WO2024259130A1

WO2024259130A1 - Methods for increasing vatiquinone plasma exposure with food

Info

Publication number: WO2024259130A1
Application number: PCT/US2024/033847
Authority: WO
Inventors: Lucy Lee; Martin J. Thoolen
Original assignee: PTC Therapeutics Inc
Current assignee: PTC Therapeutics Inc
Priority date: 2023-06-16
Filing date: 2024-06-13
Publication date: 2024-12-19
Anticipated expiration: 2025-12-16

Abstract

The present disclosure relates to vatiquinone for use in treating a mitochondrial disease and other disorders characterized by high levels of oxidative stress and dysregulation of energy metabolism, wherein vatiquinone is administered with food.

Description

METHODS FOR INCREASING VATIQUINONE PLASMA EXPOSURE WITH FOOD

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 63/508,545 filed on June 16, 2023, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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. 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).

In clinical studies, 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).

Clinically, 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).

As is known in the art, food can influence the absorption of compounds. Absorption may be delayed, but not reduced, or the total amount of the drug absorbed may be reduced. The food effect may be due to slowing gastric or anterior intestine residence time, decreasing access of the compound to absorption sites, altering the dissolution rate of the compound, or altering the pH of the stomach. Because of these effects, it is important that a specific dosage schedule be established for drugs that should be administered apart from meals or with food. Further research is necessary to optimize the dosing of vatiquinone and/or to improve patient convenience and compliance.

SUMMARY OF THE INVENTION

Without being bound by theory, vatiquinone, an oxidation product of vitamin E, 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.

Unexpected food effects 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. For example, 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.

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.

In some embodiments, food comprises a high fat meal, a low fat meal, or a liquid meal beverage. In an embodiment, food is a low fat meal. In other embodiments, food is a liquid meal beverage.

In some embodiments, 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.

Further features and advantages of the described methods and uses will become apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

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. DETAILED DESCRIPTION

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.

As used herein, common abbreviations are defined as follows:

AE: Adverse event

ANOVA: analysis of variance

ARAUC: area under the concentration-time curve

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

CI: Confidence interval

Cavg,24: average concentration over 24 hours

CL/F: total body clearance

Cmax: Maximum plasma concentration

Cmax,24: maximum concentration over 24 hours

CV: coefficient of variation

ECG: electrocardiogram

PK: Pharmacokinetics

QD: Once daily

RAAUC: accumulation ratio

SAD: Single ascending dose

SD: Standard deviation t1/2: Apparent plasma terminal elimination half life

TEAE: Treatment-emergent adverse event

TID: Three times Daily

Tmax: time to peak concentration

Tlag: time immediately prior to the first quantifiable concentration V/F: volume of distribution. In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and/or”; (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included.

As used herein, the term “administration” refers to the administration of a composition to a subject. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, 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.

As used herein, 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. In one embodiment, 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. In another embodiment, with food means that the dosage form is administered at substantially the same time as the eating the meal. In some embodiments, food is a solid food with sufficient bulk and fat content that it is not rapidly dissolved and absorbed in the stomach. Preferably, the food is a meal, such as breakfast, lunch, or dinner. In some embodiments, 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.

In some embodiments, food comprises a high fat meal, a low fat meal, or a liquid meal beverage. In an embodiment, food is a low fat meal. As used herein, the term “high fat meal” refers to a meal where fat accounts for 50% or more of the total calorie-content of the meal.

As used herein, the term “low fat meal” refers to a meal where fat accounts for about 25% to 49% of the total calorie-content of the meal.

In another embodiment, food is a liquid meal beverage. Commercially available examples of nutrition 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®, In some embodiments, 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. In an embodiment, food is PediaSure®.

The terms “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.

The term “oral dosage form,” as used herein, 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.

The term “food effect,” as used herein, 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. As used herein, the terms “with food” and “fed” can be used interchangeably. As used herein, 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.

The terms “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. In some embodiments, the suitable population may be defined as patients with renal impairment, patients with hepatic impairment, geriatrics, or pediatrics, etc. Various pharmacokinetic parameters are known to those skilled in the art, including area under the concentration vs. time curve (AUC), area under the concentration time curve from time zero until last quantifiable sample time (AUCo- t), area under the concentration time curve from time zero extrapolated to infinity (AUCo-∞), area under the concentration time curve over the steady state dosing interval (AUC_ss) or from time zero to twelve hours (AUC0-12) for twice-daily dosing, maximum concentration (e.g. blood plasma/serum) after administration (Cmax), minimum concentration (e.g. blood plasma/serum) after administration (Cmin), and time to reach maximum concentration (e.g. blood plasma/serum) after administration (Tmax). 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.

The terms “patient” or “subject” refers to a human subject.

As used herein, the act of “providing” includes supplying, acquiring, or administering (including self-administering) a composition described herein.

As used herein, the term “administering” a drug includes an individual obtaining and taking a drug on their own. For example, in some embodiments, an individual obtains a drug from a pharmacy and self-administers the drug in accordance with the methods provided herein.

In any of the embodiments described herein, methods of treatment can alternatively entail use claims, such as Swiss-type use claims. For example, 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.

In some embodiments, 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.

Those skilled in the art will understand that 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. For example, in some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, vatiquinone is administered at substantially the same time as the consumption of the food.

In some embodiments, the amount of vatiquinone can be administered in various amounts. Examples of 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, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight, or about 0.1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg total. In one embodiment, 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, In some embodiments, 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. In some embodiments of the methods described herein, vatiquinone is administered once daily. In some other embodiments, vatiquinone is administered two or more times daily. In one embodiment, vatiquinone is administered twice daily. In another embodiment, vatiquinone is administered three times daily. In some embodiments, each dose comprises one, two, three or more unit dosage forms. For example, in some embodiments, one or more units are administered to the subject one or more times per day. In some embodiments, vatiquinone is administered as multiple doses spaced throughout the day and each dose comprises a therapeutically effective amount of vatiquinone. In some embodiments, vatiquinone is administered with food three times per day. In another embodiment, vatiquinone is administered with food three times per day corresponding to the timing of breakfast, lunch, and dinner. In another embodiment, 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.

In some embodiments, 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. As used herein, the term “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. In some embodiments, the unit dosage form is, for example, a pill, capsule, or tablet. In one embodiment, the unit dosage form is a capsule.

In some embodiments, 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. As used herein, “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. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. In an embodiment, 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.

In some embodiments, the methods include administering a therapeutically acceptable amount of vatiquinone. The term “therapeutically effective amount” as used herein, 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. In some embodiments, 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.

In some embodiments of the methods described herein, food is selected from a high fat meal, a low fat meal, or a liquid meal beverage. In one embodiment, food is a low fat meal. In one embodiment, 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). In some embodiments, increasing the bioavailability of vatiquinone comprises increasing the maximal plasma concentration (Cmax) or the extent of absorption (AUC) of vatiquinone. In some such embodiments, 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. In one embodiment, the increase in Cmax of vatiquinone is about 3600%. In another embodiment, the increase in Cmax is about 400%.

In some such embodiments, 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. In one embodiment, the increase hr AUC of vatiquinone is about 2600%. In another embodiment, the increase in AUC is about 350%.

Pharmaceutical Compositions

Some embodiments include pharmaceutical 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.

In addition to the selected compound useful as described above, some embodiments include compositions containing a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term “compatible”, as used herein, 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. Some examples of 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, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen- free water; isotonic saline; and phosphate buffer solutions.

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. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modem Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

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.

The pharmaceutically-acceptable carriers suitable for tire preparation of unit dosage forms for peroral administration is well-known in the art. 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. 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. For a suspension, 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.

Such 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. Such 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.

It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the embodiments of the present invention disclosed herein are illustrative only and are not intended to limit the scope of the present invention. Any reference referred to herein is incorporated by reference for the material discussed herein, and in its entirety.

Equivalents and Scope

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

In addition, it is to be understood that 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.

EXAMPLES

Example 1

A Phase 1, Open- Label, Single Dose, 3 -Way Crossover Study to Determine Pharmacokinetics and Food Effects of EPI-743 Administered to Normal Healthy Volunteers (GCP)

Study Design

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.

Pharmacokinetic Sample Collection and NCA Pharmacokinetic Analysis

Blood samples for vatiquinone PK analysis were taken on Day 1 and 6 for both treatment groups (fasted, PediaSure®, low-fat meal). The collection timepoints were 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours. Subjects completing at least one period of the study and included in the analysis. 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 (λz); 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.

Bioanalytical Methods

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.

Safety Assessments

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.

Results

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.

Following a single 300 mg dose, vatiquinone absorption was rapid with a median tmax of 4-5 hrs regardless of meal status. The ti/2 also appeared similar between all treatment groups. However, vatiquinone drug exposures were significantly enhanced when taken with meals, either low-fat meals or PediaSure®. Relative to fasted state, mean vatiquinone Cmax and AUC were 36-fold and 22-fold higher, respectively, in subjects who consumed low-fat meals. With low-fat meals, the inter-subject variabilities appeared lower for AUC. Relative to fasted state, mean vatiquinone Cmax and AUC were 4.1 -fold and 3 -fold higher, respectively, in subjects who consumed PediaSure®. The results are summarized in Table 1:

Table 1

Parameters Fasted PediaSure® Low-Fat Meal

Cmax, ng/mL 7.65 (102) 31.2 (74) 274 (150)

Tmax, h 4 (2, 12) 5 (2, 8) 4 (2.11, 40)

AUC0-48, h.ng/mL 46.8 (97) 161 (171) 1200 (70)

Terminal T1/2, h 11.5 (10) 13 (54) 13.3 (23)

CL/F, L/h/kg 515 (16) 304 (84) 95.5 (60)

V/F, L/kg 31.6 (26) 15.8 (79) 5.29 (87)

Safety Evaluation

Overall, 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). In the PediaSure® group, 5 subjects (27.8%) reported at least one TEAE. In the 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.

Example 2

A Phase 1, Open-Label, Two-Part Study To Investigate the Pharmacokinetics of Vatiquinone and the Absorption, Metabolism, and Excretion of Vatiquinone

Part 1 - Multiple Dose of 200 and 400 mg Vatiquinone TID, (Days 1 to 6)

Part 2 - Absorption, Metabolism, and Excretion Following a Single Oral Dose of Vatiquinone at Steady State (Day 7)

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.

Study Design

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. 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.

Pharmacokinetic Sample Collection and NCA Pharmacokinetic Analysis

Blood samples for vatiquinone PK analysis were taken on Day 1 for both treatment groups (200 mg, 400 mg). The collection timepoints were 0 (predose), 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13. 14, 15, and 24 hours post dose that were taken over the course of day. 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 (λz); 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.

Bioanalytical Methods

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.

Safety Assessments

Results

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.

Vatiquinone exposures, AUC, Cavg, and Cmax, appeared to increase from 200 to 400 mg in a proportional manner. The exposure variabilities were moderate, ranging from approximately 35% to 65%. Mean Day 6 ARAUC suggested an accumulation ratio of 1.61 and 1.73, for 200 mg and 400 mg, respectively. 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.

Safety Evaluation

Overall, vatiquinone was safe and well tolerated for all treatment groups. A total of 6 subjects experienced 17 TEAEs. There were 2 subjects in the 200 mg dose group and 4 subjects in the 400-mg dose group. There were no serious TEAEs or TEAEs leading to discontinuation or death in this study. All TEAEs were mild in severity. There were no clinically meaningfill trends observed in hematology parameters, biochemistry parameters, 12-lead ECG, vital signs, physical findings, and other observations related to safety.

OTHER EMBODIMENTS It is to be understood that while the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and alterations are within the scope of the followinng claims.

Claims

What is claimed: CLAIMS

1. A method of treating a mitochondrial disease and other disorders characterized by high levels of oxidative stress and dysregulation of energy metabolism in a subject in need thereof, the method comprising administering to the subject an effective amount of vatiquinone with food.

2. A method of increasing vatiquinone plasma exposure in a subject receiving vatiquinone therapy comprising administering to the subject an effective amount of vatiquinone with food.

3. A method of increasing drug bioavailability in a subject receiving vatiquinone therapy comprising administering to the subject an 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.

4. The method of any one of claims 1 to 3, wherein food comprises a high fat meal, a low fat meal, or a liquid meal beverage.

5. The method of claim 5, wherein food is a low fat meal.

6. The method of any one of claims 1 to 3, wherein the effective amount is 0.1 mg/kg to about 300 mg/kg body weight per dose.

7. The method of any one of claims 1 to 3, wherein the administration to the subject occurs between about 30 minutes prior to about 2 hours after eating a meal.

8. The method of claim 7, wherein the effective amount is administered three times a day at breakfast, lunch, and dinner.

9. The method of claim 3, wherein increasing said bioavailability comprises increasing the maximal plasma concentration (Cmax) and/or the extent of absorption (AUC) of vatiquinone.

10. The method of claim 3, wherein said increase in bioavailability comprises one or more of:

(i) an increase in Cmax in the range of about 10% to about 4000% for vatiquinone when taken with food compared to the same amount of vatiquinone taken during a fasted condition; and

(ii) an increase in AUC in the range of about 10% to about 3000% for vatiquinone when taken with food compared to the same amount of vatiquinone taken during a fasted condition.

11. The method of any one of claim 1 to 3, wherein the disease or disorder is 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.