WO2018073141A1

WO2018073141A1 - New composition for treating sma

Info

Publication number: WO2018073141A1
Application number: PCT/EP2017/076274
Authority: WO
Inventors: Jochem Alsenz; Marvin Lloyd WOODHOUSE; Gabrielle Alice HEINIMANN; Elisabeth HAENEL
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2016-10-18
Filing date: 2017-10-16
Publication date: 2018-04-26
Also published as: TW201821081A

Abstract

The present invention provides a new pharmaceutical composition comprising olesoxime, its manufacture and its use for the treatment, delay of progression or amelioration of spinal muscular atrophy (SMA), its methods of treatment thereof.

Description

New composition for treating SMA

The present invention provides a new pharmaceutical composition comprising olesoxime, its manufacture and its use for the treatment, delay of progression or amelioration of spinal muscular atrophy (SMA) and its methods of treatment thereof.

Spinal muscular atrophy (SMA), in its broadest sense, describes a collection of inherited and acquired central nervous system (CNS) diseases characterized by progressive motor neuron loss in the spinal cord and brainstem causing muscle weakness and muscle atrophy. SMA is characterized by a degeneration of the alpha motor neurons from the anterior horn of the spinal cord leading to muscular atrophy and resulting in paralysis. This alpha motor neuron

degeneration thus substantially compromises the vital prognosis of patients. In healthy subjects, these neurons transmit messages from the brain to the muscles, leading to the contraction of the latter. In the absence of such stimulation, the muscles atrophy. Subsequently, in addition to a generalized weakness and atrophy of the muscles, and more particularly of those of the trunk, upper arms and thighs, these disorders can be accompanied by serious respiratory problems.

Infantile SMA is the most severe form of this neurodegenerative disorder. Symptoms include muscle weakness, poor muscle tone, weak cry, limpness or a tendency to flop, difficulty sucking or swallowing, accumulation of secretions in the lungs or throat, feeding difficulties, and increased susceptibility to respiratory tract infections. The legs tend to be weaker than the arms and developmental milestones, such as lifting the head or sitting up, cannot be reached. In general, the earlier the symptoms appear, the shorter the lifespan. As the motor neuron cells deteriorate, symptoms appear shortly afterward. The severe forms of the disease are fatal and all forms have no known cure. The course of SMA is directly related to the rate of motor neuron cell deterioration and the resulting severity of weakness. Infants with a severe form of SMA frequently succumb to respiratory disease due to weakness in the muscles that support breathing. Children with milder forms of SMA live much longer, although they may need extensive medical support, especially those at the more severe end of the spectrum. The clinical spectrum of SMA disorders has been divided into the following five groups:

1) Type 0 SMA (In Utero SMA) is the most severe form of the disease and begins before birth. Usually, the first symptom of Type 0 SMA is reduced movement of the fetus that can first be observed between 30 and 36 weeks of pregnancy. After birth, these newborns have little movement and have difficulties with swallowing and breathing. 2) Type I SMA (Infantile SMA or Werdnig-Hoffmann disease) presents symptoms between 0 and 6 months, form of SMA is also very severe. Patients never achieve the ability to sit, and death usually occurs within the first 2 years without ventilatory support.

3) Type II SMA (Intermediate SMA) has an age of onset at 7-18 months. Patients achieve the ability to sit unsupported, but never stand or walk unaided. Prognosis in this group is largely dependent on the degree of respiratory involvement.

4) Type III SMA (Juvenile SMA or Kugelberg-Welander disease) is generally diagnosed after 18 months. Type 3 SMA individuals are able to walk independently at some point during their disease course but often become wheelchair-bound during youth or adulthood.

5) Type IV SMA (Adult onset SMA). Weakness usually begins in late adolescence in the tongue, hands, or feet, then progresses to other areas of the body. The course of adult SMA is much slower and has little or no impact on life expectancy.

All the forms of spinal muscular atrophy are accompanied by progressive muscle weakness and atrophy subsequent to the degeneration of the neurons from the anterior horn of the spinal cord. SMA currently constitutes one of the most common causes of infant mortality. It equally affects girls or boys in all regions of the world with a prevalence of between 1/6000 and 1/10 000.

Currently an effective treatment does not exist to check the neuronal degenerations. A

therapeutic approach for protecting the neurons from dying is the supply of neurotrophic proteins. Olesoxime has been investigated as a cytoprotective agent in clinical phase II. The supposed mechanism of action of Olesoxime is linked to the protection of the SMN neurons-deficient motor neurons from neurodegeneration.

A randomized double blind, placebo-controlled, phase 2 study on olesoxime (NTC01302600) was performed on SMA type II and type III patients aged 3 to 25 years. The trial showed that olesoxime lOOmg/ml oral liquid suspension formulation at a dose of lOmg/kg per day was well tolerated and demonstrated potential to maintain motor function. The outcome of the study seems to suggest that additional investigations may be beneficial for the development of olesoxime. Brief description of the figure:

Figure 1: Content of 4-cholstenone in composition Maisine CC®, oleic acid and Maisine

CC®/oleic acid

The present invention shows surprising stability, without exhibiting phenomena of precipitation of olesoxime. Furthermore the composition being a solution will avoid the risk of a change in the distribution of polymorphic content that may present in a suspension composition.

In addition the present invention avoids the degradation of olesoxime into hydroxylamine and 4- cholestenone, for which the level has to at the lowest level as possible. Hydroxylamine is potentially mutagen. WO 2008/142231 (A2) describes pharmaceutical compositions comprising olesoxime.

The present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate.

In a particular embodiment the invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In a particular embodiment the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-lineate.

In a particular embodiment the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-lineate and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

The nomenclature used in the present application is based on IPUAC systematic nomenclature, unless indicated otherwise. Various features and embodiments of the present invention are disclosed herein, however other features of the invention, modifications and equivalents will be apparent to a person skilled in the relevant art, based on the teachings provided. The invention described is not limited to the examples and embodiments provided, various alternatives equivalents will be appreciate by those skilled in the art. As used herein, the singular forms "a", "an" and "the" include the plural unless the context clearly dictates otherwise. For example, "a" individual will also include "individuals".

Unless otherwise defined, all technical and scientific terms used in the specification and claims have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

The term "antioxidant" denotes pharmaceutically acceptable excipients, which prevent oxidation of the active pharmaceutical ingredient. Antioxidants according to the invention comprise butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) , beta carotene,

Tetrahydroxy-l,4-benzoquinone (THBQ), ascorbic acid and vitamin E.

The term "bioavailability" denotes systemic availability (as measured by, for example, blood or plasma levels) of a given dose of drug administered to a patient. In one embodiment, bioavailability refers to the fraction of an administered dose of a compound that gets into the circulatory system and then is not metabolized, complexed or excreted before it can exert its intended biological effect. Methods of determining bioavailability include the balance, serum concentration, tracer, urine increment and target system effect methods.

The term "flavoring agent," as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. Flavoring agent is selected from the group consisting of a natural flavor, an artificial flavor, and mixtures thereof. Flavoring agents include, but are not limited to, mint, peppermint, cola, apple, vanilla, orange, peach, apricot, raspberry, cherry, honey, lemon, coconut, pineapple, strawberry banana, mixed red fruit and cream flavors and mixture thereof. In particular the flavoring agent of the present invention is strawberry flavor.

The term "food coloring agent" refers to any dye, pigment or substance that imparts color when added to a medicine, food or drink. In particular "food coloring agent" refers to Brilliant Blue FCF (E133), Indigotine (E132), Fast Green FCF (E143), Erythrosine (E127), Allura Red AC (E129), Tartrazine, (E102), Sunset Yellow FCF (El 10), Quinoline Yellow (E104), Carmoisine (E122), Ponceau 4R (E124), Patent Blue V (E131), Green S (E142), Carotenoids (E160, E161, E164), chlorophyllin (E140, E141), anthocyanins (E163), and betanin (E162), Annatto (E160b), Caramel coloring (E150a-d), Carmine (E120), Elderberry juice, Lycopene (E160d), Paprika (El 60c), Turmeric (El 00). An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non- human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human. In a particular embodiment of the invention the subject is a human with spinal muscular atrophy (SMA).

"Maisine™" refers a commercial product which comprises predominantly linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself being comprised of about 56% by weight linoleic acid, 30% oleic acid, about 10% palmitic and about 3% stearic acid constituents). The physical

characteristics of MAISINE [available from the company Etablissements Gattefosse, of 36, Chemin de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)] are: up to 10% (typically 3.9 to 4.9% or, in "substantially glycerol free" batches, about 0.2%) free glycerol; about 35% (typically 30 to 40% or, in "substantially glycerol free" batches, about 32 to 36%, for example about 36%) mono-glycerides; about 50% (or, in "substantially glycerol free" batches about 46 to 48%) di-glycerides; about 10% (or, in "substantially glycerol free" batches, about 12 to 15%) triglycerides; and about 1% free oleic acid.

Maisine® CC is glycerol monolinoleate that is liquid at 20°C which is of particular importance for one of the preferred embodiment of the present invention. The Maisine® CC is available from the company Etablissements Gattefosse, of 36, Chemin de Genas, P.O. Box 603, 69804 Saint- Priest, Cedex France. Its commercial code reference is 3431.

The term "pharmaceutical composition" (or "composition") and "pharmaceutical formulation" (or "formulation") ") are used interchangeably and denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with

pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

The term "pharmaceutically acceptable" denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. The term "pharmaceutically acceptable excipient" denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products. The term "package insert" denotes instructions customarily included in commercial packages of therapeutic products that comprise information about the indications, usage, dosage,

administration, contraindications and/or warnings concerning the use of such therapeutic products.

The term "sterile" denotes that a composition or excipient has a probability of being microbial contaminated of less than 10e-6.

The term "sweetener" refers to both bulk (caloric) and intense (non-caloric) sweeteners, which impart sweet taste to the preparation. Examples of bulk sweeteners are dextrose, fructose, glucose, hydrogenated glucose syrup, isomalt, maltitol, maltose, mannitol, sorbitol, sucrose, xylitol, , ribose, deoxyribose, neuraminic acid and mixtures thereof. Examples of intense sweeteners are acesulfame, alitame, aspartame, cyclamate, dihydrochalcone sweetener, monellin, neohesperidin, neotame, saccharin, stevioside, sucralose, the pharmaceutically acceptable salts thereof such as sodium or calcium saccharin, acesulfame potassium or sodium cyclamate, and mixtures thereof. Sweetener type, combination and proportion may be varied in various compositions. The terms "treating" or "treatment" of a disease state include inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

The term "spinal muscular atrophy" (or SMA) relates to a disease caused by an inactivating mutation or deletion in the SMN1 gene on both chromosomes, resulting in a loss of SMN1 gene function. Symptoms of SMA include muscle weakness, poor muscle tone, weak cry, weak cough, limpness or a tendency to flop, difficulty sucking or swallowing, difficulty breathing,

accumulation of secretions in the lungs or throat, clenched fists with sweaty hand,

flickering/vibrating of the tongue, head often tilted to one side, even when lying down, legs that tend to be weaker than the arms, legs frequently assuming a "frog legs" position, feeding difficulties, increased susceptibility to respiratory tract infections, bowel/bladder weakness, lower- than-normal weight, inability to sit without support, failure to walk, failure to crawl, and hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells.

The term "treating spinal muscular atrophy (SMA)" or "treatment of spinal muscular atrophy (SMA)" includes one or more of the following effects: (i) reduction or amelioration of the severity of SMA; (ii) delay of the onset of SMA; (iii) inhibition of the progression of SMA; (iv) reduction of hospitalization of a subject; (v) reduction of hospitalization length for a subject; (vi) increase of the survival of a subject; (vii) improvement of the quality of life of a subject; (viii) reduction of the number of symptoms associated with SMA; (ix) reduction of or amelioration of the severity of one or more symptoms associated with SMA; (x) reduction of the duration of a symptom associated with SMA; (xi) prevention of the recurrence of a symptom associated with SMA; (xii) inhibition of the development or onset of a symptom of SMA; and/or (xiii) inhibition of the progression of a symptom associated with SMA. More particular, "treating SMA" denotes one or more of the following beneficial effects: (i) a reduction in the loss of muscle strength; (ii) an increase in muscle strength; (iii) a reduction in muscle atrophy; (iv) a reduction in the loss of motor function; (v) an increase in motor neurons; (vii) a reduction in the loss of motor neurons; (viii) protection of SMN deficient motor neurons from degeneration; (ix) an increase in motor function; (x) an increase in pulmonary function; and/or (xi) a reduction in the loss of pulmonary function.

In detail, "treating SMA" results in the functional ability or helps retain the functional ability for a human infant or a human toddler to sit up unaided or for a human infant, a human toddler, a human child or a human adult to stand up unaided, to walk unaided, to run unaided, to breathe unaided, to turn during sleep unaided, or to swallow unaided.

The term "therapeutically effective amount" denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term "mg/kg" refers to the dose in milligram of olesoxime being used per kilogram of body weight of the mammal to be treated, in particular a human (i. e. a male or female human). For example, 20mg/kg means a dose of 20 milligram of olesoxime per kilogram of body weight of the mammal to be treated, in particular a human (i. e. a male or female human). The term "mg/ml" refers to the amount of olesoxime in milligram per volume of glyceryl mono- linoleate in milliliter.

The term "at more than lOmg/kg" as used herein may in particular refer to "at dose of more than lOmg/kg" or "at a dosage of more than lOmg/kg".

The term "at lOmg/kg to 30 mg/kg" as used herein may in particular refer to "at dose of lOmg/kg to 30 mg/kg" or "at a dosage of lOmg/kg to 30mg/kg".

The term "at lOmg/kg or 20 mg/kg" as used herein may in particular refer to "at dose of lOmg/kg to 20 mg/kg" or "at a dosage of lOmg/kg to 20mg/kg".

The term "at 20mg/kg" as used herein may in particular refer to "at a dose of 20 mg/kg" or "at a dosage of 20mg/kg". The term "active pharmaceutical ingredient" (or "API") denotes the compound or molecule in a pharmaceutical composition that has a particular biological activity.

Olesoxime according to the present invention refers to a compound of formula (I)

a mixture of compounds of formula (I')and formula(I")

also known as TR019622, CAS Number 22033-87-0, Cholest-4-en-3-one oxime,

[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]- 1,2,6,7,8,9,11,12, 14, 15, 16, 17-dodecahydrocyclopenta[a]phenanthren-3-ylidene]hydroxylamine or a mixture (NZ)-N-[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]- 1,2,6,7,8,9,11,12, 14, 15, 16, 17-dodecahydrocyclopenta[a]phenanthren-3-ylidene]hydroxylamine and (NE)-N-[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]- 1,2,6,7,8,9,11,12, 14, 15, 16, 17-dodecahydrocyclopenta[a]phenanthren-3-ylidene]hydroxylamine. Method of making and using the compound are described in EP 1601363 Al.

4-cholestenone as used herein refers to a compound of formula (X)

(X) and is also known as (+)-4-Cholesten-3-one, (17P)-17-Octylandrost-4-en-3-one, 3-Oxocholest-4-ene, 4-Cholesten-3-one, Cholesterone, NSC 134926, NSC 63000, A4-Cholesten-3-one, A4-Cholestenone or CAs Number 601-57-0.

In another embodiment the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for the treatment, delaying progression and/or the amelioration of spinal muscular atrophy (SMA).

In a particular embodiment, the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for the treatment, delaying progression and/or the amelioration, in particular for the treatment, of spinal muscular atrophy (SMA) in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In a particular embodiment, the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration, in particular for the treatment, of spinal muscular atrophy (SMA) in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In another embodiment the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use as therapeutically active substances for the treatment, delaying progression and/or the amelioration of spinal muscular atrophy (SMA).

In a particular embodiment, the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use as therapeutically active substances for the treatment, delaying progression and/or the amelioration, in particular for use as therapeutically active substances for the treatment, of SMA in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In another embodiment the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment delaying progression and/or the amelioration of SMA. In another embodiment the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment of SMA.

In a particular embodiment, the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration of SMA in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In a particular embodiment, the present invention provides a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment, for the treatment or for use as therapeutically active substances of SMA in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human). In a particular embodiment, the present invention provides a pharmaceutical composition as described above, comprises optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In a particular embodiment, the present invention provides a method of the treatment, delaying progression and/or the amelioration of SMA, which method comprises administering a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In another particular embodiment, the present invention provides the use of a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In another embodiment the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for the treatment, delaying progression and/or the amelioration of SMA.

In another embodiment the present invention provides a pharmaceutical composition consisting olesoxime and glyceryl mono-linoleate, for use as therapeutically active substances for the treatment, delaying progression and/or the amelioration of spinal muscular atrophy (SMA).

In another embodiment the present invention provides a pharmaceutical composition consisting olesoxime and glyceryl mono-linoleate, for use in the treatment delaying progression and/or the amelioration of SMA.

In another embodiment the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for SMA.

In a particular embodiment, the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration of SMA in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In a particular embodiment, the present invention provides a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for use as therapeutically active substances for the treatment, delaying progression and/or the amelioration, in particular for use as therapeutically active substances for the treatment, of SMA in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

In a particular embodiment, the present invention provides a pharmaceutical composition as described above, consisting of optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In a particular embodiment, the present invention provides a method of the treatment, delaying progression and/or the amelioration of SMA, which method comprises administering a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

In another particular embodiment, the present invention provides the use of a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent. In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described herein wherein the glyceryl mono-linoleate is Maisine™, in particular Maisine CC®

In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described above wherein the SMA is type II SMA or/and type III SMA in mammal, more particularly type II and III SMA.

In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described above wherein olesoxime is being administered orally.

In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described above wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg, even more particularly at lOmg/kg or 20mg/kg, most particularly at 20mg/kg. In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described above wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

In more particular embodiment, the invention provides the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition as described above wherein olesoxime is being administered orally at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

In another embodiment, the invention provides a kit comprising a composition as described therein, prescribing information also known as "leaflet", a bottle (HDPE or glass) and a container. The prescribing information preferably includes the advice to patient regarding the administration of the olesoxime of lOmg/kg per day,20mg/kg per day or 30mg/kg per day with food, more particularly of 20mg/kg per day with food, especially to improve the bioavailability. More particularly the prescribing information preferably includes the advice to patient regarding the administration of the olesoxime twice a day of lOmg/kg or 15mg/kg per dose with food, especially to improve the bioavailability.

In a further embodiment, the invention provides a kit comprising a bottle (in particular an amber glass bottle, more particularly a glass bottle with UV filter) containing a composition as described herein, in particular containing olesoxime (in particular 6.8 g of olesoxime) and glyceryl mono-linoleate (in particular maisine CC®, more particularly 57.5 g of maisine CC®), a Press in Bottle Adaptor (PIBA), an oral dispenser (in particular a syringe) and prescribing information also known as "leaflet". The prescribing information preferably includes the advice to patient regarding the administration of the olesoxime of lOmg/kg per day or 20mg/kg per day with food, more particularly of 20mg/kg per day with food, especially to improve the

bioavailability.

In a further embodiment, the invention provides a kit comprising a bottle (in particular an amber glass bottle, more particularly a glass bottle with UV filter) containing a composition as described herein, in particular containing olesoxime (in particular 6.8 g of olesoxime) and glyceryl mono-linoleate (in particular maisine CC®, more particularly 57.5 g of maisine CC®), a Press in Bottle Adaptor (PIBA), an oral dispenser (in particular a syringe) and prescribing information also known as "leaflet". The prescribing information preferably includes the advice to patient regarding the administration of the olesoxime twice a day, of lOmg/kg in the morning with food and of lOmg/kg in the evening with food, especially to improve the bioavailability.

In a further embodiment, the invention provides a kit comprising a bottle (in particular an amber glass bottle, more particularly a glass bottle with with UV filter) containing a composition as described herein, in particular containing olesoxime (in particular 6.8 g of olesoxime) and glyceryl mono-linoleate (in particular maisine CC®, more particularly 57.5 g of maisine CC®), a Press in Bottle Adaptor (PIBA), an oral dispenser (in particular a syringe) and prescribing information also known as "leaflet". In particular, the bottle according to the kit is enclosed in a packaging (particularly aluminum foil package) with oxygen scavenger or oxygen absorber (for example ascorbate, sodium hydrogen carbonate). The prescribing information preferably includes the advice to patient regarding the administration of the olesoxime of lOmg/kg per day or 20mg/kg per day with food, more particularly of 20mg/kg per day with food, especially to improve the bioavailability.

In a further embodiment, the invention provides a kit comprising a bottle (in particular an amber glass bottle, more particularly a glass bottle with with UV filter) containing a composition as described herein, in particular containing olesoxime (in particular 6.8 g of olesoxime) and glyceryl mono-linoleate (in particular maisine CC®, more particularly 57.5 g of maisine CC®), a Press in Bottle Adaptor (PIBA), an oral dispenser (in particular a syringe) and prescribing information also known as "leaflet". In particular, the bottle according to the kit is enclosed in a packaging (particularly aluminum foil package) with oxygen scavenger or oxygen absorber (for example ascorbate, sodium hydrogen carbonate). The prescribing information preferably includes the advice to patient regarding the administration of the olesoxime twice a day, of lOmg/kg in the morning with food and of lOmg/kg in the evening with food, especially to improve the bioavailability.

According to the invention, i.e. the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition, olesoxime can be present in the pharmaceutical composition as herein described in a concentration ranging from 10 to 140 mg/ml of olesoxime in solution, particularly from 25 to 120 mg/ml of olesoxime in solution, more particularly from 50 to 100 mg/ml of olesoxime in solution, most particularly at 100 mg/mL of olesoxime in solution. In a further embodiment of the invention, i.e. the pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition, olesoxime can be present in the pharmaceutical composition as herein described in a concentration ranging from 60 to 80 mg/ml of olesoxime in solution, particularly at 75 mg/mL of olesoxime in solution.

The mammal according to the invention in particular is a human, more particularly a male or female human. The human can be of any race (e. g. , Caucasian or Oriental).

In particular embodiments, the methods, the uses, pharmaceutical compositions in accordance with the present invention, olesoxime is administered once a day or twice a day, in particular twice a day, more particularly with food, most particularly with the evening meal.

The compositions according to the present invention can be in the form of gelatin capsules or other solid form which can comprise a liquid phase or drinkable solution.

In particular embodiments, the methods, the uses, pharmaceutical compositions in accordance with the present invention, the olesoxime is made as a ready to use solution. The pharmaceutical composition can be made by weighting the required dose of olesoxime, in particular 10 g into a beaker or a flask and adding the appropriate volume of Maisine CC®, in particular 87.4 ml to obtain the appropriate concentration, in particular lOOmg/ml after having been stirred until clear solution is being obtained at room temperature.

Alternatively the pharmaceutical composition can be made by weighting the required dose of olesoxime, in particular 75 g into a beaker or a flask and adding the appropriate volume of Maisine CC®, in particular 927 ml to obtain the appropriate concentration, in particular

75mg/ml after having been stirred until clear solution is being obtained at room temperature.

The following example is intended merely to illustrate the practice of the present invention and is not provided by way of limitation.

The following abbreviations and definitions are used: Acetonitrile (MeCN);Below Limit of Detection (BLD); Below the Limit of Quantitation (BLQ); Ethanol (EtOH); Fasted State

Simulated Intestinal Fluid (FaSSIF); Fed State Simulating Intestinal Fluid (FeSSIF); g (gram); h (hour); HC1 (hydrochloric acid); M (Molar); mL (milliliter); NaOH (Sodium hydroxide);

Polyethylene Glycol 400 (PEG 400) Revolutions Per Minute (rpm); Relative Humidity (RH); Simulated Gastric Fluid (SGF); THF (tetrahydrofuran); Ultra Performance Liquid Chromatography (UPLC);

Example 1: Solubility test of olesoxime in different solvent

Weighing of olesoxime in a UPLC (waters 186000307C) glass vial, addition of a stirring bar (15x3mm), addition 1ml of vehicle and close the vial. Stir at room temperature for 24h [samples 28, 35, 36 hours are stirred at 37°C (too viscous at room temperature)] .Visual control after 24h and addition of olesoxime in case of complete dissolution. After 24h all samples were centrifuged (1x5' 3000 rpm, 1x15' 3500 rpm at 30°C).

Supernatant were filter through an ultrafree PVDV centrifugal filter (Centrifugal filter units (ultra free MCHV PVDV 0.45 urn Millipore UF30HVNB), 10 minutes at 8000 rpm, several times for some viscous samples, and then diluted with THF/MeCN 20%-80%. Analysis of the diluted solutions with UPLC.

Table 1:

Example 2: Formulation of solutions

Solution in pure Maisine CC® :

100.0 g of Olesoxime were incorporated in a 000 ml flask,. A first large portion of Maisine CC ® was poured into the 000 ml flask. Olesoxime and Maisine CC® were stirred with magnetic stirrer during 60 minutes. The volume has been topped up to the 000 ml mark of the flask with Maisine CC®. Table 2 shows the composition of the formulation.

Table 2: Composition of Olesoxime solution in Maisine for a 75 ml solution (lOOmg/ml)

Solution in pure Oleic acid : 100.0 g of Olesoxime were incorporated in a 000 ml flask,. A first large portion of Oleic acid was poured into the 000 ml flask. Olesoxime and Oleic acid were stirred with magnetic stirrer during 40 minutes. The volume has been topped up to the 000 ml mark of the flask with Oleic acid Table 3 shows the composition of the formulation. Table 3: Composition of Olesoxime solution in Oleic acid for a 75 ml solution (lOOmg/ml)

Solution in a 50/50 mixture of Maisine and Oleic acid :

100.0 g of Olesoxime were incorporated in a 000 ml flask. A first large portion of a 50/50 mixture of Oleic acid and Maisine (prepared beforehand) was poured into the 000 ml flask. Olesoxime and the solvent mixture were stirred with magnetic stirrer during 60 minutes. The volume has been topped up to the 000 ml mark of the flask with the solvent mixture. Table 4 shows the composition of the formulation.

Table 4: Composition of Olesoxime solution in Maisine/oleic acid for a 75 ml solution

(lOOmg/ml)

Solution in pure Maisine CC®

75.0 g of Olesoxime were incorporated in a 000 ml flask,. A first large portion of Maisine CC ® was poured into the 000 ml flask. Olesoxime and Maisine CC® were stirred with magnetic stirrer during 60 minutes. The volume has been topped up to the 000 ml mark of the flask with Maisine CC®. Table 5 shows the composition of the formulation. Table5: Composition of Olesoxime solution in Maisine for a 75 ml solution (75 mg/ml) Olesoxime weight 7.50 g

Weight of Maisine CC 87.14 g

Weight of 75ml solution 94.64

Example 3: Effect of water on the compositions of olesoxime

The present example was made to check how under normal use the composition will behave while being in contact with water. The three compositions were made as follows:

Oleci acid: addition of 7.5 g of Olesoxime to 59.5g of Oleic acid, stirring for 30 minutes, to obtain 75 ml of lOOmg/ml homogeneous solution

Oleic acid and Maisine CC® (50/50): addition of 7.5 g of Olesoxime to 30.4 g of Oleic acid and 30.4 g of Maisine CC®, stirring for 40 minutes, to obtain 75ml of lOOmg/ml homogeneous solution

Maisine CC®: addition of 7.5 g of Olesoxime to 63 g of Maisine CC®, stirring for 60 minutes, to obtain 75ml of lOOmg/ml homogeneous solution

Following the addition of 1.8ml of water to the above compositions, representing the 30 days use of the solution, the Oleic acid composition resulted in an Emulsion after 24h, Oleic acid and Maisine CC® resulted in an emulsion and precipitate in the bottom (homogeneous mixture of solidified excipient and Olesoxime), while the Maisine CC® composition remained clear after 24 hours.

Example 4 : Stability results

Solutions were prepared according to example 2 and were exposed to the condition mentioned in the table 5. 4-Cholestenone was detected by standard HPLC methods after the periods mentioned in Table 6. Hydroxylamine quantity is linked to the amount of 4-chlostenone. Table 6: content of 4-cholstenone

The stability results show a fast increase in the cholestenone impurity level in presence of oleic acid in the formulation. Oleic acid based formulations have thus been discarded.

Claims

1. A pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate.

2. A pharmaceutical composition consisting of olesoxime and glyceryl mono-lineate.

3. A pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration of spinal muscular atrophy.

4. The pharmaceutical composition for use according to claim 3, in the treatment of spinal muscular atrophy (SMA).

5. The pharmaceutical composition for use according to any one of claims 3 to 4, in the treatment, delaying progression and/or the amelioration of spinal muscular atrophy in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

6. The pharmaceutical composition according to any one of claims 1 to 5, which comprises or consists of in addition optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

7. A method of the treatment, delaying progression and/or the amelioration of spinal

muscular atrophy, which method comprises administering a pharmaceutical composition comprising olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

8. A use of a pharmaceutical composition comprising olesoxime and glyceryl mono- linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

9. A pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration of spinal muscular atrophy.

10. The pharmaceutical composition for use according to claim 9, consisting of olesoxime and glyceryl mono-linoleate, in the treatment of spinal muscular atrophy.

11. A pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, for use in the treatment, delaying progression and/or the amelioration of spinal muscular atrophy (SMA) in mamal,(in particular a mammal in need thereof), particularly wherein the mammal is a human (such as a male or female human).

12. The pharmaceutical composition according to any one of claims 9 to 11, further consisting of optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

13. A method of the treatment, delaying progression and/or the amelioration of spinal

muscular atrophy (SMA), which method comprises administering a pharmaceutical composition consisting of olesoxime and glyceryl mono-linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

14. A use of a pharmaceutical composition consisting of olesoxime and glyceryl mono- linoleate, and optionally one or more antioxidant, one or more food coloring agent, one or more sweetener and/or one or more flavoring agent.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the glyceryl mono-linoleate is Maisine CC®.

16. The pharmaceutical composition according to any one of claims 1 to 2 wherein

olesoxime is being administered orally.

17. The pharmaceutical composition according to any one of claims 1 to 2 or 16wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg, even more particularly at lOmg/kg or 20mg/kg, most particularly at 20mg/kg.

18. The pharmaceutical composition according to any one of claims 1 to 2, 16 or 17 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

19. The pharmaceutical composition according to any one of claims 1 to 2or 16 to 18wherein olesoxime is being administered orally at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

20. The pharmaceutical composition for use according to any one of claims 3 to 6 or 9 to 12, wherein the glyceryl mono-linoleate is Maisine CC®.

21. The pharmaceutical composition for use to any one of claims 3 to 6, 9 to 12 or 20

wherein the SMA is type II SMA or/and type III SMA in mammal, more particularly type

II and III SMA.

22. The pharmaceutical composition for use according to any one of claims to any one of claims 3 to 6 or 9 to 12, 20 or 21 wherein olesoxime is being administered orally.

23. The pharmaceutical composition for use according to any one of claims to any one of claims 3 to 6 or 9 to 12, 20 to 22 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg, even more particularly at lOmg/kg or 20mg/kg, most particularly at 20mg/kg.

24. The pharmaceutical composition for use according to any one of claims to any one of claims 3 to 6 or 9 to 12, 20 to 23 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

25. The pharmaceutical composition for use according to any one of claims to any one of claims 3 to 6 or 9 to 12, 20 to 24 wherein olesoxime is being administered orally at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

26. The method of use according to any one of claims 7 or 13, wherein the glyceryl mono- linoleate is Maisine CC®.

27. The method of use according to any one of claims 7, 13 or 26 wherein the SMA is type II SMA or/and type III SMA in mammal, more particularly type II and III SMA.

28. The method of use according to any one of claims 7, 13, 26 or 27 wherein olesoxime is being administered orally.

29. The method of use according to any one of claims 7, 13 or 26 to 28 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg, even more particularly at lOmg/kg or 20mg/kg, most particularly at 20mg/kg.

30. The method of use according to any one of claims 7, 13 or 26 to 29 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

31. The method of use according to any one of claims 7, 13 or 26 to 30 wherein olesoxime is being administered orally at a dose of lOmg/kg to 30mg/kg per day, even more

particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

32. The use of the pharmaceutical composition according to any one of claims 8 or 14,

wherein the glyceryl mono-linoleate is Maisine CC®.

33. The use of the pharmaceutical composition according to any one of claims 8, 14 or 32, wherein the SMA is type II SMA or/and type III SMA in mammal, more particularly type

II and III SMA.

34. The use of the pharmaceutical composition according to any one of claims 8, 14, 32 or 33, wherein olesoxime is being administered orally.

35. The use of the pharmaceutical composition according to any one of claims 8, 14, 32 to 34, wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg, even more particularly at lOmg/kg or 20mg/kg, most particularly at 20mg/kg.

36. The use of the pharmaceutical composition according to any one of claims 8, 14, 32 to 3435 wherein olesoxime is being administered at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

37. The use of the pharmaceutical composition according to any one of claims 8, 14, 32 to 3436 wherein olesoxime is being administered orally at a dose of lOmg/kg to 30mg/kg per day, even more particularly at lOmg/kg per day or 20mg/kg per day, most particularly at 20mg/kg per day.

38. A kit comprising a bottle containing a composition according to claims 1 to37, in

particular containing olesoxime and glyceryl mono-linoleate, a Press in Bottle Adaptor, an oral dispenser and prescribing information also known as "leaflet".

39. .The pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition, olesoxime can be present in the pharmaceutical composition according to any one of claims 1 to 37 in a concentration ranging from 10 to 140 mg/ml of olesoxime in solution, particularly from 25 to 120 mg/ml of olesoxime in solution, more particularly from 50 to 100 mg/ml of olesoxime in solution, most particularly at 100 mg/mL of olesoxime in solution.

40. The pharmaceutical composition, the pharmaceutical composition for use, the method of use, or the use of the pharmaceutical composition, olesoxime can be present in the pharmaceutical composition according to any one of claims 1 to 37 in a concentration ranging from 60 to 80 mg/ml of olesoxime in solution, particularly at 75 mg/mL of olesoxime in solution.

41. The invention as hereinbefore described.