EP4618986A1 - A novel dosage regimen using low doses of donepezil or derivative thereof for preventing or treating a compulsive disorder - Google Patents

A novel dosage regimen using low doses of donepezil or derivative thereof for preventing or treating a compulsive disorder

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Publication number
EP4618986A1
EP4618986A1 EP23808803.3A EP23808803A EP4618986A1 EP 4618986 A1 EP4618986 A1 EP 4618986A1 EP 23808803 A EP23808803 A EP 23808803A EP 4618986 A1 EP4618986 A1 EP 4618986A1
Authority
EP
European Patent Office
Prior art keywords
compound
donepezil
formula
treatment
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23808803.3A
Other languages
German (de)
French (fr)
Inventor
Salah El Mestikawy
Nicolas PIETRANCOSTA
Leora PINHAS
Philibert DURIEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universite De Mcgill
Centre National de la Recherche Scientifique CNRS
Sorbonne Universite
Ecole Normale Superieure de Paris
Original Assignee
Universite De Mcgill
Centre National de la Recherche Scientifique CNRS
Sorbonne Universite
Ecole Normale Superieure de Paris
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universite De Mcgill, Centre National de la Recherche Scientifique CNRS, Sorbonne Universite, Ecole Normale Superieure de Paris filed Critical Universite De Mcgill
Publication of EP4618986A1 publication Critical patent/EP4618986A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a donepezil and derivative thereof new daily low dosage regimens for the prevention and/or the treatment of a compulsive disorder, notably an eating disorder.
  • Acetylcholine (ACh) is a major neuromodulator of the striatal network and the key transmitter at the neuromuscular junction. After its exocytotic release, the action of ACh is rapidly stopped by its hydrolysis catalyzed by an enzyme named acetylcholinesterase (ACh E). AChE inhibitors (ACh El ) inhibit this reaction and prevent the breaking down of ACh into choline and acetate. Thereby, AChEI increase the extracellular levels and duration of action of ACh both in the central nervous system and at the neuromuscular junction.
  • striatal ACh also plays a major role in eating disorders (Favier, et al., The Journal of Clinical Investigation, 2020, 130, 12, pp 6616-6630).
  • Eating disorders such as anorexia nervosa and bulimia nervosa, in fully syndromic and subthreshold forms, affect up to 10% of the population.
  • the understanding of the neuronal basis of anorexia nervosa is currently very limited and consequently there are no specific biological treatment for this dramatic condition to date.
  • cholinergic interneurons are pivotal regulators of the striatum and of habits formation.
  • ACh activity-based anorexia model
  • mutant mice lacking ACh in the striatum were more prone to self-starvation than control mice.
  • acetylcholinesterase inhibitors could be useful in preventing and/or treating a compulsive disorder, in particular an eating disorder such as anorexia.
  • Donepezil is a reversible and selective inhibitor of AChE. It is an off-label compound produced by pharmaceutical companies Eisai and Pfizer under the trade name Aricept. Aricept has been massively used to treat Alzheimer disease at a dose of 5-10mg/day. However, the efficiency of this treatment is not clearly established and severe side effects have been reported upon the use of Aricept in Alzheimer's treatment over the years (dizziness, nausea, vomiting, heart troubles, etc, see Dunn N.R. et al. Journal of Psychopharmacology, 2000, 14(4), p.406-408 ).
  • acetylcholinesterase inhibitor i.e. donepezil or a derivative thereof, could be used for effectively preventing and/or treating a compulsive disorder, in particular an eating disorder, at doses 4 to 10 times lower than those described for the treatment of Alzheimer's disease, without causing any severe side effect.
  • the present invention relates to a compound of the following formula (I) : wherein X is an oxygen atom or a group N-OH, or a pharmaceutically acceptable salt and/or solvate thereof for use in preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject in need thereof, characterized in that the compound of formula (I) is administered to the subject at a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
  • a compulsive disorder notably an eating disorder, in particular anorexia
  • the present invention also relates to a method for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject in need thereof, comprising administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compulsive disorder notably an eating disorder, in particular anorexia
  • the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for the preparation of a medicament for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject by administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of the compound of formula (I) or the pharmaceutically acceptable salt and/or solvate thereof.
  • a compulsive disorder notably an eating disorder, in particular anorexia
  • the present invention relates to a unit dosage form comprising from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • stereoisomers used in this invention refers to configurational stereoisomers and more particularly to optical isomers. Optical isomersthat are not mirror images of one another are thus designated as “diastereoisomers”, and optical isomers, which are non- superimposable mirror images are designated as "enantiomers”. An equimolar mixture of two enantiomers of a chiral compound is designated as a racemic mixture or racemate.
  • the term "pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • pharmaceutically acceptable salt and/or solvate is intended to mean, in the framework of the present invention, a salt and/or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • the pharmaceutically acceptable salts comprise:
  • acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2- hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2- naphtalenesulfonic, propionic, succinic, dibenzoyl-L25 tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Acceptable solvates forthe therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents.
  • solvates due to the presence of water these solvates are also called hydrates
  • ethanol ethanol
  • composition in the framework of the present invention a composition having preventive and curative properties.
  • treatment adherence is understood as the extent to which a patient's behavior corresponds with the prescribed treatment, i.e. the prescribed dose regimen, including time, dosing and interval of medication intake.
  • BMI Body Mass Index
  • the compound of formula (I) for use according to the present invention can be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, diastereoisomers or tautomers, notably a racemic mixture.
  • the compound of formula (I) for use according to the present invention corresponds to the compound of formula (l-A), i.e. the donepezil:
  • the compound of formula (I) for use according to the present invention corresponds to the compound of formula (l-B) :
  • the compound of formula (I) is the donepezil.
  • compounds of formula IA and IB are in the form of hydrochloride salt.
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as described herein is used in a daily dosage of from 0.25mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, to prevent and/or treat a compulsive disorder.
  • Compulsive disorder(s) includes, without being limited to, to addiction, obsessive- compulsive disorder(s), eating disorder(s), and related behaviours thereof, in particular eating disorder(s).
  • eating disorder(s) includes, without being limited to, anorexia nervosa, bulimia nervosa and obesity.
  • anorexia in the present disclosure only refers to “anorexia nervosa”. Medical anorexia in which the patient is unable to eat due to digestive pathologies is not covered by the present invention.
  • DSM-5 Diagnostic and statistical manual of mental disorders
  • Anorexia nervosa includes two main subtypes: restricting-type and binge-eating/purging type.
  • the restricting-type (AN-R) is dominated by dieting, fasting and/or excessive exercise.
  • the binge-eating purging type includes recurrent episodes of binge eating (ie eating large amounts of food in a discrete period of time when not feeling physically hungry with a sense of lack of control) and/or with purging behavior (ie self-induced vomiting, or the misuse of laxatives, diuretics or enemas).
  • the diagnostic criteria for bulimia in the DSM are: recurrent episodes of binge eating with a sense of lack of control occurring at least twice per week for at least three months, recurrent, inappropriate compensatory behavior, such as vomiting, in orderto prevent weight gain and and self-evaluation that is unduly influenced by body shape and weight.
  • the compulsive disorder to be treated in the context of the present invention is anorexia.
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a daily dosage regimen at an amount ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
  • a compulsive disorder notably an eating disorder, in particular anorexia
  • a daily dosage regimen at an amount ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
  • the subject in need thereof according to the present invention is a mammal, notably a human.
  • the subject in need thereof is notably a human having a very restrictive eating pattern, generally leading to significant weight loss, having extreme weight control (by practicing a lot of sport, by making himself vomit, etc.), and having an erroneous perception of one's weight by always considering oneself too fat.
  • the subject in need thereof suffering of anorexia typically has a Body Mass Index (BMI) of less than 17,5 kg/m 2 .
  • BMI Body Mass Index
  • the BMI is notably comprised between 15 and 17 kg/m 2 and in subjects suffering from extreme anorexia, the BMI is less than 15 kg/m 2 .
  • the "therapeutically effective amount”, “therapeutically effective dose” or “effective amount” refers to an amount of compound of formula (I) that is effective to cause a measurable improvement in one or more symptoms of the compulsive disorder to be treated.
  • a therapeutically effective dose further refers to that amount of the compound of formula (I) sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • the improvement in the symptoms typically results in a gain in body mass, a reduced need to control weight and eat, a decrease of compulsive behaviors, notably eating compulsive behaviors, as measured by the "obsessive- compulsive test Yale Brown OCD Scale (YBOCS), questionnaire for eating disorder diagnosis (Q.-EED) and eating disorder inventory 2 (EDI).
  • the improvement in the symptoms results in a return to the baseline body weight of the subject, i.e. the subject's health weight, and notably to an increase of the BMI, notably beyond 17.5 kg/m 2 , preferably beyond 18.5 kg/m 2 , more preferably beyond 19 and less than 23 kg/m 2 .
  • the present invention relates to compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use for improving the BMI, in particular to reach a BMI of at least 17.5 kg/m 2 , preferably 18.5 kg/m 2 , more preferably comprised between 19 kg/m 2 and 23 kg/m 2 , characterized in that the compound of formula (I) or the pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need in a daily dosage regimen at an amount ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
  • the present invention relates to a method for improving BMI in a subject in need thereof, in particular to reach a BMI of at least 17.5 kg/m 2 , preferably 18.5 kg/m 2 , more preferably comprised between 19 kg/m 2 and 23 kg/m 2 , comprising administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • the daily dose of compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof ranges from 0.25 mg to 2 mg, preferably from 0.5 mg to 2.5 mg, more preferably from 0.5 mg to 1.5 mg.
  • the compound of formula (I) advantageously may be administered to a subject in need thereof for preventing and/or treating a compulsive disorder in a daily dosage regimen at an amount ranging from 0.5 mg to 2 mg, more preferably from 0.5 mg to 1.5 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be administered to a subject in need thereof in one or more administrations per day, for example in one, two, three or four administrations per day. In case of several administrations per day, the daily dose is divided so that the dose administered to the subject at each administration is either identical or different. Advantageously, the daily dose is administered at once.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is typically administered to a subject in need thereof for the time necessary to assess of a measurable improvement in one or more symptoms of the compulsive disorderto be treated or to assess of at least partial amelioration of symptoms of the compulsive disorder.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is typically administered to a subject in need thereof for the time necessary to asses a gain in body mass, a reduced need to control weight and eat, a decrease in compulsive eating behaviors and in particular an increase of the BMI, preferably to obtain a BMI of at least 17.5 kg/m 2 , preferably 18.5 kg/m 2 , more preferably comprised between 19 kg/m 2 and 23 kg/m 2 .
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be identical for the duration of the treatment, or it may increase or decrease over the day, provided that it remains in the range from 0.25 mg to 2.5 mg.
  • the daily dose starts at 0.25 mg or 0.5 mg at the beginning of the treatment.
  • symptoms of patients are re-evaluated regularly over the time period of the treatment, for example, each week, and the daily dose is adjusted depending on the evolution of symptoms. If needed, the daily dose is thus increased in 0.25 mg or 0.5 mg increments, provided that it remains in the range from 0.25 mg to 2.5 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof at a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg for a time of at least one month, preferably at least two months, preferably at least five months, more preferably for a time of between 1 months and one year, and notably for a time of between two months and six months.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be administered to a subject in need thereof by oral or parenteral (including but not limited to subcutaneous, intramuscular, intravenous), ocular, intravitreal, topical, sublingual administration, preferably by oral administration.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention for use in preventing and/or treating a compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I) as active ingredient and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, at a dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, and a pharmaceutically acceptable excipient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers.
  • the pharmaceutical composition can be in a solid or liquid (solution or suspension) dosage form.
  • a solid dosage form can be in the form of tablets, gelatin capsules, powders, granules and the like.
  • the active ingredient can be mixed with pharmaceutical vehicle(s) such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like before being compressed.
  • the tablets may be further coated, notably with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity.
  • the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with flavor correctors or sweeteners.
  • gelatin capsules the active ingredient can be introduced into soft or hard gelatin capsules in the form of a powder or granules such as mentioned previously or in the form of a liquid dosage form such as mentioned below.
  • a liquid dosage form can contain the active ingredient together with a sweetener, a taste enhancer or a suitable coloring agent in a solvent such as water.
  • the liquid dosage form can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It can be for example an emulsion, a suspension, a syrup or an elixir.
  • the composition can be in the form of an aqueous suspension or solution which may contain suspending agents and/or wetting agents.
  • the composition is advantageously sterile. It can be in the form of an isotonic solution (in particular in comparison to blood).
  • Solid and liquid dosage forms can be formulated so that they conform to a desired release profile, e.g. immediate release, delayed release and extended or sustained release.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is preferably administered to a subject in need thereof in a dosage unit form, notably an oral dosage unit form, in particular an oral solid dosage unit form such as a tablet.
  • the pharmaceutical composition of the invention comprising the compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, at a dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, and a pharmaceutically acceptable excipient, further comprises one or more other acetylcholinesterase inhibitors such as galantamine or rivastigmine.
  • the one or more acetylcholinesterase inhibitors are present in the pharmaceutical composition preferably at a lower dose than those already described.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention for use in preventing and/or treating a compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I), one or more other acetylcholinesterase inhibitors and a pharmaceutically acceptable excipient.
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof for preventing and/or treating specifically obsessive-compulsive disorder in a daily dosage regimen at an amount ranging from 0.25 mg to 10 mg, or from 0.5 mg to 10 mg, or from 0.5 mg to 5 mg, or from 2.5 mg to lOmg, or from 5 mg to 10 mg, preferably from 0.5 mg to 2.5 mg.
  • the present invention relates to a unit dosage form comprising from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound offormula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • the unit dosage form of the invention is an oral unit dosage form.
  • the unit dosage form of the invention is a solid unit dosage form.
  • the present invention relates to the unit dosage form of the present invention for its use as a drug, in particular for preventing and/or treating a compulsive disorder, such as an eating disorder, notably anorexia.
  • a compulsive disorder such as an eating disorder, notably anorexia.
  • the unit dosage form of the present invention is used once a day as a drug, in particular for preventing and/or treating a compulsive disorder, such as an eating disorder, notably anorexia.
  • a compulsive disorder such as an eating disorder, notably anorexia.
  • the present invention relates to a method for preventing and or treating a compulsive disorder, notably an eating disorder, such as anorexia, comprising the administration once a day of the unit dosage form of the invention to a subject in need thereof.
  • a compulsive disorder notably an eating disorder, such as anorexia
  • Patient #1 is a 35-year-old woman with a 21-years history of anorexia nervosa restricting type. She went into remission in late adolescence and remained well for about 4-5 yrs. However, she continued to struggle with the behavioral aspects of the disorder and cognitive ruminations that are pathognomonic of the illness. She was very restricted in her eating, in terms of restricting caloric intake and avoiding foods that were high in sugar, carbohydrates or fats. She also exercised for minimum an hour a day and struggled to allow herself to rest or sit down. She also endorsed significant body image dissatisfaction, weight and shape concerns and eating disorder cognitions and ruminations.
  • Patient #2 is a 21-year-old woman who developed anorexia nervosa restricting type in adolescence. She was very restricted in the types of food she ate and could not eat food that was processed or high in sugar or fats. She exercised 3-4 hours a day. She was unable to reduce her exercising even minimally with becoming flooded with debilitating anxiety. She was unable to eat enough to maintain a healthy weight. Her BMI was 18.5 kg/m2 and was medically stable when she started donepezil.
  • the treatment started with a daily dose of donepezil of 0.5 mg for 10 days then the daily dose was increased to 1 mg for 7 days then increased to 1.5mg for 71 days (2 months and 10 days) then increased to 2 mg for 22 days and then increased to 2.5 mg and remains on this dose for 4 months and 18 days.
  • GID-7 Generalized Anxiety Disorders Assessment
  • the score obtained with questionary GAD-7 is classified as follows: 5-9 : mild anxiety; 10-14 : moderate anxiety; 15-21: severe anxiety A diminution of her anxiety was thus also observed for patient #2 further to the treatment with donepezil.
  • Patient #2 depression symptoms have also been evaluated with Patient Health Questionnaire (PHQ-9) (available on https://med.stanford.edu/fastlab/research/imapp/msrs/Jcr_content/main/accordion/accor dion_content3/download_256324296/file.res/PHQ9%20id%20date%2008.03.pdf) before and after the treatment.
  • PHQ-9 Patient Health Questionnaire
  • OCD obsessive-compulsive disorders
  • the score obtained with questionnaire Y-BOCS is classified as follows :
  • Patient #3 is a 36-year-old woman with a 2O-year history of anorexia nervosa binge/purge type who had been in recovery for two years before relapsing following a relationship trauma. She was slowly losing weight and was bingeing and purging multiple times every evening. She also was waking up every morning at 4am to exercise obsessively for hours. She was spending all her disposable income on binge foods and was slowly draining her savings. At times she was stealing food to binge on.
  • the treatment started with a daily dose of donepezil of 0.5 mg for 10 days and then the daily dose was increased to 1 mg for 9 days and then increased to 1.5 mg for 17 days and then increased to 2 mg for 7 days and then increased to 2.5 mg for 16 days and then discontinued.
  • Patient#4 is a 19-year-old girl with a 10-year history of anorexia nervosa restricting type who was struggling to gain weight. She did not over exercise but severely restricted her intake. She was struggling to gain weight and had struggled with significant body image distortion and eating disorder cognitions and ruminations. She felt that she was already too heavy despite having a BMI below 15 kg/m2. She had managed to gain weight over the course of a year and her BMI went from a low of 11 kg/m2 to 15 kg/m2. However, she was unable to gain weight during subsequent 7 months and her BMI plateaued.
  • Patient #4 was treated with donepezil with the protocol as follow: The treatment started with a daily dose of donepezil of 0.5 mg for 13 days then the daily dose was increased to 0.75 mg for 9 days then increased to 1 mg for 17 days and then increased to 1.5 mg and remained at this dosage for a month then stopped for two months and then restarted with a daily dose of 1.5 mg that remains within 1 month and then discontinued.
  • Eating Disorder Examination Questionnaire (EDE-q) (available on https://www.corc.uk.net/outcome-experience-measures/eating-disorder-examination- questionnaire-ede-q/) which has given the following results:
  • a score of 4 or greater is indicative of the clinical range, while a score greater than 2.8 is indicative of possible clinically significant pathology (Jennings KM, Phillips KE. Arch Psychiatr Nurs. 2017 (6):578- 581. doi: 10.1016/j.apnu.2017.08.002; and Velkoff EA,et al. Eat Disord. 2023 ;31(5):464-478. doi: 10.1080/10640266.2023.2191488). Results on anxiety
  • the score obtained with questionnaire GAD-7 is classified as follows:
  • OCD obsessive-compulsive disorders
  • the score obtained with questionnaire Y-BOCS is classified as follows: 0-7 subclinical ; 8-15 : mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms
  • Donepezil was taken at a rate of 2.5 mg per day for 2 months.
  • the patient #5 began to eat more easily, she set up daily lunches with relatives and managed to go from 27 kg to 36 kg in 3 months.
  • Patient #6 was treated with donepezil with the protocol as follow:
  • the treatment started with a daily dose of donepezil of 0.5 mg for 8 days and then the daily dose was increased to 1 mg for 9 days and then increased to 1.67 mg for 62 days and then increased to 2.5 mg.
  • a score of 4 or greater is indicative of the clinical range, while a score greater than 2.8 is indicative of possible clinically significant pathology.
  • the score obtained with questionnaire GAD-7 is classified as follows: 5-9: mild anxiety; 10-14: moderate anxiety; 15-21: severe anxiety
  • OCD obsessive-compulsive disorders
  • the score obtained with questionnaire Y-BOCS is classified as follows:
  • Patienttl treated with 5mg PO OD experienced severe side effect (high blood pressure and severe headache). Other patients were treated with lower doses (0.5-2.5mg PO OD) and were improved without severe side effects.

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Abstract

The present invention relates to a donepezil and a derivative or a pharmaceutically acceptable salt and/or solvate thereof new daily low dosage regimens for the prevention and/or the treatment of a compulsive disorder, notably an eating disorder. The present invention also relates to a unit dosage form comprising from 0.25 mg to 2.5 mg of donepezil, a derivative or a pharmaceutically acceptable salt and/or solvate thereof, in particular for use in the prevention and/or the treatment of a compulsive disorder, notably an eating disorder.

Description

A novel dosage regimen using low doses of donepezil or derivative thereof for preventing or treating a compulsive disorder
Field of the invention
The present invention relates to a donepezil and derivative thereof new daily low dosage regimens for the prevention and/or the treatment of a compulsive disorder, notably an eating disorder.
Background of the invention
Acetylcholine (ACh) is a major neuromodulator of the striatal network and the key transmitter at the neuromuscular junction. After its exocytotic release, the action of ACh is rapidly stopped by its hydrolysis catalyzed by an enzyme named acetylcholinesterase (ACh E). AChE inhibitors (ACh El ) inhibit this reaction and prevent the breaking down of ACh into choline and acetate. Thereby, AChEI increase the extracellular levels and duration of action of ACh both in the central nervous system and at the neuromuscular junction.
The inventors have recently discovered that striatal ACh also plays a major role in eating disorders (Favier, et al., The Journal of Clinical Investigation, 2020, 130, 12, pp 6616-6630).
Eating disorders such as anorexia nervosa and bulimia nervosa, in fully syndromic and subthreshold forms, affect up to 10% of the population. Anorexia nervosa has the highest mortality rates of all mental-health diseases (= 5% per decade). However, the understanding of the neuronal basis of anorexia nervosa is currently very limited and consequently there are no specific biological treatment for this dramatic condition to date.
The inventors demonstrated that cholinergic interneurons are pivotal regulators of the striatum and of habits formation. To investigate the role of ACh in habitual behaviors, the inventors have specifically silenced ACh signaling in the striatum in a mouse model and then established that decreased ACh transmission makes mice more prone to excessive habits. To understand if these excessive habits could lead to dysfunctional eating, the inventors then used a model of pathological eating in a second rodent model: the activity-based anorexia model (ABA, a model of anorexia nervosa (Klenotich and Dulawa, 2012)). In the ABA model, mutant mice lacking ACh in the striatum were more prone to self-starvation than control mice. On the basis of these unexpected findings, the inventors have postulated that acetylcholinesterase inhibitors could be useful in preventing and/or treating a compulsive disorder, in particular an eating disorder such as anorexia.
Donepezil is a reversible and selective inhibitor of AChE. It is an off-label compound produced by pharmaceutical companies Eisai and Pfizer under the trade name Aricept. Aricept has been massively used to treat Alzheimer disease at a dose of 5-10mg/day. However, the efficiency of this treatment is not clearly established and severe side effects have been reported upon the use of Aricept in Alzheimer's treatment over the years (dizziness, nausea, vomiting, heart troubles, etc, see Dunn N.R. et al. Journal of Psychopharmacology, 2000, 14(4), p.406-408 ).
There is thus a need for an effective treatment of a compulsive disorder, in particular an eating disorder, with limited to no side effects, notably peripheral side effects, and improved treatment adherence.
Summary of the invention
In this context, the inventors have surprisingly discovered that a well-known and already available acetylcholinesterase inhibitor, i.e. donepezil or a derivative thereof, could be used for effectively preventing and/or treating a compulsive disorder, in particular an eating disorder, at doses 4 to 10 times lower than those described for the treatment of Alzheimer's disease, without causing any severe side effect.
According to a first aspect, the present invention relates to a compound of the following formula (I) : wherein X is an oxygen atom or a group N-OH, or a pharmaceutically acceptable salt and/or solvate thereof for use in preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject in need thereof, characterized in that the compound of formula (I) is administered to the subject at a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
The present invention also relates to a method for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject in need thereof, comprising administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for the preparation of a medicament for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a subject by administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of the compound of formula (I) or the pharmaceutically acceptable salt and/or solvate thereof.
According to another aspect, the present invention relates to a unit dosage form comprising from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
Detailed description
Definitions
The term "stereoisomers" used in this invention refers to configurational stereoisomers and more particularly to optical isomers. Optical isomersthat are not mirror images of one another are thus designated as "diastereoisomers", and optical isomers, which are non- superimposable mirror images are designated as "enantiomers". An equimolar mixture of two enantiomers of a chiral compound is designated as a racemic mixture or racemate.
Forthe purpose of the invention, the term "pharmaceutically acceptable" is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
The term "pharmaceutically acceptable salt and/or solvate" is intended to mean, in the framework of the present invention, a salt and/or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
The pharmaceutically acceptable salts comprise:
(1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2- hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2- naphtalenesulfonic, propionic, succinic, dibenzoyl-L25 tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
(2) base addition salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Acceptable solvates forthe therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or ethanol.
The term "pharmaceutical composition" is meant in the framework of the present invention a composition having preventive and curative properties.
The term "treatment adherence", as used in the present invention, is understood as the extent to which a patient's behavior corresponds with the prescribed treatment, i.e. the prescribed dose regimen, including time, dosing and interval of medication intake.
The term "Body Mass Index" (BMI) is calculated by dividing the body mass of an individual (in kg) by his height (in m2). The BMI is generally used to evaluate if an individual suffers from under nutrition or on the contrary if he/she suffers from overweight or obesity.
Compound of formula (I) The compound of formula (I) for use according to the present invention can be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, diastereoisomers or tautomers, notably a racemic mixture.
When X is an oxygen atom, the compound of formula (I) for use according to the present invention corresponds to the compound of formula (l-A), i.e. the donepezil:
When X is a group N-OH, the compound of formula (I) for use according to the present invention corresponds to the compound of formula (l-B) :
According to a preferred embodiment, the compound of formula (I) is the donepezil. According to a preferred embodiment, compounds of formula IA and IB are in the form of hydrochloride salt.
Compulsive disorders
The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as described herein is used in a daily dosage of from 0.25mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, to prevent and/or treat a compulsive disorder.
The term "compulsive disorder(s)" includes, without being limited to, to addiction, obsessive- compulsive disorder(s), eating disorder(s), and related behaviours thereof, in particular eating disorder(s). The term "eating disorder(s)" includes, without being limited to, anorexia nervosa, bulimia nervosa and obesity. The terms "anorexia" in the present disclosure only refers to "anorexia nervosa". Medical anorexia in which the patient is unable to eat due to digestive pathologies is not covered by the present invention.
According to the fifth edition of the Diagnostic and statistical manual of mental disorders (DSM-5), to be diagnosed with anorexia nervosa the following criteria must be met:
Restriction of energy intake relative to requirements leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health;
Disturbed perception of one's body weight or shape, undue influence of weight or shape on self-evaluation, or denial of the seriousness of the current low body weight.
Anorexia nervosa (AN) includes two main subtypes: restricting-type and binge-eating/purging type. The restricting-type (AN-R) is dominated by dieting, fasting and/or excessive exercise. The binge-eating purging type (AN-BP) includes recurrent episodes of binge eating (ie eating large amounts of food in a discrete period of time when not feeling physically hungry with a sense of lack of control) and/or with purging behavior (ie self-induced vomiting, or the misuse of laxatives, diuretics or enemas).
The diagnostic criteria for bulimia in the DSM are: recurrent episodes of binge eating with a sense of lack of control occurring at least twice per week for at least three months, recurrent, inappropriate compensatory behavior, such as vomiting, in orderto prevent weight gain and and self-evaluation that is unduly influenced by body shape and weight.
According to a preferred embodiment, the compulsive disorder to be treated in the context of the present invention is anorexia.
Dosage regimens
In the present invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof for preventing and/or treating a compulsive disorder, notably an eating disorder, in particular anorexia, in a daily dosage regimen at an amount ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg. The subject in need thereof according to the present invention is a mammal, notably a human. In the context of anorexia, the subject in need thereof is notably a human having a very restrictive eating pattern, generally leading to significant weight loss, having extreme weight control (by practicing a lot of sport, by making himself vomit, etc.), and having an erroneous perception of one's weight by always considering oneself too fat. In particular, the subject in need thereof suffering of anorexia typically has a Body Mass Index (BMI) of less than 17,5 kg/m2. In subjects suffering from severe anorexia, the BMI is notably comprised between 15 and 17 kg/m2 and in subjects suffering from extreme anorexia, the BMI is less than 15 kg/m2.
The daily dose of compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, corresponds to the therapeutically effective amount. The "therapeutically effective amount", "therapeutically effective dose" or "effective amount" refers to an amount of compound of formula (I) that is effective to cause a measurable improvement in one or more symptoms of the compulsive disorder to be treated. A therapeutically effective dose further refers to that amount of the compound of formula (I) sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
In the context of the treatment of anorexia, the improvement in the symptoms typically results in a gain in body mass, a reduced need to control weight and eat, a decrease of compulsive behaviors, notably eating compulsive behaviors, as measured by the "obsessive- compulsive test Yale Brown OCD Scale (YBOCS), questionnaire for eating disorder diagnosis (Q.-EED) and eating disorder inventory 2 (EDI). In particular, the improvement in the symptoms results in a return to the baseline body weight of the subject, i.e. the subject's health weight, and notably to an increase of the BMI, notably beyond 17.5 kg/m2, preferably beyond 18.5 kg/m2, more preferably beyond 19 and less than 23 kg/m2.
In a particular aspect, the present invention relates to compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use for improving the BMI, in particular to reach a BMI of at least 17.5 kg/m2, preferably 18.5 kg/m2, more preferably comprised between 19 kg/m2 and 23 kg/m2, characterized in that the compound of formula (I) or the pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need in a daily dosage regimen at an amount ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg.
In other words, the present invention relates to a method for improving BMI in a subject in need thereof, in particular to reach a BMI of at least 17.5 kg/m2, preferably 18.5 kg/m2, more preferably comprised between 19 kg/m2 and 23 kg/m2, comprising administering to the subject a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
In some embodiments, the daily dose of compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof ranges from 0.25 mg to 2 mg, preferably from 0.5 mg to 2.5 mg, more preferably from 0.5 mg to 1.5 mg. In other words, the compound of formula (I) advantageously may be administered to a subject in need thereof for preventing and/or treating a compulsive disorder in a daily dosage regimen at an amount ranging from 0.5 mg to 2 mg, more preferably from 0.5 mg to 1.5 mg.
The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be administered to a subject in need thereof in one or more administrations per day, for example in one, two, three or four administrations per day. In case of several administrations per day, the daily dose is divided so that the dose administered to the subject at each administration is either identical or different. Advantageously, the daily dose is administered at once.
The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is typically administered to a subject in need thereof for the time necessary to assess of a measurable improvement in one or more symptoms of the compulsive disorderto be treated or to assess of at least partial amelioration of symptoms of the compulsive disorder. In the context of the prevention and/or the treatment of anorexia, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is typically administered to a subject in need thereof for the time necessary to asses a gain in body mass, a reduced need to control weight and eat, a decrease in compulsive eating behaviors and in particular an increase of the BMI, preferably to obtain a BMI of at least 17.5 kg/m2, preferably 18.5 kg/m2, more preferably comprised between 19 kg/m2 and 23 kg/m2. The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be identical for the duration of the treatment, or it may increase or decrease over the day, provided that it remains in the range from 0.25 mg to 2.5 mg. According to some embodiments, the daily dose starts at 0.25 mg or 0.5 mg at the beginning of the treatment. Then, symptoms of patients are re-evaluated regularly over the time period of the treatment, for example, each week, and the daily dose is adjusted depending on the evolution of symptoms. If needed, the daily dose is thus increased in 0.25 mg or 0.5 mg increments, provided that it remains in the range from 0.25 mg to 2.5 mg.
According to some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof at a daily dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg for a time of at least one month, preferably at least two months, preferably at least five months, more preferably for a time of between 1 months and one year, and notably for a time of between two months and six months.
The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention may be administered to a subject in need thereof by oral or parenteral (including but not limited to subcutaneous, intramuscular, intravenous), ocular, intravitreal, topical, sublingual administration, preferably by oral administration.
The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention for use in preventing and/or treating a compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I) as active ingredient and a pharmaceutically acceptable excipient.
The pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, at a dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, and a pharmaceutically acceptable excipient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers.
Preferably, notably in the context of oral administration, the pharmaceutical composition can be in a solid or liquid (solution or suspension) dosage form. A solid dosage form can be in the form of tablets, gelatin capsules, powders, granules and the like. In tablets, the active ingredient can be mixed with pharmaceutical vehicle(s) such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like before being compressed. The tablets may be further coated, notably with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity. In powders or granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with flavor correctors or sweeteners. In gelatin capsules, the active ingredient can be introduced into soft or hard gelatin capsules in the form of a powder or granules such as mentioned previously or in the form of a liquid dosage form such as mentioned below.
A liquid dosage form can contain the active ingredient together with a sweetener, a taste enhancer or a suitable coloring agent in a solvent such as water. The liquid dosage form can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It can be for example an emulsion, a suspension, a syrup or an elixir.
For parenteral administration, the composition can be in the form of an aqueous suspension or solution which may contain suspending agents and/or wetting agents. The composition is advantageously sterile. It can be in the form of an isotonic solution (in particular in comparison to blood).
Solid and liquid dosage forms can be formulated so that they conform to a desired release profile, e.g. immediate release, delayed release and extended or sustained release.
The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention is preferably administered to a subject in need thereof in a dosage unit form, notably an oral dosage unit form, in particular an oral solid dosage unit form such as a tablet.
According to some embodiments, the pharmaceutical composition of the invention, comprising the compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, at a dose ranging from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg, and a pharmaceutically acceptable excipient, further comprises one or more other acetylcholinesterase inhibitors such as galantamine or rivastigmine. In such embodiment, the one or more acetylcholinesterase inhibitors are present in the pharmaceutical composition preferably at a lower dose than those already described.
In otherterms, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to the invention for use in preventing and/or treating a compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I), one or more other acetylcholinesterase inhibitors and a pharmaceutically acceptable excipient.
In an alternative embodiment, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is administered to a subject in need thereof for preventing and/or treating specifically obsessive-compulsive disorder in a daily dosage regimen at an amount ranging from 0.25 mg to 10 mg, or from 0.5 mg to 10 mg, or from 0.5 mg to 5 mg, or from 2.5 mg to lOmg, or from 5 mg to 10 mg, preferably from 0.5 mg to 2.5 mg.
Unit dosage form
In other aspect the present invention relates to a unit dosage form comprising from 0.25 mg to 2.5 mg, preferably from 0.5 mg to 2.5 mg of a compound offormula (I) or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the unit dosage form of the invention is an oral unit dosage form. In particular, the unit dosage form of the invention is a solid unit dosage form.
In some other aspects, the present invention relates to the unit dosage form of the present invention for its use as a drug, in particular for preventing and/or treating a compulsive disorder, such as an eating disorder, notably anorexia.
Advantageously, the unit dosage form of the present invention is used once a day as a drug, in particular for preventing and/or treating a compulsive disorder, such as an eating disorder, notably anorexia.
According to a further aspect of the present invention, the present invention relates to a method for preventing and or treating a compulsive disorder, notably an eating disorder, such as anorexia, comprising the administration once a day of the unit dosage form of the invention to a subject in need thereof.
Examples 6 anorexic patients were treated with donepezil: 5 of them with a daily dose according to the present invention and 1 with a higher dose (comparative).
The studies were led in hospital. Each case is presented below.
Case 1 (comparative)
Description of the patient
Patient #1 is a 35-year-old woman with a 21-years history of anorexia nervosa restricting type. She went into remission in late adolescence and remained well for about 4-5 yrs. However, she continued to struggle with the behavioral aspects of the disorder and cognitive ruminations that are pathognomonic of the illness. She was very restricted in her eating, in terms of restricting caloric intake and avoiding foods that were high in sugar, carbohydrates or fats. She also exercised for minimum an hour a day and struggled to allow herself to rest or sit down. She also endorsed significant body image dissatisfaction, weight and shape concerns and eating disorder cognitions and ruminations.
Treatment with a daily dose of donepezil of 5 mg
She was medically stable when she began with Donepezil at a daily dose of 5 mg Per Os (orally). Within 5 days, she reported side-effects of drowsiness and headaches that responded to over- the-counter pain medications. Within a week her blood pressure started to rise from her previously normal blood pressure of 120/70 mmHg to 175/120 mmHg. She also reported a severe headache that woke her from sleep and did not respond over the counter pain medications. She also reported groggy. She was seen in the local emergency department where her blood pressure was 183/124 mmHg. After a thorough medical assessment, where no other cause for the high blood pressure was found, she was instructed to discontinue donepezil. Her blood pressure slowly dropped overthe next few weeks but remained elevated at 140/95 mmHg.
Case 2 (invention)
Description of the patient
Patient #2 is a 21-year-old woman who developed anorexia nervosa restricting type in adolescence. She was very restricted in the types of food she ate and could not eat food that was processed or high in sugar or fats. She exercised 3-4 hours a day. She was unable to reduce her exercising even minimally with becoming flooded with debilitating anxiety. She was unable to eat enough to maintain a healthy weight. Her BMI was 18.5 kg/m2 and was medically stable when she started donepezil.
Treatment with a daily dose ofdonepezil of 0.5-2.5 mg
Patient #2 was treated with donepezil with the protocol as follow:
The treatment started with a daily dose of donepezil of 0.5 mg for 10 days then the daily dose was increased to 1 mg for 7 days then increased to 1.5mg for 71 days (2 months and 10 days) then increased to 2 mg for 22 days and then increased to 2.5 mg and remains on this dose for 4 months and 18 days.
Benefits ofdonepezil for Patient #2:
Her blood pressure was monitored and remained unaffected. She had no other side-effects. Over the next 5 months, she reported a decrease in ruminations and compulsions to exercise. She was able to decrease her exercise to her goal of 90 minutes a day. She was able to be more flexible with her eating and incorporate a wider variety of foods, including foods containing sugar. She was also able to be flexible about when she ate and exercised. She was able get to a BMI over 20 kg/m2 for the first time ever and was able to maintain it. She also was much less preoccupied with her weight or appearance and was able to tolerate her weight gain.
Results on anxiety
Patient #2 anxiety has also been evaluated with Generalized Anxiety Disorders Assessment (GAD-7) questionnaire (available on https://adaa.org/sites/default/files/GAD-7_Anxiety- updated_O.pdf) before and after the treatment. The following scores have been obtained:
The score obtained with questionary GAD-7 is classified as follows: 5-9 : mild anxiety; 10-14 : moderate anxiety; 15-21: severe anxiety A diminution of her anxiety was thus also observed for patient #2 further to the treatment with donepezil.
Results on depression
Patient #2 depression symptoms have also been evaluated with Patient Health Questionnaire (PHQ-9) (available on https://med.stanford.edu/fastlab/research/imapp/msrs/Jcr_content/main/accordion/accor dion_content3/download_256324296/file.res/PHQ9%20id%20date%2008.03.pdf) before and after the treatment. The following scores have been obtained :
The score obtained with questionnaire PHQ-9 is classified as follows:
5-9 : mild depression ; 10-14 : moderate depression; 15-19: moderately severe depression; 20-27: severe depression
A diminution of her depression symptoms was thus also observed for patient #2 further to the treatment with donepezil.
Results on Obsessive-compulsive disorders
Patient #2 obsessive-compulsive disorders (OCD) symptoms have also been evaluated with the Yale-Brown Obsessive Compulsive Scale questionnaire (Y-BOCS) (available on https://pcl.psychiatry.uw.edu/wp-content/uploads/2021/12/YBOCS.pdf) before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire Y-BOCS is classified as follows :
0-7 : subclinical ; 8-15 : mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms
A diminution of OCD symptoms was thus also observed for patient #2 further to the treatment with donepezil. Case 3 (invention)
Description of the patient
Patient #3 is a 36-year-old woman with a 2O-year history of anorexia nervosa binge/purge type who had been in recovery for two years before relapsing following a relationship trauma. She was slowly losing weight and was bingeing and purging multiple times every evening. She also was waking up every morning at 4am to exercise obsessively for hours. She was spending all her disposable income on binge foods and was slowly draining her savings. At times she was stealing food to binge on.
Treatment with a daily dose ofdonepezil of 0.5-2.5 mg
Patient #3 was treated with donepezil with the protocol as follow:
The treatment started with a daily dose of donepezil of 0.5 mg for 10 days and then the daily dose was increased to 1 mg for 9 days and then increased to 1.5 mg for 17 days and then increased to 2 mg for 7 days and then increased to 2.5 mg for 16 days and then discontinued.
Benefits ofdonepezil for Patient #3:
Within a month of starting the medication, she was able to reduce her bingeing (and consequent purging) significantly. She was only spending a maximum of $5.00 on binge foods and had stopped stealing food completely. She has stopped needing to dip into her savings to pay for binge foods. She remains in treatment.
Case 4 (invention)
Patient#4 is a 19-year-old girl with a 10-year history of anorexia nervosa restricting type who was struggling to gain weight. She did not over exercise but severely restricted her intake. She was struggling to gain weight and had struggled with significant body image distortion and eating disorder cognitions and ruminations. She felt that she was already too heavy despite having a BMI below 15 kg/m2. She had managed to gain weight over the course of a year and her BMI went from a low of 11 kg/m2 to 15 kg/m2. However, she was unable to gain weight during subsequent 7 months and her BMI plateaued.
Treatment with a daily dose ofdonepezil of 0.5 to 1.5 mg
Patient #4 was treated with donepezil with the protocol as follow: The treatment started with a daily dose of donepezil of 0.5 mg for 13 days then the daily dose was increased to 0.75 mg for 9 days then increased to 1 mg for 17 days and then increased to 1.5 mg and remained at this dosage for a month then stopped for two months and then restarted with a daily dose of 1.5 mg that remains within 1 month and then discontinued.
Benefits of donepezil for Patient #4:
Within a month at a daily dose of 1.5 mg, she reported being more flexible with her eating and less preoccupied with her eating disordered cognitions and urges to restrict and lose weight. She also saw her weight rise to a BMI of 15.6 kg/m2. However, after the 1st month, she did not renew her medication and over the next two months, experienced an increasing rigidity in her eating disordered cognitions, and in her preoccupation with having to restrict and lose weight. She has decided to restart the donepezil for a month at a daily dose of 1.5 mg. She became more flexible with her eating, and she started to gain weight slowly and she continued to see gradual improvements, even after discontinuing the treatment.
The eating disorders of patient #4 before and after treatment have been evaluated with the Eating Disorder Examination Questionnaire (EDE-q) (available on https://www.corc.uk.net/outcome-experience-measures/eating-disorder-examination- questionnaire-ede-q/) which has given the following results:
The score obtained with questionnaire EDE-q is classified as follows:
A score of 4 or greater is indicative of the clinical range, while a score greater than 2.8 is indicative of possible clinically significant pathology (Jennings KM, Phillips KE. Arch Psychiatr Nurs. 2017 (6):578- 581. doi: 10.1016/j.apnu.2017.08.002; and Velkoff EA,et al. Eat Disord. 2023 ;31(5):464-478. doi: 10.1080/10640266.2023.2191488). Results on anxiety
Patient #4 anxiety has also been evaluated with questionnaire GAD-7 before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire GAD-7 is classified as follows:
5-9 : mild anxiety ; 10-14 : moderate anxiety; 15-21: severe anxiety
A diminution of her anxiety was thus also observed for patient #4 further to the treatment with donepezil.
Results on depression
Patient #4 depression symptoms have also been evaluated with questionnaire PHQ-9 before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire PHQ-9 is classified as follows:
5-9 : mild depression ; 10-14 : moderate depression; 15-19: moderately severe depression;
20-27: severe depression
A diminution of her depression symptoms was thus also observed for patient #4 further to the treatment with donepezil.
Results on Obsessive-compulsive disorders
Patient #4 obsessive-compulsive disorders (OCD) symptoms have also been evaluated with questionnaire Y-BOCS- before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire Y-BOCS is classified as follows: 0-7 subclinical ; 8-15 : mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms
A diminution of OCD symptoms was thus also observed for patient #4 further to the treatment with donepezil.
Case 5 (invention)
A 43-year-old patient who has suffered from anorexia nervosa since the age of 36 during her second pregnancy. She has been vigilant about her caloric intake and body image since her adolescence. She also suffers from recurrent depression treated with venlafaxine 75 mg per day and a generalized anxiety disorder. Undernutrition worsened markedly at 41 years old, reaching a minimum BMI of 11 kg/m2. The maximum lifetime BMI excluding pregnancy is 19.8 kg/m2. The symptomatology is dominated by qualitative and quantitative food restriction and physical hyperactivity. There is a period of several months of hyperphagia and provoked vomiting. Neurocognitive executive functions are preserved, there is a high tolerance of delayed reward measured by Delay Discounting Task.
Treatment with a daily dose of donepezil of 2.5 mg
Donepezil was taken at a rate of 2.5 mg per day for 2 months.
Benefits of donepezil for Patient #5:
At the end of the treatment period, the patient #5 began to eat more easily, she set up daily lunches with relatives and managed to go from 27 kg to 36 kg in 3 months.
Case 6 (invention)
A 34-year-old woman with a 20-year history of anorexia nervosa-binge/purge subtype and a comorbid history or obsessive-compulsive disorder. She has been very symptomatic throughout her adolescence and went into a partial remission in early adulthood. Over the next 10 years, her symptoms waxed and waned and she had 2 major relapses that she had slowly recovered from. She was currently weight restored but following some environmental stresses, was starting to relapse. She was struggling with increasing eating disordered ruminations and cognitions, increasing body image distortions and dissatisfaction. She was becoming more rigid and restrictive in her eating. She also saw a rise in her obsessive- compulsive disorder symptoms. Treatment with a daily dose ofdonepezil of 0.5 mg to 2.5 mg
Patient #6 was treated with donepezil with the protocol as follow:
The treatment started with a daily dose of donepezil of 0.5 mg for 8 days and then the daily dose was increased to 1 mg for 9 days and then increased to 1.67 mg for 62 days and then increased to 2.5 mg.
She remains on donepezil at a higher dose (5 mg daily) to treat her obsessive-compulsive disorder.
Over the course of 3 months, she experienced a significant decrease in her eating disordered cognitions and ruminations and a reduction in the intensity of her body image distress.
The eating disorders of patient #6 before and after treatment have been evaluated with EDE- q questionnaire which has given the following results:
The score obtained with questionnaire EDE-q are classified as follows:
A score of 4 or greater is indicative of the clinical range, while a score greater than 2.8 is indicative of possible clinically significant pathology.
Results on anxiety
Patient #6 anxiety has also been evaluated with questionnaire GAD-7 before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire GAD-7 is classified as follows: 5-9: mild anxiety; 10-14: moderate anxiety; 15-21: severe anxiety
A strong diminution of her anxiety was thus also observed for patient #6 further to the treatment with donepezil.
Results on depression
Patient #6 depression symptoms have also been evaluated with questionnaire PHQ-9 before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire PHQ-9 is classified as follows:
5-9 : mild depression ; 10-14 : moderate depression; 15-19: moderately severe depression;
20-27: severe depression
A diminution of her depression symptoms was thus also observed for patient #6 further to the treatment with donepezil.
Results on Obsessive-compulsive disorders
Patient #6 obsessive-compulsive disorders (OCD) symptoms have also been evaluated with questionnaire Y-BOCS- before and after the treatment. The following scores have been obtained:
The score obtained with questionnaire Y-BOCS is classified as follows:
0-7: subclinical; 8-15: mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms A diminution of OCD symptoms was thus also observed for patient #6 further to the treatment with donepezil.
Conclusion
Patienttl treated with 5mg PO OD experienced severe side effect (high blood pressure and severe headache). Other patients were treated with lower doses (0.5-2.5mg PO OD) and were improved without severe side effects.
These clinical cases show that a low dose of donepezil comprised between 0.5 and 2.5 mg/day is useful to treat anorexia and related compulsive behaviors, without causing any side effects. In consequence, the patient's adherence to treatment is improved.

Claims

Claims
1. A compound of the following formula (I): wherein X is an oxygen atom or a group N-OH, or a pharmaceutically acceptable salt and/or solvate thereof for use in preventing and/or treating a compulsive disorder in a subject in need thereof, characterized in that the compound of formula (I) is administered to the subject at a daily dose ranging from 0.25 mg to 2.5 mg.
2. The compound for use according to claim 1, characterized in that the daily dose ranges from 0.5 mg to 2 mg, preferably from 0.5 mg to 1.5 mg.
3. The compound for use according to claim 1 or 2, characterized in that X is an oxygen atom and the compound of formula (I) is donepezil.
4. The compound for use according to any one of claims 1 to 3, characterized in that the compulsive disorder is an eating disorder, preferably anorexia.
5. The compound for use according to any one of claims 1 to 4, administered as a pharmaceutical composition comprising the compound of formula (I) as active ingredient and a pharmaceutically acceptable excipient.
6. The compound for use according to any one of claims 1 to 5, administered orally.
7. The compound for use according to any one of claims 1 to 6, administered in a solid unit dosage form.
8. The compound for use according to any one of claims 1 to 7, characterized in that the daily dose is administered at once.
9. A unit dosage form comprising from 0.25 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
10. A unit dosage form according to claim 9, for use as a drug.
11. A unit dosage form according to claim 10, for preventing and/or treating a compulsive disorder, such as an eating disorder, notably anorexia.
12. A unit dosage form according to claim 11, characterized in that the compulsive disorder is an eating disorder, notably anorexia.
13. A unit dosage form according to any one of claims 10 to 12, administered to a subject in need thereof once a day.
EP23808803.3A 2022-11-17 2023-11-17 A novel dosage regimen using low doses of donepezil or derivative thereof for preventing or treating a compulsive disorder Pending EP4618986A1 (en)

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PCT/EP2023/082293 WO2024105268A1 (en) 2022-11-17 2023-11-17 A novel dosage regimen using low doses of donepezil or derivative thereof for preventing or treating a compulsive disorder

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