EP4171232A1 - Formulations à libération modifiée de formes modifiées de trimétazidine - Google Patents

Formulations à libération modifiée de formes modifiées de trimétazidine

Info

Publication number
EP4171232A1
EP4171232A1 EP21832842.5A EP21832842A EP4171232A1 EP 4171232 A1 EP4171232 A1 EP 4171232A1 EP 21832842 A EP21832842 A EP 21832842A EP 4171232 A1 EP4171232 A1 EP 4171232A1
Authority
EP
European Patent Office
Prior art keywords
imb
hours
trimetazidine
dose
hpmc
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21832842.5A
Other languages
German (de)
English (en)
Inventor
Andrew D. LEVIN
Jaikrishna Patel
George MOONEY
Scott Herbig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Imbria Pharmaceuticals Inc
Original Assignee
Imbria Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imbria Pharmaceuticals Inc filed Critical Imbria Pharmaceuticals Inc
Publication of EP4171232A1 publication Critical patent/EP4171232A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the invention relates pharmaceutical compositions containing modified-release formulation of modified forms of trimetazidine and the use of such compositions to treat medical conditions, including angina and heart failure.
  • Heart disease is the leading cause of death worldwide, accounting for 15 million deaths across the globe in 2015. In many forms of 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 angina, 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.
  • CV-8972 (US patent number 10,556,013, the content of which is incorporated by reference herein in its entirety), a modified form trimetazidine, was recently identifi ed as a promising therapeutic candidate for cardiovascular conditions.
  • CV-8972 has the IUPAC name 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-l-yl]ethyl pyridine-3-carboxylate and the following structure:
  • CV-8972 is broken down sequentially into several specific, biologically active metabolites when CV-8972 is provided to humans.
  • CV-8972 is initially broken down into niacin and a modified form of trimetazidine, which is identified also identified in US patent number 10,556,013 as CV-8814, having the following structure:
  • CV-8814 is subsequently converted in the body to trimetazidine.
  • trimetazidine and CV-8814 promote glucose oxidation by blocking 3-ketoacyl-CoA thiolase, and thus both are active pharmaceutical ingredients (APIs).
  • APIs active pharmaceutical ingredients
  • CV-8972 is metabolized in the body into individual components that exert distinct biochemical effects to promote glucose oxidation and improve overall mitochondrial respiration in the heart. Because CV-8972 yields different metabolic products that act synergistically, CV-8972 is useful as a therapeutic agent for treating heart diseases characterized by elevated fatty acid oxidation.
  • the CV-8814 and trimetazidine produced from CV-8972 shift cardiac metabolism from fatty acid oxidation to glucose oxidation to allow the use of a more efficient source of energy.
  • the niacin produced from CV-8972 stimulates metabolic pathways that are common to oxidation of both glucose and fatty acids and that may also be impaired in patients with heart disease.
  • This invention recognizes that CV-8972 is rapidly broken down in the body to niacin and CV-8814.
  • the invention also recognizes that high amounts of niacin in the body can have certain side effects, such as flushing.
  • the invention further recognizes that a formulation that slows and/or controls the breakdown of CV-8972 into niacin and CV-8814 would provide a beneficial effect of reducing or eliminating any niacin side effects (e g., flushing) while also prolonging the efficacy of a single dose of CV-8972, thereby leading to less frequent dosing.
  • a formulation that slows and/or controls the breakdown of CV-8972 into niacin and CV-8814 would provide a beneficial effect of reducing or eliminating any niacin side effects (e g., flushing) while also prolonging the efficacy of a single dose of CV-8972, thereby leading to less frequent dosing.
  • the invention provides modified-release formulations of CV-8972 that promote gradual metabolism of CV-8972 in the digestive tract.
  • the modified-release formulations of the invention have improved therapeutic properties because they lead to less acute and more prolonged increases of the pharmacologically active products of CV-8972 in circulation.
  • the formulations provided herein greatly increase the utility of this promising new drug candidate.
  • compositions of the invention contain a mixture that includes a modified form of trimetazidine, such as CV-8972, and an erodible polymer, such as hydroxypropyl methylcellulose (HPMC).
  • a modified form of trimetazidine such as CV-8972
  • HPMC hydroxypropyl methylcellulose
  • the mixture absorbs water in the digestive tract, and the polymer gradually breaks down. Consequently, maximum levels of the active pharmaceutical ingredients in the subject's plasma are achieved two or more hours after administration of the compositions, and peak levels are about 50% lower than those produced by conventional formulations containing the same dose of the therapeutic agent.
  • the compositions of the invention thus provide extended periods in which the metabolic products of CV-8972 or other modified forms of trimetazidine are maintained in the body above a therapeutic threshold while mitigating side effects that result from high peak levels.
  • the invention further provides methods of treating cardiac conditions by providing the compositions described herein.
  • compositions of the invention are useful for treating any condition that can be ameliorated by improving cardiac mitochondrial function.
  • the compositions are useful for treating cardiovascular conditions, such as angina and heart failure.
  • the compositions can be easily administered orally, e.g , as a tablet or capsule.
  • the compositions need only be taken once or twice per day.
  • the invention provides pharmaceutical compositions containing a mixture that includes a modified form of trimetazidine and an erodible polymer that promotes swelling of the mixture in an aqueous environment.
  • the modified form of trimetazidine may be any compound that is structurally related to trimetazidine, has a similar biochemical function to trimetazidine, or is metabolized in the body to produce trimetazidine.
  • the modified form of trimetazidine may have a structure of one of Formulas (IX) and (X):
  • the erodible polymer may be any biocompatible polymer that breaks down in the body and promotes swelling of a mixture containing the modified form of trimetazidine.
  • the polymer may be biodegradable.
  • the polymer may be hydrophilic.
  • the polymer may promote formation of a hydrogel.
  • the polymer may be a cellulose derivative.
  • the polymer may be methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, or sodium carboxymethylcellulose.
  • the mixture may contain multiple polymeric forms of HPMC.
  • the different polymeric forms of HPMC may differ in one or more properties.
  • the different polymeric forms of HPMC may differ in one or more of viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, and average molecule weight.
  • Each polymeric form of HPMC may independently have a defined viscosity.
  • the viscosity may be from about 2 cP to about 4 cP, from about 4 cP to about 6 cP, from about 5 cP to about 8 cP, from about 12 cP to about 18 cP, from about 40 cP to about 60 cP, from about 80 cP to about 120 cP, from about 300 cP to about 500 cP, from about 1200 cP to about 2400 cP, from about 2500 cP to about 5000 cP, from about 9000 cP to about 18,000 cP, from about 12,000 cP to about 24,000 cP, from about 12,000 cP to about 24,000 cP, from about 75,000 cP to about 150,000 cP, at least about 2 cP at least about 4 cP at least about 5 cP at least about 12 cP at least about 40 cP at least about 80 cP at least about 300
  • Each polymeric form of HPMC may independently have a defined degree of methoxyl substitution.
  • the degree of methoxyl substitution may be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, from about 27% to about 30%, or from about 28% to about 32%.
  • Each polymeric form of HPMC may independently have a defined degree of hydroxypropoxyl substitution.
  • the degree of hydroxypropoxyl substitution may be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.
  • Each polymeric form of HPMC may independently have a defined average molecular weight.
  • the average molecular weight may be about 10 kDa, about 13 kDa, about 20 kDa, about 26 kDa, about 41 kDa, about 63 kDa, about 86 kDa, about 110 kDa, about 120 kDa, about 140 kDa, about 180 kDa, or about 220 kDa.
  • HPMC may contain one polymeric form at a defined amount.
  • the HPMC may contain about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight of one polymeric form.
  • the mixture may contain a defined amount of the modified form of trimetazidine.
  • the mixture may contain at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% by weight of the modified form of trimetazidine.
  • the pharmaceutical composition may be formulated for a particular route of administration.
  • the pharmaceutical may be formulated for oral, enteral, intravenous, or rectal administration.
  • the pharmaceutical composition may be formulated as a unit dosage containing a defined amount of the modified form of trimetazidine.
  • the unit dosage may contain about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 50 mg, from about 5 mg to about 100 mg, from about 5 mg to about 200 mg, from about 5 mg to about 500 mg, from about 10 mg to about 20 mg, from about 10 mg to about 50 mg, from about 10 mg to about 100 mg, from about 10 mg to about 200 mg, from about 10 mg to about 500 mg, from about 20 mg to about 50 mg, from about 20 mg to about 100 mg, from about 20 mg to about 200 mg, from about 20 mg to about 500 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 500 mg, from about 100 mg to about 200 mg, from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg
  • the pharmaceutical composition may be formulated such that the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject is achieved at a defined interval after the pharmaceutical composition has been provided to the subject.
  • the metabolite of the modified form of trimetazidine may be any compound produced when the modified form of trimetazidine is metabolized in the body.
  • the metabolite of the modified form of trimetazidine may be a compound of Formula (IX), trimetazidine, nicotinic acid, nicotinamide, or nicotinamide riboside.
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, from about 1 hour to about 5 hours, from about 2 hours to about 5 hours, from about 3 hours to about 5 hours, or from about 4 hours to about
  • the sample in which the modified form of trimetazidine or metabolite of the modified form of trimetazidine is measured may be any fluid-containing sample from the subject.
  • the sample may be a plasma sample, blood sample, serum sample, saliva sample, urine sample, sputum sample, phlegm sample, stool sample, or gastric sample.
  • the pharmaceutical composition may be formulated such that, when the composition is provided to a subject, the interval between a first time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and a second time point at which a half-maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is achieved in a sample from the subject is defined.
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half-maximal level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours
  • the pharmaceutical composition may be formulated such that, when the composition is provided to a subject, the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject does not exceed a defined value.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be less than about 6 pg/mL, less than about 5 pg/mL, less than about 4 pg/mL, less than about 3 pg/mL, less than about 2 pg/mL, or less than about 1 pg/mL.
  • the invention provides pharmaceutical compositions containing a mixture that includes a modified form of trimetazidine and hydroxypropyl methylcellulose (HPMC) in a defined weight ratio.
  • the mixture may contain the modified form of trimetazidine and HPMC in a weight ratio of about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 3:2, about 2:l, about 3:l, about 4:1, about 5:1, from about 1:100 to about 100:1, from about 1:100 to about 50:1, from about 1:100 to about 20:1, from about 1:100 to about 10:1, from about 1:100 to about 5:1, from about 1:100 to about 2:1, from about 1:50 to about 100:1, from about 1:50 to about 50:1, from about 1:50 to about 20:1, from about 1:50 to about 10:1, from about 1:50 to about 5:1, from about 1:50 to about2:l, from about 1:20 to about 100:1, from about 1:20 to about 50:1, from about 1:20 to about 20:1, from about 1:20 to about 10:1, from about 1:20 to about 5:1, from about 1:20 to about 2:1, from about 1:10 to about 100:1, from about 1:10 to about 50:1, from
  • trimetazidine may be any compound that is structurally related to trimetazidine, such as any of those described above.
  • the mixture may contain multiple polymeric forms of HPMC.
  • the different polymeric forms of HPMC may differ in one or more properties.
  • the different polymeric forms of HPMC may differ in one or more of viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, and average molecule weight.
  • Each polymeric form of HPMC may independently have a defined viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecule weight, such as any of the values for those parameters described above.
  • Mixtures containing multiple polymeric forms of HPMC may contain one polymeric form at a defined amount, such as any of the amounts described above.
  • the mixture may contain a defined amount of the modified form of trimetazidine, such as any of the amounts described above.
  • the pharmaceutical composition may be formulated for a particular route of administration.
  • the pharmaceutical may be formulated for oral, enteral, intravenous, or rectal administration.
  • the pharmaceutical composition may be formulated as a unit dosage containing a defined amount of the modified form of trimetazidine, such as any of the amounts described above.
  • the pharmaceutical composition may be formulated such that a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subj ect is achieved at a defined interval after the pharmaceutical composition has been provided to the subject.
  • the metabolite of the modified form of trimetazidine may be any of the compounds described above.
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be any of the intervals described above.
  • the sample in which the modified form of trimetazidine is measured may be any of the samples described above.
  • the pharmaceutical composition may be formulated such that, when the composition is provided to a subject, the interval between a first time point at which a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and a second time point at which a half-maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is achieved in a sample from the subject is defined.
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half-maximal level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be any of the intervals described above
  • the pharmaceutical composition may be formulated such that, when the composition is provided to a subject, the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject does not exceed a defined value.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be any of the values described above.
  • the invention provides methods of treating a disease, disorder, condition in a subject by providing to the subject a pharmaceutical composition containing a mixture that includes a modified form of trimetazidine and an erodible polymer that promotes swelling of the mixture in an aqueous environment.
  • trimetazidine may be any compound that is structurally related to trimetazidine, such as any of those described above.
  • the erodible polymer may be any biocompatible polymer that promotes swelling of a mixture containing the modified form of trimetazidine.
  • the polymer may be biodegradable.
  • the polymer may be hydrophilic.
  • the polymer may promote formation of a hydrogel.
  • the polymer may be a cellulose derivative.
  • the polymer may be methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, or sodium carboxymethylcellulose.
  • the mixture may contain multiple polymeric forms of HPMC.
  • the different polymeric forms of HPMC may differ in one or more properties.
  • the different polymeric forms of HPMC may differ in one or more of viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, and average molecule weight.
  • Each polymeric form of HPMC may independently have a defined viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecule weight, such as any of the values for those parameters described above.
  • Mixtures containing multiple polymeric forms of HPMC may contain one polymeric form at a defined amount, such as any of the amounts described above.
  • the mixture may contain a defined amount of the modified form of trimetazidine, such as any of the amounts described above.
  • the pharmaceutical composition may be provided to the subject by a particular route of administration.
  • the pharmaceutical may be provided to the subject orally, enterally, intravenously, or rectally.
  • the method may yield a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject at a defined interval after the pharmaceutical composition has been provided to the subject.
  • the metabolite of the modified form of trimetazidine may be any compound produced when the modified form of trimetazidine is metabolized in the body.
  • the metabolite of the modified form of trimetazidine may be a compound of Formula (IX), trimetazidine, nicotinic acid, nicotinamide, or nicotinamide riboside.
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, from about 1 hour to about 5 hours, from about 2 hours to about 5 hours, from about 3 hours to about 5 hours, or from about 4 hours to about
  • the sample in which the modified form of trimetazidine or metabolite of the modified form of trimetazidine is measured may be any fluid-containing sample from the subject.
  • the sample may be a plasma sample, blood sample, serum sample, saliva sample, urine sample, sputum sample, phlegm sample, stool sample, or gastric sample.
  • the method may yield a defined interval between a first time point at which a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and a second time point at which a half-maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is achieved in a sample from the subject.
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half-maximal level of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, from about 1 hour to about 5 hours, from about 2
  • the method may yield a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject that does not exceed a defined value.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be less than about 6 pg/mL, less than about 5 pg/mL, less than about 4 pg/mL, less than about 3 pg/mL, less than about 2 pg/mL, or less than about 1 pg/mL.
  • the disease, disorder, or condition may be any condition that can be ameliorated by improving cardiac mitochondrial function.
  • the disease, disorder, or condition may be a cardiovascular condition.
  • the disease, disorder, or condition may be aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral vascular disease, congenital heart disease coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, high blood pressure (hypertension), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.
  • CAD congenital heart disease coronary artery disease
  • the invention provides methods of treating a disease, disorder, condition in a subject by providing to the subject a pharmaceutical composition containing a mixture that includes a modified form of trimetazidine and hydroxypropyl methylcellulose (HPMC), wherein the mixture comprises the modified form of trimetazidine and HPMC in a defined weight ratio.
  • a pharmaceutical composition containing a mixture that includes a modified form of trimetazidine and hydroxypropyl methylcellulose (HPMC), wherein the mixture comprises the modified form of trimetazidine and HPMC in a defined weight ratio.
  • the mixture may contain the modified form of trimetazidine and HPMC in one of the ratios described above.
  • trimetazidine may be any compound that is structurally related to trimetazidine, such as any of those described above.
  • the mixture may contain multiple polymeric forms of HPMC.
  • the different polymeric forms of HPMC may differ in one or more properties.
  • the different polymeric forms of HPMC may differ in one or more of viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, and average molecule weight.
  • Each polymeric form of HPMC may independently have a defined viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecule weight, such as any of the values for those parameters described above.
  • Mixtures containing multiple polymeric forms of HPMC may contain one polymeric form at a defined amount, such as any of the amounts described above.
  • the mixture may contain a defined amount of the modified form of trimetazidine, such as any of the amounts described above.
  • the pharmaceutical composition may be provided to the subject by a particular route of administration.
  • the pharmaceutical may be provided to the subject orally, enterally, intravenously, or rectally.
  • the method may yield a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject at a defined interval after the pharmaceutical composition has been provided to the subject.
  • the metabolite of the modified form of trimetazidine may be any of the compounds described above.
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be any of the intervals described above.
  • the sample in which the modified form of trimetazidine is measured may be any of the samples described above.
  • the method may yield a defined interval between a first time point at which a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and a second time point at which a half-maximum level of the modified form of trimetazidine or the metabolite of the modified form of trimetazidine is achieved in a sample from the subject.
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half-maximal level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be any of the intervals described above.
  • the method may yield a maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject that does not exceed a defined value.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be any of the values described above.
  • the disease, disorder, or condition may be any condition that can be ameliorated by improving cardiac mitochondrial function, such as any of those described above.
  • FIG. 1 is a schematic of the pathways of hydrolysis and metabolism of CV-8972.
  • FIG. 2 is graph of the aqueous solubility of CV-8972 as a function of pH generated via dynamic methods due to instability.
  • FIG. 3 is a process flow diagram for manufacture of the CV-8972 prototype dry compression MR tablet formulations.
  • FIG. 4 is a process flow diagram for manufacture of the CV-8972200 and 50 mg wet granulated, MR Tablet formulations used for pilot lots.
  • FIG. 5 is graph showing the dissolution profile of 50 mg and 200 mg 4-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C.
  • FIG. 6 is graph showing the dissolution profile of 50 mg and 200 mg 8-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C.
  • FIG. 7 is graph showing the dissolution profiles of 200 mg 8-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C following storage under indicated conditions.
  • FIG. 8 is a graph showing CV-8814 plasma levels in dogs following oral dosing of 200 mg (free base equivalent) of CV-8972 under fasted conditions.
  • FIG. 9 is a graph showing the simulated combined plasma levels of CV-8814 and trimetazidine projected in humans following oral dosing 200mg IMB-1018972 MR tablets as 8- hour release tablets under MAD dosing (QD and BID) and fed conditions.
  • FIG. 10 is a table of the disposition of subjects of an FIH study of IMB-1018972.
  • FIG. 11 is a table of assessments given for the Single-Dose MR Part of an FIH study of IMB-1018972
  • FIG. 12 is a table of assessments given for the Multiple-Dose MR part of an FIH study of IMB-1018972.
  • FIG. 13 is a table of analysis data sets for the Single-Dose MR Part of an FIH study of IMB-1018972.
  • FIG. 14 a table of analysis data sets for the Multiple-Dose MR Part of an FIH study of IMB-1018972.
  • FIG. 15 is a table of a summary of demographic characteristics - Single-Dose MR Part (Safety Set) of an FIH study of IMB-1018972.
  • FIG. 16 is a table of a summary of demographic characteristics - Multiple-Dose MR Part (Safety Set) of an FIH study of IMB-1018972.
  • FIG. 17 is a table of the Extent of Exposure - Single-Dose MR Part (Safety Set) of an FIH study of IMB-1018972.
  • FIG. 18 is a table of the Extent of Exposure - Multiple-Dose MR Part (Safety Set) of an FIH study of IMB-1018972.
  • FIG. 19 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profries (Linear) - Single-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 20 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set) of an FIH study of IMB- 1018972.
  • FIG. 21 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - Single-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 22 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set) of an FIH study of IMB- 1018972.
  • FIG. 23 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Linear) - Single-Dose MR Part (PK Set) of an FIH study of IMB- 1018972.
  • FIG. 24 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 25 is a table of Summary Statistics Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - Single- Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 26 is a table of Exploratory Analysis of Food Effect for IMB-1028814 and Trimetazidine following Administration of 200 mg 8-hour MR IMB-1018972 - Single-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 27 is a graph of Geometric Mean EMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 28 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 29 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 30 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR 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 from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 32 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi -Logarithmic Scale) - Multiple- Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 33 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 34 is a graph of Geometric Mean EMB-1028814 Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 35 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 36 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 37 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 38 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple- Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 39 is a table of Summary Statistics Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - Multiple-Dose MR Part (PK Set) of an FIH study of IMB-1018972.
  • FIG. 40A and FIG. 40B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - Single-Dose MR Part (Safety Set) of an FIH study of IMB- 1018972.
  • FIG. 41 is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - Single-Dose MR Part (Safety Set) of an FIH study of IMB-1018972.
  • FIG. 42 is a table Summary of All TEAEs by Treatment, Relationship, and Severity- Single-Dose MR Part (Safety Set) of an FIH study of IMB- 1018972.
  • FIG. 43 is a table Summary of All TEAEs by Treatment, Relationship, and Severity -
  • the invention provides pharmaceutical compositions that contain a mixture of a modified form of trimetazidine, such as CV-8972, and an erodible polymer, such as hydroxypropyl methylcellulose (HPMC).
  • a modified form of trimetazidine such as CV-8972
  • HPMC hydroxypropyl methylcellulose
  • the polymer absorbs water to promote swelling of the mixture when the compositions are in an aqueous environment, such as the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the polymer gradually breaks down in an aqueous milieu to allow controlled release of the modified form of trimetazidine, which then breaks-down into niacin and CV-8814 in a controlled manner, thereby providing a controlled and modified release of niacin into the body.
  • compositions when the compositions are administered orally to a subject, levels of active pharmaceutical ingredient (API) in the blood exhibit both lower peaks and longer durations above the minimum therapeutic threshold than when the same dosage of the same modified form of trimetazidine is provided in a conventional formulation and side effects from niacin are minimized.
  • API active pharmaceutical ingredient
  • the modified-release formulations of the invention confer several advantages over prior formulations for oral delivery of modified forms of trimetazidine.
  • the pharmaceutical compositions of the invention can be administered less frequently than prior compositions.
  • oral formulations containing CV-8972 provided herein are suitable for once-per-day or twice-per-day dosing regimens.
  • peak levels of API in the blood are as much as 50% lower than levels achieved with prior compositions, the formulations of the invention reduce side effects that result from niacin and interaction between the API and unintended targets in vivo.
  • the aforementioned attributes improve the overall therapeutic efficacy of modified forms of trimetazidine, such as CV-8972. Modified forms of trimetazidine
  • Trimetazidine has the following structure:
  • Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and has long been used to treat angina.
  • Trimetazidine promotes glucose oxidation by inhibiting oxidation of fatty acids.
  • Glucose oxidation and fatty acid oxidation are energy-producing metabolic pathways that compete with each other for substrates.
  • 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. The remaining steps in energy production from oxidation of glucose or fatty acids are common to the two pathways.
  • Trimetazidine inhibits oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, thus causing cells to rely on glucose oxidation to support energy production.
  • the overall efficiency of energy production by cardiac mitochondria is diminished due in part to an increased reliance on fatty acid oxidation over glucose oxidation.
  • Glucose oxidation is a more efficient pathway for energy production, as measured by the number of ATP molecules produced per O2 molecule consumed, than is fatty acid oxidation.
  • overall cardiac efficiency can be increased by agents that promote glucose oxidation, such as trimetazidine.
  • CV-8972 was recently identified as a trimetazidine-derivative having improved pharmacological properties.
  • CV-8972 has the IUPAC name 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-l-yl]ethyl pyridine-3 -carboxylate and the structure of Formula (X):
  • CV-8972 When CV-8972 is administered to a subject, it is initially broken into nicotinic acid and CV- 8814, which has the IUPAC name 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-l-yl]ethanol and the structure of Formula (IX):
  • CV-8814 is a hydroxy ethyl derivative of trimetazidine, and the hydroxy ethyl group is subsequently removed in the body to provide trimetazidine.
  • CV-8972 and its metabolic products are described in U.S. Patent No. 10,556,013, the contents of which are incorporated herein by reference.
  • the improved therapeutic properties of CV-8972 are due in part to the effect of nicotinic acid.
  • Nicotinic acid serves as a precursor for synthesis of nicotinamide adenine dinucleotide (NAD + ), the oxidized form of an essential coenzyme in the mitochondrial electron transport reaction.
  • NAD + nicotinamide adenine dinucleotide
  • Supplying a NAD + precursor ensures that mitochondrial redox reactions occur robustly to drive ATP synthesis, regardless of whether oxidation of glucose or fatty acids is used to feed the citric acid cycle.
  • the nicotinic acid product of CV-8972 promotes mitochondrial respiration.
  • the stepwise breakdown of CV-8972 to CV-8814 and then to trimetazidine also contributes to the improved therapeutic properties of CV-8972.
  • CV-8814 inhibits 3-ketoacyl-CoA thiolase, so CV-8972 delivers two different active pharmaceutical ingredients (APIs).
  • APIs active pharmaceutical ingredients
  • CV-8814 does not produce the same undesirable side effects as trimetazidine.
  • the level of circulating trimetazidine following a dose of CV-8972 is much lower than the level following of comparable dose of trimetazidine itself. Therefore, compared to unadulterated trimetazidine, CV-8972 provides a more sustained level of circulating API and fewer side effects.
  • trimetazidine that may be used in compositions of the invention are described in, for example, U.S. Patent Nos. 4,100,285 and 4,574,156, the contents of each of which are incorporated herein by reference.
  • compositions that contain mixtures that include erodible polymers that promote swelling of the mixture in an aqueous environment.
  • An erodible polymer is any polymer that breaks down inside the body within a physiologically relevant time frame.
  • the erodible polymer may have other characteristics that promote the gradual release of the modified form of trimetazidine from the mixture.
  • the polymer may be one or more of the following: biocompatible, i.e., not harmful to living tissue; hydrophilic; hygroscopic; tending to form a hydrogel.
  • the polymer-containing mixtures may promote gradual release by one or more mechanisms.
  • swelling of the mixture by absorption of water may facilitate diffusion of the modified form of trimetazidine from the mixture.
  • Degradation of the polymer may also allow the modified form of trimetazidine to be released from the mixture.
  • Osmotic pressure due the high concentration gradient of compound between the inside and outside of the mixture may also contribute to diffusion of the modified form of trimetazidine from the mixture.
  • the polymer may be a cellulose derivative, a gelatin derivative, e.g., a cross-linked gelatin derivative, or a polyester derivative.
  • Derivatives of cellulose is a linear chain b(1 4) linked D-glucose units, include polymers that contain substitutions on one of more of the hydroxyl groups of each glucose unit. Substituents may be organic or inorganic and are typically attached via ester or ether linkages.
  • Cellulose ester derivatives include carboxymethyl cellulose (CMC), e.g., sodium carboxymethyl cellulose, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and methylcellulose.
  • CMC carboxymethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • Cellulose ether derivatives include cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, cellulose sulfate, cellulose triacetate, and nitrocellulose.
  • cellulose-based polymers to form biodegradable hydrogels is known in the art and described in, for example, Sannino, et ah, Biodegradable Cellulose-based Hydrogels: Design and Applications, Materials 2009, 2, 353-373; doi: 10.3390/ma2020353, the contents of which are incorporated herein by reference.
  • the mixture may contain multiple polymers or multiple polymeric forms of the same polymer.
  • HPMC polymeric forms may differ in a variety of physical properties, including viscosity, degree of methoxyl substitution, degree of hydroxypropoxyl substitution, or average molecule weight.
  • the viscosity of a HMPC polymeric form may be determined by testing under standard conditions, including the concentration of HMPC in the solution and the temperature of the solution.
  • the HPMC concentration may be 1%, 1.5%, 2%, 2.5%, or 3%.
  • the temperature of the solution may be 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C.
  • a polymeric form of a cellulose derivative, such as HPMC may have a defined viscosity.
  • a polymeric form of HPMC may have a viscosity of from about 2 cP to about 4 cP, from about 4 cP to about 6 cP, from about 5 cP to about 8 cP, from about 12 cP to about 18 cP, from about 40 cP to about 60 cP, from about 80 cP to about 120 cP, from about 300 cP to about 500 cP, from about 1200 cP to about 2400 cP, from about 2500 cP to about 5000 cP, from about 9000 cP to about 18,000 cP, from about 12,000 cP to about 24,000 cP, from about 12,000 cP to about 24,000 cP, from about 75,000 cP to about 150,000 cP, at least about 2 cP at least about 4 cP at least about 5 cP at least about 12
  • Polymeric forms of cellulose derivatives may vary in their degree of substitution of the glucose units.
  • the degree of substitution may be expressed as a weight percentage of the substituent or as a molar ratio of substituent to glucose unit.
  • the polymeric form may be described by the degree of substitution for each substituent.
  • Each polymeric form of HPMC may independently have a defined degree of methoxyl substitution.
  • the degree of methoxyl substitution may be from about 19% to about 24%, from about 22% to about 24%, from about 27% to about 30%, from about 27% to about 30%, or from about 28% to about 32%.
  • Each polymeric form of HPMC may independently have a defined degree of hydroxypropoxyl substitution.
  • the degree of hydroxypropoxyl substitution may be from about 4% to about 8%, from about 7% to about 10%, from about 7% to about 12%, from about 8% to about 10%, from about 8% to about 11%, or from about 9% to about 12%.
  • Each polymeric form of HPMC may independently have a defined average molecular weight.
  • the average molecular weight may be about 10 kDa, about 13 kDa, about 20 kDa, about 26 kDa, about 41 kDa, about 63 kDa, about 86 kDa, about 110 kDa, about 120 kDa, about 140 kDa, about 180 kDa, or about 220 kDa.
  • a polymer such as HPMC
  • a polymer such as HPMC
  • compositions of the invention include modified-release formulations that contain one or more modified forms of trimetazidine.
  • the formulations contain mixtures that include one or more modified forms of trimetazidine and one or more erodible polymers that promote swelling of the mixture in an aqueous environment.
  • the hygroscopic and erodible properties of the polymers may allow the mixture to form a hydrogel that slowly breaks down in the digestive tract of the subject. Consequently, the mixture promotes the steady release of the modified form of trimetazidine and metabolic products thereof into circulation.
  • the mixture may contain a defined amount of the modified form of trimetazidine.
  • the mixture may contain at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% by weight of the modified form of trimetazidine.
  • the mixture may contain the modified form of trimetazidine and the polymer in a defined weight ratio.
  • the mixture may contain the modified form of trimetazidine and the polymer in a weight ratio of about 1:5, about 1 :4, about 1 :3, about 1 :2, about 1:1, about 3:2, about 2:1, about 3:1, about 4:1, about 5:1, from about 1:100 to about 100:1, from about 1:100 to about 50:1, from about 1:100 to about 20:1, from about 1:100 to about 10:1, from about 1:100 to about 5:1, from about 1:100 to about 2:1, from about 1:50 to about 100:1, from about 1:50 to about 50:1, from about 1:50 to about 20:1, from about 1:50 to about 10:1, from about 1 : 50 to about 5:1, from about 1 : 50 to about 2:1, from about 1 :20 to about 100: 1, from about 1:20 to about 50:1, from about 1:20 to about 20:1, from about 1:20 to about 10:1, from about 1 :20 to about 10
  • the pharmaceutical composition may be formulated for a particular route of administration.
  • the pharmaceutical may be formulated for oral, enteral, intravenous, or rectal administration.
  • the pharmaceutical composition may be formulated as a unit dosage containing a defined amount of the modified form of trimetazidine.
  • the unit dosage may contain about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 50 mg, from about 5 mg to about 100 mg, from about 5 mg to about 200 mg, from about 5 mg to about 500 mg, from about 10 mg to about 20 mg, from about 10 mg to about 50 mg, from about 10 mg to about 100 mg, from about 10 mg to about 200 mg, from about 10 mg to about 500 mg, from about 20 mg to about 50 mg, from about 20 mg to about 100 mg, from about 20 mg to about 200 mg, from about 20 mg to about 500 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 500 mg, from about 100 mg to about 200 mg, from about 100 mg to about 500 mg, or from about 200 mg to about 500 mg
  • the pharmaceutical composition may be formulated such that it produces a defined value for one or more parameters, as described below in relation to methods of the invention.
  • the parameter may be Cmax, the interval between administration and achieving Cmax, T1/2, or AUC.
  • compositions of the invention may contain excipients.
  • the composition may contain sweetening agents, flavoring agents, coloring agents, or preserving agents.
  • the compositions may contain one or more of mannitol, starch, and magnesium stearate.
  • the invention provides methods of treating a disease, disorder, condition in a subject by providing any of the compositions described above.
  • the modified release formulations of the invention provide steadier release of the modified form of trimetazidine than do conventional formulations.
  • the superior release profile may be reflected in one or more parameters described below.
  • One parameter that may be used to distinguish formulations of the invention from other compositions that contain the same dosage of modified form of trimetazidine is Cmax, the maximum level of a drug or metabolite of the drug in a sample following the administration of a dose of the drug but prior to administration of a second dose.
  • the formulations of the invention may yield Cmax values that are lower than those produced by conventional formulations that contain the same dosage.
  • the lower Cmax may be expressed in relative terms, e.g., by comparison to a Cmax resulting from administration of another formulation, or in absolute terms, e.g., by comparison to a defined threshold value.
  • the Cmax may be for the modified form of trimetazidine or a metabolite of the compound.
  • the Cmax of the compound of Formula (X) may be determined, or the Cmax of the compound of Formula (IX), trimetazidine, or nicotinic acid may be determined.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be less than about 20 pg/mL, less than about 15 pg/mL, less than about 12 pg/mL, less than about 10 pg/mL, less than about 8 pg/mL, less than about 6 pg/mL, less than about 5 pg/mL, less than about 4 pg/mL, less than about 3 pg/mL, less than about 2 pg/mL, less than about 1 pg/mL, less than about 0.8 pg/mL, less than about 0.6 pg/mL, less than about 0.4 pg/mL, less than about 0.2 pg/mL, or less than about 0.1 pg/mL.
  • the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine in a sample from the subject may be less than about 10%, less than about 20%, less than about 30%, less than about 40%, less than about 50%, less than about 60%, less than about 70%, less than about 80%, less than about 90% of the maximum level resulting from administration of a different composition that contains the same amount of the modified form of trimetazidine.
  • Another parameter that may be used to distinguish formulations of the invention from other compositions that contain the same dosage of modified form of trimetazidine is the interval between administration of the composition to the subject and the time point at which the modified form of trimetazidine or a metabolite of the modified form of trimetazidine achieves its Cmax in a sample from the subject.
  • the modified-release formulations of the invention may yield longer intervals to Cmax than do other formulations.
  • the interval to Cmax may be expressed in relative terms, e.g., by comparison to the interval for another formulation, or in absolute terms, e g., by comparison to a defined period of time.
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from about 1 hour to about 6 hours, from about 2 hours to about 6 hours, from about 3 hours to about 6 hours, from about 4 hours to about 6 hours, from about 1 hour to about 5 hours, from about 2 hours to about 5 hours, from about 3 hours to about 5 hours, or from
  • the interval between the time point at which the composition is provided to the subject and the time point at which the maximum level of the modified form of trimetazidine or metabolite of the modified form of trimetazidine is achieved in a sample from the subject may be at least 10%, least 20%, least 30%, least 40%, least 50%, least 60%, least 70%, least 80%, least 90%, least 100%, least 120%, least 150%, least 200%, least 250%, least 300%, least 400% greater than the interval following administration of another composition containing the same dosage of modified form of trimetazidine.
  • T 1/2 Another parameter that may be used to distinguish formulations of the invention from other compositions that contain the same dosage of modified form of trimetazidine is T 1/2, the interval between the time point at Cmax of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved and the time point at which the concentration of the compound or metabolite reaches its half-maximum value.
  • the modified-release formulations of the invention may yield higher T1/2 values, i.e., longer intervals, than those produced by other formulations containing the same dosage of modified form of trimetazidine.
  • the T1/2 may be expressed in relative terms, e.g., by comparison to the T1/2 for another formulation, or in absolute terms, e.g., by comparison to a defined period of time.
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half- maximal level of the modified form of trimetazidine is achieved in a sample from the subject may be at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, from about 1 hour to about 8 hours, from about 2 hours to about 8 hours, from about 3 hours to about 8 hours, from about 4 hours to about 8 hours, from about 1 hour to about 7 hours, from about 2 hours to about 7 hours, from about 3 hours to about 7 hours, from about 4 hours to about 7 hours, from
  • the interval between the time point at which the maximum level of the modified form of trimetazidine or a metabolite of the modified form of trimetazidine is achieved in a sample from the subject and the time point at which the half- maximal level of the modified form of trimetazidine is achieved in a sample from the subject may be at least 10%, least 20%, least 30%, least 40%, least 50%, least 60%, least 70%, least 80%, least 90%, least 100%, least 120%, least 150%, least 200%, least 250%, least 300%, least 400% greater than the interval following administration of another composition containing the same dosage of modified form of trimetazidine.
  • AUC area under the curve
  • the modified-release formulations of the invention may yield higher AUC values than those produced by other formulations containing the same dosage of modified form of trimetazidine.
  • the AUC may be expressed in relative terms, e.g., by comparison to the AUC for another formulation, or in absolute terms, e.g., by comparison to a defined threshold.
  • the AUC the modified form of trimetazidine or a metabolite of the modified form of trimetazidine may be at least 10%, least 20%, least 30%, least 40%, least 50%, least 60%, least 70%, least 80%, least 90%, least 100%, least 120%, least 150%, least 200%, least 250%, least 300%, least 400% greater than the AUC following administration of another composition containing the same dosage of modified form of trimetazidine.
  • the sample in which the modified form of trimetazidine is measured may be any fluid- containing sample from the subject.
  • the sample may be a plasma sample, blood sample, serum sample, saliva sample, urine sample, sputum sample, phlegm sample, stool sample, or gastric sample.
  • composition may be provided to the subject by a particular route of administration.
  • the pharmaceutical may be provided to the subject orally, enterally, intravenously, or rectally.
  • composition may be provided according to a dosing regimen.
  • a dosing regimen may include one or more of a dosage, dosing frequency, and duration.
  • 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 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 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months or more.
  • the methods of the invention may be used to treat a disease, disorder, or condition in a subject.
  • the disease, disorder, or condition may be any condition that can be ameliorated by improving cardiac mitochondrial function.
  • the disease, disorder, or condition may be a cardiovascular condition.
  • the disease, disorder, or condition may be aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral vascular disease, congenital heart disease coronary artery disease (CAD), coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, high blood pressure (hypertension), ischemic heart disease, pericardial disease, peripheral arterial disease, refractory angina, rheumatic heart disease, stable angina, stroke, transient ischemic attack, unstable angina, or valvular heart disease.
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • CAD congenital heart disease coronary artery disease
  • Angina pectoris is chest pain or pressure that is typically due to insufficient blood flow to the heart muscle.
  • the pain or discomfort is retrosternal or left-sided and may radiate to the left arm, neck, jaw, or back.
  • Several classifications of angina are known.
  • Stable angina also called effort angina, is related to myocardial ischemia.
  • chest discomfort and associated symptoms are usually triggered by some physical activity, such as running or walking, but symptoms are minimal or non-existent when the patient is at rest or has taken sublingual nitroglycerin.
  • Symptoms typically abate several minutes after activity and recur when activity resumes. Symptoms may also be induced by cold weather, heavy meals, and emotional stress.
  • Unstable angina is angina that changes or worsens. Unstable angina has at least one of the following features: (1) it occurs at rest or with minimal exertion, usually lasting more than
  • Cardiac syndrome X also called microvascular angina, is angina-like chest pain, in the context of normal epicardial coronary arteries on angiography. Its primary cause is unknown, but factors apparently involved are endothelial dysfunction and reduced flow in the tiny resistance blood vessels of the heart. Microvascular angina may be part of the pathophysiology of ischemic heart disease.
  • Refractory angina is a chronic condition (> 3 months in duration) in which angina (1) occurs in the context of coronary artery disease (CAD), (2) cannot be controlled by a combination of optimal medical therapy, angioplasty, or bypass surgery, and (3) in which reversible myocardial ischemia has been clinically established to be the cause of the symptoms.
  • CAD coronary artery disease
  • Example 1 Wet granulated formulations containing 50 mg or 200 mg free base equivalent of CV-
  • 8972 were prepared according to the composition shown in Table 1 for the 200 mg.
  • Total tablet fill weight may vary ⁇ 5%
  • wet granulation formulations are based on the previous direct compression, blended powders, which were filled into a single punch by hand and compressed individually.
  • the two sets of formulations differ very slightly in composition to allow for the switch to wet granulation, but are identical in terms of specifications and performance.
  • the 200 mg MR 8-hour release tablet is designed to be taken twice daily (BID) by patients.
  • CV-8972 used for formulations has the following structure and properties:
  • This molecule is a hybrid NCE which undergoes hydrolytic cleavage and metabolism as it is absorbed orally to produce CV-8814, Nicotinic acid, trimetazidine (TMZ), and potentially other metabolites systemically.
  • FIG. 1 is a schematic of the pathways of hydrolysis and metabolism of CV-8972. Note that there are other potential routes of metabolism not yet evaluated in humans. CV-8972 as a salt is relatively insoluble in most organic solvents, but is much more so as the free base. However, as the most basic, estimated pKa is about 7.9, the molecule always exists as a charged ion in the physiological pH range of 1-8.
  • FIG. 2 is graph of the aqueous solubility of CV-8972 as a function of pH generated via dynamic methods due to instability.
  • the acute drop in solubility between pH 6.1-9.2 suggests that dissolution kinetics could dramatically change on passage from gastric (pH 1-2) to the intestinal fluids (pH 6.5-8).
  • the saturated base solubility is 5-10 mg/mL, a dose of 200 mg base is likely to be dissolving under sink conditions throughout the GI tract.
  • the hydrolysis proceeds via the first step shown in FIG. 1, as Nicotinic acid and CV- 8814 are the only decomposition products generated.
  • the optimal pH for solution stability appears to be around pH 5-5.1 for a 1 mg/mL solution with acid-catalyzed hydrolysis increasing at pH values less than 5.0 and base-catalyzed hydrolysis increasing above pH 5.0.
  • excipients used in the formulation are standard for an erodible, hydrogel tablet to create a modified release product.
  • CV- 1018972 salt is very soluble
  • Hypromellose polymers of different molecular weights and degrees of cross-linking are used to hydrate gel and slowly release the soluble drug.
  • Mannitol is included as a soluble sugar that balances the ingress of water into the formulation and Magnesium Stearate is used as a lubricant. Extensive screening of drug stability with a large array of excipients was previously performed, in addition to detailed stability evaluation of the drug in prototypical excipient blends and formulations.
  • Total tablet fill weight may vary ⁇ 5%
  • the formulations used for the studies were direct compression, blended powders filled into a single punch by hand and compressed individually at 50 mg and 200 mg free base equivalent of CV-8972 according to the composition shown in Table 3.
  • FIG. 3 is a process flow diagram for manufacture of the CV-8972 prototype dry compression MR tablet formulations.
  • the 8-hour MR release tablets were chosen for further studies and only at the doses of
  • compositions are shown in Table 4.
  • the pilot demonstration lots were manufactured at the 5 kg level total batch size to evaluate performance with scale-up and equipment train compatibility for future GMP lots.
  • FIG. 4 is a process flow diagram for manufacture of the CV-8972200 and 50 mg wet granulated, MR Tablet formulations used for pilot lots. The wet granulation was adopted with minor changes in composition as described in Table 1 and scaled up for manufacture of clinical supply lots each of 43,000 tablets approximately or ⁇ 24 kg in total batch size.
  • the target LOD is NMT 2.0% at a target LOD temperature of 85°C.
  • FIG. 5 is graph showing the dissolution profile of 50 mg and 200 mg 4-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C.
  • FIG. 6 is graph showing the dissolution profile of 50 mg and 200 mg 8-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C.
  • FIG. 7 is graph showing the dissolution profiles of 200 mg 8-hour modified release hydrogel tablets in 0.1 M HC1 pH 1.0 at 37°C following storage under indicated conditions. Tablet were stored at either 25°C/60% RH or 40°C/75% RH for 1 week, 2 weeks, 6 weeks, 3 months, or 6 months, with or without desiccant.
  • Table 5 shows the proposed dissolution test specifications and the range of means obtained over the ongoing 6-month pilot lot stability study.
  • CV-8972 is very soluble as a salt and a free base with a minimal solubility of around 10 mg/mL as the free base and > 100 mg/mL as the salt.
  • a 250 mL volume of neutral pH aqueous solution can dissolve up to 2.5 g of CV-8972, which is significantly higher by 5-10x that of the potential maximal daily dose of 250-500 mg
  • CV-8972 can therefore be considered as BCS Class 1 per se, but the pre-systemic metabolism to CV-8814 and possibly other metabolites may complicate and impact the actual biopharmaceutical absorption profile found in humans.
  • CV-8972 in dog is estimated to have a >50% bioavailability when given as solution versus IV CV-8814
  • CV-8972 The solution stability of CV-8972 was evaluated in multiple media currently used to simulate dissolution and stability conditions in the various sections of the GI tract. As CV-8972 will be subject to hydrolysis as it is dissolving in the GI tract, it will be important to understand these kinetics in terms of designing instant and controlled-release formulations. HPLC methods were used to perform these assessments. A summary of the decomposition kinetics vs. media for CV-8972 at 37°C and 0.2 mg/mL is shown in Table 7. Table 7.
  • FaSSGF FaSSIF
  • FeSSIF FeSSIF
  • CV-8972 is likely to be relatively unstable in the GI tract (per its design), but may be stable enough at the intestinal brush border and the enzymes within it to allow sufficient absorption to occur in intact form.
  • FIG. 8 is a graph showing CV-8814 plasma levels in dogs following oral dosing of 200 mg (free base equivalent) of CV-8972 under fasted conditions.
  • CV-8972 was provided as an instant release powder in a capsule, (b) a 4-hour release rate modified release tablet, or an 8-hour release rate modified release tablet.
  • Table 8 summarizes the comparison of the calculated in vitro release rate constant (Kd hrs 1 ) and time to release 90% (T9o% hrs) with the corresponding in vivo absorption rate constant (K a hrs 1 ) and time to absorb 90% of the dose (Ti>o% hrs) as calculated via the Wagner-Nelson technique 2
  • the in vivo data seemed to show faster absorption than is predicted by in vitro data by a factor of ⁇ 2x for the 4-hour and 8-hour release tablets. Due to metabolic differences between dog and human, the predictive value of these data to humans may be limited, but the estimation of absorption kinetic parameters is considered useful at this stage of development. This approach will be used similarly in humans to de-convolute the absorption PK curves and correlate the in vivo and in vitro release rates.
  • FIG. 9 is a graph showing the simulated combined plasma levels of CV-8814 and trimetazidine projected in humans following oral dosing 200mg IMB-1018972 MR tablets as 8- hour release tablets under MAD dosing (QD and BID) and fed conditions.
  • Table 9 shows projected Cmax, Cmin, and Cmax/Cmm ratio for of CV-8814, trimetazidine, and both in humans following oral dosing 200mg IMB-1018972 MR tablets as 8-hour release tablets under MAD dosing (QD and BID) and fed conditions
  • the primary objective is to assess the safety and tolerability of single oral doses of modified-release (MR) formulations of IMB-1018972, and multiple oral doses of the 200 mg 8- hour MR formulation of IMB-1018972 in healthy subjects.
  • MR modified-release
  • Secondary objectives include: To assess the pharmacokinetic (PK) profile of single oral doses of MR formulations of IMB-1018972, and multiple oral doses of the 200 mg 8-hour MR formulation of IMB-1018972 in healthy subjects; To assess the absorption and PK profile of the 200 mg 8-hour MR formulation of IMB-1018972 following multiple oral doses taken with food in healthy subjects; and To evaluate the safety and tolerability of the 200 mg 8-hour MR formulation of IMB-1018972 following multiple oral doses taken with food in healthy subjects. Design and Treatments
  • the single-dose MR part 1 group of 12 healthy subjects (all on active drug) was included.
  • the subjects received a single oral dose of 1 of 4 MR formulations of IMB-1018972 under fasted conditions (an overnight fast of at least 10 hours) on Days 1, 4, 7, and 10 in a fixed order that was the same for all subjects.
  • the MR formulation of IMB-1018972 to be administered on Day 13 under fed conditions was 1 of the 4 MR formulations administered on Days 1, 4, 7, and 10 under fasted conditions.
  • the formulation chosen for administration on Day 13 was the 200 mg 8-hour MR formulation as determined by the Sponsor based on the available safety, tolerability, and PK results of the 4 MR formulations.
  • Single-dose MR part 12 healthy male or female subjects; for this 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
  • Multiple-dose MR part 12 healthy male or female subjects; for this 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 Main Criteria for Inclusion
  • Age 18 years to 65 years, inclusive, at screening
  • Ischemic cardiovascular disease Strength 50 mg MR formulation and 200 mg MR formulation with 4-hour and 8- hour dissolution profile (based on free base)
  • Dosage form oral MR tablet(s) to be used in the MR parts
  • Manufacturer Pharmacy at PRA Batch number: 2479-1810-00441 (drug substance)
  • Active medication Drug product: Vastarel MR (trimetazidine dihydrochloride)
  • Activity Fatty acid oxidation inhibitor
  • Dosage form Oral modified-release tablet Manufacturer: Servier Research & Pharmaceuticals (Pakistan) (Pvt.) Ltd. Batch number: 273782 (drug product)
  • Variables Safety Adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, continuous cardiac monitoring (telemetry), and physical examination
  • Pharmacokineti cs Plasma concentrations of IMB-1018972, IMB-1028814, and trimetazidine Urine concentrations of IMB-1018972, IMB-1028814, and trimetazidine Single-dOSe MR part: Cmax, tmax, AUCo-t, AUCo-inf, %AUCextra, kel, tl/2,
  • MR part Cmax, tmax, Cmin, kei, ti/2, AUCO- T , CL SS /F (IMB-1028814 only), Vz/F (IMB-1028814 only), and Rac Urine PK parameters estimated using noncompartmental analysis, as appropriate: Aem-mc, Mit and CLR Statistical Methods
  • 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 single doses of MR formulations of IMB-1018972, and multiple doses of the 200 mg 8-hour MR formulation of IMB-1018972, 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
  • TEAE moderate treatment-emergent adverse event
  • ALT alanine aminotransferase
  • 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 ALT increased was reported by a subject of the single-dose MR part. This subject was withdrawn from the study as a result of this TEAE.
  • the TEAE of ALT increased (up to 149 IU/L on Day 11) was considered by the Investigator to be possibly 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.
  • tmax for IMB-1028814 was earlier with the 8-hour MR formulation (2 hours for 50 mg and 200 mg IMB-1018972) than with the 4-hour MR formulation (5 hours for 50 mg IMB- 1018972 and 3 hours for 200 mg IMB-1018972).
  • W for trimetazidine was later with the 8- hour MR formulation (8 hours for 50 mg IMB-1018972 and 5 hours for 200 mg IMB-1018972) than with the 4-hour MR formulation (6 hours for 50 mg IMB-1018972 and 3 hours for 200 mg IMB-1018972).
  • tmax for IMB-1028814 + trimetazidine was similar for the 8-hour MR formulation (5 hours for 50 mg IMB-1018972 and 2.5 hours for 200 mg IMB-1018972) and the 4-hour MR formulation (5 hours for 50 mg IMB-1018972 and 3 hours for 200 mg IMB- 1018972).
  • Cmax for IMB-1028814 was 35% and 32% lower, respectively, Cmax for trimetazidine was 20% and 24% lower, respectively, and Cmax for IMB-1028814 + trimetazidine was 21% and 34% lower, respectively, for the 8-hour MR formulation relative to the 4-hour MR formulation.
  • AUCo-t for IMB-1028814 was 26% lower, AUCo-t for trimetazidine was 12% lower, and AUCo-t for IMB-1028814 + trimetazidine was 18% lower after the 8-hour MR formulation than after the 4- hour MR formulation.
  • AUCo-t for IMB-1028814 was 6% higher, AUCo-t for trimetazidine was 4% higher, and AUCo-t for IMB- 1028814 + trimetazidine was 5% higher after the 8-hour MR formulation than after the 4-hour MR formulation.
  • geometric mean tl/2 ranged between 3 35 hours and 4.27 hours for IMB-1028814, between 8 11 hours and 9 35 hours for trimetazidine, and between 6.95 hours and 7.96 hours for IMB-1028814 + trimetazidine.
  • Median IMB-1028814 tmax was reached at 3 hours postdose under both conditions. Median trimetazidine tmax was reached at 5 hours postdose relative to 3 hours postdose under fasted conditions.
  • Cmax was approximately 42% higher following administration of a single dose of 200 mg 8-hour MR IMB-1018972 after an FDA-defmed high-fat breakfast relative to administration under fasted conditions (estimate of 1.42; 90% Cl ranging from 1.24 to 1.63).
  • trimetazidine exposure parameters Cmax estimate of 1.10; 90% Cl ranging from 0.99 to 1.21
  • AUCo-t estimate of 0.99; 90% Cl ranging from 0.91 to 1.09
  • AUCo-inf estimate of 0.97; 90% Cl ranging from 0.88 to 1.07
  • median IMB- 1028814 tmax was 2 hours on Day 1 and Day 5, and median tmax was 5.5 hours and 5 hours for trimetazidine on Day 1 and Day 5, respectively.
  • Geometric mean R* for IMB-1028814, trimetazidine, and IMB-1028814 + trimetazidine were 1.22, 2.28, and 1.66 on Day 5 relative to Day 1. This indicates minimal accumulation of IMB-1028814 in plasma, moderate accumulation of trimetazidine in plasma, and moderate accumulation of IMB-1028814 + trimetazidine in plasma.
  • the geometric mean half-life of the 200 mg 8-hour MR IMB- 1018972 dose was 3.85 hours, 9.52 hours, and 8.64 hours for IMB- 1028814, trimetazidine, and IMB-1028814 + trimetazidine, respectively.
  • IMB-1018972 could be measured in only few plasma samples taken during this study.
  • 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.
  • MR formulations of IMB-1018972 50 mg and 200 g dose strengths of IMB-1018972, each with a 4-hour dissolution profile and an 8-hour dissolution profile.
  • the objectives of these MR formulations were two-fold: the first objective was to lower the Cmax of IMB-1018972 and its subsequent metabolites; the second was to extend the absorption time and preserve total exposure as measured by the AUCs. The expectation was that lower Cmax would improve overall tolerability and extended absorption time with preserved AUCs was expected to decrease the variability seen in the exposures of the IR formulation.
  • the formulation chosen by the Sponsor for administration under fed conditions in the single-dose MR part was the 200 mg 8-hour MR formulation. This MR formulation testing was important as it was planned to use this formulation in the Phase 2 proof-of-concept studies planned to commence in the year 2020.
  • a final part (multiple-dose MR part) was added assessing the safety, tolerability, and PK profile of multiple doses (every 12 hours [ql2h] for 5 consecutive days) of the MR formulation with a 200 mg dose strength and an 8-hour dissolution profile (200 mg 8- hour MR formulation), taken with food.
  • This dose and formulation were tested in the fasted and fed states in the singledose MR part. This dose and formulation are targeted for use in a patient population in later studies, and data collected from the subject cohort in this final part would inform that decision.
  • the single-dose MR part 1 group of 12 healthy subjects (all on active drug) was included.
  • the subjects received a single oral dose of 1 of 4 MR formulations of IMB-1018972 under fasted conditions (an overnight fast of at least 10 hours) on Days 1, 4, 7, and 10 in a fixed order that was the same for all subjects.
  • the MR formulation of IMB- 1018972 to be administered on Day 13 under fed conditions was 1 of the 4 MR formulations administered on Days 1, 4, 7, and 10 under fasted conditions as determined by the Sponsor based on the available safety, tolerability, and PK results of the 4 MR formulations.
  • the single-dose MR part consisted of:
  • the multiple-dose MR part 1 group of 12 healthy subjects (all on active drug) was included. Subjects received multiple oral doses of the MR formulation of IMB-1018972 ql2h under fed conditions for 5 consecutive days; on Day 5 only a single morning dose was administered. The MR formulation of IMB-1018972 administered was the same as that administered in the single-dose MR part under both fasted and fed conditions.
  • the multiple-dose MR part consists of:
  • Subjects signed the study-specific ICF prior to any study-specific screening procedures being performed The written informed consent was obtained for all subjects, regardless of their eligibility for the study.
  • the signed ICFs were retained and archived at PRA and a copy was provided to the subject.
  • Subjects were in the clinic for 1 treatment period. 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 single-dose MR part were discharged on Day 16 (72 hours after the last study drug administration on Day 13) after completion of the assessments.
  • Subjects of the multiple-dose MR part were discharged on Day 7 (48 hours after the last study drug administration on Day 5) after completion of the assessments
  • the follow-up assessments were performed 7 to 14 days after the last PK blood sample (between Day 23 and Day 30).
  • the follow-up assessments were performed 6 to 8 days after the last PK blood sample (Day 14 ⁇ 1 day).
  • the multiple-dose MR part 12 healthy subjects received multiple oral doses of the MR formulation of IMB-1018972 ql2h under fed conditions for 5 consecutive days; on Day 5 only a single morning dose was administered.
  • the MR formulation of IMB-1018972 administered was the same as that administered in the single-dose MR part.
  • the safety, tolerability, and PK of multiple doses of this MR formulation taken with food were evaluated.
  • 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 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.
  • a serious adverse reaction i.e., an SAE considered at least possibly related to the study drug administration.
  • An overall pattern of clinically significant changes in any safety parameter e.g., moderate or severe AEs in >1 subject
  • any safety parameter e.g., moderate or severe AEs in >1 subject
  • the formulation chosen for administration on Day 13 was the 200 mg 8-hour MR formulation as determined by the Sponsor based on the available safety, tolerability, and PK results of the 4 MR formulations administered on Days 1, 4, 7, and 10 under fasted conditions The following treatments were administered in the single-dose MR part:
  • Ischemic cardiovascular disease Strength 50 mg MR formulation and 200 mg MR formulation with 4-hour and 8- hour dissolution profile (based on free base)
  • Dosage form oral MR tablet(s) to be used in the MR 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.
  • 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.
  • 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.
  • 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-8x2 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 x2 for trimetazidine on Day 26 at this dose was 15,042, and 13,834 ng*h/mL for males and females, respectively.
  • trimetazidine Vastarel
  • 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 afternoon/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 the single-dose MR part 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).
  • 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 oral doses of MR formulations of IMB-1018972, and multiple oral doses of the 200 mg 8-hour MR formulation of IMB-1018972. 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
  • Pregnancy test females only: b-human chorionic gonadotropin in serum 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.
  • 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 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.
  • Urine samples could be kept for a maximum of 1 year for further analysis of metabolites in urine in case unknown metabolites were found in plasma.
  • 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
  • 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 12 Urine IMB-1018972, IMB-1028814, and Trimetazidine Parameters
  • 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.
  • Subject 505 of the single-dose MR part was withdrawn from the study due to a moderate TEAE of ALT increased (possibly related; up to 149 IU/L on Day 11) and did not receive the last single oral dose of 200 mg 8-hour MR formulation of IMB-1018972 under fed conditions on Day 13. None of these discontinued subjects were replaced. All 88 subjects were included in the PK and safety sets.
  • FIG. 10 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.
  • FIG. 11 is a table of assessments given for the Single-Dose MR Part, with the following notations: a. Physical examination: at screening, on Day -1 (admission; this was a directed examination only done at the discretion of the Investigator), and at follow-up. On other days, a physical examination could be done on indication only at the discretion of the Investigator. b. Clinical laboratory tests (including clinical chemistry, hematology, coagulation, and urinalysis): at screening, on Day -1 (admission), at 24 hours after each dose, and at follow-up. c.
  • 12-lead ECG at screening, on Day -1 (admission), prior to each dose and just prior to the PK sampling time points of 1, 4, 6, 12, 24, and 48 hours after each dose, and at follow-up.
  • Vital signs (supine systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate): at screening, on Day -1 (admission), prior to each dose and at 1, 4, 6, 12, 24, and 48 hours after each dose, and at follow-up.
  • the MR formulation of IMB-1018972 to be administered on Day 13 under fed conditions was 1 of the 4 MR formulations administered on Days 1, 4, 7, and 10 under fasted conditions.
  • g. AEs were recorded from admission until completion of the follow-up visit.
  • Blood sampling for genotyping was mandatory.
  • FIG. 12 is a table of assessments given for the Multiple-Dose MR part, with the following notations: a Physical examination: at screening, on Day -1 (admission; this was a directed examination only done at the discretion of the Investigator), and at follow-up. On other days, a physical examination could be done on indication only at the discretion of the Investigator. b. Clinical laboratory tests (including clinical chemistry, hematology, coagulation, and urinalysis): at screening, on Day -1 (admission), at 24 hours after the last dose, and at follow-up.
  • c 12-lead ECG at screening, on Day -1 (admission), just before the time points of 1, 4, 6, 12, 24, and 48 hours after the first dose on Day 1 and after the last dose on Day 5, and at follow-up.
  • Vital signs (supine systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate): at screening, on Day -1 (admission), before the last dose, at 1, 4, 6, 12, 24, and 48 hours after the last dose, and at follow-up.
  • Study drug 200 mg 8-hour MR formulation was administered twice daily for 5 days; on Day 5 only a single morning dose was administered Study drug administration was conducted under fed conditions.
  • FIG. 13 is a table of analysis data sets for the Single-Dose MR Part
  • FIG. 14 a table of analysis data sets for the Multiple-Dose MR Part Demographic and Other Baseline Characteristics Single-Dose MR Part
  • FIG. 15 is a table of a summary of demographic characteristics - Single-Dose MR Part (Safety Set).
  • FIG. 16 is a table of a summary of demographic characteristics - Multiple-Dose MR Part (Safety Set).
  • FIG. 17 is a table of the Extent of Exposure - Single-Dose MR Part (Safety Set)
  • FIG. 18 is a table of the Extent of Exposure - Multiple-Dose MR Part (Safety Set)
  • tmaxfor IMB-1028814 was earlier with the 8-hour MR formulation (2 hours for 50 mg and 200 mg IMB-1018972) than with the 4-hour MR formulation (5 hours for 50 mg IMB- 1018972 and 3 hours for 200 mg IMB-1018972).
  • tmax for trimetazidine was later with the 8-hour MR formulation (8 hours for 50 mg IMB-1018972 and 5 hours for 200 mg IMB- 1018972) than with the 4-hour MR formulation (6 hours for 50 mg IMB-1018972 and 3 hours for 200 mg IMB-1018972).
  • tmax for IMB-1028814 + trimetazidine was similar for the 8-hour MR formulation (5 hours for 50 mg IMB-1018972 and 2.5 hours for 200 mg IMB-1018972) and the 4-hour MR formulation (5 hours for 50 mg IMB-1018972 and 3 hours for 200 mg IMB- 1018972).
  • Cmax for IMB-1028814 was 35% and 32% lower, respectively, Cmax for trimetazidine was 20% and 24% lower, respectively, and Cmax for IMB-1028814 + trimetazidine was 21% and 34% lower, respectively, for the 8-hour MR formulation relative to the 4-hour MR formulation (Table 28).
  • AUCo-t for IMB-1028814 was 26% lower, Cmax for trimetazidine was 12% lower, and Cmax for IMB- 1028814 + trimetazidine was 18% lower after the 8-hour MR formulation than after the 4-hour MR formulation.
  • AUCO-t for IMB-1028814 was 6% higher, Cmax for trimetazidine was 4% higher, and Cmax for IMB-1028814 + trimetazidine was 5% higher after the 8-hour MR formulation than after the 4-hour MR formulation.
  • Cmax was approximately 42% higher following administration of a single dose of 200 mg 8-hour MR IMB-1018972 after an FDA-defined high-fat breakfast relative to administration under fasted conditions (estimate of 1.42; 90% Cl ranging from 1.24 to 1.63).
  • trimetazidine exposure parameters Cmax estimate of 1.10; 90% Cl ranging from 0.99 to 1.21
  • AUCo-t estimate of 0.99; 90% Cl ranging from 0.91 to 1.09
  • AUCo-inf estimate of 0.97; 90% Cl ranging from 0.88 to 1.07
  • FIG. 19 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Linear) - Single-Dose MR Part (PK Set)
  • FIG. 20 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set)
  • FIG. 21 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Linear) - Single-Dose MR Part (PK Set)
  • FIG. 22 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set)
  • FIG. 23 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Linear) - Single-Dose MR Part (PK Set)
  • FIG. 24 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles (Semi-Logarithmic Scale) - Single-Dose MR Part (PK Set)
  • FIG. 25 is a table of Summary Statistics Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - Single- Dose MR Part (PK Set)
  • FIG. 26 is a table of Exploratory Analysis of Food Effect for IMB-1028814 and Trimetazidine following Administration of 200 mg 8-hour MR IMB-1018972 - Single-Dose MR Part (PK Set) Multiple-Dose MR Part
  • Geometric mean Rac for IMB-1028814, trimetazidine, and IMB-1028814 + trimetazidine were 1.22, 2.28, and 1.66 on Day 5 relative to Day 1. This indicates minimal accumulation of IMB-1028814 in plasma, moderate accumulation of trimetazidine in plasma, and moderate accumulation of IMB-1028814 + trimetazidine in plasma.
  • the geometric mean half-life of the 200 mg 8-hour MR IMB-1018972 dose was 3.85 hours, 9.52 hours, and 8.64 hours for IMB-1028814, trimetazidine, and IMB-1028814 + trimetazidine, respectively.
  • FIG. 27 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 28 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set)
  • FIG. 29 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 30 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set)
  • FIG. 31 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 32 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles from Day 1 through Day 5 (Semi -Logarithmic Scale) - Multiple- Dose MR Part (PK Set)
  • FIG. 33 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 34 is a graph of Geometric Mean IMB-1028814 Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set)
  • FIG. 35 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 36 is a graph of Geometric Mean Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple-Dose MR Part (PK Set)
  • FIG. 37 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Linear) - Multiple-Dose MR Part (PK Set)
  • FIG. 38 is a graph of Geometric Mean IMB-1028814 + Trimetazidine Plasma Concentration-Time Profiles after Day 1 through Day 5 (Semi-Logarithmic Scale) - Multiple- Dose MR Part (PK Set)
  • FIG. 39 is a table of Summary Statistics Geometric Mean [Range]) of IMB-1028814, Trimetazidine, and IMB-1028814 + Trimetazidine Plasma Pharmacokinetic Parameters - Multiple-Dose MR Part (PK Set)
  • IMB-1018972 could be measured in only few plasma samples taken during this study.
  • the geometric mean ti/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 tl/2 did not increase with increasing IMB-1018972 dose.
  • trimetazidine Within 48 hours following administration of a single oral dose of 35 mg trimetazidine, on average 54.47% of the dose was excreted in urine as trimetazidine. ⁇ Following 14 days of twice daily dosing with 150 mg and 50 mg IMB-1018972 under fed conditions, no relevant accumulation was observed of IMB-1028814 (R ac of 1.18 and 1.10 for 150 mg and 50 mg, respectively) and accumulation of trimetazidine was modest (Rac of 1.63 and 1.89 for 150 mg and 50 mg, respectively) was observed.
  • TEAEs A total of 37 TEAEs was reported by 10 of 12 (83.3%) subjects who received IMB- 1018972. There were no deaths reported. Subject 505 of the single-dose MR part was withdrawn from the study due to a moderate TEAE of ALT increased. This TEAE is described below and more extensively in Section 12.2.2. The majority of the TEAEs were transient and resolved without sequelae by follow-up. Three TEAEs were still ongoing at follow-up: aphthous ulcer, catheter site hematoma, and catheter site related reaction. Thirty-six of 37 TEAEs were of mild severity and 1 TEAE was of moderate severity. No severe TEAEs were reported.
  • the moderate TEAE was an event of ALT increased (up to 149 IU/L on Day 11) that was considered by the Investigator not to be related to the study drug.
  • the subject (Subject 505) was withdrawn from the study due to this TEAE and did not receive the last single oral dose of 200 mg 8-hour MR formulation of IMB-1018972 underfed conditions on Day 13.
  • TEAEs A total of 40 TEAEs was reported by 12 of 12 (100%) subjects who received IMB- 1018972. 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. Four TEAEs were still ongoing at follow-up: dermatitis contact, erythema, influenza like illness, oropharyngeal pain, and medical device site irritation.
  • Nervous system disorders with 9 TEAEs reported by 7 (58.3%) subjects (6 TEAEs of headache, 2 TEAEs of dizziness, and 1 TEAE of dizziness postural).
  • FIG. 40A and FIG. 40B is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - Single-Dose MR Part (Safety Set)
  • FIG. 41 is a table Summary of All TEAEs by System Organ Class, Preferred Term and Treatment - Single-Dose MR Part (Safety Set)
  • FIG. 42 is a table Summary of All TEAEs by Treatment, Relationship, and Severity- Single-Dose MR Part (Safety Set)
  • FIG. 43 is a table Summary of All TEAEs by Treatment, Relationship, and Severity - Multiple-Dose MR Part (Safety Set)
  • Subject 505 was a 21-year old white male with a BMI of 21.5 kg/m2.
  • the subject participated in the single-dose MR part and was planned to receive 50 mg of the 8-hour MR formulation on Day 1 under fasted conditions, 50 mg of the 4-hour MR formulation on Day 4 under fasted conditions, 200 mg of the 8-hour MR formulation on Day 7 under fasted conditions, 200 mg of the 4-hour MR formulation on Day 10 under fasted conditions, and 200 mg 8-hour MR formulation of IMB-1018972 on Day 13 under fed conditions.
  • a TEAE of ALT increased was reported for this subject starting on Day 5, 1 day after dosing with 50 mg of the 4-hour MR formulation on Day 4.
  • ALT values for this subject were within normal range (0-68 IU/L) at screening (29 IU/L), on Day -1 (34 IU/L), and on Day 2 (31 IU/L). ALT levels increased to values above the upper limit of normal (68 IU/L) of 72 IU/L on Day 5, 97 IU/L on Day 8, and 149 IU/L on Day 11, and then decreased again to 102 IU/L on Day 14, and 84 IU/L on Day 16.
  • ALT levels had returned to 42 IU/L, which was within the normal range. This was also the day that this TEAE was recorded to have recovered.
  • the high ALT level of 149 IU/L on Day 11 was considered by the Investigator to be clinically significant abnormal, based on which the Investigator decided to withdraw the subject from the study (receive no further doses). Throughout this entire period, AST levels were within normal range.
  • the subject did not receive the planned last single oral dose of 200 mg 8-hour MR formulation of IMB-1018972 under fed conditions on Day 13. After withdrawal on Day 11, the subject returned on Day 24 for a follow-up with safety assessments conducted as planned.
  • the subject also reported mild TEAEs of dermatitis contact on Day 1 (not related), skin exfoliation from Day 3 to Day 6 (not related), and abdominal pain from Day 13 to Day 14 (not related).
  • ALT values for this subject were within normal range (0-68 IU/L) at screening (29 IU/L), on Day -1 (34 IU/L), and on Day 2 (31 IU/L). ALT levels increased to values above the upper limit of normal (68 IU/L) of 72 IU/L on Day 5, 97 IU/L on Day 8, and 149 IU/L on Day 11, and then decreased again to 102 IU/L on Day 14, and 84 IU/L on Day 16.
  • ALT levels had returned to 42 IU/L, which was within the normal range. This was also the day that this TEAE was recorded to have recovered.
  • the high ALT level of 149 IU/L on Day 11 was considered by the Investigator to be clinically significant abnormal, based on which the Investigator decided to withdraw the subject from the study. Throughout this entire period, AST levels for Subject 505 were within normal range. No other cases of clinically significant abnormal laboratory parameters were recorded at any time during this study.
  • Subject 519 received gelomyrtol 3 times a day for 2 days and 500 mg paracetamol 3 times a day for 2 days because of flu like symptoms (preferred term: influenza like illness).
  • 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.
  • TEAE of ALT increased (up to 149 IU/L on Day 11) was considered by the Investigator to be possibly related to the study drug and resolved without intervention.
  • 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 200 mg 8-hour MR IMB-1018972 formulation has been chosen to be most suitable to be used in Phase 2 proof-of-concept studies.
  • IMB-1018972 could be measured in only few plasma samples taken during this study.
  • the geometric mean ti/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.

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Abstract

L'invention concerne des compositions pharmaceutiques qui contiennent des formulations à libération modifiée de formes modifiées de trimétazidine, telles que CV-8972. Les compositions comprennent un polymère érodable, tel que l'hydroxypropylméthylcellulose (HPMC), qui permet une libération prolongée de la forme modifiée de trimétazidine et de ses produits métaboliques dans le corps. L'invention concerne également des méthodes de traitement de pathologies, notamment d'une angine et d'une insuffisance cardiaque, à l'aide de ces compositions.
EP21832842.5A 2020-06-30 2021-06-28 Formulations à libération modifiée de formes modifiées de trimétazidine Pending EP4171232A1 (fr)

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