior to (the first) administration of the study drug or any event already present that worsened in either severity or frequency following exposure to the study drug.
• An AE that occurred prior to (the first) administration of the study drug was considered a pretreatment AE.
• the severity of the AEs was rated as mild, moderate, or severe; the relationship between the AEs and the study drug was indicated as none, unlikely, possibly, likely, or definitely. Adverse events assessed as possibly, likely, or definitely were considered related to the study drug; AEs assessed as none or unlikely were considered not related to the study drug.
• Concomitant medication or other therapy required in case of any AEs was recorded. Concomitant medications were classified according to the World Health Organization Drug Dictionary (Version 22.0).
• Clinical chemistry serum quantitatively: total bilirubin, alkaline phosphatase, gamma glutamyl transferase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, creatinine, urea, total protein, glucose, inorganic phosphate, sodium, potassium,
• Hematology blood quantitatively: leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, partial automated differentiation (lymphocytes, monocytes, eosinophils, basophils, and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration
• Coagulation blood quantitatively: prothrombin time (reported in seconds and as international normalized ratio), activated partial thromboplastin time, and fibrinogen
• Urinalysis hemoglobin, urobilinogen, ketones, glucose, and protein
• Drug and alcohol screen opiates, methadone, cocaine, amphetamines (including ecstasy), cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol
• Urine for urinalysis was taken from the PK urine collection container at the end of a collection interval.
• Systolic and diastolic blood pressure and pulse were recorded after the subject had been resting for at least 5 minutes in the supine position. These assessments were made using an automated device. Body temperature and respiratory rate were measured subsequently.
• a standard 12-lead ECG was recorded after the subject had been resting for at least 5 minutes in the supine position.
• the ECG was recorded using an ECG machine equipped with computer-based interval measurements (with no/minimal disturbance by procedures).
• the following ECG parameters were recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTcF -interval, and the interpretation of the ECG profile by the Investigator.
• a 12-lead ECG was recorded continuously by telemetry from 2 hours before to 12 hours after drug administration on Day 1, and from 2 hours before to 24 hours after drug administration on Day 14.
• ECGs may or may not be analyzed for the purpose of concentration-effect modeling, based on future development decisions for IMB-1018972. If analyzed, results of the modeling were not to be included in this CSR, but to be included in a separate report.
• blood samples of 3 mL per time point were taken for the analysis of IMB-1018972, IMB-1028814, and trimetazidine in plasma samples.
• the blood samples were taken via an indwelling intravenous catheter or by direct venipuncture. The exact times of blood sampling were recorded in the eCRF.
• Plasma samples may (in the future) also be used for research purposes such as evaluation of the activity of IMB-1018972 and trimetazidine, identification of exploratory biomarkers that are predictive of activity, cytochrome P450 profiling, or other exploratory evaluations that may help characterize the molecular mechanisms of IMB-1018972 and trimetazidine.
• the samples will be stored for a maximum of 15 years for this purpose.
• Urine collection for PK was only conducted in the SAD part, but not in the second period of the FE group A4.
• urine was collected for the analysis of IMB-1018972, IMB-1028814, and trimetazidine. The subjects were instructed to empty their bladders completely before study drug administration and at the end of each collection interval. A blank urine sample was collected within 12 hours prior to study drug administration. The exact times of urine collection and the urine weight of the entire interval (before and after addition of any urine stabilizers, if used) were recorded in the eCRF.
• a blood sample of a maximum of 7 mL was collected for genotyping to better understand the effects of genotype, such as CYP alleles, on PK data.
• This blood sample was optional for subjects that had already been screened prior to IEC approval of protocol Version 3.0 (25 Mar 2019), whereas it was mandatory for subjects participating in this study that had been screened after IEC approval of protocol Version 3.0 (25 Mar 2019).
• the blood sample was double coded (1 code at PRA and 1 code at the Sponsor), and the sample was kept until 15 years after completion of the study.
• the blood sample was taken via an indwelling intravenous catheter or by direct venipuncture. The exact time of blood sampling was recorded in the eCRF.
• Pharmacokinetic variables were the plasma and urine concentrations of IMB-1018972, IMB-1028814, and trimetazidine, and their PK parameters.
• the PK parameters that were determined or calculated using noncompartmental analysis are given in Table 3.
• Table 3 Plasma IMB-1018972, IMB-1028814, and Trimetazidine Parameters
• IMB-1028814 and trimetazidine concentrations and PK parameters was calculated corrected for molecular weights of 310 kDa for IMB-1028814 and 266 kDa for trimetazidine. Plasma trough levels of IMB-1018972, IMB-1028814, and trimetazidine were also determined (MAD part only).
• the AUCs were calculated using the linear up/log down trapezoidal rule, expressed in units of concentration x time.
• Table 4 Urine IMB-1018972, IMB-1028814, and Trimetazidine Parameters
• Safety and tolerability were assessed through AEs, clinical laboratory, vital signs, ECGs, continuous cardiac monitoring (telemetry), and physical examination findings, and any other parameter that was relevant for safety assessment.
• Descriptive statistics (number, arithmetic mean, SD, coefficient of variation, minimum, maximum, median, and geometric mean) were calculated for plasma and urine PK parameters of IMB-1028814, trimetazidine, and IMB-1028814 + trimetazidine in the PK population, where applicable.
• Dose proportionality of IMB-1018972, IMB-1028814 and trimetazidine was explored for SAD Groups Al to A4 (fasted) using a regression (power) model relating log-transformed Cmax, AUCo-t, and AUCo-inf.
• Subjects with R2 below 0.80 or %AUCextra>20% were not excluded from the dose-proportionality evaluation based on AUCo-inf.
• a point estimate and 95% CI were produced for the slope.
• a slope of 1 i.e., a 95% CI containing 1) means that no evidence of a deviation from dose proportionality was found. Since there were only 2 dose levels in the MAD part, no dose-proportionality analysis was performed for the MAD part.
• Subject 129 of the FE arm Group A4 withdrew consent on Day 1 of the second period after receiving the single oral dose of 150 mg IMB-1018972 under fed conditions.
• Subject 131 of the FE arm Group A4 was withdrawn from the study due to an SAE of influenza like illness (of moderate severity and unlikely related) in the first period and only received the single oral dose of 150 mg IMB-1018972 under fasted conditions and not the fed dose in the second treatment period.
• FIG. 2 is a table of the disposition of subjects.
• Study drug was administered in the clinical research center. To ensure treatment compliance, administration of the study drug was supervised by the Investigator or authorized designee. There was no indication of noncompliance based on observations during study drug administration. In addition, bioanalytical assessment of IMB-1018972, IMB-1028814, and trimetazidine in plasma and urine samples confirmed treatment compliance.
• ALT levels measured for 1 subject were above the normal range and considered to be clinically significant abnormal.
• HBsAg hepatitis B surface antigen
• HCV hepatitis C virus
• PK pharmacokinetic(s)
• FIG.4 is a table of assessments given for the SAD part (and integrated FE arm) Groups Al to
• HBsAg hepatitis B surface antigen
• HCV hepatitis C virus
• Subjects were in the clinic for 1 period, except for subjects of Group A4 also participating in the FE arm who were in the clinic for 2 periods; a period was from Day - 1 until 48 hours (Day 3) postdose.
• b. The planned confinement period, day of discharge, and follow-up period could be adapted depending on emerging study results. Also, the timing, type, and number of safety and PK assessments could be changed during the study.
• Clinical laboratory tests including clinical chemistry, hematology, coagulation, and urinalysis: at screening, each period on Day -1 (admission) and at 24 hours postdose, and at follow-up.
• 12-lead ECG for Groups Al, A2, A3, and A4 first period only: at screening, on Day -1 (admission), at 48 hours postdose, and at follow-up.
• Data for 12-lead ECGs at predose and 1, 2, 4, 6, 12, and 24 hours postdose were taken from the 12-lead ECG prints from telemetry.
• the predose baseline value was the average values of the 3 predose telemetry 12-lead ECGs at -1.25, -1.0, and -0.75 hours predose.
• 12-lead ECG for Group A4 (second period only): on Day -1 (admission), at predose and 1, 2, 4, 6, 12, 24, and 48 hours postdose, and at follow-up.
• 12-lead ECG reads were printed at -1.25, -1.0, and -0.75 hours predose and just prior to the PK sampling time points of 0.25, 0.5, 1, 2, 4, 6, 12, and 24 (Day 2) hours postdose.
• Vital signs (supine systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate): at screening, each period on Day -1 (admission), each period at predose and 1, 2, 4, 6, 12, 24, and 48 hours postdose, and at follow-up. h In Groups Al, A2, A3, and, A4, and in the first period of Group A4 also participating in the FE arm, study drug administration was conducted under fasted conditions. In the second period of Group A4, drug administration was conducted under fed conditions (FDA-defined high-fat breakfast). i.
• Blood sampling for PK of IMB-1018972, IMB-1028814, and trimetazidine in plasma each period at predose and 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 hours postdose.
• j Only in the SAD part; not in the second period of Group A4 also participating in the FE arm: Urine collection for PK of IMB-1018972, IMB-1028814, and trimetazidine in urine: each period at predose (within 12 hours prior to dosing) and over 0-6, 6-12, 12-24, 24-36, and 36-48 hours postdose collection intervals.
• AEs were recorded from (first) admission until completion of the follow-up visit.
• HBsAg hepatitis B surface antigen
• HCV hepatitis C virus
• MAD multiple ascending dose
• the planned confinement period, day of discharge, and follow-up period could be adapted depending on emerging study results. Also, the timing, type, and number of safety and PK assessments could be changed during the study.
• Clinical laboratory tests including clinical chemistry, hematology, coagulation, and urinalysis: at screening, on Day -1 (admission), before the morning dose on Day 8 and at the same time on Day 15, and at follow-up.
• 12-lead ECG at screening, on Day -1 (admission), on Day 1 at 24 hours after the morning dose, on Day 8 at predose and 1, 2, 4, 6, 12 (prior to the evening dose) and 24 hours after the morning dose, on Day 16 (day of discharge) at the same time as before the morning dose on dosing days, and at follow-up.
• Data for 12-lead ECGs on Day 1 at predose and 1, 2, 4, 6, and 12 hours postdose, and on Day 14 at predose and 1, 2, 4, 6, 12, and 24 hours postdose were taken from the 12-lead ECG prints from telemetry.
• the predose baseline value on Day 1 and Day 14 was the respective average values of the 3 predose telemetry 12-lead ECGs at -1.25, -1.0, and -0.75 hours predose.
• 12-lead ECG reads were printed at -1.25, -1.0, and -0.75 hours before the morning dose and just prior to the PK sampling time points of 0.25, 0.5, 1, 2, 4, 6, 12, and 24 (Day 14 only) hours after the morning dose.
• Vital signs (supine systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate): at screening, on Day -1 (admission), on Days 1, 8, and 14 at predose and 1, 2, 4, 6, 12 (prior to the evening dose on Days 1 and 8) and 24 hours after the morning dose, on Day 16 (day of discharge) at the same time as before the morning dose on dosing days, and at follow-up.
• the study drug was administered twice daily for 14 days; on Day 14 only a single morning dose wasadministered. Study drug administration was conducted under fed conditions as determined based on the results of Group A4 in the FE arm.
• FIG. 6 is a table of analysis data sets for the SAD Part (and integrated FE Arm) per dose level and total for IMB-1018972.
• FIG. 7 is a table of analysis data sets for the MAD Part per dose level and total for IMB- 1018972.
• FIG. 8 is a table of a summary of demographic characteristics - SAD Part (and Integrated FE Arm) (Safety Set).
• FIG. 9 is a table of a summary of demographic characteristics - MAD Part (Safety Set).
• IMB-1018972 In each of Groups Al, A2, A3 and A4 of the SAD part, 6 subjects received a single dose of IMB-1018972 and 2 subjects received a single dose of matching placebo under fasted conditions. IMB-1018972 doses ranged from 50 mg to 400 mg over these 4 groups. Subjects of SAD Groups Al, A2, and A3 participated in 1 single-dose treatment period, and subjects of SAD Group A4 (the FE group) participated in 2 singledose treatment periods with fasted dosing in the first period and fed dosing in the second period.
• Subject 131 of FE Group A4 only received the fasted IMB-1018972 dose in the first treatment period and not the fed dose in the second treatment period since the subject was withdrawn from the study in the first period due to a moderate SAE of influenza like illness (unlikely related).
• Group A5 of the SAD part 8 subjects received a single oral dose of 35 mg trimetazidine under fasted conditions.
• FIG. 10 is a table of the Extent of Exposure - SAD Part (and Integrated FE Arm) (Safety Set)
• FIG. 11 is a table of the Extent of Exposure - MAD Part
• the lower limit of quantification was 0.5 ng/mL for IMB-1018972, IMB- 1028814 and trimetazidine plasma concentrations, 10 ng/mL for IMB-1028814 urine concentrations, and 50 ng/mL for trimetazidine urine concentrations.
• the geometric mean concentration-time profiles for IMB-1028814, metabolite trimetazidine, and IMB-1028814 + trimetazidine showed a clear dose-dependent increase in plasma concentrations following administration of single doses of IMB-1018972 under fasted conditions in the dose range of 50 mg to 400 mg IMB-1018972.
• the geometric mean Cmax increased with dose and ranged between 104 ng/mL and 870 ng/mL for IMB-1028814, between 36.9 ng/mL and 274 ng/mL for trimetazidine, and between 516 nmol/L and 3,839 nmol/L (molar units to account for differences in molecular weight) for IMB-1028814 + trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB- 1018972 under fasted conditions.
• the geometric mean AUCO-t increased with dose and ranged between 290 ng.h/mL and 2,795 ng.h/mL for IMB-1028814, between 424 ng.h/mL and 3,305 ng.h/mL for trimetazidine, and between 2,970 nmol.h/L and 22,365 nmol.h/L for IMB- 1028814 + trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB-1018972 under fasted conditions.
• Detectable individual IMB-1028814 concentrations were observed until 10, 12, 16, or 24 hours postdose after 50 mg, and until 16 or 24 hours postdose after 150 mg and 400 mg IMB- 101897.
• Detectable individual trimetazidine concentrations were observed until 24, 36, or 48 hours postdose after 50 mg, until 36 or 48 hours postdose after 150 mg, and until 48 hours postdose after 400 mg IMB-1018972.
• IMB-1028814 and trimetazidine concentration-time profile was observed for Subject 108 who had received a single oral dose of 50 mg IMB-1018972 under fasted conditions.
• IMB-1028814 and trimetazidine tmax was much later for this subject (5.00 hours for IMB- 1028814 and 8.00 hours for trimetazidine) than for the other subjects who received the same dose (between 0.50 and 1.02 hours for IMB-1028814 and between 1.00 and 2.00 hours for trimetazidine). Therefore, absorption of IMB-1018972 by this subject is much slower than for the other subjects who received the same dose.
• Dose proportionality for IMB-1028814 and trimetazidine was explored by plotting the dose-normalized exposure parameters Cmax, AUCo-t, and AUCo-inf on a linear scale.
• the 95% Cis of the slopes of all 3 exposure parameters included 1 for both IMB-1028814 and trimetazidine. This indicates that no evidence of a deviation from dose proportionality of IMB-1028814 and trimetazidine was found over the IMB-1018972 single-dose range of 50 to 400 mg.
• trimetazidine plasma concentrations were below the LLOQ for trimetazidine plasma concentrations.
• detectable trimetazidine concentrations were generally seen between 15 and 30 minutes postdose.
• Median trimetazidine tmax was 5 hours, and geometric mean values were 68.6 ng/mL for Cmax, 912 ng.h/mL for AUC0- t, and 929 ng.h/mL for AUCo-inf.
• trimetazidine occurred in a monophasic fashion up to the last time point above LLOQ with a geometric mean ti/2 of 7.49 hours. Detectable individual trimetazidine concentrations were observed until the last sampling time point of 48 hours postdose.
• FIG. 12 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Linear) - SAD Part (PK Set)
• FIG. 13 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi -Logarithmic) - SAD Part (PK Set)
• FIG. 14 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - SAD Part (PK Set)
• FIG. 15 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi -Logarithmic) - SAD Part (PK Set)
• FIG. 16 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic) - SAD Part (PK Set)
• FIG. 17 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic) - SAD Part (PK Set)
• FIG. 18 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - SAD Part (PK Set)
• FIG. 19 is a table of Exploratory Analysis of Dose Proportionality for IMB-1028814 and Trimetazidine over the Dose Range of 50 mg to 400 mg IMB-1018972 under Faster Conditions - SAD Part (PK Set)
• FIG. 20 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 Cmax over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• FIG. 21 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 AUCo-t over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• FIG. 22 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized IMB-1028814 AUCo-inf over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• FIG. 23 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine Cmax over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• FIG. 24 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine AUCo-t over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• FIG. 25 is a graph of Plot of Combined Individual and Geometric Mean Dose- Normalized Trimetazidine AUCo-inf over the Dose Range of 50 mg to 400 mg IMB-1018972 under Fasted Conditions - SAD Part (PK Set)
• trimetazidine plasma concentrations under fed conditions increased less rapidly than after study drug administration under fasted conditions and median tmax was reached at 4 hours postdose under fed conditions relative to 1.5 hours postdose under fasted conditions ⁇
• trimetazidine exposure parameters Cmax estimate of 0.91; 90% CI ranging from 0.85 to 0.98
• AUCo-t and AUCo-inf both with an estimate of 1.04 and 90% CI ranging from 0.98 to 1.10.
• FIG. 26 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set)
• FIG. 27 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi -Logarithmic Scale) - FE Arm of SAD Part (PK Set)
• FIG. 28 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set)
• FIG. 29 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi -Logarithmic Scale) - FE Arm of SAD Part (PK Set)
• FIG. 30 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Linear) - FE Arm of SAD Part (PK Set)
• FIG. 31 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - FE Arm of SAD Part (PK Set)
• FIG. 32 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-128814 + Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - FE Arm of SAD Part (PK Set)
• FIG. 33 is a table of Exploratory Analysis of Food Effect for IMB-1028814 and Trimetazidine following Administration of 150 mg IMB-1018972 - FE Arm of SAD Part (PK Set)
• Urinary excretion of IMB-1028814 and trimetazidine was determined in urine samples from subjects who received a single oral dose of IMB-1018972 in the range of 50 mg to 400 mg under fasted conditions. Further, urinary excretion of trimetazidine was determined in urine samples from subjects who received a single oral dose of 35 mg trimetazidine.
• the arithmetic mean percent of the dose excreted in urine ranged between 3.99% and 5.74% for IMB-1028814, and between 23.11% and 32.55% for trimetazidine within 48 hours after a single oral IMB-1018972 dose over the studied dose range of 50 mg to 400 mg.
• an arithmetic mean of 54.47% was excreted in urine as trimetazidine.
• the geometric mean renal clearance (CLR) ranged between 3.76 L/h and 5.37 L/h for IMB-1028814, and between 18.1 L/h and 20.8 L/h for trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB-1018972.
• Geometric mean CLR for trimetazidine was 20.4 L/h following administration of a single oral dose of 35 mg trimetazidine.
• the renal clearance of trimetazidine is greater than glomerular filtration rate (125 mL/min or 7.5 L/h), indicating that trimetazidine undergoes net tubular secretion.
• FIG. 34 is a table of Summary Statistics (Arithmetic Mean [SD]) of Urine Pharmacokinetic Parameters for IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine - SAD Part (PK Set)
• Urinary excretion of IMB-1028814 and trimetazidine was determined in urine samples from subjects who received a single oral dose of IMB-1018972 in the range of 50 mg to 400 mg under fasted conditions. Further, urinary excretion of trimetazidine was determined in urine samples from subjects who received a single oral dose of 35 mg trimetazidine.
• the arithmetic mean percent of the dose excreted in urine ranged between 3.99% and 5.74% for IMB-1028814, and between 23.11% and 32.55% for trimetazidine within 48 hours after a single oral IMB-1018972 dose over the studied dose range of 50 mg to 400 mg.
• an arithmetic mean of 54.47% was excreted in urine as trimetazidine.
• the geometric mean renal clearance (CLR) ranged between 3.76 L/h and 5.37 L/h for IMB-1028814, and between 18.1 L/h and 20.8 L/h for trimetazidine over the studied single-dose range of 50 mg to 400 mg IMB-1018972.
• Geometric mean CLR for trimetazidine was 20.4 L/h following administration of a single oral dose of 35 mg trimetazidine.
• the renal clearance of trimetazidine is greater than glomerular filtration rate (125 mL/min or 7.5 L/h), indicating that trimetazidine undergoes net tubular secretion.
• the geometric mean concentration-time profiles for IMB-1028814, metabolite trimetazidine, and IMB-1028814 + trimetazidine on Day 1 and Day 14 showed a dose dependent increase in plasma concentrations following administration of multiple doses of IMB-1018972 under fed conditions of 50 mg ql2h and 150 mg ql2h.
• Cmax and AUCo- T were higher after 150 mg fed than after 50 mg fed for IMB-1028814 (297% and 336% higher for Cmax and AUCO-T, respectively), trimetazidine (154% and 163% higher for Cmax and AUCO-T, respectively), and IMB-1028814 + trimetazidine (257% and 239% higher for Cmax and AUCO-T, respectively).
• geometric mean Cmax was 97% higher on Day 1 after 150 mg fed in the MAD part than after a single dose of 150 mg fed in the SAD part for IMB-1028814.
• geometric mean Cmax was 32% lower on Day 1 after 150 mg fed in the MAD part than after a single dose of 150 mg fed in the SAD part.
• Cmax and AUCO-T were higher after 150 mg fed than after 50 mg fed for IMB-1028814 (377% and 367% higher for Cmax and AUCO-T, respectively), trimetazidine (127% and 126% higher for Cmax and AUCO-T, respectively), and IMB-1028814 + trimetazidine (286% and 211% higher for Cmax and AUCO-T, respectively).
• Geometric mean R ac for IMB-1028814 was 1.18 and 1.10 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating minimal accumulation of IMB-1028814 in plasma.
• Geometric mean R ac for trimetazidine was 1.63 and 1.89 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating modest accumulation of trimetazidine in plasma.
• Geometric mean R ac for IMB-1028814 + trimetazidine was 1.39 and 1.52 after the 150 mg fed dose and 50 mg fed dose, respectively, indicating modest accumulation of IMB-1028814 + trimetazidine in plasma.
• the geometric mean tl/2 of 4.48 hours after 150 mg fed was longer than that of 2.79 hours after 50 mg fed.
• the geometric mean tl/2 of 9.36 hours after 150 mg fed was similar to that of 9.32 hours after 50 mg fed.
• the geometric mean tl/2 of 8.90 hours for IMB-1028814 after 150 mg fed was similar to that of 9.08 hours after 50 mg fed.
• FIG. 35 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 36 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 37 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 38 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 39 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 40 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 41 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 42 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 43 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 44 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 45 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Linear) - MAD Part (PK Set)
• FIG. 46 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Dosing on Day 1 through Day 14 (Semi-Logarithmic Scale) - MAD Part (PK Set)
• FIG. 47 is a table of Summary Statistics (Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - MAD Part (PK Set)
• FIG. 48A and FIG. 48B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - SAD Part (and integrated FE Arm) (Safety Set) with the following notifications:
• FIG. 49A and FIG. 49B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - MAD Part (Safety Set)
• FIG. 50 is a table Summary of All TEAEs by Treatment, Relationship, and Severity- SAD Part (and Integrated FE Arm) (Safety Set)
• FIG. 51 is a table Summary of All TEAEs by Treatment, Relationship, and Severity - MAD Part (Safety Set)
• niacin flushing events observed in this study were typically shortlasting with generalized cutaneous vasodilation and to varying degrees associated with an intense burning and tingling sensation of the skin, a feeling of warmth, and/or generalized erythema, starting shortly after intake of the drug and lasting about 1 to 2.5 hours.
• Nervous system disorders with 9 TEAEs reported by 7 (29.2%) subjects (4 TEAEs of dizziness, 3 TEAEs of headache, and 1 TEAE each of burning sensation and somnolence).
• Vascular disorders with 7 TEAEs reported by 7 (29.2%) subjects (6 TEAEs of flushing and 1 TEAE of peripheral coldness).
• the predefined target exposure level was approximately 3 to 4 ‘trimetazidine equivalents’, ie, the ratio of the combined exposure of the active metabolites of IMB 1018972 to the single oral doses of 35 mg MR trimetazidine as seen in published literature.
• TEAEs A total of 35 TEAEs was reported by 14 of 18 (77.8%) subjects who received IMB- 1018972, and a total of 17 TEAEs was reported by 5 of 6 (83.3%) subjects who received placebo. All TEAEs were of mild severity and there were no deaths reported. The majority of the TEAEs were transient and resolved without sequelae by follow-up. Three TEAEs were still ongoing at follow-up: vessel puncture site hematoma, medical device site irritation, and paresthesia of the left hand.
• Subject 131 was a 25-year old white male with a BMI of 21.9 kg/m2.
• the subject participated in the FE arm Group A4 and was planned to receive 150 mg IMB-1018972 under fasted conditions in the first treatment period and 150 mg IMB-1018972 under fed conditions in the second treatment period.
• he reported no relevant medical history and received no concomitant medication at baseline.
• the subject received a single dose of 150 mg IMB-1018972 under fasted conditions on Day 1 of the first period.
• the subject Within half an hour after dosing, the subject reported mild short-lasting TEAEs of dizziness, feeling hot, flushing, nausea, and dysphagia, which were all considered by the Investigator to be likely related.
• the subject did not receive the planned dose of 150 mg IMB-1018972 under fed conditions in the second treatment period.
• the subject returned on Day 15 for a follow-up with safety assessments conducted as planned.
• the subject received 37.5 mg tramadol twice daily on Days 6 and 7 and 1000 mg paracetamol twice daily on Days 7 and 8 because of the flu like symptoms.
• the subject also reported mild TEAEs of back pain from Day 1 to Day 2 (not related), medical device site pruritus on Day 2 (not related), erythema on Day 2 (unlikely related), and burning sensation from Day 2 to Day 5 (unlikely related).
• One subject (Subject 129; 150 mg IMB-1018972 under fasted conditions [fasted-fed group]) received 1000 mg paracetamol once or twice per day twice because of headache, and once because of muscular cramps of the upper legs (preferred term: muscle spasms). The same subject also received 5 mg oxycodone 4 times a day for 12 days, 1000 mg paracetamol 4 times a day for 5 days, 80 mg macrogol 4 times a day for 12 days, and 200 mg celecoxib once daily for 5 days because of tonsillitis.
• the predefined target exposure level was approximately 3 to 4 ‘trimetazidine equivalents’, ie, the ratio of the combined exposure of the active metabolites of IMB- 1018972 to the single oral doses of 35 mg MR trimetazidine as seen in published literature.
• Nicotinic acid is an immediate hydrolysis product of IMB-1018972 and constitutes approximately 30% of the molecular mass of IMB-1018972.
• TEAEs of flushing of which the characteristics were consistent with the flushing seen with the administration of niacin, were reported. All events were transient and resolved without intervention. No subjects dropped out and no modification of the dose was needed due to the TEAEs of flushing.
• SAD (IR) part of the study the most common AEs were 6 TEAEs of flushing (reported terms were ‘niacin flush’ and ‘flushing neck’), of which 5 TEAEs were of moderate severity and 1 TEAE was of mild severity.
• One subject was withdrawn from the study.
• One subject of the FE arm Group A4 was withdrawn from the study due to a moderate SAE of ‘influenza like illness’ following administration of a single oral dose of 150 mg IMB-1018972 under fasted conditions.
• the SAE of influenza like illness was considered by the Investigator unlikely to be related to the study drug.
• TEAEs The most frequently reported TEAEs during the study were of the SOC vascular disorders (mainly TEAEs of flushing), general disorders and administration site conditions, nervous system disorders, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. The majority of the TEAEs reported during the study were considered by the Investigator not to be related to the study drug.
• the predefined target exposure level was approximately 3 to 4‘trimetazidine equivalents’, ie, the ratio of the combined exposure of the active metabolites of IMB-1018972 to the single oral doses of 35 mg MR trimetazidine as seen in published literature.
• IMB-1018972 could be measured in only few plasma samples taken during this study.
• IMB-1018972 metabolites IMB-1028814 and trimetazidine in this single-dose and multiple-dose FIH study, further clinical development of IMB-1018972 is warranted.
• the primary objective is to evaluate the impact of 200 mg of formula (X) on rest and stress myocardial energetics (PCr/ATP).
• Other objectives include: to evaluate the metabolic response, specifically the impact on PDH flux using hyperpolarized 13 C-pyruvate MRS, as a measure of the compound’s ability to promote glucose oxidation; to assess the effect on cardiac systolic and diastolic function, as measured by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE); to measure the impact on myocardial steatosis.
• CMR cardiac magnetic resonance
• TTE transthoracic echocardiography
• Fig. 52 The preliminary baseline characteristics of randomized participants is detailed in Fig. 52.
• the preliminary baseline characteristics of completers is detailed in Fig. 53.
• Fig. 54 details adverse events as of the data cut-off date of September 20.
• HbAlc appears to be a predictor of cardiac energetic response. If confirmed, these data will guide patient selection in future studies of diabetic patients, e.g. in those with heart failure with preserved ejection fraction (HFpEF).
• HFpEF preserved ejection fraction
• myocardial TG content is known to be independently associated with impaired LV diastolic function in Type 2 diabetes, a key contributor to impaired cardiac performance in HFpEF.

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