WO2018051355A1 - Tamoxifène ou tamoxifène en combinaison avec de l'arginine/citrulline destinés à être utilisés dans le traitement de la dystrophie musculaire - Google Patents

Tamoxifène ou tamoxifène en combinaison avec de l'arginine/citrulline destinés à être utilisés dans le traitement de la dystrophie musculaire Download PDF

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Publication number
WO2018051355A1
WO2018051355A1 PCT/IL2017/051052 IL2017051052W WO2018051355A1 WO 2018051355 A1 WO2018051355 A1 WO 2018051355A1 IL 2017051052 W IL2017051052 W IL 2017051052W WO 2018051355 A1 WO2018051355 A1 WO 2018051355A1
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Prior art keywords
tamoxifen
muscular dystrophy
subject
kit
arginine
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PCT/IL2017/051052
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English (en)
Inventor
Shmuel Ben-Sasson
Talya DOR
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Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Hadasit Medical Research Services & Development Ltd.
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Publication of WO2018051355A1 publication Critical patent/WO2018051355A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention is in the field of muscular dystrophy treatment.
  • Muscular Dystrophy is a group of genetic disorders characterized by progressive loss of muscle strength and integrity.
  • Classical histological findings of muscular dystrophies consist of pathological fiber size variation, muscle cell degeneration (necrosis) and regeneration, and replacement of muscle by connective and adipose tissue.
  • DMD Duchenne muscular dystrophy
  • DMD corticosteroids
  • mdx mice the mouse model for DMD
  • beneficial effects of steroids were observed, including improvement in muscle strength and attenuation in muscle fibrosis and muscle tissue damage.
  • Studies have also demonstrated improvement in patient' s muscle strength as a result of such treatment.
  • Treatment is usually started at the ages of 4-6 years. Upon initiation of treatment there is usually apparent improvement in ambulation in most children for 6-12 months, followed by stabilization for about 2 years and long term slower deterioration than untreated patients.
  • Tamoxifen is a selective estrogen receptor modulator, that acts as an estrogen antagonist in breast tissue, but may function as an estrogen agonist in others. Tamoxifen itself is a prodrug, which is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4 -hydroxy tamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen), which exhibit 30-100 times greater affinity for the estrogen receptor than tamoxifen itself.
  • Estrogen receptors are also expressed in muscle cells, and preliminary data suggests that in mdx mice, tamoxifen administration improved muscle structure and overall strength (Am J Pathol. 2013 Feb;182(2):485-504, Dorchies, OM, et al.)
  • the present invention provides methods of treating Duchenne muscular dystrophy (DMD), as well as methods of reducing the dose of steroids used to treat DMD.
  • Kits comprising tamoxifen and citrulline, arginine or a combination thereof, are also provided.
  • a method of treating Duchenne muscular dystrophy (DMD) in a subject in need thereof comprising: administering to the subject 10 to 20 mg a day of tamoxifen.
  • DMD Duchenne muscular dystrophy
  • a method of treating DMD in a subject in need thereof comprising: administering to the subject about 0.5 mg/kg/day of tamoxifen.
  • the subject is not administered more than 40 mg tamoxifen in a day. In some embodiments, about 20 mg of tamoxifen a day is administered.
  • the subject is a human child. In some embodiments, the child is between the ages of 5 and 16. In some embodiments, the child is a male child. In some embodiments, the subject weighs between 18 kg and 45 kg.
  • the subject is administered an oral corticosteroid for at least 10 weeks prior to a first dose of tamoxifen.
  • the treating comprises improving or maintaining ambulation in said subject.
  • the improving or maintaining ambulation is tested using the 6-minute walk test (6mwt) or the North-Star Ambulatory Assessment (NSAA).
  • the distance walked in 6 minutes does not decrease by more than 20% in half a year.
  • the treating comprises improving or maintaining pulmonary function.
  • the daily administering persists for at least 52 weeks. In some embodiments, the administering persists continuously for the life of the subject.
  • a method for treating a muscular dystrophy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: tamoxifen; and an agent selected from citrulline, arginine, or a combination thereof.
  • a method of reducing the dose of steroids administered to a subject suffering from DMD comprising administering to the subject a therapeutically effective amount of tamoxifen or tamoxifen and an agent selected from citrulline, arginine, or a combination thereof.
  • tamoxifen and an agent selected from citrulline, arginine, or a combination thereof for the treatment of a muscular dystrophy.
  • tamoxifen and an agent selected from citrulline, arginine, or a combination thereof for the reduction of a dose of steroids administered to a subject suffering from DMD.
  • tamoxifen and an agent selected from citrulline, arginine, or a combination thereof for the production of a medicament for treatment of a muscular dystrophy or for the reduction of a dose of a steroid administered to a subject suffering from DMD.
  • the muscular dystrophy is selected from a congenital muscular dystrophies (CMD), dystrophinopathies, limb girdle muscular dystrophies (LGMD), distal myopathies, type I and type II myotonic dystrophies (DM1, DM2), facio- scapulo-peroneal muscular dystrophy (FSHD), autosomal and X-linked Emery-Dreifuss muscular dystrophy (EDMD), and oculopharyngeal muscular dystrophy (OPMD).
  • CMD congenital muscular dystrophies
  • LGMD limb girdle muscular dystrophies
  • DM1, DM2 type I and type II myotonic dystrophies
  • FSHD facio- scapulo-peroneal muscular dystrophy
  • EDMD autosomal and X-linked Emery-Dreifuss muscular dystrophy
  • OPMD oculopharyngeal muscular dystrophy
  • the muscular dystrophy is selected from Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In some embodiments, the muscular dystrophy is DMD.
  • the muscular dystrophy comprises at least one of an acquired myopathy, an inflammatory myopathy, toxic and drug- induced myopathy, muscle neoplasm, a disorder of the neuromuscular junction, and acquired immune -positive or antibody negative autoimmune myasthenia gravis. In some embodiments, the muscular dystrophy comprises impaired sarcolemma function.
  • the muscular dystrophy comprises a condition that secondarily affects muscle.
  • the condition that secondarily affects muscle is selected from muscle atrophy and a muscle wasting disorder.
  • the muscle wasting disorder is selected from sarcopenia and cachexia.
  • the muscle atrophy is Intensive Care Unit (ICU)- and surgery-induced muscle weakness.
  • ICU Intensive Care Unit
  • the therapeutically effective amount of tamoxifen is 20 to 40 mg for an adult, and 10 to 20 mg for a child.
  • the therapeutically effective amount of tamoxifen is 0.5 mg/kg/day, and is not more than 40 mg/day. In some embodiments, the therapeutically effective amount of tamoxifen is about 20 mg/day.
  • the therapeutically effective amount of citrulline, arginine, or a combination thereof is 1 to 10 grams a day.
  • the administering is selected from: administering said tamoxifen and said citrulline, arginine, or a combination thereof as one combination pharmaceutical composition, administering said tamoxifen and said citrulline, arginine, or a combination thereof as separate pharmaceutical compositions at the same time, and administering said tamoxifen and said citrulline, arginine, or a combination thereof as separate pharmaceutical composition at different times.
  • the subject is a human child. In some embodiments, the child is between the ages of 5 and 16. In some embodiments, the child is a male child.
  • the steroid is a corticosteroid.
  • the reducing is at least a 10% reduction in dose.
  • kits comprising at least one of: tamoxifen adapted or identified for co-administration with an agent selected from citrulline, arginine, or a combination thereof; an agent selected from citrulline, arginine, or a combination thereof adapted or identified for co-administration with tamoxifen; and tamoxifen and an agent selected from citrulline, arginine, or a combination thereof.
  • the kit further comprises an adjuvant, excipient or carrier.
  • the agent is citrulline.
  • the citrulline is a drug grade citrulline pharmaceutical formulation at a precise pre-defined dose.
  • the kit comprises tamoxifen adapted or identified for coadministration with an agent selected from citrulline, arginine or a combination thereof and said agent adapted or identified for co-administration with tamoxifen.
  • the tamoxifen, the agent or both are formulated for oral administration.
  • the oral formulation is selected from the group consisting of: a fast dispersing dosage forms (melts), multi-particulate drug delivery systems, orally dispersible tablets (ODTs), orally dispersible films (ODFs), and chewable formulations.
  • the tamoxifen, the agent or both are formulated as a powder or liquid easily ingested by infants and children.
  • kits of the invention are for use in the treatment of a muscular dystrophy.
  • the muscular dystrophy is selected from a congenital muscular dystrophies (CMD), dystrophinopathies, limb girdle muscular dystrophies (LGMD), distal myopathies, type I and type II myotonic dystrophies (DM1, DM2), facio- scapulo-peroneal muscular dystrophy (FSHD), autosomal and X-linked Emery-Dreifuss muscular dystrophy (EDMD), and oculopharyngeal muscular dystrophy (OPMD).
  • CMD congenital muscular dystrophies
  • LGMD limb girdle muscular dystrophies
  • DM1, DM2 type I and type II myotonic dystrophies
  • FSHD facio- scapulo-peroneal muscular dystrophy
  • EDMD autosomal and X-linked Emery-Dreifuss muscular dystrophy
  • OPMD oculopharyngeal muscular dystrophy
  • the muscular dystrophy is selected from Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In some embodiments, the muscular dystrophy is DMD.
  • the muscular dystrophy comprises at least one of an acquired myopathy, an inflammatory myopathy, toxic and drug- induced myopathy, muscle neoplasm, a disorder of the neuromuscular junction, and acquired immune -positive or antibody negative autoimmune myasthenia gravis. In some embodiments, the muscular dystrophy comprises impaired sarcolemma function.
  • the muscular dystrophy comprises a condition that secondarily affects muscle.
  • the condition that secondarily affects muscle is selected from muscle atrophy and a muscle wasting disorder.
  • the muscle wasting disorder is selected from sarcopenia and cachexia.
  • the muscle atrophy is Intensive Care Unit (ICU)- and surgery-induced muscle weakness.
  • ICU Intensive Care Unit
  • Figure 1 A graph of the trend of DMD 6-minutes-walk distances as has been reported in the art.
  • Figure 2 A line graph of the 6-minutes-walk distances of the three subjects over the course of the trial.
  • Figure 3 A line graph of the CPK levels of the three subjects over the course of the trial.
  • the present invention provides methods of treating Duchenne muscular dystrophy (DMD), as well as methods of reducing the dose of steroids used to treat DMD, by administering tamoxifen.
  • the present invention further concerns a method of treating DMD by administering tamoxifen together with the treatment by citrulline, arginine or combinations thereof.
  • a kit comprising tamoxifen and citrulline, arginine or a combination thereof, is also provided.
  • a method of treating Duchenne muscular dystrophy (DMD) in a subject in need thereof comprising administering to the subject 10 to 20 mg a day of tamoxifen.
  • DMD Duchenne muscular dystrophy
  • a method of treating DMD in a subject in need thereof comprising administering to the subject about 0.5 mg/kg/day of tamoxifen.
  • a method for treating a disease comprising a muscular dystrophy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of: a. tamoxifen; and b. an agent selected from citrulline, arginine, or a combination thereof.
  • Muscular dystrophies include, but are not limited to congenital muscular dystrophies (CMD), dystrophinopathies such as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), limb girdle muscular dystrophies (LGMD), distal myopathies, type I and type II myotonic dystrophies (DM1, DM2), facio-scapulo-peroneal muscular dystrophy (FSHD), autosomal and X-linked Emery-Dreifuss muscular dystrophy (EDMD), and oculopharyngeal muscular dystrophy (OPMD).
  • CMD congenital muscular dystrophies
  • DMD Duchenne muscular dystrophy
  • BMD Becker muscular dystrophy
  • LGMD limb girdle muscular dystrophies
  • FSHD facio-scapulo-peroneal muscular dystrophy
  • EDMD autosomal and X-linked Emery-Dreifuss muscular dystrophy
  • OPMD oculopharynge
  • the muscular dystrophy comprises impaired sarcolemma function.
  • Diseases comprising a muscular dystrophy include conditions that secondarily affect muscle include muscle atrophy and muscle wasting disorders.
  • the muscle wasting disorder is selected from sarcopenia, and cachexia.
  • the muscle atrophy is Intensive Care Unit (ICU)- and surgery-induced muscle weakness.
  • ICU Intensive Care Unit
  • Sarcopenia is the degenerative loss of skeletal muscle mass and function associated with aging.
  • Cachexia is a multifactorial syndrome resulting in a reduced life expectancy and accompanies many chronic disorders such as cancer, AIDS, sepsis, immune disorders, chronic heart failure, and chronic obstructive pulmonary disease.
  • the disease comprising a muscular dystrophy is DMD.
  • DMD is well known in the art, and methods of diagnosing DMD are also well known. Determining the severity of DMD symptoms, as well as the success of treatment of those symptoms, is also well known and may include, but is not limited to, administering at least one of: the 6-minute walk test (6mwt), the North-Star ambulatory assessment (NSAA), creatine phosphokinase (CPK) assessment, and an oral questionnaire for the parents of the DMD patient to describe the symptoms.
  • 6mwt 6-minute walk test
  • NSAA North-Star ambulatory assessment
  • CPK creatine phosphokinase
  • the subject is a human. In some embodiments, the subject is a human child. In some embodiments, the child is between the ages of 1 and 18, 1 and 17, 1 and 16, 1 and 15, 1 and 14, 1 and 13, 1 and 12, 2 and 18, 2 and 17, 2 and 16, 2 and 15, 2 and 14, 2 and 13, 2 and 12, 3 and 18, 3 and 17, 3 and 16, 3 and 15, 3 and 14, 3 and 13, 3 and 12, 4 and 18, 4 and 17, 4 and 16, 4 and 15, 4 and 14, 4 and 13, 4 and 12, 5 and 18, 5 and 17, 5 and 16, 5 and 15, 5 and 14, 5 and 13, or 5 and 12 years old. Each possibility represents a separate embodiment of the invention. In some embodiments, the child is between 5 and 16 years of age.
  • the child is a male child. It will be understood to one of skill in the art that DMD is an X-linked disease as dystrophin is found on the X chromosome. As such the vast majority of DMD patients are male.
  • the subject is a prepubertal male. In some embodiments, the subject is a teen-age male. In some embodiments, the subject is an adult male.
  • the subject weighs between 10 and 80 kg, 10 and 70 kg, 10 and 60 kg, 10 and 55 kg, 10 and 50 kg, 10 and 49 kg, 10 and 48 kg, 10 and 47 kg, 10 and 46 kg, 10 and 45 kg, 10 and 44 kg, 10 and 43 kg, 10 and 42 kg, 10 and 41 kg, 10 and 40 kg, 10 and 35 kg, 10 and 30 kg, 12 and 80 kg, 12 and 70 kg, 12 and 60 kg, 12 and 55 kg, 12 and 50 kg, 12 and 49 kg, 12 and 48 kg, 12 and 47 kg, 12 and 46 kg, 12 and 45 kg, 12 and 44 kg, 12 and 43 kg, 12 and 42 kg, 12 and 41 kg, 12 and 40 kg, 12 and 35 kg, 12 and 30 kg, 14 and 80 kg, 14 and 70 kg, 14 and 60 kg, 14 and 55 kg, 14 and 50 kg, 14 and 49 kg, 14 and 48 kg, 14 and 47 kg, 14 and 46 kg, 14 and 45 kg, 14 and 44 kg, 14 and 43 kg, 14 and 42 kg, 14 and 41 kg, 14 and 41 kg, 14 and 40 kg
  • the subject has received a steroid or corticosteroid to treat DMD before performance of the methods of the instant invention.
  • Steroid treatment for DMD is well known in the art.
  • the steroid is a corticosteroid.
  • the steroid is an oral steroid.
  • the steroid is a glucocorticoid.
  • the steroid is selected from prednisone, prednisalone and deflazacort.
  • the steroid is prednisone.
  • the steroid is prednisalone.
  • the steroid is deflazacort.
  • the subject is administered the steroid for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 15 weeks, 16 weeks, 20 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or a year prior to the first dose of tamoxifen.
  • Each possibility represents a separate embodiment of the invention.
  • the subject begins steroid treatment at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, 15 weeks, 16 weeks, 20 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or a year prior to the first dose of tamoxifen.
  • the subject is administered an oral corticosteroid for at least 10 weeks prior to a first dose of tamoxifen.
  • steroid administration is daily.
  • the steroid administration is intermittent. In some embodiments, intermittent administration is 10 days of administration followed by 10 days without administration.
  • a method of reducing the dose of steroids administered to a subject suffering from DMD comprising administering to the subject a therapeutically effective amount of (i) tamoxifen or (ii) tamoxifen and an agent selected from citrulline, arginine, or a combination thereof.
  • the reduction in dose is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% reduction in the dose of corticosteroids.
  • the reduction in dose is a reduction in the frequency of dosing. It will be understood by one skilled in the art, that receiving steroids every other day when the dose had previously been administered daily would be considered a reduction in dose.
  • an intermittent dosing schedule that had been 10 days steroid/ 10 days without, that is changed to 10 days steroid/ 15 days without, or 5 days steroid/10 days without, or similar alterations, would also be considered a reduction in dose. Any reduction in the amount of steroid that the subject receives over a given period of time, is to be considered a reduction in dose.
  • administering refers to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.
  • One aspect of the present subject matter provides for oral administration of a therapeutically effective amount of tamoxifen to a patient in need thereof.
  • Other suitable routes of administration can include parenteral, subcutaneous, intravenous, intramuscular, or intraperitoneal.
  • the administering is any one of oral, intravenous and intramuscular.
  • the tamoxifen or tamoxifen and an agent selected from citrulline, arginine, or a combination thereof is administered daily. In some embodiments, half a dose is administered twice a day. In some embodiments, the dose is calculated on a weekly scale, such that the subject receives a total of seven full doses in one week. In some embodiments, the tamoxifen is administered weekly.
  • the administering is selected from: (i) administering the tamoxifen and the citrulline, arginine, or a combination thereof as one combination pharmaceutical composition; (ii) administering the tamoxifen and the citrulline, arginine, or a combination thereof as separate pharmaceutical compositions at the same time; and (iii) administering the tamoxifen and the citrulline, arginine, or a combination thereof as separate pharmaceutical composition at different times.
  • combined pharmaceutical preparation or “combined pharmaceutical composition” are used interchangeably and refer to a pharmaceutical combination product that comprises tamoxifen and an agent selected from citrulline, arginine, or a combination of citrulline and arginine, in pharmaceutical purity, within one and the same administration or dosage form.
  • the combined pharmaceutical preparation of the invention is administered alone, in which case the active ingredients of the preparation are administered staggered (at an interval) or jointly in combination.
  • the dose of tamoxifen administered is a therapeutically effective amount.
  • the therapeutically effective amount of tamoxifen is 20 to 40 mg for an adult, and 10 to 20 mg for a child.
  • the therapeutically effective amount of tamoxifen is 10 to 20 mg.
  • the therapeutically effective amount of tamoxifen is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mg/kg body weight/day.
  • Each possibility represents a separate embodiment of the invention.
  • the therapeutically effective amount of tamoxifen is about 0.5 mg/kg body weight/day. In some embodiments, the amount of tamoxifen administered in a day is not greater than 40 mg. In some embodiments, the amount of tamoxifen administered is about 20 mg per day.
  • citrulline is L-citrulline.
  • arginine is L- arginine.
  • a salt of citrulline or arginine is administered.
  • salts refers to both salts of carboxyl groups and to acid addition salts of amino or guanido groups of the peptide molecule.
  • Salts of carboxyl groups may be formed by means known in the art and include inorganic salts, for example sodium, calcium, ammonium, ferric or zinc salts, and the like, and salts with organic bases such as salts formed for example with amines such as triethanolamine, piperidine, procaine, and the like.
  • Acid addition salts include, for example, salts with mineral acids such as, for example, acetic acid or oxalic acid.
  • the dose of citruUine, arginine, or a combination thereof is a therapeutically effective amount of citruUine, arginine, or a combination thereof.
  • a therapeutically effective amount of citruUine, arginine, or a combination thereof is 0.1 to 20, 0.5 to 20, 1 to 20, 0.1 to 10, 0.5 to 10, or 1 to 10 grams/day. Each possibility represents a separate embodiment of the invention.
  • a therapeutically effective amount of citruUine, arginine, or a combination thereof is 1 to 10 grams per day.
  • citruUine is a more potent compound that arginine due to the latter' s metabolism in the liver.
  • the dose of citruUine is lower than the dose of arginine.
  • a therapeutically effective amount of citruUine is 0.1 to 20, 0.5 to 20, 1 to 20, 2 to 20, 4 to 20, 5 to 20, 0.1 to 10, 0.5 to 10, 1 to 10, 2 to 10, 4 to 10 or 5 to 10 grams/day. Each possibility represents a separate embodiment of the invention.
  • a therapeutically effective amount of citruUine is 0.1 to 10 grams per day.
  • a therapeutically effective amount of arginine is 0.1 to 30, 0.5 to 30, 1 to 30, 2 to 30, 4 to 30, 6 to 30, 8 to 30, 0.1 to 20, 0.5 to 20, 1 to 20, 2 to 20, 4 to 20, 6 to 20, 8 to 20, 0.1 to 10, 0.5 to 10, 1 to 10, 2 to 10, 4 to 10, 6 to 10 or 8 to 10 grams/day.
  • a therapeutically effective amount of arginine is 1 to 20 grams per day.
  • tamoxifen or tamoxifen and an agent selected from citruUine, arginine, or a combination thereof is administered indefinitely for the life of the subject.
  • the administering persists for at least 6 months, a year, 52 weeks, 100 weeks, or 2 years. Each possibility represents a separate embodiment of the invention. In some embodiments, the administering persists indefinitely.
  • treatment encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured.
  • a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, reduce the progression of the disease or provide improvement to a patient or subject's quality of life.
  • treating comprises improving or maintaining ambulation in the subject. In some embodiments, treating comprises slowing the deterioration in ambulation in the subject. In some embodiments, treating comprises improving or maintaining pulmonary function in the subject. In some embodiments, treating comprises slowing the deterioration in pulmonary function in the subject.
  • DMD effects multiple areas of the body, multiple muscle groups and the ability to perform multiple functions. A treatment that improves one muscle group, or the ability to perform one function may not improve a separate group or the ability to perform a separate function.
  • Methods of testing ambulation and pulmonary function in DMD subjects are well known in the art. Any method by which ambulation ability or pulmonary function can be measured and compared at different dates can be used to practice the methods of the invention.
  • improving, maintaining or slowing deterioration of ambulation is tested using the 6-minute walk test (6mwt) or the North-Star Ambulatory Assessment (NSAA).
  • improving, maintaining or slowing deterioration of ambulation is tested using the 6mwt.
  • improving, maintaining or slowing deterioration of ambulation is tested using the NSAA.
  • the 6mwt or the NSAA are administered every month, every 2 months, every 3 months, every 4 months, every 5 months, or every 6 months.
  • improving, maintaining or slowing deterioration of pulmonary function is tested by measuring Maximum Inspiratory/ Expiratory Pressure (MIF/MAF) and/or Forced Vital Capacity (FVC).
  • MIF/MAF Maximum Inspiratory/ Expiratory Pressure
  • FVC Forced Vital Capacity
  • slowing deterioration of ambulation comprises a decrease in distance walked in 6 minutes of less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25% of the distance walked previously.
  • slowing deterioration of ambulation comprises no decrease in the distance walked in 6 minutes as compared to the distance walked previously.
  • slowing deterioration of ambulation comprises a decrease in the NSAA score of less than 1 point, 2 points, 3 points, 4 points or 5 points from the previous assessment.
  • slowing deterioration of ambulation comprises no decrease in the NSAA score as compared to the previous assessment.
  • kits comprising tamoxifen and an agent selected from citrulline, arginine, or a combination thereof.
  • the kit is for use in treating a muscular dystrophy.
  • the muscular dystrophy is DMD.
  • the kit further comprises an adjuvant, excipient or carrier.
  • the tamoxifen, citrulline, arginine or combination thereof is formulated in a pharmaceutical composition comprising an adjuvant, excipient or carrier.
  • carrier refers to any component of a pharmaceutical composition that is not the active agent.
  • pharmaceutically acceptable carrier refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • 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 cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl
  • substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations.
  • Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present.
  • any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein.
  • Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the "Inactive Ingredient Guide," U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety.
  • CTFA Cosmetic, Toiletry, and Fragrance Association
  • Examples of pharmaceutically acceptable excipients, carriers and diluents useful in the present compositions include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman's: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.
  • compositions may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum.
  • liposomes include emulsions, foams, micelies, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol.
  • the selection of lipids is generally determined by considerations such as liposome size and stability in the blood.
  • a variety of methods are available for preparing liposomes as reviewed, for example, by Coligan, J. E. et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.
  • the carrier may comprise, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.
  • the citrulline is a drug grade citrulline pharmaceutical formulation at a precisely predefined dose.
  • the tamoxifen, the agent or both are formulated for oral administration.
  • the tamoxifen, the agent or both are formulated for administration to a child.
  • the tamoxifen, the agent or both are formulated for oral administration to a child.
  • a formulation for oral administration to a child comprises any one of a powder, a liquid, a strip, a chewable pill or a melt.
  • the powder, liquid, strip, chewable or melt is formulated for easy ingestion and/or digesting by an infant or child.
  • an oral formulation is selected from the group consisting of: a fast dispersing dosage form (FDDF, a melt), a multi-particulate drug delivery system, an orally disintegrating/dissolving tablet (ODT, or chewable), orally disintegrating/dissolving film (ODF, or strip), and other chewable formulations.
  • FDDF fast dispersing dosage form
  • ODT orally disintegrating/dissolving tablet
  • ODF orally disintegrating/dissolving film
  • an adaptive is added to the formulation to improve the taste for children.
  • oral formulations for children include, but are not limited to, Calpol Fast Melts® (Pfizer Consumer Health), Nurofen® Meltlets (Crookes Healthcare), Benadryl® orodispersible tablets, Viracept® oral powder, Singulair® oral granule and Depakote® Sprinkle capsules.
  • Multi Particulate (MP) oral compositions can reformulate a drug into a tasteless, non- gritty MP formulation (i.e. a powder) that can be taken directly, or sprinkled onto food or liquid for children to take.
  • Multiparticulate drug delivery systems are composed of a number of discrete units such as granules, pellets or minitablets.
  • Multiparticulate products provide improved patient acceptability over single-unit solid dosage forms (i.e., tablets and capsules) by dint of their reduced size and thus improved ease of swallowing plus the increased dose flexibility provided by their multi-unit composition.
  • multiparticulate products are usually suitable for controlled release and taste masking by means of film-coating technologies, which can also benefit patient's compliance. Characteristic advantages and limitations of multiparticulate drug delivery systems are summarized.
  • Orally dispersible/dissolvable tablets are designed to disintegrate in the oral cavity within a matter of seconds, avoiding the need for swallowing the tablet as a whole. In some cases, when the disintegration/dissolution is sufficiently fast, the use of water can also be avoided.
  • Drug-loaded ODFs based on polymeric matrices can be designed to disintegrate quickly in the mouth releasing the active ingredient. Swallowing is aided by the quick disintegration/dissolution of ODFs in the oral cavity in a similar fashion to their predecessor ODTs, eliminating the need of water for their administration.
  • ODFs possess an elegant appearance and may be preferred by some patients.
  • kits of the invention comprise at least one dosing form of any one of 5, 10, 15 and 20 mg tamoxifen. Each possibility represents a separate embodiment of the invention.
  • kits of the invention comprise at least one dosing form of any one of, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and grams of agent selected from citrulline, arginine, or a combination of citrulline and arginine.
  • half doses are provided for a twice-daily dosing regimen.
  • a length of about 1000 nanometers (nm) refers to a length of 1000 nm+- 100 nm.
  • Example 1 Compassionate cohort treated with 10 mg tamoxifen for 2 years.
  • Example 2 Clinical study of tamoxifen and tamoxifen with L-citrulline to treat DMD
  • a study is conducted to test tamoxifen treatment, and tamoxifen with citrulline for prevention of deterioration in muscle strength and function (ambulation) in patients with DMD. Safety and tolerability of the treatment is also monitored. The added clinical value of tamoxifen or tamoxifen/citrulline in combination with steroid treatment is assessed, as is the ability to lower steroid dose with these additional treatments.
  • DMD is confirmed in the patients by at least one of:
  • Secondary endpoints include change from baseline in physical function as measured by the North Star Ambulatory Assessment (NSAA), and change from baseline in timed function tests (time to stand from supine and time to run/walk 10 meters).
  • NSAA North Star Ambulatory Assessment
  • Boys aged 5-16 years, diagnosed with DMD and already on steroid treatment are included in the study. Patients on prednisone, prednisolone or deflazacort must have been on it for at least 3 months prior to screening. Patients on stable dose of any combination of creatine, glutamine, coenzyme Q10, vitamin E, C or D, arginine, calcium, must have taken these medications for at least 2 months prior to screening. Following a baseline assessment period, the subjects are treated for at least 12 months, with an option to extend to 3 years, and are monitored routinely at visits every 3 months (+2 weeks).
  • Patients in the tamoxifen group receive 5-10 mg tamoxifen twice daily in addition to the steroid treatment they have been receiving before the study.
  • Patients in the tamoxifen/citrulline group receive 5-10 mg tamoxifen twice daily, and 2-4 grams L-citrulline twice daily, in addition to the steroid treatment they have been receiving before the study. Tamoxifen and citrulline are administered orally only.
  • 6MWT is the distance that the child walks during 6 minutes in a 25-meter course which was adapted from the American Thoracic Society guidelines, has been validated in DMD and is currently used as a primary endpoint in therapeutic trials in most ambulatory boys with DMD.
  • the course on which the 6MWT is performed is on a flat surface, has linear markings and a "safety chaser" to provide standardized encouragements and assist with falls.
  • 95% CI are calculated for the rate of seizures per week based on a seizure diary.
  • the data are analyzed using the SAS ® version 9.3 (SAS Institute, Cary North Carolina).

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Abstract

L'invention concerne des méthodes de traitement de la dystrophie musculaire de Duchenne (DMD), ainsi que des méthodes de réduction de la dose de stéroïdes utilisés pour traiter la DMD. L'invention concerne également des Kits comprenant du tamoxifène et de la citrulline, de l'arginine ou une combinaison de ceux-ci.
PCT/IL2017/051052 2016-09-19 2017-09-18 Tamoxifène ou tamoxifène en combinaison avec de l'arginine/citrulline destinés à être utilisés dans le traitement de la dystrophie musculaire WO2018051355A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10226467B2 (en) 2014-11-14 2019-03-12 Universitat De Valencia Compounds for the treatment of myotonic dystrophy
WO2023175010A1 (fr) * 2022-03-15 2023-09-21 Centre D'etude Des Cellules Souches (Cecs) Utilisation du bazedoxifene pour augmenter la survie musculaire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10226467B2 (en) 2014-11-14 2019-03-12 Universitat De Valencia Compounds for the treatment of myotonic dystrophy
WO2023175010A1 (fr) * 2022-03-15 2023-09-21 Centre D'etude Des Cellules Souches (Cecs) Utilisation du bazedoxifene pour augmenter la survie musculaire

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