Method for treating nonsense mutation mediated duchenne muscular dystrophy in pediatric patients

Abstract

To provide a method for ameliorating or managing nonsense mutation mediated Duchenne muscular dystrophy (nmDMD) in a pediatric patient.SOLUTION: Provided is a method for ameliorating or managing nonsense mutation mediated nmDMD in a pediatric patient, the method comprising administering an effective amount of ataluren to the patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application was filed on April 10, 2019, the contents of which are incorporated herein by reference. Priority is claimed to filed U.S. Provisional Application No. 62 / 831,931.

[0002] (Field) Nonsense mutation-mediated Duchenne myocardial infarction in pediatric patients in need A method for ameliorating or managing nmDMD, comprising administering an effective amount of Provided herein are methods comprising administering taluren to the patient. [Background technology]

[0003] (background) Nonsense mutation Duchenne muscular dystrophy (nmDMD) causes muscle dysfunction and impaired mobility. A rare X-linked disorder that results in decreased mobility and early death due to respiratory or cardiac failure Sexual disorder 1,2,3 Approximately 10-15% of boys with DMD have a mutation in the DMD gene. Contains a nonsense mutation that results in a stop codon and loss of functional dystrophin protein are 1,4,5,6 Loss of dystrophin production causes muscle fibers to shrink due to repeated contractions. This can cause tears, which can lead to muscle damage and wasting, ultimately resulting in progressive loss of function. leads to 7 Ataluren inhibits ribosomal reading of the premature termination codon in the DMD gene. promotes read-through, allowing the formation of full-length functional dystrophin protein It is the only treatment option that addresses the underlying cause of nmDMD. 8,9 ,10,11 .

[0004] Infants and boys with nmDMD have significantly elevated serum creatine kinase levels at birth. and have a history of gross and fine motor skills before the age of 3 years compared with age-matched peers The onset of nmDMD occurs before birth, demonstrating a measurable deficit in motor function. It is known that 14 Substantial damage caused by the pathological absence of dystrophin Early intervention in the disease process of nmDMD, before muscle weakness and fibrosis progress, is crucial. The importance of DM has been noted by the US Food and Drug Administration (FDA). Dystrophin restoration therapy at an earlier age, before the development of characteristic symptoms of D-related damage The start of the 10,14,15,16,17 At age under 5 If ataluren could be used for dystrophin restoration therapy, it would be possible to prevent the unstoppable dystrophin-related complications associated with DMD. This may ensure that function is maintained for a longer period despite a slight decline, This will fulfill an urgent unmet medical need. Summary of the Invention

[0005] (overview) In one embodiment, nonsense-mediated Duchenne muscular dystrophy (nmD) A method for improving or managing nmDMD in a human pediatric patient with nmDMD. Patients aged 2 years or older and less than 5 years old are given a therapeutically effective amount of atalure based on the patient's weight. Oral administration of at least about 1 μg / mL to about 20 μg / mL over a 24-hour period The method includes achieving an average plasma concentration in the range of L.

[0006] In another embodiment, nonsense-mediated Duchenne muscular dystrophy (nm The method was to improve or manage nmDMD in human pediatric patients. Therapeutic effective doses based on patient weight are administered to patients aged 6 months or older and less than 2 years. of ataluren orally administered to a patient in need thereof, the patient's daily dose is at least about 1 μg / mL to about 2 μg / mL over a 24-hour period. The method of any of the methods provided herein, comprising achieving a mean plasma concentration in the range of 0 μg / mL. will be done.

[0007] In one embodiment, the approved therapeutically effective amount of ataluren is 40 mg / kg based on the patient's weight. kg / day of ataluren; wherein the mean plasma concentration achieved in the patient is The range of the present invention is from about 1 μg / mL to about 20 μg / mL for a period of time. In another embodiment provided, the therapeutically effective amount of 40 mg / kg / day is 10 mg / kg It is administered as a morning dose of 10 mg / kg, a midday dose of 10 mg / kg, and an evening dose of 20 mg / kg; wherein the period between the morning dose and the midday dose is 6 hours; and the period between the midday dose and the evening dose is , 6 hours; and the period between the evening dose and the following morning dose is 12 hours.

[0008] In another embodiment, the therapeutically effective amount of ataluren is about 80 mg / kg of the patient's body weight. g / day of ataluren; wherein the mean plasma concentration achieved in the patient is The range of the present invention is from at least about 1 μg / mL to about 20 μg / mL over a period of time. In another embodiment provided, the therapeutically effective amount of about 80 mg / kg / day is 20 mg / kg It was administered as a morning dose of 20 mg / kg, a midday dose of 20 mg / kg, and an evening dose of 40 mg / kg; wherein the period between the morning dose and the midday dose is 6 hours; and the period between the midday dose and the evening dose is , 6 hours; and the period between the evening dose and the following morning dose is 12 hours.

[0009] In another embodiment provided herein, the dose is optionally administered within 30 minutes of a meal. It is given.

[0010] In one embodiment provided herein, a method for treating nmDMD in a human pediatric patient with nmDMD is A therapeutically effective amount administered in a method for improving or managing muscle stiffness is: i) a dose that is administered to the muscle of the patient; ii) improving the expression of dystrophin protein in the mouse; ii) timed functional test (ti Improving patient performance on a med function test iii) Improve patient performance in gait or quality of life assessments. and iv) improving or managing the onset, progression, and / or worsening of locomotor decline. and (v) the onset and progression of cardiopulmonary decline associated with nmDMD and the absence of dystrophin. ameliorating or managing the progression and / or worsening of the cardiac functions associated with nmDMD; ameliorating or managing the onset, progression, and / or worsening of cognitive decline; and vii) ameliorate or prevent the onset, progression, and / or worsening of lung function decline associated with nmDMD The present invention provides an effect selected from the group consisting of: [Brief explanation of the drawings]

[0011] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]Figure 1A shows the difference in mean time to complete a timed functional test of descending four steps at baseline and at weeks 28 and 52; Figure 1B shows the difference in mean time to complete a timed functional test of climbing four steps at baseline and at weeks 28 and 52; Figure 1C shows the difference in mean time to complete a timed functional test of standing from a supine position at baseline and at weeks 28 and 52; Figure 1D shows the difference in mean time to run / walk 10 meters at baseline and at weeks 28 and 52.

[0012] [Figure 2] Figure 2A shows the results of the 16-item NSAA (Northstar Ambulatory Assessment); Figure 2B shows the results of the 8-item NSAA; and Figure 2C shows the results of the 3-item NSAA. The mean (SD) value (n=13) of the 3-item NSAA total score at week 28 was 5.8 (±0.38), a 10.26% improvement from the baseline value of 5.4 (±0.65). DETAILED DESCRIPTION OF THE INVENTION

[0013] (Detailed explanation) In one embodiment, nonsense-mediated Duchenne muscular dystrophy (nmD) A method for improving or managing nmDMD in a human pediatric patient with nmDMD. Patients aged 2 years or older and less than 5 years are given a therapeutically effective dose of ataluren based on the patient's weight. Orally administered, the dose ranges from at least about 1 μg / mL to about 20 μg / mL over a 24-hour period. The method includes achieving a mean plasma concentration within the range.

[0014] In another embodiment, nonsense-mediated Duchenne muscular dystrophy (nm The method was to improve or manage nmDMD in human pediatric patients. In patients aged 6 months or older and less than 2 years, a therapeutically effective dose of attacin based on the patient's weight is administered. Oral administration of luren to a patient receiving at least about 1 μg / mL to about 20 μg of luren over a 24-hour period The method provided herein comprises achieving an average plasma concentration in the range of 1 / mL. .

[0015] In one embodiment, the approved therapeutically effective amount of ataluren is 40 mg / kg based on the patient's weight. kg / day of ataluren; wherein the mean plasma concentration achieved in the patient is The range of the present invention is from about 1 μg / mL to about 20 μg / mL for a period of time. In another embodiment provided, the therapeutically effective amount of 40 mg / kg / day is 10 mg / kg It is administered as a morning dose of 10 mg / kg, a midday dose of 10 mg / kg, and an evening dose of 20 mg / kg; wherein the period between the morning dose and the midday dose is 6 hours; and the period between the midday dose and the evening dose is , 6 hours; and the period between the evening dose and the following morning dose is 12 hours.

[0016] In another embodiment, the therapeutically effective amount of ataluren is about 80 mg / kg of the patient's body weight. g / day of ataluren; wherein the mean plasma concentration achieved in the patient is The range of the present invention is from at least about 1 μg / mL to about 20 μg / mL over a period of time. In another embodiment provided, the therapeutically effective amount of about 80 mg / kg / day is 20 mg / kg It was administered as a morning dose of 20 mg / kg, a midday dose of 20 mg / kg, and an evening dose of 40 mg / kg; wherein the period between the morning dose and the midday dose is 6 hours; and the period between the midday dose and the evening dose is , 6 hours; and the period between the evening dose and the following morning dose is 12 hours.

[0017] In another embodiment provided herein, the dose is optionally administered within 30 minutes of a meal. It is given.

[0018] In one embodiment provided herein, a method for treating nmDMD in a human pediatric patient with nmDMD is A therapeutically effective amount administered in a method for improving or managing muscle stiffness is: i) a dose that is administered to the muscle of the patient; ii) improve the expression of dystrophin protein in timed functional assays; iii) improve the patient's performance in gait assessment or quality of life assessment; iv) To improve the patient's performance in the field of gait rehabilitation; ameliorating or managing the progression and / or worsening of nmDMD and dystrophin dysfunction; Ameliorate or manage the onset, progression, and / or worsening of cardiopulmonary decline associated with the presence (vi) ameliorating the onset, progression, and / or worsening of cardiac dysfunction associated with nmDMD. and vii) the development of nmDMD-related lung function decline. and / or improving or managing the progression and / or deterioration of the disease. Provide.

[0019] (definition) As used herein, the term "atalurene" refers to a compound of formula (I): [ka] 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazolium] It refers to the compound [benzoic acid]-3-yl.

[0020] In one embodiment provided herein, ataluren is a compound of the formula (I) or (II) of the formula (II ... No. 6,992,096, U.S. Pat. ... No. 7,202,262, U.S. Pat. No. 7,419,991, U.S. Pat. No. 8,227,499 No. 4, U.S. Patent No. 8,486,982, U.S. Patent No. 8,975,287, U.S. Patent No. No. 9,205,088, U.S. Pat. No. 10,071,081, U.S. Pat. No. 7,863,4 56, U.S. Patent No. 8,101,641, U.S. Patent No. 8,394,966, U.S. Patent No. 8,691,511, U.S. Pat. No. 8,748,625, U.S. Pat. No. 9,309,2 No. 06, U.S. Patent No. 10,028,939, U.S. Patent No. 7,678,922, U.S. Patent Nos. 8,129,540 and 8,367,841. can be prepared or characterized by

[0021] In another embodiment provided herein, ataluren is a compound selected from the group consisting of benzodiazepines, ... Nos. 7,772,259, 8,799,000, and 8,799,000, which are incorporated herein by reference. No. 6,322, U.S. Patent No. 9,861,617, U.S. Patent No. 8,716,321, U.S. Patent No. US Patent No. 9,474,743, US Patent No. 10,034,863, US Patent No. 7,6 83,082, U.S. Patent No. 8,017,636, U.S. Patent No. 8,183,782, U.S. Patent No. 8,299,105, U.S. Patent No. 9,226,919, U.S. Patent No. 9,5 22,137, U.S. Patent No. 9,737,513, U.S. Patent No. 9,877,952, and can be used by the method described in US Pat. No. 10,172,836.

[0022] In another embodiment provided herein, ataluren inhibits the transcription of dystrophin in the dystrophin gene. in the DMD gene after the presence of a nonsense mutation was determined by genetic testing. It is indicated for the treatment of Duchenne muscular dystrophy, which is caused by a nonsense mutation in On July 31, 2014, the European Medicines Agency (EMA) The approval of ataluren for the treatment of children with nmDMD, as demonstrated by the study, is supported by the Clinical Based on the results of numerous clinical trials from studies posted to Trials.gov there were: [Table 1]

[0023] In particular, the NCT00264888 Phase 2a clinical trial is investigating the potential of dystrophin restoration therapy The feasibility of using ataluren was demonstrated in NCT005, which was conducted in 174 patients with nmDMD. A randomized, double-blind, placebo-controlled, dose-ranging, multicenter Phase 2b study of 92553 demonstrated favorable benefits. The fit / risk ratio and safety profile of ataluren consistent with previous studies showed 9,11 NCT01826 was conducted in boys with nmDMD aged approximately 7 to approximately 16 years. 487 Results of a multicenter, randomized, double-blind, placebo-controlled phase 3 trial showed that ataluren was generally well tolerated. The study showed that ataluren was well tolerated, supporting its benefit in preserving muscle function. 12,1 3 .

[0024] In another embodiment provided herein, ataluren is used to treat Miyoshi myopathy (Wang , J. et al., "Function of dysferlin-deficient human myotubes by nonsense suppression" Membrane blebbing as an assessment of rescue n assessment of functional rescue of dyspraxia ferlin-deficient human myotubes via nons ense suppression), J. Appl. Physiol., 20 10, 109, 901-905); Childhood neuronal ceroid lipofuscinosis (INC) L) (Sarkar, C. et al., "Stop codon readthrough at PTC124 Palmitoyl-protein thioesterase-1 in cultured cells from patients with INCL Induce cytotoxicity, reduce thioester load, and inhibit apoptosis (Stop coagulation) don read-through with PTC124 induces pal mitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses ap optosis in cultured cells from INCL pati ents)”, Mol. Genet. Metab., 2011, 104 (3 ), 338-345); Late-onset childhood ceroid lipofuscinosis (LINCL) (M J. Iller et al., "Nansen in Neuronal Ceroid Lipofuscinosis" The role of nonsense-mediated degradation decay in neuronal ceroid lipofuscinosis )”, Human Molecular Genetics, 2013, 22 ( 13) 2723-2734); ataxia-telangiectasia (Du, L. et al., " A new series of small molecules blocks all three nonsense mutations in the ATM gene A new series of small moles ular weight compounds induce read throug h of all three types of nonsense mutatio ns in the ATM gene)”, Mol. Therapy, 2013 , 21(9), 1653-1660); Usher syndrome (USCH1C) (Gol dmann, T. et al., "Nonsense mutations causing Usher syndrome type 1C" PTC124-mediated translation read-through rational readthrough of a nonsense mutat ion causing Usher syndrome type 1C)”, Hu man Gene Therapy, May 2011, 22, 537-547; and Goldmann, T. et al., "Translation for the Treatment of USH1C Nonsense Mutations" Comparative evaluation of lead-through efficacy among NB30, NB54, and PTC124 (A comparative evaluation of NB30, NB54 and PTC124 in translational read-through ef ficacy for treatment of an USH1C nonsens EMBO Mol. Med., 2012, 4, 11 86-1199); Long QT syndrome (Yu, H. et al., "Long QT syndrome-related Aminoglycosides and HERG inhibitors for rescuing nonsense mutations in the HERG gene Comparison of read-th rough effects of aminoglycosides and PTC 124 on rescuing nonsense mutations of HE RG gene associated with long QT syndrome )”, Intl. Journal of Mol. Med., 2014, 33 , 729-735; Pseudoxanthoma elasticum (Zhou, Y. et al., "ABCC6 Premature stop codon readthrough in the gene: A promising treatment for pseudoxanthoma elasticum (Pr emature Termination Codon Read-Through i n the ABCC6 Gene: Potential Treatment fo r Pseudoxanthoma Elasticum)”, Journal of Investigat. Derm., 2013, 133, 2672-2677 xeroderma pigmentosum (Kuschal, C. et al., "Translational readout of premature stop codons"); Repair of UV light damage in xeroderma pigmentosum group C cells induced by rue of UV photolesions in xeroderma pigment osum group C cells induced by translation nal readthrough of premature termination codons)”, PNAS, 2013, 110 (48), 19483-1 9488); Total choroidal atrophy (Moosajee, M. et al., "Total choroidal atrophy" Clinical utility gene cards rd for: Choroideremia)”, European Journa l of Human Genetics, 2014, 22, e1-e4);Muji Chromosome atrophy (Gregory-Evans, CY et al., "Postnatal manipulation of Pax6 levels" Reversing congenital histopathological defects (Postnatal manipulation) on of Pax6 dosage reverses congenital ti ssue malformation defects)”, J. Clin. In vest., 2014, 124(1), 111-116); Hereditary pulmonary arterial hypertension (Drake, KM et al., "Ataluren in Pulmonary Arterial Hypertension" Correction of nonsense BMPR2 and SMAD9 mutations nsense BMPR2 and SMAD9 Mutations by Atal uren in Pulmonary Arterial Hypertension) ”, Am. J. Respir. Cell Mol. Biol., 2013 September, 49 (3), 403-409); Carnitine palmitoyltransferase CPT1A deficiency (Tan, L. et al., "PTC124 is a CPT1A R160X nan Improved readthrough of sense mutations and increased enzyme activity (PTC124 impr oves readthrough and increases enzymatic activity of the CPT1A R160X nonsense mu tation)”, J. Inherit. Metabol. Dis., 201 1, 34, 443-447); propionic acidemia (Sanchez-Alcudia , R. et al., "Nonsense as a Novel Therapeutic Approach in Propionic Acidemia" Feasibility of Nonsense Mutation ation Readthrough as a Novel Therapeutic al Approach in Propionic Acidemia)”, Hum an Mutation, 2012, 33, 973-980); Maroteaux-Lamy Syndrome MPS VI (Bartolomeo, R. et al., "Mucopolysaccharidosis VI" Pharmacological readthrough of nonsense ARSB mutations as a promising therapeutic approach armacological read-through of nonsense A RSB mutations as a potential therapeutic approach for mucopolysaccharidosis VI) , J. Inherit. Metab. Dis., 2013, 36, 363 , 371); Hurler syndrome (Keeling, unpublished); or Shwachman-Dai Shwachman-Diamond syndrome in bone marrow Restoration of Diamond syndrome protein function by ataluren (Ataluren-dri) ven restoration of Shwachman‐Bodian‐Diam ond syndrome protein function in Shwachm ``Diamond bone syndrome marrow)'', Ameri can Journal of Hematology, April 2018, 93(4 ), 527-536) to improve a disease or disorder mediated by a nonsense mutation selected from the group consisting of It has demonstrated therapeutic activity in preventing or managing

[0025] In another aspect provided herein, ataluren is used to treat color blindness, adrenoleukodystrophy, Fee, Alagille syndrome, Alport syndrome, aniridia, ataxia-telangiectasia, Autosomal dominant polycystic kidney disease (ADPKD), Charcot-Marie-Tooth syndrome (X-linked chain type), cancer, Cowden disease, Darier's disease, Emery-Dreifuss muscular dystrophy, epidermis Hydrocele, epilepsy, Fabry disease, hereditary hemorrhagic telangiectasia, hereditary spastic paraplegia, Lehrer syndrome, Marfan syndrome, MPS I, MPS II, MPS IV, multiple myeloma Hereditary exostosis, congenital myotonia (recessive), myotonic dystrophy, nail-patella syndrome, nerve Fibromatosis type 1, neurofibromatosis type 2, ocular albinism, osteogenesis imperfecta, optic atrophy, papillon-leu Febvre syndrome, Parkinson's disease (familial), Peutz-Jeghers syndrome, primary ciliary syndrome Neuropathy, renal cell carcinoma, retinitis pigmentosa, retinoblastoma, Rett syndrome, spinal muscular atrophy, nodules Sclerosis, Usher syndrome, von Hippel-Lindau syndrome, Wermer syndrome, Selected from Wilson's disease, Wolfram syndrome, or agammaglobulinemia (X-linked) Promising therapeutic activities to ameliorate or manage diseases or disorders mediated by nonsense mutations It has sexuality.

[0026] In one aspect provided herein, ataluren is administered in the pharmaceutical composition provided herein. The present invention provides a method for the preparation of medicaments for the treatment of rhodium, rhodium, erythritol, thiazolinone ... In another embodiment provided herein, ataluren is administered in the presence of a pharmaceutical composition provided herein, and pharmaceutically acceptable salts for use in the processes and methods provided herein. In another aspect provided, ataluren is administered in the pharmaceutical compositions, processes, and a pharmaceutically acceptable anhydrous free acid or salt for use in the method.

[0027] As used herein, the term "pediatric patient" refers to a patient ranging in age from newborn to about 18 years of age. In one embodiment, a pediatric patient is a patient from about newborn to 1 In another embodiment, the pediatric patient is between about 18 and 20 years of age. In another embodiment, the pediatric patient is in the age range of newborn to 2 years, inclusive. The subjects are between about 2 months and about 6 months, about 4 months and about 6 months, or over about 6 months of age / year. In another embodiment, the pediatric patient is a neonate between the ages of 2 and 5 years, inclusive. In another embodiment, the pediatric patient is between 5 and 18 years of age, inclusive. Age.

[0028] As used herein, the term "nonsense mutation" encodes a premature stop codon mutation, When transcribed, it produces messenger ribonucleic acid ( mRNA) triplet (e.g., CAG) is a stop codon (i.e., a premature stop codon ) into a triplet (e.g., UAG) that is interpreted as a single This refers to a genetic or somatic change in the mRNA. This leads to the production of truncated, non-functional proteins and consequent disease.

[0029] As used herein, the term "premature stop codon" refers to a codon that replaces an amino acid in an mRNA. It refers to the result of a DNA mutation that encodes a stop codon.

[0030] As used herein, the term "therapeutically effective amount" refers to a dose of at least about 1 mg / kg of cereals administered over a 24-hour period. sufficient to achieve a mean plasma concentration in patients ranging from about 20 μg / mL to about 20 μg / mL This refers to the amount of ataluren administered to patients based on their weight. Modeling the data (264888) suggests that mean plasma concentrations vary slightly over a 24-hour period. It is shown that the range is at most approximately 0.9 μg / mL to approximately 17.6 μg / mL. 6-minute walking distance The effective plasma concentration range that produces the greatest benefit, as expressed by the 6MWD, is usually: It has been shown that the range seen within 2 hours after the morning dose is 2-19 ug / mL.

[0031] In one embodiment, the therapeutically effective amount of ataluren is about 40 mg / kg / day of patient weight. wherein the mean plasma concentration achieved in the patient is The range of the present invention is at least about 1 μg / mL to about 20 μg / mL. In another embodiment, the therapeutically effective amount of about 40 mg / kg / day is a 10 mg / kg morning dose, administered as a 10 mg / kg midday dose and a 20 mg / kg evening dose; The time period between the morning dose and the midday dose is 6 hours; the time period between the midday dose and the evening dose is 6 hours. and the period between the evening dose and the following morning dose is 12 hours.

[0032] In one embodiment, the therapeutically effective amount of ataluren is about 80 mg / kg / day of patient weight. wherein the mean plasma concentration achieved in the patient is The range is at least about 1 μg / mL to about 20 μg / mL. In some embodiments, the therapeutically effective amount of about 80 mg / kg / day is a morning dose of 20 mg / kg; 20 mg / kg midday dose and 40 mg / kg evening dose; The period between the midday dose and the evening dose is 6 hours; the period between the midday dose and the evening dose is 6 hours. and the period between the evening dose and the following morning dose is 12 hours.

[0033] In another embodiment provided herein, the dose is optionally administered within 30 minutes of a meal. can be.

[0034] In one embodiment provided herein, a method for treating nmDMD in a human pediatric patient with nmDMD is A therapeutically effective amount administered in a method for improving or managing muscle stiffness is: i) a dose that is administered to the muscle of the patient; ii) improve the expression of dystrophin protein in timed functional assays; iii) improve the patient's performance in gait assessment or quality of life assessment; iv) To improve the patient's performance in the field of gait rehabilitation; ameliorate or manage the decline and / or deterioration of cardiopulmonary function associated with nmDMD; ameliorating or managing the onset, progression, and / or worsening of: Ameliorating or managing the onset, progression, and / or worsening of associated cardiac decline; and and vii) ameliorating the onset, progression, and / or worsening of nmDMD-associated lung function decline. The present invention provides an effect selected from the group consisting of causing or managing the

[0035] As used herein, the term "functional" in the context of a functional readthrough protein ) is produced in sufficient quantities to treat, prevent, or ameliorate a disease caused by a deficiency of the protein. The term also refers to a protein that fully possesses the functional activity of the wild-type protein. a protein that has a beneficial effect on a cell or subject (otherwise Mutations (e.g., nansense mutations) in the nucleic acid sequence (e.g., gene) encoding the protein As a result of the mutation, the wild-type protein is not produced or is produced in insufficient amounts. In a specific embodiment, a functional readthrough protein is a The invention provides a method for the treatment of a disease in a mammalian animal, the mammalian target of which is a mammalian target of a human disease. In another particular embodiment, the functional readthrough protein is a full-length wild-type protein. In some embodiments, the protein produced performs one, two, three or more of the functions of the protein. The functional readthrough protein is a functional non-wild-type protein. The functional readthrough protein produced is a functional wild-type protein. In aspects, the functional non-wild-type protein produced is full-length. The functional wild-type protein produced is full-length. In other embodiments, the functional wild-type protein produced is not full-length. It's not long.

[0036] As used herein, the term "full-length" in the context of a functional readthrough protein "Substantially performs the function of the wild-type protein" means that the functional readthrough protein is that perform at least one, two, three or more functions of the wild-type protein of interest. This means that...

[0037] As used herein, the term "nonsense-mediated DMD" refers to a nonsense-mediated DMD. A nonsense mutation in a gene encodes a premature stop codon in the mRNA, preventing it from functioning. Duchenne muscular dystrophy, which results in decreased production of the dystrophin protein Point.

[0038] As used herein, "in combination" in the context of administering a treatment refers to the administration of more than one treatment. The use of the term "in combination" refers to the administration of a treatment to a subject with a disease. In some embodiments, one or more therapies are administered to a subject with a disease. This includes, but is not limited to, administering a first therapeutic agent to a subject having or susceptible to a disease. The first treatment is given prior to the second treatment (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes). , 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours (before, 1, 2, 3, 4, 5, 6, 8 or 12 weeks prior to the first treatment) at or following the second treatment (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later). These treatments include the first treatment described above. These treatments may be administered in the unit dosage forms described herein in combination with another treatment. and can act together to provide greater benefit than if the therapy were administered alone. As such, they are administered to the subject consecutively and within a certain time interval.

[0039] As used herein, the term "improvement or management" or "to improve or manage" means slowing the inevitable functional decline associated with nmDMD and thus reducing the symptoms of nmDMD A pediatric patient from administration of a therapeutically effective amount of ataluren as provided herein. It refers to the beneficial effects elicited by nonsense mutations in genes or somatic cells in pediatric patients. If a patient has been diagnosed with nmDMD associated with a genetic disorder, the patient may receive an effective amount of attaquinone as described herein. administering to the pediatric patient: i) increasing the level of dystrophin protein in the patient's muscles; ii) improve patient performance on timed functional tests; iii) improve patient performance in gait or quality of life assessments; iv) ameliorating or managing the onset, progression, and / or worsening of locomotor decline; (v) the onset, progression, and / or worsening of cardiopulmonary decline associated with nmDMD; vi) To improve or manage the onset and progression of cardiac decline associated with nmDMD. and vii) improving or managing the progression and / or worsening of any condition associated with nmDMD. and / or manage the onset, progression, and / or worsening of the decline in lung function associated with

[0013] The present invention provides a method for treating nmDMD in a patient with nmDMD by providing a therapeutically beneficial effect selected from the group consisting of: D can be improved or managed.

[0040] As used herein, the terms "about" or "approximately" mean any quantity that can be measured using a method as determined by one of ordinary skill in the art. means the tolerance for a particular value, which is related to how that value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to 1, 2, 3, or In certain embodiments, the term "about" or "approximately" refers to a given 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4% of the value or range This means within 3%, 2%, 1%, 0.5% or 0.05%.

[0041] As used herein, the term "wild-type" in the context of a protein refers to a protein that is found in nature. Proteins whose loss is often, but not always, associated with disease A protein is a protein that is the predominant protein in a given sequence, and is referred to as a standard or reference protein. Can be named.

[0042] (Ataluren salt form) In some aspects, the methods provided herein involve the use of L-arginine, L-histidine, L- Lysine, N-methylglucamine, magnesium methoxide, potassium hydroxide, sodium hydroxide The present invention includes the use of salt forms of ataluren, including salts selected from sodium or tromethamine (e.g., No. 6,299,499, filed March 5, 2015, which is incorporated herein by reference in its entirety. International application PCT / US2015, published under publication number WO2015 / 134711 More specifically, the methods provided herein involve the production of L-lysine, natrium-2-ol, and thiamin-2-ol. This includes the use of a salt form of ataluren selected from sodium, and tromethamine.

[0043] (Pharmaceutical composition) Pharmaceutical compositions and single unit dosage forms containing an effective amount of ataluren are provided in accordance with the methods provided herein. Individual dosage forms may be used, including oral, transdermal, mucosal (including but not limited to sublingual, buccal, rectal, nasal or vaginal) or parenteral (including but not limited to subcutaneous, intramuscular, intra-arterial, Intraperitoneal, subarachnoid, intraventricular, intraurethral, ​​intrasternal, intracranial, intrasynovial, intravesical or intravenous The preferred pharmaceutical compositions and single doses are suitable for administration to the eye. The dosage form is preferably for oral administration.

[0044] In certain embodiments, the pharmaceutical composition comprises from about 0.1% to about 99%, from about 5% to about 90%, from about 5% to about 50%, about 10% to about 40%, about 20% to about 30%, about 0.1% to about 5%, About 0.1% to about 2.5%, about 0.1% to about 1%, or about 0.25% to about 0.5% by weight In some embodiments, the pharmaceutical composition contains about 0.1%, about 0.25%, about 0 0.5%, approx. 1%, approx. 2%, approx. 5%, approx. 10%, approx. 15%, approx. 20%, approx. 25%, approx. 30% , about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% by weight In some embodiments, the pharmaceutical composition contains about 0.25%, about 0.5%, or about 1% ataluren. % by weight of ataluren.

[0045] In certain embodiments, the pharmaceutical compositions provided herein contain from about 1 mg to about 5,000 mg, Approximately 10 mg to approximately 2,000 mg, approximately 50 mg to approximately 1,000 mg, approximately 100 mg to In some embodiments, the ataluren is about 1,000 mg, or about 100 mg to about 500 mg. The pharmaceutical compositions provided herein may be administered in dosages of about 125 mg, about 200 mg, about 325 mg, In some embodiments, the compositions provided herein contain ataluren at about 400 mg or about 500 mg. The pharmaceutical composition may be administered in an amount of about 120 mg to about 130 mg, about 195 mg to about 205 mg, about 32 mg to about 405 mg, or about 45 mg to about 500 mg. 0 mg to about 330 mg, about 395 mg to about 405 mg, or about 495 mg to about 50 Contains 5mg of ataluren.

[0046] In some embodiments, the ataluren in the pharmaceutical compositions provided herein is a compound selected from the group consisting of benzodiazepines, ... It is the free acid of ataluren that is used.

[0047] In some embodiments, the ataluren in the pharmaceutical compositions provided herein is a compound selected from the group consisting of benzodiazepines, ... It is a salt form of ataluren that can be used.

[0048] The pharmaceutical compositions provided herein may be provided in unit dosage form or multi-dosage form. As used herein, unit dosage form refers to a dosage form delivered to a human or animal subject using packaging known in the art. Each unit dose refers to a physically discrete unit suitable for administration. The formulation contains a predetermined quantity of the active ingredient(s) in association with the excipient(s) sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include, but are not limited to, individually packaged packets, sachets, or bottles or individual tablets. A unit-dosage form may be administered in separate doses or in multiples thereof. A plurality of identical unit dosage forms packaged in one container, and may be used as separate or combined unit dosage forms. Examples of multiple dose forms include packets or sachets of granules or powders, , vials or bottles of tablets or capsules, or parenterally, or orally, or by eye drops Fluid ounce, pint, or gallon solution bottles for administration into the eye by a syringe Examples include:

[0049] The pharmaceutical compositions provided herein can be administered as divided doses over a period of time. The exact dosage and duration of treatment may vary depending on the age, weight, and condition of the patient being treated. using known test protocols or in vivo or in vitro by extrapolation from existing test or diagnostic data, or by observation of specific clinical factors It is understood that the specific dosage regimen for any particular individual may be empirically determined. Each formulation should be based on the individual need and the professional judgment of the person administering or supervising the administration of pharmaceutical compositions. It is further understood that adjustments may be made over time.

[0050] (oral formulation) The pharmaceutical compositions provided herein are formulated for oral administration. The pharmaceutical compositions for oral administration provided herein are in solid, semi-solid or liquid dosage form for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include tablets, sublingual or buccal films (i.e., "fast dissolve"). -melt), chewable tablets, effervescent tablets, dispersible tablets et), minitablets, capsules, pills, strips, troches, lozenges, pastes tablets, oral films, wafers, pellets, medicated chewing gum, powders of active ingredients or Granules, effervescent or non-effervescent powders or granules, oral mists, liquids, emulsions, suspensions, This includes, but is not limited to, sprays, sprinkles, elixirs, and syrups. In addition to the active ingredient, pharmaceutical compositions may contain binders, fillers, diluents, disintegrants, wetting agents, etc. agents, surfactants, lubricants, glidants, pH adjusters, colorants, dye transfer inhibitors (dye- migration inhibitor), sweetener, flavoring, emulsifier, suspending and dispersing agent, preservative including, but not limited to, preservatives, solvents, solvating agents, non-aqueous liquids, organic acids, and carbon dioxide sources. The composition may contain one or more pharmaceutically acceptable carriers or excipients that are not .

[0051] Binders and granulators give the tablet a sticky texture that lasts even after compression. Suitable binders or granulating agents include, for example, Corn starch, potato starch, pregelatinized starch (e.g., STARCH 1500) and other starches; gelatin; e.g., sucrose, glucose, dextrose (dextrose) sugars such as molasses and lactose; e.g. gum arabic, alginic acid, alginates , Irish moss extract, panwar gum, ghatti gum hatti gum, isabgol husk mucus, carbo Dimethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum (Veegum), larch arabogalactan, tiger Natural and synthetic rubbers such as guar gum and guar gum; e.g., ethyl cellulose, cellulose acetate; Cellulose, carboxymethylcellulose (CMC), carboxymethylcellulose calcium um, sodium carboxymethylcellulose, methylcellulose, hydroxyethyl Cellulose (HEC), Hydroxypropyl Cellulose (HPC), Hydroxypropyl Cellulose such as methylcellulose (HPMC); for example AVICEL®-P H-101, AVICEL (registered trademark)-PH-103, AVICEL (registered trademark) RC -581, AVICEL(R)-PH-105(FMC Corp., Marcu microcrystalline cellulose, such as cellulose acetate (Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, Rosin, cellulose powder, dextrate, kaolin, mannitol , silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. These include, but are not limited to:

[0052] Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, sorbitol, Sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried Examples include, but are not limited to, starch and powdered sugar, such as mannitol, lactose, Certain diluents, such as sorbitol, sucrose, and inositol, when present in sufficient amounts, Some compressed tablets can be given properties that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0053] Suitable disintegrants include agar; bentonite; e.g., methylcellulose and carboxymethylcellulose. Cellulose such as methylcellulose; wood products; sponges; cation exchange resins; alginic acid; e.g. Gums such as guar gum and VEEGUM® HV; citrus pulp; Crosslinked cellulose, e.g., croscarmellose; crosslinked polysaccharides, e.g., crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate Crystalline cellulose; polacrilin potassium ); e.g., corn starch, potato starch, tapioca starch, and pregelatinized starch. starches such as corn; clays; aligns; and mixtures thereof. The pharmaceutical compositions provided herein may contain a disintegrant in an amount of from about 0.5 to about 1000 mg / kg. The composition may contain from about 1 to about 15% by weight or from about 1 to about 5% by weight.

[0054] Suitable lubricants include calcium stearate; magnesium stearate; mineral oil; Light mineral oil; glycerin; sorbitol; mannitol; e.g., glycerol behenate and polyisoprene Glycols such as polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate Sodium; talc; peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and Hydrogenated vegetable oils such as soybean oil; zinc stearate; ethyl oleate; ethyl laureth Ethyl laureate; agar; starch; agave; e.g. AERO SIL® 200 (WR Grace, Baltimore, MD) and CAB-O-SIL® (Cabot Corporation, Boston, MA). and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant.

[0055] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® ) (Cabot Corporation, Boston, MA) and asbestos-free talc. Suitable coloring agents include, but are not limited to, approved, certified, water-soluble FD&C colorants. C pigment and water-insoluble alumina suspended in alumina hydrate FD&C dyes and dye lakes and mixtures thereof, but Dye lakes are formed by the adsorption of water-soluble dyes to hydrous oxides of heavy metals. which results in the pigment being in an insoluble form. Suitable flavorings include, for example, fruit flavorings. natural fragrances extracted from plants, as well as good flavorings such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, synthetic mixtures of compounds that produce a sweet taste. Flavoring agents include sucrose, lactose, mannitol, syrup, glycerin, and e.g. These include, but are not limited to, artificial sweeteners such as guar gum and aspartame. Suitable emulsifying agents include gelatin, gum arabic, tragacanth, bentonite, and For example, polyoxyethylene sorbitan monooleate (TWEEN® 20), Polyoxyethylene sorbitan monooleate 80 (TWEEN® 80) and These include, but are not limited to, surfactants such as triethanolamine oleate. Suitable suspending and dispersing agents include sodium carboxymethylcellulose, pectin, and tragacanth. Gum, veegum, gum arabic, sodium carbomethylcellulose (sodium ca hydroxypropyl methylcellulose and poly Suitable preservatives include, but are not limited to, vinylpyrrolidone. Glycerin, methylparaben and propylparaben, benzoic acid dd), sodium benzoate and alcohol. Suitable wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate nolaurate) and polyoxyethylene lauryl ether, Suitable solvents include, but are not limited to, glycerin, sorbitol, ethanol, and silane. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, Suitable organic acids include, but are not limited to, mineral oil and cottonseed oil. Examples include, but are not limited to, citric acid, fumaric acid, ascorbic acid, and tartaric acid. Suitable carbon dioxide sources include sodium bicarbonate and sodium carbonate. Many carriers and excipients have multiple functions, even within the same formulation. Please understand that this can be achieved.

[0056] The pharmaceutical compositions provided herein as tablets for oral administration may be compressed tablets, molded tablets, thiazolinone tablets, or thiazolinone tablets. chewable lozenges, fast dissolving tablets, effervescent tablets, mini tablets, beads, coated beads, multi They can be provided as layered or enteric-coated tablets, sugar-coated tablets or film-coated tablets. The tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine. The enteric coating is a fatty acid , fat, phenyl salicylate, wax, shellac, ammoniated shellac and acetic acid Sugar-coated tablets are tablets coated with sugar, but not limited to cellulose phthalate. Compressed tablets coated with a coating to mask any unpleasant taste or odor and protect the tablets from oxidation. Film-coated tablets are tablets that are coated with a thin layer or film of a water-soluble substance. It is a compressed tablet. The film coating is made of hydroxyethyl cellulose, carbo Sodium hydroxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate Film coatings include, but are not limited to, sugar coatings. Multi-layer compressed tablets offer the same general characteristics as layered tablets and press-coated tablets. Compressed tablets are manufactured by multiple compression cycles, including dry-coated tablets or press-coated tablets.

[0057] Tablet dosage forms consist of the active ingredient in powder, crystalline or granular form, alone or in the presence of a binder, disintegrant, , a release controlling polymer, a lubricant, a diluent and / or a colorant, etc., as described herein. Or it can be prepared in combination with multiple carriers or excipients. is particularly useful in the formation of chewable tablets and lozenges.

[0058] The pharmaceutical compositions provided herein for oral administration may be prepared using gelatin, methylcellulose, dendrimer, or the like. It is offered as a soft or hard capsule, which can be made from punch or calcium alginate. Hard gelatin capsules are available as dry-filled capsules (DFCs). Also known as a psule, it consists of two parts, one covering the other and thus forming the active component. The capsule is completely enclosed. ule)) is a soft, spherical shell, e.g., a gelatin shell, and is made of glycerin, sorbitol, The soft gelatin shell is plasticized by adding ethanol or similar polyols. The composition may also contain a preservative to prevent the growth of bacteria. Suitable preservatives are those described herein. , methylparaben and propylparaben, and sorbic acid. Liquid, semi-solid and solid dosage forms can be encapsulated within capsules. and semi-solid dosage forms, including solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsule may also contain a turbidifying agent to alter or maintain dissolution of the active ingredient. For this purpose, the material may be coated as known by those skilled in the art.

[0059] The pharmaceutical compositions provided herein for oral administration may be in the form of emulsions, solutions, suspensions, elixirs, or the like. They can be provided in liquid and semi-solid dosage forms, such as syrups and syrups. Emulsions are those in which one liquid is mixed with another. A two-phase system in which small globules are dispersed throughout one liquid, which is an oil-in-water system. Emulsions can be prepared by dissolving pharmaceutical compositions in non-aqueous liquids or solvents that are pharmaceutically acceptable. Suspensions may contain pharmaceutically acceptable carriers, solvents, solvating or emulsifying agents, and preservatives. The aqueous alcoholic solution may contain a suspending agent and a preservative. Di(lower alkyl) acetals of aldehydes, for example, acetaldehyde diethyl acetate acetals such as propylene glycol and ethanol; and a water-miscible solvent having one or more hydroxyl groups. Elixirs are clear and A syrup is a sweetened hydroalcoholic solution. It is an aqueous solution and may contain a preservative. The solution in ethanol is prepared in a sufficient quantity of a medicament acceptable for easy measurement at the time of administration. It may be diluted with an acceptable liquid carrier, such as water.

[0060] Other useful liquid and semi-solid dosage forms include those containing the active ingredients provided herein and 2-Dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol -350-dimethyl ether, polyethylene glycol-550-dimethyl ether, poly Polyethylene glycol-750-dimethyl ether (where 350, 550 and 750 are refers to the approximate average molecular weight of polyethylene glycol) These include, but are not limited to, those containing alkylene glycols or poly-alkylene glycols. These formulations contain, for example, butylhydroxytoluene (BHT), butylhydroxyapatite (BHT), Nisole (BHA), Propyl gallate, Vitamin E, Ethylenediaminetetraacetic acid (EDT) A), hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, Ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite One or more of ammonium, thiodipropionic acid and its esters, and dithiocarbamates The above antioxidants may further be included.

[0061] The pharmaceutical compositions for oral administration provided herein may also be formulated in liposomes, micelles, microspheres, or the like. It may also be provided in the form of a fair or nanosystem.

[0062] The pharmaceutical compositions provided herein for oral administration are intended to be reconstituted into a liquid dosage form. It can be provided as either non-effervescent or effervescent tablets or as granules and powders. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders include diluents The pharmaceutically acceptable salts used in the effervescent granules or powders may also contain sweeteners and wetting agents. Possible carriers and excipients may include organic acids and carbon dioxide sources.

[0063] In some embodiments, the pharmaceutical composition is formulated as a solid oral dosage form. The pharmaceutical composition is formulated as a liquid oral dosage form. In some embodiments, the unit dosage form is a liquid containing water, milk, or the like. , carbonated drinks, juice, fruit juice, fruit punch, applesauce, yogurt, pudding Do not use any of the following products: ice cream, baby food, infant formula, or soy or grain-based products. mixed in a pharmaceutically acceptable liquid or semi-solid solvating agent, including but not limited to It is provided as a suspension.

[0064] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable salts thereof. Provided herein are pharmaceutical compositions comprising an acceptable excipient. In one embodiment, the pharmaceutical composition is formulated as a finely divided powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. In another embodiment, the pharmaceutical composition is formulated as a granule. , polydextrose, mannitol, poloxamer, polyethylene glycol, hydrochloride Hydroxyethylcellulose, crospovidone, artificial flavors, and magnesium stearate In some embodiments, the artificial flavoring is an artificial vanilla flavoring.

[0065] Also, about 25% by weight of ataluren; about 1% by weight of colloidal silicon dioxide; and one or more Pharmaceutical compositions containing the above additional pharmaceutically acceptable excipients are also provided herein. In an aspect, the pharmaceutical compositions provided herein comprise ataluren and polydextrose, poly Poloxamer (e.g., poloxamer 407), polyethylene glycol (e.g., polyethylene Ethylene Glycol 3350), Mannitol, Hydroxyethylcellulose, Artificial Vanilla Flavoring, crospovidone, colloidal silicon dioxide, and magnesium stearate (e.g., and one or more excipients selected from the group consisting of those derived from plants. The pharmaceutical compositions provided herein also provide ataluren, a suspending agent, and a taste masking agent. and one or more excipients selected from binders, surfactants, and disintegrants that can disintegrate the food product. Excipients may be present. In one embodiment, the pharmaceutical composition is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. In another embodiment, ataluren is present in an amount such as, for example, about 25% by weight. In another embodiment, the one or more excipients are selected from the group consisting of polydextrose, mannitol, polysaccharide, and the like. Crosamer, polyethylene glycol, hydroxyethyl cellulose, crospovidone, In another embodiment, the hydroxybenzoate is selected from the group consisting of: artificial vanilla flavoring, and magnesium stearate. In this case, the one or more excipients (and their proportion of the total formulation weight) may be, for example, about 26% by weight. Suspension of Litesse® Ultra [purified polydextrose] etc. a binder such as about 26% by weight mannitol, a binder such as about 10.0% by weight polyethylene glycol, ethylene glycol 3350 and about 4% by weight of Lutrol® Micro F127 [Poloxamer 407 powder] and other surfactants, such as about 5% by weight of crospovidone disintegrants, such as Cab-O-Sil™, hydroxyethyl cellulose, about 1 % by weight of magnesium stearate (non-bovine), and about 1 and less than about 2% by weight each of other excipients, such as colloidal silicon dioxide. is selected from.

[0066] Additionally, about 25% by weight of ataluren, about 26% by weight of polydextrose, about 26% by weight of % mannitol, about 3% by weight poloxamer, and about 10% by weight polyethylene glycol , about 2% by weight of hydroxyethyl cellulose, about 5% by weight of crospovidone, about 1% by weight artificial vanilla flavor, about 1% by weight colloidal silicon dioxide, and about 1% by weight stearin Also provided herein are pharmaceutical compositions comprising magnesium phosphate. is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. The pharmaceutical composition is formulated as granules.

[0067] Additionally, ataluren in the range of about 120 mg to about 1005 mg, about 133 mg to about 1 Polydextrose in the range of about 0.30 mg, Mannitol in the range of about 137 mg to about 901 mg thor, ranging from about 19 mg to about 147 mg; poloxamer, ranging from about 52 mg to about 402 mg; g of polyethylene glycol, and about 7 mg to about 59 mg of hydroxyethyl cellulose, in the range of about 26 mg to about 201 mg, crospovidone, in the range of about 3 mg to about 29 mg artificial vanilla flavoring, and colloidal silicon dioxide, ranging from about 5 mg to about 39 mg and a pharmaceutical composition comprising magnesium stearate in the range of about 5 mg to about 39 mg. In one embodiment, the pharmaceutical composition is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as a nanoparticle. In one embodiment, the pharmaceutical composition is formulated as granules.

[0068] In addition, approximately 130 mg of ataluren, approximately 133 mg of polydextrose, and approximately 137 mg of g of mannitol, approximately 19 mg of poloxamer, approximately 52 mg of polyethylene glycol, Approximately 7 mg of hydroxyethylcellulose, approximately 26 mg of crospovidone, approximately 3 mg of artificial Vanilla flavor, approximately 5 mg colloidal silicon dioxide, and approximately 5 mg magnesium stearate Provided herein is a pharmaceutical composition comprising the compound. In one aspect, the pharmaceutical composition is a powder. In one embodiment, the pharmaceutical composition is formulated as a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. The composition is formulated as granules.

[0069] In addition, approximately 205 mg of ataluren, approximately 210 mg of polydextrose, and approximately 216 mg g of mannitol, approximately 30 mg of poloxamer, approximately 82 mg of polyethylene glycol, Approximately 12 mg of hydroxyethylcellulose, approximately 41 mg of crospovidone, and approximately 6 mg of vanilla flavor, approximately 8 mg colloidal silicon dioxide, and approximately 8 mg magnesium stearate Provided herein are pharmaceutical compositions comprising sodium. In one aspect, the pharmaceutical composition is a dispersion of sodium. In one embodiment, the pharmaceutical composition is formulated as a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. The composition is formulated as granules.

[0070] In addition, approximately 330 mg of ataluren, approximately 338 mg of polydextrose, and approximately 348 mg of g mannitol, approximately 48 mg poloxamer, and approximately 132 mg polyethylene glycol , about 19 mg hydroxyethylcellulose, about 66 mg crospovidone, about 9 mg Artificial vanilla flavor, approximately 13 mg colloidal silicon dioxide, and approximately 13 mg stearic acid Provided herein is a pharmaceutical composition comprising magnesium. is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. The pharmaceutical composition is formulated as granules.

[0071] In addition, approximately 405 mg of ataluren, approximately 415 mg of polydextrose, and approximately 427 mg of g mannitol, approximately 59 mg poloxamer, and approximately 162 mg polyethylene glycol , approximately 24 mg of hydroxyethylcellulose, approximately 81 mg of crospovidone, approximately 12 mg of artificial vanilla flavor, approximately 16 mg of colloidal silicon dioxide, and approximately 16 mg of stearin Provided herein is a pharmaceutical composition comprising magnesium phosphate. In one embodiment, the pharmaceutical composition is formulated as a finely divided powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. Therefore, the pharmaceutical composition is formulated as granules.

[0072] In addition, approximately 505 mg of ataluren, approximately 518 mg of polydextrose, and approximately 453 mg g mannitol, approximately 74 mg poloxamer, and approximately 202 mg polyethylene glycol , about 30 mg hydroxyethylcellulose, about 101 mg crospovidone, about 15 m g of artificial vanilla flavor, approximately 20 mg of colloidal silicon dioxide, and approximately 20 mg of stearyl alcohol. Provided herein are pharmaceutical compositions comprising magnesium phosphate. In one embodiment, the pharmaceutical composition is formulated as a finely divided powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. In this case, the pharmaceutical composition is formulated as granules.

[0073] In addition, approximately 1005 mg of ataluren, approximately 1030 mg of polydextrose, approximately 90 1 mg mannitol, approximately 147 mg poloxamer, approximately 402 mg polyethylene glycol Cole, approximately 59 mg hydroxyethylcellulose, approximately 201 mg crospovidone, approximately 29 mg of artificial vanilla flavor, approximately 39 mg of colloidal silicon dioxide, and approximately 39 mg of sugar. Provided herein is a pharmaceutical composition comprising magnesium tearate. The pharmaceutical composition is formulated as a powder. In one embodiment, the pharmaceutical composition is a micronized powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. In some embodiments, the pharmaceutical composition is formulated as granules.

[0074] In one embodiment, the unit dosage form contains from about 35 mg to about 5,600 mg of ataluren, about 35 mg g to about 2800 mg of ataluren, about 35 mg to about 1,400 mg of ataluren, about 125 mg to approximately 1,000 mg of ataluren, approximately 250 mg to approximately 1,000 mg of ataluren Ataluren, about 325 mg to about 1,000 mg of ataluren, or about 500 mg to about 1 Contains 1,000mg of ataluren.

[0075] In some embodiments, the unit dosage form contains about 35 mg, about 50 mg, about 70 mg, about 100 mg, about 125mg, about 140mg, about 175mg, about 200mg, about 250mg, about 280mg , about 325mg, about 350mg, about 400mg, about 450mg, about 500mg, about 560 mg, approx. 700mg, approx. 750mg, approx. 1,000mg, approx. 1,400mg, approx. 2800 mg, or approximately 5600 mg of ataluren.

[0076] In certain embodiments, the unit dosage form is about 125 mg, about 250 mg, or about 1,000 mg. Contains g of ataluren.

[0077] In more particular embodiments, the unit dosage form contains 125 mg, 250 mg, or 1,000 mg of Includes taluren.

[0078] In one embodiment, the pharmaceutical composition is formulated as a powder. In one embodiment, the pharmaceutical composition is formulated as nanoparticles. In another aspect, the pharmaceutical compositions provided herein are formulated as granules. In some embodiments, the pharmaceutical compositions provided herein are packaged in packets or pouches. In some embodiments, the pharmaceutical compositions provided herein are packaged in a heat-sealed aluminum laminate. In some embodiments, the pharmaceutical compositions provided herein are packaged in packets or pouches. In some embodiments, the compositions provided herein are packaged in a sealed packet or pouch. The pharmaceutical composition may be polyethylene terephthalate, polyethylene ne), packaged in a packet or pouch containing layers of aluminum foil, adhesive, and sealing film. In some embodiments, the pharmaceutical composition may comprise any suitable material, including, but not limited to, high density polyethylene (HDPE). It may be provided in a bottle, such as a PE bottle.

[0079] In certain aspects, the pharmaceutical compositions provided herein are formulated as granules for reconstitution. In certain aspects, the pharmaceutical compositions provided herein are formulated for reconstitution as an oral suspension. It is formulated as granules.

[0080] In certain aspects, the pharmaceutical compositions provided herein are suitable for use in a variety of animal products, including, but not limited to, water, cattle, and the like. Milk, carbonated drinks, juice, fruit juice, fruit punch, applesauce, yogurt, pudding such as ice cream, baby food, milk powder or soy or grain-based products. Mix the suspension with any pharmaceutically acceptable liquid or semi-solid solvating agent. It is reconstituted prior to administration.

[0081] In some embodiments, the pharmaceutical compositions provided herein are mixed to form a suspension with water. In one embodiment, a 125 mg unit of ataluren is prepared by reconstituting the formulation before administration. To reconstitute the dosage form, add at least approximately 5 mL of water directly to the bottle containing ataluren. by achieving a nominal concentration of at least about 25 mg / mL in the total volume of suspending agent. In another embodiment, the reconstitution of the 250 mg unit dose formulation of ataluren contains ataluren. Add at least about 10 mL of water directly to the bottle to obtain a suspension containing at least about 25 mL of water. In another embodiment, the nominal concentration is 500 mg / mL. To reconstitute the unit dose formulation of Ataluren, add at least approximately 20 mL of the product to the bottle containing Ataluren. Water should be added directly to achieve a nominal concentration of at least about 25 mg / mL in the total volume of the suspension. In another embodiment, the 1000 mg unit dose formulation of ataluren is reconstituted. Add at least about 40 mL of water directly to the bottle containing Ataluren to obtain the total amount of suspension. This is achieved by achieving a nominal concentration of at least about 25 mg / mL.

[0082] In other aspects, unit dosage forms containing the pharmaceutical compositions provided herein are prepared by the method of claim 1. The entire contents of each unit dosage form is suspended in a liquid or semi-solid solvating agent. wherein the liquid is at least 30 mL (1 oz), or A semisolid is at least 3 tablespoons. The prepared dose should be mixed thoroughly before administration. The amount of liquid or semi-solid solvating agent can be increased depending on patient preference. .

[0083] In certain aspects, the pharmaceutical compositions provided herein comprise ataluren as a free acid or as a pharmaceutical. as a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is a magnesium salt, Potassium salt, sodium salt, tromethamine salt, L-lysine salt, L-arginine salt, N-methamine salt It is a tilglucamine salt or an L-histidine salt.

[0084] (particle size) In certain aspects, the pharmaceutical compositions provided herein comprise micronized pharmaceutical compositions with enhanced solubility. In some embodiments, the pharmaceutical compositions provided herein include ataluren in the form of It includes ataluren in nanoparticulate form having solubility and / or dissolution rate.

[0085] In certain aspects, the pharmaceutical compositions provided herein contain ataluren in micronized form. wherein >90% of the particles of ataluren are about 1-10 microns in size with improved solubility. Diameter of the 90 In certain aspects, the pharmaceutical compositions provided herein have The above-mentioned solubility is about 10 microns, about 9 microns, about 8 microns, about 7 microns, and about 6 microns, about 5 microns, about 4 microns, about 3 microns, about 2 microns, or about 1 micron Ron's D 90 In some embodiments, the ataluren provided herein is in micronized form having a value of 0.01%. The provided pharmaceutical compositions comprise approximately 1-5 micron particles having improved solubility and / or dissolution rate. D 90 In some embodiments, the compositions provided herein include ataluren in micronized form having a value of 0.01%. The pharmaceutical compositions are of about 5 microns, about 4 microns, and about 5 microns, which have improved solubility and / or dissolution rate. D of about 3 microns, about 2 microns, or about 1 micron 90 of micronized form having value In some embodiments, the pharmaceutical compositions provided herein contain ataluren. In certain embodiments, the pharmaceutical compositions provided herein include ataluren in nanoparticulate form having the formula: The composition comprises ataluren in nanoparticulate form, wherein >90% of the particles of ataluren are Approximately 0.1 microns, approximately 0.09 microns, approximately 0.08 microns, approximately 0.07 microns, approximately 0.06 microns, approximately 0.05 microns, approximately 0.04 microns, approximately 0.03 microns, approximately 0.02 microns, or approximately 0.01 microns D 90 It has a value.

[0086] Atta in micronized form with a volume-weighted mean diameter D[4,3] of about 2 μm to about 12 μm The present invention provides a method for producing fluororesin having a surface-weighted average diameter D[ of about 1 μm to about 3 μm. Also provided herein is a micronized form of ataluren having a molecular weight of about 5 μm. D ranging from 100 μm to approximately 26 μm 90 Form having particle size in the range of about 1 μm to about 6 μm D5 0 particle size, D ranging from about 0.1 μm to about 1.5 μm 10 In the form of particle size Ataluren is provided herein.

[0087] (kit) The pharmaceutical compositions provided herein are prepared using packaging materials well known to those skilled in the art. Examples of pharmaceutical packaging materials include blister packs, bottles, packets, Sachets, tubes, inhalers, pumps, bags, vials, containers, syringes, eyedroppers, etc. and any packaging materials appropriate for the selected dosage form and intended mode of administration and treatment. However, the present invention is not limited to these.

[0088] For use by physicians, this can simplify the administration of the correct amount of active ingredient to the subject. In one aspect, the kits provided herein comprise: , the containers and dosage forms of the pharmaceutical formulations provided herein, and instructions for their use. In some embodiments, the instructions included in the kit provide dosages and / or dosage information for administration of ataluren. Or guidance regarding dosing regimens may be provided.

[0089] In some embodiments, the kit comprises a pharmaceutical composition comprising a pharmaceutical composition in a container containing one or more other therapeutic agents described herein. The pharmaceutical formulations provided herein include a container containing the pharmaceutical formulation in a dosage form. The pharmaceutical agent is provided as a white to off-white powder for oral suspension. The pharmaceutical formulation comprises a carrier and / or a suspending agent, a surfactant, and / or an excipient. In embodiments, the pharmaceutical formulation is provided as granules for oral suspension. Pharmaceutical preparations for oral suspension are available in dosages containing 125, 250, or 1000 mg of active pharmaceutical ingredient. Packaged in child-resistant aluminum foil packets by strength. The kit contains one or more dosage strengths of pharmaceutical preparations for oral suspension (125, 250, or The study included packets or sachets containing 1000 mg of the active ingredient (or 1000 mg of the active ingredient, or a matching placebo).

[0090] The kits provided herein may further include a device used to administer the active ingredient. Examples of devices include syringes, needleless injectors, intravenous bags, and syringes. These include, but are not limited to, nicotine, eye drops, and inhalers.

[0091] The kits provided herein include a pharmaceutical that can be used to administer the active ingredient. For example, if the active ingredient is administered parenterally, it may further comprise a suitable vehicle. If the product is provided in a solid form that must be reconstituted before administration, the kit may contain The active ingredient can be dissolved in the solution to form a particle-free, sterile solution that is suitable for parenteral administration. or a suitable vehicle that can be reconstituted as a suspension for oral administration. The vehicle may comprise a sealed container of the vehicle. Examples of pharmaceutically acceptable vehicles include: including, but not limited to, Water for Injection, USP, Sodium Chloride Injection, Ringer's Injection , glucose injection, glucose and sodium chloride injection, and lactated Ringer's injection, etc. aqueous vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol and water-miscible vehicles such as, but not limited to, polypropylene glycol; Corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, myristic acid Non-aqueous vehicles include, but are not limited to, isopropyl, and benzyl benzoate. Not determined.

[0092] (How to use) Ataluren is licensed in the EU member states, Iceland, Liechtenstein and Norway. Walking ages 2 years and older or 5 years and older in Israel, Korea, Chile, and Ukraine Duchenne muscular dystrophy caused by a nonsense mutation in the DMD gene in a patient with Duchenne muscular dystrophy It is indicated for the treatment of nonsense mutations in the dystrophin gene. The presence of a mutation should be determined by genetic testing. Evaluating the efficacy of any dystrophin restoration therapy in children (e.g., under 5 years of age) is currently underway. This is difficult due to the small number of patients diagnosed with nmDMD in this age range. Children tend to show stabilization and improvement in muscle function as a result of growth and maturation. Therefore, routine methods used to assess muscle function may not detect beneficial drug effects. unlikely to occur 14 Additionally, no efficacy evaluations have been performed in the age group ≥2 to <5 years. In some instances, assessments such as the 6-minute walk distance (6MWD) require patient cooperation and therefore may not be acceptable for use in young children 14 Furthermore, natural history data Children with nmDMD in the ≥2 to <5 year age group should also undergo developmental muscle function assessments such as TFT. suggest that the study may demonstrate improvement and / or stabilization in some of the measures routinely used to treat is doing 14 In another example, boys under the age of four were asked to stand on one leg and jump. North, a commonly used feature evaluation in nmDMD, such as features like Many of the functions in the NSAA are also achieved by typically developing boys. It is not guaranteed 18 By age 3, 85% of typically developing boys have NSAA Eight of the 17 items (standing, walking 10 m, standing up from a seated position, right-handed He is able to perform all three functions perfectly (walking up steps with his left leg, walking up steps with his left leg, sitting, jumping, running). 100% of the participants were able to perform three of these tasks (standing, walking 10 meters, and sitting in a chair). By age 4, 85% of typically developing boys can stand up from a standing position. All 17 items of the AA can be performed. Therefore, boys in the age group ≥ 2 years to < 5 years can Revise the NSAA scale to include only items that can be reliably performed (i.e. The 8-item and 3-item NSAA were the most appropriate approaches to functional assessment in this young population. It is Chi 18 .

[0093] Dystrophin restoration therapy in young boys may offer greatest long-term benefits 16 For this reason, the NCT02819557 Phase 2, multiple-dose, open-label study described herein The safety and efficacy of ataluren in boys aged ≥2 to <5 years with nmDMD was evaluated. PK was evaluated. Similar safety and PK in this younger patient population was also observed with Atal The efficacy data from Ren could support the extrapolation of treatment for nmDMD in younger children. This may help overcome some of the challenges associated with The study only considered the assessment of the effects of ataluren on muscle function. Given the inherent challenges of demonstrating efficacy in patients as young as 5 years of age and the lack of a control group, Considering the limited feasibility of such studies, a definitive assessment of the efficacy of ataluren is not possible. The values ​​of the TFTs and NSAAs used in the studies described herein could not be estimated. Secondary endpoints should be interpreted with caution in patients in this age range. Predicting functional decline in nmDMD patients, including rate of gait decline and progression toward worsening Can be used for 19 Therefore, TFT and NSAA are the best solutions when no other methods exist. It is a useful tool for assessing the benefit of drugs.

[0094] Due to the difficulty of assessing efficacy in younger populations for rare genetic conditions, Accepted practice is that PK and safety data obtained in younger patient populations Once shown to correlate with a corresponding older patient population, the older It has been suggested that this comparison may allow for extrapolation of efficacy data from populations. is an acceptable methodology and demonstrates the efficacy of drugs in the nmDMD patient population ≥2 to <5 years of age. This may be the only feasible way to demonstrate benefit compared with that seen in older children. Similar plasma levels and safety of the drug in this setting may translate to similar efficacy and safety in younger populations. A plausible indicator of a favorable benefit-risk profile. PK and safety In addition to efficacy data, extrapolation of efficacy requires the use of the same investigational drug, comparable dose levels, and mechanisms of action. , based on other factors such as expected disease progression, and production of measurable biomarkers. It is possible.

[0095] The limitations of the NCT02819557 trial are the small sample size and the lack of a formal efficacy evaluation. The use of population PK analysis and the lack of a control group for younger patients The use of sparse PK sampling, as recommended in populations, is necessary to calculate PK parameters using conventional methods. Furthermore, the population in question (age range 2 to 5 years) Efficacy assessments in patients with DMD must also be interpreted with caution, as this Children are expected to begin to improve and / or stabilize their motor skills during this time. Therefore, it is unclear to what extent functional improvement can be attributed to ataluren therapy. It is not clear whether 14 Furthermore, the TFT and NSAA results described herein The data obtained at 28 and 52 weeks of ataluren treatment indicate that the younger These findings suggest a benefit of ataluren therapy in patients with mDMD. 1) Time to descend four steps 2) Time to climb four flights of stairs, 3) Time to stand up from a supine position, and 4) Time to walk 10 meters This is demonstrated by the TFT results described herein, which relate to walking / running time. The effect of ataluren treatment was to reduce overall serotonin levels from baseline over the entire study period, respectively. In addition, the mean 16-item NSAA score showed significant improvement compared to baseline. Similar improvements were observed in the NSAA 8-item and 3-item assessments (although the latter was to a lesser extent due to ceiling effects).

[0096] In this nmDMD patient population, optimal atal therapy is in patients ≥2 to <5 years of age. Achieving plasma concentration ranges of acetaminophen similar to those seen in patients ≥5 years of age is expected to result in long-term treatment outcomes. Therefore, it is expected that a younger patient population, such as that in this study, will be able to demonstrate a therapeutic benefit. The safety and PK results of ataluren in a group (≥2 and <5 years of age) were compared with those in older patients in a previous study. To compare the safety and PK results of ataluren obtained from a population of nmDMD patients (≥5 years old) This allows for extrapolation of potential efficacy to younger populations.

[0097] Treatment options are scarce for the younger nmDMD patient population, making treatment more difficult for older By extrapolating the safety, efficacy, and PK results of ataluren from the nmDMD patient population, Therefore, dystrophin restoration therapy for the younger population of nmDMD patients may potentially address the averted symptoms associated with DMD. This ensures that functionality is maintained for a longer period despite any irreversible degradation. It can be shown that this is possible, thus addressing an urgent unmet medical need. It is expected to meet the needs of [Example]

[0098] (Example) Safety of ataluren from older nmDMD populations (≥5 years) in previous studies Comparison of efficacy and PK results will be consistent with the safety and efficacy results obtained in the younger nmDMD population. Potential efficacy in the younger nmDMD population (≥2 to <5 years) based on PK results It is a statistically acceptable means of demonstrating the likelihood of

[0099] Plasma ataluren in a younger population compared with that seen in older children The levels and safety were determined to be similar, and therefore, comparable efficacy and benefit were expected. The limitations of this study are the small sample size and The main reason for this was the lack of a control group for formal efficacy evaluation. Use of samples taken at 8 and 10 hours, followed by population PK analysis (over a 24-hour period) Calculations are made using conventional methods (determining mean plasma concentrations based on estimated exposure over a period of time). In either case, the PK parameters that could be obtained were limited. Any efficacy assessment for this population will depend on the developmental progress that patients in this age group are expected to achieve. This must be weighed against the milestones that motor functioning in these early years can have. Therefore, such simultaneous factors (as discussed herein) younger patients) as in the TFT and NSAA results described and shown in It must be evaluated in light of the inevitable progressive decline in motor function experienced as we age. It must be.

[0100] Pediatric patients, as indicated below, were treated with NCT028195, briefly described in Table I below. Safety and PK associated with ataluren treatment from 57 clinical trials were investigated: (Table 1: Clinical protocol overview) [Table 2]

[0101] (investigational drug) The investigational drug ataluren used in this study was packaged in a child-resistant aluminum foil pouch. It was in the form of a white to off-white powder / granules for suspension packaged in packets or sachets. Each packet or sachet contained 25% of the drug substance by weight.

[0102] (Test Design) A total dose of 40 mg / kg / day of study drug was administered in three divided doses per day. The first dose given was 10 mg / kg in the morning and the second dose given was 10 mg / kg in the afternoon. mg / kg and the third dose administered was 20 mg / kg in the evening.

[0103] Dosing was based on patient weight at baseline. Weight was measured at the time of clinic visit. If the patient's weight changed by ≥10% from baseline, the actual dose was adjusted. , and recalculated.

[0104] The first dose of study medication was administered at the clinic and the date and time of administration was recorded. Dosing was continued for 4 weeks during the PK portion of the study and for an additional 48 weeks during the extension period. The long-term study was designed to evaluate the long-term safety and efficacy of ataluren in this patient population. It was.

[0105] The evaluation included blood sampling for gene sequencing, blood sampling for ataluren PK, and biopsy. Tal signs, height, weight, physical examination, hematology, urinalysis, 12-lead ECG, appetite test Surveys, adverse events (AEs), concomitant medications, and non-DMD-related AEs were included. For plasma concentration, blood samples were collected on Day 1 (2nd visit) and Day 28 (3rd visit). The plasma concentrations of ataluren were measured before and 1, 2, 4, 6, 8, and 10 hours after administration. , a validated liquid chromatograph with a limit of quantitation (LOQ) of 0.500 μg / mL The efficacy was determined using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Modified TFTs and NSAAs were included as shown below.

[0106] (Treatment regimen) Patients were given ataluren for 52 weeks as described above. Each patient received their own kilogram The study drug was administered at a dose of 10 mg / kg in the morning and 10 mg / kg in the afternoon. / kg in the morning and 20 mg / kg in the evening three times a day (TID). from one or more foil packets or sachets containing 125, 250, or 1000 mg of investigational drug The selected combination of unit dose packages was administered on a patient weight basis.

[0107] Dosing was based on patient weight at baseline. Weight was measured at the time of clinic visit. If the patient's weight changed by ≥10% from baseline, the administered dose was discontinued. The amounts were recalculated.

[0108] Each dose was taken within approximately 30 minutes after a meal. The dosing interval was 10 minutes between the morning and afternoon doses. Approximately 6 hours (±1 hour), between the daytime dose and the evening dose, approximately 6 hours (±1 hour), between the evening dose and the next dose The interval between the morning dose and the next dose was approximately 12 hours (± 1 hour). Each prepared dose was administered immediately after preparation. The prepared dose was administered at 100 mg / kg / day when stored refrigerated (2-8°C). If not consumed within 24 hours or stored at room temperature (15-30°C), If the sample was not prepared within three hours, it was to be discarded. The number of specific sachets to be taken from each kit for each patient or parent / guardian is to be Caregivers were briefed and given detailed verbal instructions regarding drug preparation. In addition, drug supplies were Provide detailed written drug mixing and dosing instructions to the patient or parent / caregiver when the medication is dispensed. was provided to.

[0109] (Statistical considerations) The target sample size of 12 patients for this study was not based on formal statistical considerations. Preliminary results from population PK simulations suggest that study design (sample size and sparse sample) Although the screening policy was in place, there was a normal possibility of subject dropouts and / or sample shortages. However, this does not provide sufficient accuracy for the prediction of PK parameters (CL / F and Vd / F). It was shown that 20,21 .

[0110] Observed ataluren plasma concentrations were summarized by dose level at each visit and time point. Statistics (n, mean, standard deviation [SD], coefficient of variation [CV%], median, minimum, and maximum) ), and the geometric mean and its CV% were calculated. PK parameters (AUC 0-6 , AU C 0-10 , C max (0-6 hours) C trough (0-6 hours), t max (0-6 hours) , accumulation rate (AR)(AUC), AR(C max )) the actual sampling and administration times Concentrations below the LOQ were calculated using non-compartmental analysis (NCA) parameters. was set to zero for the calculation of the

[0111] For timed functional tests (TFTs), baseline values ​​(study day 1), post-baseline values The results were summarized as follows: i) 10-meter walk / run ii) Climb four flights of stairs; iii) Descend four flights of stairs; and iv) Stand up from a supine position. Each of the four tests was analysed separately, including the time taken to walk 10 m / The driving test was evaluated once. If the time required to perform TFT exceeded 30 seconds, or if the subject was unable to perform the TFT due to exacerbation of the disease, 30 seconds Values ​​were set in the analysis summary. Time values ​​in seconds were used for descriptive statistics: n, mean, SD, median The observed and baseline values ​​for TFT were summarized using the 95% confidence intervals. Changes from were summarized for the evaluable population accordingly.

[0112] Some ratings on the NSAA 16-point scale reflect the developmental stage of the pediatric patient population. For example, "raise head" was removed from the overall list and revised to reflect the NSAA scale. Items 3 and 8 were further revised to detect changes in younger groups of children. 18 ,22 The same analysis was used for all subjects (n=14).

[0113] (result) A total of 14 pediatric patients with nmDMD were screened and enrolled. All were followed for safety, P All patients included in the K and evaluable populations completed the study, including the PK and continuation phases. The subjects were males with a mean age of 3.4 years (range 2 to 4 years); 6 of the subjects (42.9%) were taking corticosteroids at baseline. Len's dosing is measured as milligrams of drug per kilogram (kg) of the patient's body weight, assessed every 12 weeks. All patients received ataluren at 40 mg / kg / day. in the morning, midday, and evening for 4 weeks during the PK portion of the study and for 48 weeks during the extension period. , 10, 10, and 20 mg / kg, respectively, administered three times daily. The study period was designed to evaluate the long-term safety and effectiveness of ataluren in this patient population. The results obtained support the efficacy of atalantastat administered over a 52-week period in this pediatric population. The required assessment of Ren's safety, PK, and potential clinical benefits was provided.

[0114] (Existing population pharmacokinetic model) This expanded model (2013 / 2014) was based on the data previously used to develop the model. Data from studies 026 and 030 (data from patients with nmCF) pooled with data from (excluding 23 2013 / 2014 collective penalty kicks The analysis was based on pooled data from healthy adults, nmDMD patients, and nmCF patients. The most robust fit is a two-compartment model with first-order absorption and linear clearance. The rate of absorption was found to be dose-dependent and the relative bioavailability Irritability may be related to time (decreasing over time), formulation (day 1), or disease state (steady state). The apparent oral clearance and central compartment volume were dependent on body weight. The effect of diurnal variation was included on clearance. This model is called the "nmDMD Relative F Model (2017)" (nmDMD Relati The study was conducted on healthy volunteers and subjects aged 2 years or older, and was called the ve F Model (2017). Considered the definitive population PK model for children with DMD.

[0115] (nmDMD relative F model (2017) and nmDMD clearance model (2017 ) for comparison of steady-state exposure using To assess the sensitivity of predicted ataluren exposure in patients with nmDMD, AUC 0- 24 , C ave , and C max The posterior estimates of both models: nmDMD relative F model (2017) and the nmDMD clearance model (2017). As shown, the competing models predict lower exposure on day 1 and higher exposure at steady state. There is a clear assessment of which model provides more accurate exposures. Although it is not possible to estimate the difference in exposure predicted by the two models, it is possible that, overall, the difference in exposure predicted by the two models is relatively small. It is important to note that the ave The overall distribution of When comparing the two models, they are not dramatically different at steady state. (Table 2: Percentage differences in individual estimates of exposure) [Table 3]

[0116] (Pharmacokinetics) The mean (SD) plasma ataluren concentration-time profiles are shown in Table 3. The concentrations followed a similar pattern on days 1 and 28, with peak concentrations in most subjects. was observed approximately 2 hours after the morning dose and 8 hours after the morning dose (i.e., 2 hours after the midday dose). The second dose of ataluren was administered 6 hours after the first dose. As such, the values ​​of some PK parameters were similar between visits and between doses. where AUC is expressed as (hr*μg / mL). Plasma concentrations were expressed as (μg / mL), and tmax (0-6 hours) was expressed as (hr). and AUC 0-6 and the accumulation rate (AR) of Cmax (0-6 hours) were, respectively: 0.99 and 1.02, showing no obvious accumulation. (Table 3. Ataluren plasma pharmacokinetic results) [Table 4]

[0117] (Pharmacokinetic results) The PK of ataluren was calculated for all 14 subjects. AUC0-6, AUC0- 10. Cmax (0-6 hours), Ctrough @ 6 hours, and tmax (0-6 hours) data were provided for visits 2 and 3. Mean plasma concentration versus time curves were obtained for both The PK visits followed a similar pattern. The accumulation rates of AUC0-6 and Cmax were The values ​​were 0.99 and 1.02.

[0118] (Efficacy evaluation) Evaluation of ataluren efficacy after 28 and 52 weeks of treatment is shown in the figures. Treatment with CIRRHOSIS® significantly improved timed functional testing from baseline at weeks 28 and 52. In these analyses, one patient completed any TFT at week 28. This patient was not able to receive the TFTs and was therefore not included in any of the week 28 TFT analyses. The second patient did not have a baseline time to descend four flights of stairs and had a baseline time of 28 weeks and 52 weeks. None of the four steps down the ladder were included in the analysis.

[0119] Functionality results were obtained in tests such as those shown in Figures 1A, 1B, 1C, and 1D. As shown in Figure 1A, the mean time (SD) required to descend four steps was At 28 weeks, the mean baseline score of 7.1 was higher among the 12 patients included in this analysis. The mean time to presentation time (TPS) was reduced by 0.6 (±1.93) seconds from 0.05 seconds to 0.6 seconds (±1.93) seconds at week 52 in the 13 patients included in the analysis. During the week, the mean baseline time was reduced by 2.2 (±2.58) seconds from 7.5 seconds. Comparing the results for the 52nd and 6th weeks, the results were 7.17 (±26.43) percent and 7.17 (±26.43) percent, respectively. The mean percent improvement (SD) for each was 24.22 (±28.32) percent. .

[0120] As shown in Figure 1B, the average time to climb four steps was 13 patients for whom data was collected. Data were collected at week 28 (N=13) and at week 52 (N=14). N = 14), the reductions were 1.8 (±4.85) seconds and 2.6 (±5.0) seconds, respectively. Comparing the results for weeks 28 and 52, the difference was 9.10 (±29.63) percentage points, respectively. The mean percent improvement (SD) was 23.36 (±26.25) percent for each group. is shown.

[0121] As shown in Figure 1C, the mean change from baseline in standing from supine position was Improvement was observed in patients evaluated at week 28 (N=13) and week 52 (N=1 4) were similar.

[0122] As shown in Figure 1D, the mean time for the 10-m walk / run assessment at baseline was 1.2 times faster than the mean time for the 10-m walk / run assessment at baseline. Among the 13 patients, the mean age was 6.7 (±2.46) seconds, and at 28 weeks it was 0.8 (±1.5) seconds. 4) seconds and a base of 1.1 (±1.35) seconds at week 52 for the 14 patients evaluated The mean reduction from baseline was shown. Comparing the results for weeks 28 and 52, The mean percentage improvement was 8.35% at week 28 and 14.54% at week 52, respectively. do.

[0123] North Star Ambulatory Assessment (NSAA) results are shown in Figures 2A, 2B, and 2C. Similar to the results described in the TFT analysis, NSA Patients who failed to complete A were excluded from the analysis. However, all patients were included in the baseline Patients were included at baseline and 52-week evaluations.

[0124] As shown in Figure 2A, the 16 NSAAs obtained at weeks 28 and 52 were The mean (SD) value of the NSAA total score at week 28 was calculated based on the data collected. For the 13 patients, the mean age was 19.8 (±6.17) (N=13), and for the 13 patients, the mean age was 16.2 (±4. 76) improved by 3.5 (±3.43) points or 24.88% from baseline. The mean (SD) value of the NSAA total score at week 52 was 14 subjects for whom data was collected. The mean mean for patients was 21.5 (±6.48) (N=14), and the mean mean for patients was 16.0 (±4.66). This was an improvement of 5.5 (±4.43) points or 36.63% from baseline.

[0125] As shown in Figure 2B, the results of the eight NSAAs obtained at weeks 28 and 52 were compared. The mean (SD) NSAA score for the eight items at 28 weeks was 12.1 (±3.12). ) (N=13), a 15.14% improvement from a baseline value of 10.5 (±2.67). The mean (SD) 8-item NSAA score at week 52 was 12.8 (+ / - 3. 12) (N=14), a 23.31% increase from a baseline value of 10.5 (±2.56). This was an improvement.

[0126] As shown in Figure 2C, the results of the three NSAAs obtained at weeks 28 and 52 were compared. The mean (SD) value of the three-item NSAA score at 28 weeks was 5.8 (±0.38). (N=13), a 10.26% improvement from a baseline value of 5.4 (±0.65). The mean (SD) value of the three-item NSAA score at week 52 was 5.6 (+ / - 0.63). (N=14), a 6.31% improvement from a baseline value of 5.4 (±0.63). It was.

[0127] (Efficacy results) All timed functional test assessments demonstrated an overall improvement from baseline.

[0128] The mean (SD) time required to descend four standard steps was 28 weeks (5th visit) and At week 52 (7th visit), the incidence rates were 7.17 (26.433) percent and 2.0 (1.033) percent, respectively. A similar trend was observed in the stair climbing test. , which was 9.10 (29.630) percent and 52 weeks, respectively. The mean (SD) improvement was 23.36 (26.249) percent.

[0129] Improvements in supine standing assessment were similar at weeks 28 and 52. 10 The meter run / walk assessment was 8.35 (22.778) percent at week 28 and 5. The mean (SD) improvement at 2 weeks was 14.54 (14.862) percent. ) The 16-item NSAA total score showed an improvement from the baseline value of 16.0 (4.66). The top was seen.

[0130] The mean (SD) total score at week 28 was 19.8 (6.17), and the SD was 24.88. The mean (SD) total score at week 52 was 27.203 percent improvement. , 21.5 (6.48), an improvement of 36.63 (29.956) percent. .

[0131] Similar improvements were seen to a lesser extent using the 8-item and 3-item NSAA subscales. In terms of preference characteristics, 10 of the respondents (71.5%) said that this medication Based on the child's response, they either agreed or strongly agreed that the experience was comfortable. However, 2 (14.3%) disagreed. Only 2 (14.3%) of the respondents agreed with the drug. reported problems administering the drug to patients.

[0132] Pediatric patients, as indicated below, were treated with atata according to the clinical trials briefly described in Table 2 below. Safety and PK associated with treatment with Luren can be investigated: (Table 2: Clinical protocol overview) [Table 5] TIFF2025160227000007.tif223170TIFF2025160227000008.tif66170

[0133] (International Market) 1 Pichavant C , Aartsma-Rus A , Clemens P R , Davies KE , Dickson G , Takeda S , Wilto n SD, Wolff JA, Wooddell CI, Xiao X, Tre mblay JP. Current Status of Pharmaceuticals al and genetic therapeutic approaches to treat DMD. Mol Ther. May 2011;19(5):830- 40. doi: 10.1038 / mt.2011.59

[0134] 2 Yiu EM, Kornberg AJ. Duchenne muscle r dystrophy. J Paediatr Child Health , 20 8 / 15; 51(8):759-64. doi: 10.1111 / jpc.12 868

[0135] 3 [ PubMed ] Birnkrant DJ, Bushby K, Bann CM, Apko n SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR , Hadjiyannakis S , Pandya S , Street N , Tomezsko J , Wagner KR , Ward LM , Weber DR; DMD Care Considerations Work ing Group. Diagnosis and management of D unequal muscular dystrophy, part 1: diag nose, and neuromuscular, rehabilitation , endocrine, and gastrointestinal and nutritional tritional management. Lancet Neurol. 201 March 8;17(3):251-267. doi: 10.1016 / S1474-4 422(18)30024-3

[0136] 4 Bladen CL, Salt D, Monks S, Foncu berta ME, Kekou K, Kosma Kら. The TREAT-N MD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. April 2015;36(4):395- 402

[0137] 5 Bello L, Pegoraro E. Genetic diagnosis s as a tool for personalized treatment f Duchenne muscular dystrophy. Acta Myol . . . . Dec 2016;35(3):122-127

[0138] 6 Aartsma-Rus A, Van Deutekom JC, Fokke ma IF, Van Ommen GJ, Den Dunnen JT. Entr ies in the Leiden Duchenne muscular dyst rophy mutation database: an overview of mutation types and paradoxical cases tha t confirm the reading-frame rule. Muscle Nerve. August 2006;34(2):135-44

[0139] 7 Deconinck N, Dan B. Pathophysiology o f duchenne muscular dystrophy: current h ypotheses. Pediatr Neurol. January 2007;36(1) :1-7

[0140] 8 European Medicines Agency. Translarna TM summary of product characteristics, h ttp: / / www.ema.europa.eu / docs / en GB / docum ent_library / EPAR_-_Product_Information / h uman / 002720 / WC500171813.pdf

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[0142] 10 麦克唐纳CM、坎贝尔C、托里切利 RE等人;临床评估员培训小组; 杜氏肌营养不良症无义突变患者的阿他芦胺(ACT DMD)研究组。 患有无义突变杜氏肌营养不良症(ACT DMD):一项多中心、 随机、双盲、安慰剂对照 的3期试验。《柳叶刀》。2017年9月23日;3 90(10101):1489 - 1498。doi: 10.1016 / S0140 - 6736(17)31611 - 2

[0143] 11 PTC治疗公司。2014年。PTC治疗公司 在欧盟获得Translarna的有条件批准 用于治疗无义突变杜氏肌营养不良症。可从:ht TM tp: / / ir.ptcbio.com / releasedetail.cfm?rel easeid = 863914 获取。 tp: / / ir.ptcbio.com / releasedetail.cfm?rel easeid = 863914

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[0156] While the specific embodiments described herein are for illustrative purposes, the description is not intended to be limiting unless otherwise specified. It will be understood that the scope is not limited by the particular embodiments disclosed. These aspects are intended as illustrations of some of the aspects described. Any such embodiment is intended to be within the scope of the present description. It will be readily apparent to those skilled in the art that various modifications of this disclosure in addition to those shown and described herein may be readily apparent to those skilled in the art. However, as will become apparent from the above description, such modifications are also within the scope of this description. It is intended to be something.

Claims

1. Human children with nonsense-mediated Duchenne muscular dystrophy (nmDMD) A method for improving or managing nmDMD in a patient, the patient being 2 years of age or older and 5 years of age or older. Patients in the age range of less than 18 years were orally administered a therapeutically effective amount of ataluren based on the patient's weight. , a mean blood glucose concentration in the range of at least about 1 μg / mL to about 20 μg / mL during a 24-hour period achieving a plasma concentration.

2. 10. The method of claim 1, wherein the patient is in the age range of 6 months or older and less than 2 years old. 。

3. The therapeutically effective amount of ataluren is 40 mg / kg / day of ataluren based on the patient's weight. Yes; and The achieved mean plasma concentration in the patient is at least about 1 μg / m during a 24-hour period.

10. The method of claim 1, wherein the concentration of ATP in the blood is in the range of 100 μg / mL to about 20 μg / mL.

4. The therapeutically effective amount of 40 mg / kg / day is a 10 mg / kg morning dose, a 10 mg / kg administered as a midday dose and an evening dose of 20 mg / kg; the time period between the morning dose and the midday dose is 6 hours; the period between the midday dose and the evening dose is 6 hours; and the period between the evening dose and the following morning dose is 12 hours; The method of claim 3.

5. The therapeutically effective amount of ataluren is 80 mg / kg / day of ataluren based on the patient's weight. Yes; and The achieved mean plasma concentration in the patient is at least about 1 μg / m during a 24-hour period.

10. The method of claim 1, wherein the concentration of ATP in the blood is in the range of 100 μg / mL to about 20 μg / mL.

6. The therapeutically effective amount of 80 mg / kg / day is a 20 mg / kg morning dose, a 20 mg / kg administered as a midday dose and an evening dose of 40 mg / kg; the time period between the morning dose and the midday dose is 6 hours; the period between the midday dose and the evening dose is 6 hours; and the period between the evening dose and the following morning dose is 12 hours; The method of claim 5.

7. 10. The method of claim 4 or 6, wherein the dose is optionally administered within 30 minutes of a meal.

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