WO2024259130A1 - Procédés pour augmenter l'exposition au plasma de vatiquinone avec des aliments - Google Patents

Procédés pour augmenter l'exposition au plasma de vatiquinone avec des aliments Download PDF

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WO2024259130A1
WO2024259130A1 PCT/US2024/033847 US2024033847W WO2024259130A1 WO 2024259130 A1 WO2024259130 A1 WO 2024259130A1 US 2024033847 W US2024033847 W US 2024033847W WO 2024259130 A1 WO2024259130 A1 WO 2024259130A1
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vatiquinone
food
subject
disease
administered
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Lucy Lee
Martin J. Thoolen
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates generally, in one or more embodiments, to methods of administering vatiquinone for the treatment of mitochondrial diseases and other disorders characterized by high levels of oxidative stress and dysregulation of energy metabolism.
  • Vatiquinone, or alpha-tocotrienol quinone also known as 2[(3R,6E,10E)-3-hydroxy- 3,7, 11 , 15-tetramethylhexadeca-6, 10, 14-trien-l -yl]-3, 5, 6-trimethylcyclohexa-2,5-diene-l ,4- dione, is the quinone oxidation product of alpha-tocotrienol, one of the eight naturally occurring forms of vitamin E, and is a member of the parabenzoquinone class of drugs.
  • the chemical structure of vatiquinone is shown below:
  • Vatiquinone is a potent inhibitor that prevents ferroptotic cell death by inhibiting 15- lipoxygenase (15-LO), a key enzyme in the ferroptosis pathway, and alleviates oxidative stress and lipid peroxidation, thereby preventing neuronal dysfunction and cell death that underpins the development of mitochondrial disease.
  • the oxidoreductase enzyme, 15-LO controls the process of inflammation, oxidative stress, glutathione (GSH) depletion, and a type of cell death involving lipid peroxidation known as ferroptosis.
  • 15- LO The activity of 15- LO is particularly enhanced in patients with mitochondrial diseases and other disorders characterized by high levels of oxidative stress, which ultimately leads to depletion of endogenous antioxidants such as GSH (Riederer et al. J Neurochem. 1989;52(2):515-520 and Piemonte et al. Eur J Clin Invest. 2001 ;31(11):1007-1011).
  • vatiquinone has been found to increase GSH levels and decrease the ratio of oxidized GSH to reduced GSH (OX/GSH), correlating with clinical improvement in disease symptoms, and arrest or reversal of disease progression (Blankenberg et al. Mol Genet Metab. 2012;107(4):690-699 and Pastore et al. Mol Genet Metab. 2013;109(2):208- 214).
  • the critical role of 15-LO as a key enzyme in the biological process of ferroptosis has been implicated in a number of central nervous system (CNS) diseases, e.g. Alzheimer's disease and Parkinson's disease (Joshi et al. Trends Pharmacol Sci. 2015;36(3): 181 -186 and Guiney et al. Neurochem Int. 2017; 104:34-48).
  • CNS central nervous system
  • vatiquinone has been studied in children and adults with mitochondrial diseases and other disorders characterized by high levels of oxidative stress such as Leigh’s syndrome and Friedreich’s ataxia. Vatiquinone crosses the blood-brain barrier and promotes its pharmacological activities by targeting oxidoreductases that are critical to energy metabolism, oxidative stress, and inflammation. As of December 2021, 621 subjects and patients have received vatiquinone, with the longest treatment duration over 10 years. Data from these studies demonstrate a reduction of seizure and disease-related morbidity in patients with mitochondrial disease-associated seizures and a long-term improvement in neurological and neuromuscular function in patients with Friedreich ataxia. Clinical safety data suggest that vatiquinone is well tolerated with no dose-limiting toxicities reported (Zesiewicz et al. Neurodegener Dis Manag. 2018;8(4):233-242).
  • vatiquinone an oxidation product of vitamin E
  • vatiquinone is expected to follow the lipid absorption pathway of vitamin E derivatives, wherein food, especially fat, increases bile flow, which then aids the emulsification of the lipid (and vatiquinone) to form micelles, facilitating absorption through the enterocyte into the lymphatic system.
  • vatiquinone treatments have now been identified for vatiquinone treatments. Described herein are clinical trials that reveal that the administration of vatiquinone with food unexpectedly increases the bioavailability of the drug, indicating a positive food effect.
  • the administration of vatiquinone with either a low fat meal or a liquid meal beverage significantly improves the plasma maximum concentration (Cmax) and the extent of absorption (AUC) of vatiquinone in the subject when compared to administration without food, thereby improving the efficacy of the treatment.
  • Cmax plasma maximum concentration
  • AUC extent of absorption
  • Some embodiments of the present disclosure relate to methods of administering vatiquinone to treat a patient suffering from a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism, comprising administering a therapeutically effective amount of vatiquinone in combination with food.
  • Some embodiments of the present disclosure relate to methods of increasing drug bioavailability in vatiquinone therapy to treat a subject suffering from a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism, comprising: administering to a subject a therapeutically effective amount of vatiquinone with food, wherein the bioavailability of vatiquinone is increased compared to the bioavailability of the same amount of vatiquinone administered without food.
  • food comprises a high fat meal, a low fat meal, or a liquid meal beverage.
  • food is a low fat meal.
  • food is a liquid meal beverage.
  • the subject is suffering from and/or been diagnosed with a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism.
  • FIG. 1A is a graph illustrating the linear scale of the mean plasma concentration of vatiquinone over time following a single 300 mg dose in fed and fasted subjects.
  • FIG. IB is a graph illustrating the log scale of the mean plasma concentration of vatiquinone over time following a single 300 mg dose in fed and fasted subjects.
  • FIG. 2A is a graph illustrating the steady state plasma concentration of vatiquinone over time following continuous TID dosing with 200 mg doses on Day 1 and Day 6.
  • FIG. 2B is a graph illustrating the mean plasma concentration of vatiquinone following 6 days of continuous TID dosing with 200 mg and 400 mg doses.
  • Various embodiments described herein provide methods of increasing the bioavailability of vatiquinone by administering vatiquinone with food.
  • Increasing the bioavailability of vatiquinone has various benefits. For example, increased bioavailability can result in more effective dosing. In some embodiments, more effective dosing allows for a lower dosage of vatiquinone to be administered to an individual. In some embodiments, administration of vatiquinone with food can also reduce the frequency and/or severity of adverse effects associated with vatiquinone, or other drugs.
  • AUC area under the concentration- time curve
  • AUC0-24 area under the concentration-time curve over the time interval 0 to 24 hours
  • AUC0-48 area under the concentration-time curve over the time interval 0 to 48 hours
  • BID Twice daily
  • ECG electrocardiogram
  • administration refers to the administration of a composition to a subject.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreal.
  • an “effective amount” of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit the desired response.
  • a therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • An effective amount also encompasses an amount sufficient to confer benefit, e.g., clinical benefit.
  • the term “with food” is defined to mean, in general, the condition of having consumed food during the period between from about 1 hour prior to the administration of vati quinone to about 2 hours after the administration of vatiquinone.
  • with food means that the dosage form is administered to a patient between about 30 minutes prior to about 2 hours after eating a meal.
  • with food means that the dosage form is administered at substantially the same time as the eating the meal.
  • food is a solid food with sufficient bulk and fat content that it is not rapidly dissolved and absorbed in the stomach.
  • the food is a meal, such as breakfast, lunch, or dinner.
  • the food is at least about 100 calories, about 200 calories, about 250 calories, about 300 calories, about 400 calories, about 500 calories, about 600 calories, about 700 calories, about 800 calories, about 900 calories, about 1000 calories, about 1250 calories, about 1500 calories.
  • food comprises a high fat meal, a low fat meal, or a liquid meal beverage.
  • food is a low fat meal.
  • high fat meal refers to a meal where fat accounts for 50% or more of the total calorie-content of the meal.
  • low fat meal refers to a meal where fat accounts for about 25% to 49% of the total calorie-content of the meal.
  • food is a liquid meal beverage.
  • nutritional shake or meal replacement beverage include the Ensure® branded adult products (such as Ensure® Original, Ensure® Plus, Ensure® Enlive, Ensure® High Protein, Ensure® Clear, and Ensure® Light), Glucema®, Choice DM®, Slim Fast®, PediaSure®, Glytrol®, and Resource®,
  • the liquid meal beverage is PediaSure®.
  • PediaSure® is a pediatric nutritional supplement that contains 240 calories per 8 fluid ounces with a caloric distribution of 14% protein, 12% fat and 12% carbohydrate.
  • food is PediaSure®.
  • without food “fasted,” or “on an empty stomach” are defined to mean the condition of not having consumed food within the time period of about 1 hour prior to the administration of vatiquinone to about 2 hours after the administration of vatiquinone. In some embodiments, food has not been consumed for about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours prior to administration of vatiquinone.
  • oral dosage form has its ordinary meaning as understood by those skilled in the art and thus includes, by way of non-limiting example, a formulation of a drug or drugs in a form administrable to a human, including pills, tablets, cores, capsules, caplets, loose powder, solutions, and suspensions.
  • food effect refers to a phenomenon that can influence the absorption of drugs following administration.
  • a food effect can be designated “negative” when absorption is decreased, or “positive” when absorption is increased and manifested as an increase in bioavailability (e.g., as reflected by AUC).
  • Food effects can also refer to changes in maximum concentration (Cmax), or the time to reach maximum concentration (Tmax), independently of overall absorption. As a result, some drugs can preferably be taken in either fasted or fed conditions to achieve an optimum desired effect.
  • Cmax maximum concentration
  • Tmax time to reach maximum concentration
  • some drugs can preferably be taken in either fasted or fed conditions to achieve an optimum desired effect.
  • the terms “with food” and “fed” can be used interchangeably.
  • the terms “without food,” “fasted,” and “fasting” can be used interchangeably.
  • Bioavailability means the extent or rate at which an active agent is absorbed into a living system or is made available at the site of physiological activity. For active agents that are intended to be absorbed into the bloodstream, bioavailability data for a given formulation may provide an estimate of the relative fraction of the administered dose that is absorbed into the systemic circulation. “Bioavailability” can be characterized by one or more pharmacokinetic parameters.
  • pharmacokinetic profile or “pharmacokinetics,” as used herein, have their ordinary meaning as understood by those skilled in the art and thus include, by way of non-limiting example, a characteristic of the curve that results from plotting concentration (e.g. blood plasma, serum or tissue) of a drug over time, following administration of the drug to a subject.
  • a pharmacokinetic profile thus includes a pharmacokinetic parameter or set of parameters that can be used to characterize the pharmacokinetics of a particular drug or dosage form when administered to a suitable population.
  • the suitable population may be defined as patients with renal impairment, patients with hepatic impairment, geriatrics, or pediatrics, etc.
  • AUC area under the concentration vs. time curve
  • AUCo- t area under the concentration time curve from time zero until last quantifiable sample time
  • AUCo- ⁇ area under the concentration time curve from time zero extrapolated to infinity
  • AUC ss area under the concentration time curve over the steady state dosing interval
  • AUC0-12 time zero to twelve hours
  • AUC last indicates the area under the blood plasma concentration vs. time curve from the time of administration until the time of the last quantifiable concentration.
  • Pharmacokinetic parameters may be measured in various ways known to those skilled in the art, e.g., for single dose or steady-state. Differences in one or more of the pharmacokinetic parameters (e.g., Cmax) may indicate pharmacokinetic distinctness between two formulations or between two methods of administration.
  • patient or “subject” refers to a human subject.
  • the act of “providing” includes supplying, acquiring, or administering (including self-administering) a composition described herein.
  • administering includes an individual obtaining and taking a drug on their own.
  • an individual obtains a drug from a pharmacy and self-administers the drug in accordance with the methods provided herein.
  • methods of treatment can alternatively entail use claims, such as Swiss-type use claims.
  • a method of treating a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism with a composition can alternatively entail the use of a composition in the manufacture of a medicament for the treatment of a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism.
  • the mitochondrial diseases and other disorders characterized by high levels of oxidative stress and dysregulation of energy metabolism may include, but not necessarily be limited to, Friedreich’s ataxia, Leigh syndrome, Leber’s Hereditary Optic Neuropathy (LHON), (proliferative, non-proliferative, diabetic or hypertensive) retinopathy, refractory epilepsy, mitochondrial disease-associated seizures, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), ischemic stroke, a cardiomyopathy (e.g. cardiac ischemia-reperfusion injury, myocardial infarction, Barth cardiomyopathy, hypertrophic cardiomyopathy or heart failure), renal injury; renal ischemia reperfusion injury or acute renal failure.
  • a cardiomyopathy e.g. cardiac ischemia-reperfusion injury, myocardial infarction, Barth cardiomyopathy, hypertrophic cardiomyopathy or heart failure
  • renal injury renal ischemia rep
  • pharmacokinetic parameters may be determined by comparison to a reference standard using clinical trial methods known and accepted by those skilled in the art, e.g., as described in the examples set forth herein. Since the pharmacokinetics of a drug can vary from patient to patient, such clinical trials generally involve multiple patients and appropriate statistical analyses of the resulting data (e.g., ANOVA at 90% confidence). Comparisons of pharmacokinetic parameters can be on a dose- adjusted basis, as understood by those skilled in the art.
  • Some embodiments of the present disclosure relate to methods of administering vatiquinone to treat a subject suffering from a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism, comprising administering a therapeutically effective amount of vatiquinone in combination with food.
  • the methods disclosed herein include administering vatiquinone to a patient or subject with food.
  • Vatiquinone can be administered any time of day with food.
  • the food can be consumed at any time during the period between from about 1 hour prior to the administration of vatiquinone to about 2 hours after the administration of vatiquinone.
  • the food can be consumed within the time period of about 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes prior to the administration of vatiquinone.
  • the food can be consumed within the time period of about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, or about 2 hours after the administration of vatiquinone.
  • the administration of vatiquinone to the patient is immediately after the consumption of food (e.g., within about 1 minute after food consumption) up to about 1 hour after food consumption.
  • vatiquinone is administered at substantially the same time as the consumption of the food.
  • the amount of vatiquinone can be administered in various amounts.
  • daily dosages which can be used are an effective amount within the dosage range of about 0.1 mg/kg to about 300 mg/kg body weight, or within about 0.1 mg/kg to about 100 mg/kg body weight, or within about 0.1 mg/kg to about 80 mg/kg body weight, or within about 0.1 mg/kg to about 50 mg/kg body weight, or within about 0.1 mg/kg to about 30 mg/kg body weight, or within about 0.1 mg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 80 mg''kg body weight, or within about 1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 80 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg''kg to about 200 mg/kg body weight
  • vatiquinone is administered 300 mg per day. In one embodiment, vatiquinone is administered 600 mg per day. In another embodiment, vatiquinone is administered 900 mg per day. In another embodiment, vatiquinone is administered 1200 mg per day.
  • the dosing may be once or twice or three times daily, with one or more units per dose,
  • the effective daily intake of vatiquinone is administered as one, two, three, four, five, six, or more doses administered separately at appropriate intervals throughout the day.
  • vatiquinone is administered once daily.
  • vatiquinone is administered two or more times daily.
  • vatiquinone is administered twice daily.
  • vatiquinone is administered three times daily.
  • each dose comprises one, two, three or more unit dosage forms.
  • one or more units are administered to the subject one or more times per day.
  • vatiquinone is administered as multiple doses spaced throughout the day and each dose comprises a therapeutically effective amount of vatiquinone.
  • vatiquinone is administered with food three times per day.
  • vatiquinone is administered with food three times per day corresponding to the timing of breakfast, lunch, and dinner.
  • vatiquinone is administered with food three times per day on a 6-hour interval (6-6-12 schedule) that corresponds to the timing of breakfast, lunch, and dinner.
  • Vatiquinone can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms.
  • Vatiquinone can also be administered in a liposome formulation.
  • Vatiquinone can also be administered as a prodrug, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
  • vatiquinone is administered to the subject in a unit dosage form comprising about 25 mg to about 500 mg, or about 50 mg to about 400 mg, or about 100 mg to about 200 mg vatiquinone per unit. In an embodiment, vatiquinone is administered to the subject in a unit dosage form comprising about 50 mg of vatiquinone per capsule or tablet. In another embodiment, vatiquinone is administered to the subject in a unit dosage form comprising about 200 mg of vatiquinone per capsule or tablet.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of vatiquinone calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the unit dosage form is, for example, a pill, capsule, or tablet. In one embodiment, the unit dosage form is a capsule.
  • vatiquinone is administered to the subject in a liquid dosage form comprising 25 mg to about 500 mg, or about 50 mg to about 400 mg, or about 100 mg to about 200 mg vatiquinone per mL. In an embodiment, vatiquinone is administered to the subject as a liquid dosage form comprising about 100 mg vatiquinone per mL.
  • liquid dosage forms for may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art. such as water or oil.
  • compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • the liquid dosage form is a liquid solution comprising one or more vegetable- derived oils, such as sesame oil, and/or one or more animal- derived oils, and/or one or more fish -derived oils.
  • the methods include administering a therapeutically acceptable amount of vatiquinone.
  • therapeutically effective amount refers to an amount of vatiquinone sufficient to treat, ameliorate, or prevent the identified disease or condition, or to exhibit a detectable therapeutic effect. The effect may be detected by any means known in the art.
  • the precise effective amount for a subject can depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation may be determined by routine experimentation that is within the skill and judgment of the clinician.
  • food is selected from a high fat meal, a low fat meal, or a liquid meal beverage.
  • food is a low fat meal.
  • food is a liquid meal beverage, hr an embodiment, the liquid meal beverage is PediaSure®.
  • Some embodiments of the present disclosure relate to methods of increasing drug bioavailability in vatiquinone therapy to treat a subject suffering from a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism comprising administering a therapeutically effective amount of vatiquinone in combination with food, wherein the bioavailability of vatiquinone is increased compared to the bioavailability of the same amount of vatiquinone administered without food
  • An increase in bioavailability can be determined using one or more measures known to one of skill in the art, such as an increase in AUG or Cmax, which can each independently be an increase that is, is about, is at least, or is at least about, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, or more, or within a range defined by any two of these values (e.g., 5%-5000%, 10%-1500%, or 20%-1000%), wherein the increase is as compared to a reference treatment (e.g., a fasted state or a different fed state).
  • a reference treatment e.g., a fasted state or a different fed state
  • increasing the bioavailability of vatiquinone comprises increasing the maximal plasma concentration (Cmax) or the extent of absorption (AUC) of vatiquinone.
  • the increase in bioavailability comprises an increase in Cmax of vatiquinone in the range of about 10% to about 4000%, about 15% to about 1000%, or about 20% to about 400% when vatiquinone is taken with food compared to the same amount of vatiquinone taken during a fasted condition.
  • the increase in Cmax of vatiquinone is about 3600%. In another embodiment, the increase in Cmax is about 400%.
  • the increase in bioavailability comprises an increase in AUC of vatiquinone in the range of about 10% to about 3000%, about 15% to about 1000%, or about 20% to about 500% when vatiquinone is taken with food compared to the same amount of vatiquinone taken during a fasted condition.
  • the increase hr AUC of vatiquinone is about 2600%. In another embodiment, the increase in AUC is about 350%.
  • the subject is suffering from and/or been diagnosed with a mitochondrial disease and other disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism.
  • compositions comprising: (a) a safe and therapeutically effective amount of vatiquinone.
  • Vatiquinone can be formulated into pharmaceutical compositions for use in treatment of various conditions or disorders. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety.
  • compositions containing a pharmaceutically-acceptable carrier include compositions containing a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically- acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as tire TWEENS; wetting agents
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric- coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance.
  • inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose
  • binders such as starch, gelatin and sucrose
  • disintegrants such as starch, alginic acid and croscarmelose
  • lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
  • Per-oral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in tire art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
  • compositions described herein may optionally include other drug actives.
  • any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any compound; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
  • This study was an open-label, randomized, three-treatment, 3 -way crossover study that aimed to evaluate vatiquinone pharmacokinetics when administered as single dose of 300 mg (3 x 100 mg capsules) under fasted, fed with liquid food such as PediaSure®, and fed with a low-fat meal. Subjects received the assigned treatment at each visit according to the randomization scheme. A minimum of 7-day washout was included between treatments.
  • Subjects in the fasted treatment group were required to fast for at least 10 hours prior to dosing.
  • Subjects in the low-fat treatment group ingested their meals within a 30-minute period followed by study medication which was taken with 240 mL of water within 15 minutes after completion of the full meal.
  • Subjects in the PediaSure® treatment group ingested the liquid meals at the same time as dosing. All subjects fasted for 4 hours after receiving their dose of study medication. Water restriction was implemented one hour before and one hour after dosing.
  • Vatiquinone PK parameters were computed with non-compartmental analysis (NCA) using Phoenix WinNonlin 5.2 or higher. PK parameters included Cmax; time to peak concentration (Tmax); apparent terminal elimination rate constant ( ⁇ z); apparent elimination half-life (tl/2); area under the concentration-time curve from time 0 to time t (AUCO t), and from 0 to infinity (AUCO ⁇ ).
  • a regression analysis was performed on the terminal linear phase of the semi-logarithmic plots of individual concentration-time data. During the analysis, regressions using the last 3 points with non-zero concentrations, then the last 4 points, and the last 5 points, and so forth, were repeated. Points prior to Cmax (including Cmax) were not used.
  • a total of 4 mL of whole blood sample was collected via venipuncture into Vacutainer® tubes with K2-EDTA (BD product number 367861). Immediately after blood collection, the Vacutainer® blood collection tube was gently inverted 8 to 10 times to allow mixing with the anticoagulant. The blood samples were placed on ice during the processing. Each blood sample was centrifuged within 30 minutes of collection to separate the plasma.
  • the safety set which included subjects who received study drug and had at least one safety assessment post-baseline, was employed in the analysis of tolerability and safety variables.
  • Drug safety was evaluated by pre- and post-dose assessments including vital signs (blood pressure, respiratory rate, and heart rate), ECGs, clinical laboratory values (chemistry, hematology, urinalysis), physical examinations, and monitoring of adverse events (incidence, severity, relationship).
  • a follow-up visit occurred 7 days after the last clinic day.
  • vatiquinone Following a single 300 mg dose, vatiquinone exhibited an absorption phase followed by multiphasic disposition phases regardless of meal status. Absorption appeared enhanced when vatiquinone was administered with meals, either low-fat meals or PediaSure®.
  • Figs. 1 A and IB shows mean plasma vatiquinone concentrations following single 300 mg vatiquinone dose by treatment groups.
  • a single dose of vatiquinone was safe and well tolerated for all treatment groups.
  • Five subjects reported a total of 6 adverse experiences, In the fasted group, one subject (5.9%) reported at least one treatment emergent adverse event (TEAE).
  • TEAE treatment emergent adverse event
  • PediaSure® group 5 subjects (27.8%) reported at least one TEAE.
  • low-fat meal group 3 subjects (17.6%) reported at least one TEAE. There were no deaths and no serious adverse experiences. All adverse experiences were of mild intensity and resolved during the study. There were no clinically significant findings for laboratory safety values, vital signs, or ECG data.
  • Study Participants The study enrolled male and female subjects who were between 18 and 55 years of age. inclusive, with BMI 18 - 32 kg/m2. Both male and female agreed to use birth control for the duration of the study and for at least 1 month post last dose. Subjects were determined to be healthy based on medical history, physical examination, laboratory assessments, 12-lead electrocardiogram (ECG), and vital signs at screening. Subjects must not have participated in any other investigational trial within 28 days prior to study drug administration or have known hypersensitivity to the study drugs or any of their excipients. Strong CYP3 A4 inhibitors/inducers were prohibited 1 week prior and during the study. Other key exclusion criteria included subjects with any current condition or history of significant endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, urological, immunological, or neurological disorders with clinical manifestations or a history of gastrointestinal surgery.
  • Part 1 This was a Phase 1 , open-label, nonrandomized, multiple dose study in healthy male and female subjects (Part 1) followed by a single dose study in healthy male subjects (Part 2). This evaluation only included the evaluation from Part 1.
  • Part 1 of this study consisted of 2 groups; 8 subjects were to be enrolled into each group for a total of up to 16 subjects. At least 3 males were to be enrolled in each group. Subjects were admitted into the study site on Day -1. From Days 1 to 6, all subjects in Group 1 received a 200 mg oral dose of vatiquinone administered on a three times daily schedule (TID) while all subjects in Group 2 received a 400 mg oral dose of vatiquinone.
  • TID three times daily schedule
  • the TID dosing schedule was based on a 6-hour interval that corresponded to the timing of breakfast, lunch, and dinner.
  • the drug was administered within 30 minutes after consuming a low-fat meal.
  • Breakfast, lunch, and dinner consisted of at least 25% fat of the total caloric content.
  • Vatiquinone PK parameters were computed using Phoenix WinNonlin 6.3 or higher and employing a non-compartmental analysis of plasma concentration-time profiles based on actual blood sampling times.
  • PK parameters derived from the analysis included but not limited to Cmax; time to peak concentration (Tmax); apparent terminal elimination rate constant ( ⁇ z); apparent elimination half-life (t1/2); area under the concentration-time curve from time 0 to time t (AUCo-t), and from 0 to infinity (AUC0- ⁇ ).
  • a regression analysis was performed on the terminal linear phase of the semi-logarithmic plots of individual concentration-time data. During the analysis, regressions using the last 3 points with non-zero concentrations, then the last 4 points, and the last 5 points, and so forth, were repeated. Points prior to Cmax (including Cmax) were not used.
  • a total of 4 ml of whole blood sample was collected via vena puncture into Vacutainer® tubes with K2-EDTA (BD product number 367861). Immediately after blood collection, the Vacutainer® blood collection tube was gently inverted 8 to 10 times to allow mixing with the anticoagulant. The blood samples were placed on ice during the processing. Each blood sample was centrifuged within 30 minutes of collection to separate the plasma.
  • the safety set which included subjects who received study drug and had at least one safety assessment post-baseline, was employed in the analysis of tolerability and safety variables.
  • Drug safety was evaluated by pre- and post-dose assessments including vital signs (blood pressure, respiratory rate, and heart rate), ECGs, clinical laboratory values (chemistry, hematology, urinalysis), physical examinations, and monitoring of adverse events (incidence, severity, relationship).
  • a follow-up visit occurred 7 days after the last clinic day.
  • TID dosing on 6-6-12 schedule exhibited 3 peaks over the course of 24 hours.
  • the typical individual PK profile clearly demonstrated 3 peaks that corresponded to the timing of vatiquinone administration during meals (breakfast, lunch, and dinner). The 3 peaks were consistently observed on both Day 1 and after multiple dosing on Day 6. Delayed absorption was observed after the first morning dose.
  • the mean PK profile at steady state (Day 6) suggested that all subjects exhibited multiple peaks over the 24 hour period.
  • the multiple peaks in mean PK concentration profile compared to the individual profile appeared flatter due to the variabilities in the timing of the 3 peaks.
  • Figs. 2A and 2B show vatiquinone plasma concentration profiles versus time profile following continuous TID dosing schedule.
  • Table 2 provides a summary of the mean (CV%) vatiquinone pharmacokinetic parameters following 7 days of continuous 200 or 400 mg 6-6- 12 TID dosing schedule.
  • vatiquinone was safe and well tolerated for all treatment groups.

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Abstract

La présente divulgation concerne de la vatiquinone destinée à être utilisée dans le traitement d'une maladie mitochondriale et d'autres troubles caractérisés par des niveaux élevés de stress oxydatif et de dérégulation du métabolisme énergétique, la vatiquinone étant administrée avec des aliments.
PCT/US2024/033847 2023-06-16 2024-06-13 Procédés pour augmenter l'exposition au plasma de vatiquinone avec des aliments Pending WO2024259130A1 (fr)

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WO2010126909A1 (fr) * 2009-04-28 2010-11-04 Edison Pharmaceuticals, Inc. Préparation de quinones de tocotriénol pour le traitement de maladies ophtalmiques
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WO2010126909A1 (fr) * 2009-04-28 2010-11-04 Edison Pharmaceuticals, Inc. Préparation de quinones de tocotriénol pour le traitement de maladies ophtalmiques
WO2013006736A1 (fr) * 2011-07-06 2013-01-10 Edison Pharmaceuticals, Inc Traitement du syndrome de leigh et du syndrome de type leigh, comprenant des complications de mutations de sucla2, par des tocotriénol quinones
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