Methods and compositions for treatment of rett syndrome

Abstract

To provide methods of treating Rett syndrome.SOLUTION: Disclosed herein is a method for treating Rett syndrome, comprising administering trofinetide to a subject in need thereof, where a dosage is provided that may reduce or avoid underexposure, for example, in low body weight subjects, and / or may provide other benefits.SELECTED DRAWING: Figure 12

Description

Detailed Description of the Invention

[0001] [Technical field] [Background technology] FIELD OF THE INVENTION The present disclosure provides a method of treating Rett Syndrome, comprising administering to a subject in need thereof a trophine The method includes administering a medicament to the patient.

[0002] background Rett syndrome (RTT) is a severely debilitating neurodevelopmental disorder for which there is currently no approved treatment. Its prevalence is reported to be 1 in 10,000-15,000 live births. (Bienvenu et al., “The incidence of Rett syndrome in France,”Pediatr.Neurol. 2006, 34(5), 372-375, Neul et al., “Rett syn drome:revised diagnostic criteria and no menclature,”Ann.Neurol.2010,68(6),944-95 0) Although the majority of patients with RTT are female, men who meet the criteria for RTT have also been identified. (Neul et al., “The array of clinical phenotypes of males with mutations in Me thyl-CpG binding protein 2,”Am.J.Genet.B .Neuropsychiatr.Genet.2019,180(1),55-67) .

[0003] Rett syndrome includes "typical" and "atypical" forms, which are classified as "classic" and "atypical," respectively. Atypical RTTs are generally referred to as variants of typical RTTs. It involves some, but not all, of the criteria required for the diagnosis of TT, and is discussed in more detail below. Patients with typical RTT have apparently normal psychomotor development during the first 6 months of life. However, it was soon observed that the child did not reach normal developmental milestones, and subsequently, and a period of developmental regression with loss of normal use of speech and loss or impairment of walking. It is observed (Samaco and Neul, “Complexities of R ett syndrome and MeCP2,J.Neurosci.2011,3 1(22),7951-7959). The developmental regression period is responsible for many, but not all, RTTs. associated with transient autistic symptoms in individuals with development and regression in Rett synd rome,Clin.Genet.2013,84(6),572-576,Neul et al.,”Developmental delay in Rett synd rome:data from the natural history study ,”J.Neurodevelop.Dis.2014,6(20),1-9).Social Skill loss appears to stabilize or reverse after a period of regression, and some with RTT Individuals demonstrate social intentions through eye contact (Young et al., “Th e diagnosis of autism in a female:could it be Rett syndrome? Eur.J.Pediatr.2008, 167(6), 661-669, Djukic and McDermott”Soci al preferences in Rett syndrome,”Pediatr .Neurol.2012,46(4),240-242, Urbanowicz et al. al.,”An exploration of the use of eye g aze and gestures in females with Rett sy ndrome,”J.Speech Lang.Hear.Res.2016,59(6 ), 1373-1383). Nevertheless, social interaction and communication are restricted. remains limited (Mount et al., “Features of autoimmunity” sm in Rett syndrome and severe mental re tardation,”J.Autism Dev.Disord.2003,33(4 ), 435-442, Urbanowicz et al., “Aspects of speech language abilities are influenced by MECP2 mutation type in girls with Re tt syndrome,”Am.J.Med.Genet.2015,167A(2) , 354-362, Rose et al., “Rett syndrome:an e ye-tracking study of attention and recog nition memory,”Dev.Med.Child Neurol.2013 ,55(4),364-371,Kaufmann et al.,”Social i mpairments in Rett syndrome:characterist ics and relationship to clinical severit y,”J.Intellect.Disabil.Res.2012,56(3),23 3-247, Woodyatt and Ozanne, “A longitudina l study of cognitive skills and communication ation behaviors in children with Rett s yndrome,”J.Intellect.Disabil.Res.1993,37 (Ptr), 419-435). The intellectual disability in RTT appears to be serious. However, However, most individuals suffer from severe communication and motor disabilities, which can lead to cognitive impairment. Accurate measurement of the degree of impairment is difficult (Byiers and Symons ,”Issues in estimating developmental lev el and cognitive function in Rett syndrome me,”In:Hodapp,RM(ed.),International Re view of Research in Intellectual and Dev elopmental Disabilities,Waltham,MA:Elsev ier Inc.;2012,43,147-185, Clarkson et al. ,”Adapting the Mullen Scales of Early Le arning for a standardized measure of cog in children with Rett syndrome,”I ntellect.Dev.Disabil.2017,55(6),419-431) .

[0004] Seizures are common but not diagnostic. Commonly observed symptoms include awakening disordered breathing. , scoliosis, and interest in social interaction (engaged eye communication) (Neul 2010, supra; Percy et al., “Profiling s coliosis in Rett syndrome,”Pediatr.Res.2 010,67(4),436-439). Gastrointestinal symptoms, including constipation, and difficulty chewing and swallowing is observed in the majority of patients with RTT (Motil et al., “Gast rointestinal and nutritional problems oc cur frequently throughout life in girls and women with Rett syndrome,”J.Pediatr. Gastroenterol.Nutr.2012,55(3,292-298). Mood Sudden changes in mood, screaming, and inconsolable crying are common in children and adolescents with RTT. This is a common behavior (Mount et al., “Behavioral and motional features in Rett syndrome,”Disa bil.Rehabil.2001,23(3-4),129-138,Mount e t al.,”The Rett Syndrome Behavior Quest ionnaire (RSBQ):Refining the behavioral phenotype of Rett syndrome,”J.Child Psy chol.Psychiatry 2002, 43(8), 1099-1110, Rob ertson et al.,”The association between b ehavior and genotype in Rett syndrome us ing the Australian Rett syndrome database e,”Am.J.Med.Genet.2006,141B(2),177-183,C ianfaglione et al.,”A national survey of Rett syndrome:behavioural characteristi cs,” J.Neurodev.Disord.2015,7(1),11). The disability exacerbates other symptoms and interferes with activities of daily living, including educational, recreational, and therapeutic opportunities. (Epstein et al., “Conceptualizing a quality of life framework for girls with Rett syndrome using qualitative methods ,”Am.J.Med.Genet.A 2016,170(3),645-653,P erry et al.,”Brief report: cognitive and adaptive functioning in 28 girls with Re tt syndrome,”J.Autism Dev.Disord.1991,21 (4), 551-556, Thompson and Iwata, “A descri ptive analysis of social consequences fo slowing problem behavior,”J.Appl.Behav.A nal.2001,34(2),169-178, Iemmi et al.,”Pos itive behavioral support for children a nd adolescents with intellectual disability entities whose behavior challenges:an explo ration of the economic case,”J.Intellect Disabil.2015,20(3),281-295). Cardiac and respiratory dysfunction Autonomic symptoms, including peripheral circulatory abnormalities, are thought to be primarily CNS in origin. RTT is also characterized by growth disorders that affect the brain and other organ systems.

[0005] Loss of purposeful hand use is common during the onset of regression in subjects with RTT. observed in at least 30% of individuals without any kind of intentional hand use. (Downs et al., “Level of purposefulness” and function as a marker of clinical sev erity in Rett syndrome,”Dev.Med.Child Ne Urol.2010, 52(9), 817-823). Individuals who self-feed vary in their level of ability to reach and grasp objects. lf-feed) ability is observed in 25-43% (Cass et al., “Fi ndings from a multidisciplinary clinical case series of females with Rett syndrome me,”Dev.Med.Child Neurol.2003,45,325-337 , Larsson et al., “Rett syndrome from a fa. mily perspective:the Swedish Rett Center Survey,”Brain Dev.2005,27 Suppl 1,S14-1 9, Downs et al. 2011). The level of poor hand function is related to age and motor impairment. (Downs et al., “Longitudina l hand function in Rett syndrome,”J.Chil d Neurol.2011,26(3),334-340).

[0006] In adulthood, a period of slow motor deterioration occurs, with worsening dystonia, stiffness, and In some cases, it is characterized by decreased walking ability and parkinsonian symptoms. The annual mortality rate is 1-2%, with 25% of all deaths characterized as sudden and unexpected. (Kerr et al., "Rett syndrome: analysis" of deaths in the British survey,”Eur.Ch ild Adolesc.Psychiatry 1997,6 Suppl 1,71 -74; Samaco and Neul 2011, supra). Women with RTT are 5 They can live into their teens, and sometimes even longer (Samaco and Neul 2018). 11, above).

[0007] There are no medications approved for the treatment of Rett syndrome. Current treatment options are tailored to each patient's condition. The focus is on managing the situation, and even that is often unsatisfactory, leading to poor performance. The effect on good is limited. Therefore, the burden on family and other caregivers is high (Pal acios-Cena et al.,”'Living an obstacle c ourse':A qualitative study examining the experiences of caregivers of children ith Rett syndrome,”Int.J.Environ.Res.Pub lic Health 2018,16(1),41).

[0008] In 96–98% of patients diagnosed with classic RTT, the disease is due to an X-linked MECP2 It is caused by a genetic mutation (Percy et al., “When Ret t syndrome is due to genes other that ME CP2,”Transl.Sci.Rare Dis.2018,3(1),49-53 MECP2 primarily activates transcription by binding to methylated CpG dinucleotides. Methyl regulates gene expression not only by activating but also by repressing transcription. Re-encodes CpG-binding protein 2 (MeCP2) (Ip et al., “Re tt syndrome:insights into genetic, molecule lar and circuit mechanisms,”2018,19(6),3 68-382, Neul et al., “Specific mutations i n methyl-CpG-binding protein 2 confer di fferent severity in Rett syndrome,”Neuro logy 2008,70(16),1313-1321, Kriaucionis e t al.,”DNA methylation and Rett syndrome ,”Hum.Mol.Genet.2003,12 Spec No 2,R221-2 27, Hite et al., “Recent advances in MeCP2 structure and function,”Biochem.Cell Bi ol.2009,87(1),219-227). The activity of MeCP2 protein is It is decreased in both neurons and astrocytes (Yasui et al., “MeCP2 modulates gene expression pathways in a strocytes,” Mol.Autism 2013,4(1),3). Proteins are important for the development of the nervous system, especially the brain. Mutations can reduce protein production. Without sufficient levels of the protein, the brain cannot function properly. It does not always develop, leading to Rett syndrome. Eight MEs make up the majority of Rett syndrome cases. CP2 mutations are present, and the location and type of mutation influence the onset and severity of symptoms of the syndrome. , MECP2 T158M and MECP2 R106W mutations are the most common (Ami r et al.,”Rett syndrome is caused by mut ations in X-linked MECP2,”Nature Genetic s 1999, 23(2), 185-188, Percy et al.,”Rett syndrome:North American database,”J.Chil d Neurol.2007,22(12),1338-1341).

[0009] Trofinetide binds to the glycine-proline-glutamine peptide, which is naturally occurring in the brain. GPE is a synthetic analog of glypromate (also known as glypromate or GPE). It is the n-terminal tripeptide of the insulin-like growth factor 1 (IGF-1) protein. The structure of inetide is shown below. [ka]

[0010] Trofinetide crosses the blood-brain barrier after oral administration. In the brain, it promotes the production of IGF-1 and GP. Normalizes the decreased bioavailability of E and suppresses pathologically activated glycoproteins. Both conditions are thought to have an anti-inflammatory effect on RTT cells. contributes to the functional maturation of synaptic plasticity and deficits in synaptic development, underlying the long-lasting effects Mechanistically, trophinetide reduces neuroinflammation and inhibits microglial activation and apoptosis. Reduces strogliosis, normalizes protein synthesis and dendritic cell morphology, and improves excitability and It is hypothesized that this restores homeostasis of inhibitory neuronal signaling (Lu et al., Glycyl-L-2-methylprolyl-L-glutamic acid, a glypromate analog,attenuates brain isc hemia-induced non-convulsive seizures in rats,”J.Cerebr.Blood Flow & Metab.2009, 29, 1924-1932, Wei et al., “Glycyl-L-2-meth ylprolyl-L-glutamic acid treatment inhib its neuroinflammation and pro-inflammato ry cytokine expression induced by experi mental penetrating ballistic-like brain injury in rats,”J.Neuroinflammation 2009 ,6,19,Deacon et al.,”NNZ-2566,a novel an alog of(1-3)IGF-1, as a potential therapy utic agent for fragile X syndrome,”Neuro Mol.Med.2015,17,1). Treatment with GPE was shown to be effective in MeCP2 mutant mice. reversed Rett-like symptoms in patients with rheumatoid arthritis (Tropea et al., "Partial reversal of versatile of Rett syndrome-like symptoms in MeCP2 mutant mice,”Proc.Natl.Acad.Sci.U SA 2009,106,2029-2034). Therefore, trophinetide is This represents an opportunity for the treatment of RTT syndrome. Such treatment could result in a wide range of RTT symptomatic improvement. Brain structure and function, such as dendritic length, branching, and long-term synergism, are predicted to play a role. It may have an effect on function.

[0011] Pharmacokinetic data are based on previous clinical trials of trophinetide in healthy subjects and in Clinical trials of trofinetide in subjects with the syndrome (first in adolescents and adults) and a second one in children and adolescents) are available from (Oosterhof lt et al.,”Population pharmacokinetics o f NNZ-2566 in healthy subjects,”Eur.J.Ph arm.Sci.2017,15,109S,S98-107, Glaze et al .,”A double-blind,randomized,placebo-con trolled study of trophinetide in pediatri c Rett syndrome,”Neurology 2019,92(16),e However, in interventional clinical trials, a significant proportion of subjects responded positively. and did not achieve the expected levels of trophinetide exposure.

[0012] [Summary of the Invention] As discussed in detail herein, analysis of the results of human clinical trials has demonstrated the efficacy of trophinetide. This indicates that lower than expected exposures are associated with low body weight in children. The methods presented herein aim to alleviate this problem and / or improve the trophinetide exposure level in subjects. improve performance, provide other benefits, or at least provide useful options to the public. In particular, the applicant has surprisingly found that In addition, high doses of trophinetide have been safely administered to underweight children to treat Rett syndrome. It was discovered that it can be administered to the entire body.

[0013] In one aspect, the present disclosure provides a method for treating Rett syndrome in a subject in need thereof. A method of treating a patient suffering from atopic dermatitis, comprising administering a therapeutically effective amount of trophinetide to: a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g per day amount, c) If the subject weighs 20.1 to 35.0 kg, 14.1 to 18.0 g per day amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g per day Amount, or e) If the subject weighs 50.1 to 150 kg, the daily dose is 22.1 to 26 g. The method includes administering to an elephant.

[0014] In another aspect, the present disclosure provides a trophoblast for use in treating Rett Syndrome in a subject. trophinetide, a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g per day amount, c) If the subject weighs 20.1 to 35.0 kg, 14.1 to 18.0 g per day amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g per day Amount, or e) If the subject weighs between 50.1 and 150 kg, administer a daily dose of 22.1 to 26 g. Trofinetide is administered.

[0015] In another aspect, the present disclosure provides a method for manufacturing a medicament for treating Rett Syndrome in a subject. Use of trophinetide for the treatment of rheumatoid arthritis, comprising administering to the patient: a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g per day amount, c) If the subject weighs 20.1 to 35.0 kg, 14.1 to 18.0 g per day amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g per day Amount, or e) If the subject weighs between 50.1 and 150 kg, administer a daily dose of 22.1 to 26 g. To be given, to provide for use. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating Rett syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of trophinetide to: a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) a daily dose of 10.1 to 14.0 g if the subject weighs 12.0 to 20.0 kg; c) a daily dose of 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg; d) a daily dose of 18.1 to 22.0 g if the subject weighs 35.1 to 50.0 kg; or e) administering to the subject a daily dose of 22.1 to 26 g when the subject weighs 50.1 to 150 kg. (Item 2) Item 10. The method according to item 1, wherein the subject weighs 8 to 11.9 kg. (Item 3) 3. The method of claim 2, wherein the trophinetide is administered to the subject in a daily dose of 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or 10 g. (Item 4) Item 1. The method according to item 1, wherein the subject has a body weight of 12.0 to 20.0 kg. (Item 5) 5. The method of claim 4, wherein the trophinetide is administered to the subject in a daily dose of 11 g, about 12 g, about 13 g, or 14 g. (Item 6) Item 1. The method according to item 1, wherein the subject has a body weight of 20.1 to 35.0 kg. (Item 7) 7. The method of claim 6, wherein the trophinetide is administered to the subject in a daily dose of 15 g, about 16 g, about 17 g, or 18 g. (Item 8) Item 1. The method according to item 1, wherein the subject has a body weight of 35.1 to 50.0 kg. (Item 9) 9. The method of claim 8, wherein the trophinetide is administered to the subject in a daily dose of 19 g, about 20 g, about 21 g, or 22 g. (Item 10) Item 1. The method according to item 1, wherein the subject weighs 50.1 to 100 kg. (Item 11) 11. The method of claim 10, wherein the trophinetide is administered to the subject in a daily dose of 23 g, about 24 g, about 25 g, or 26 g. (Item 12) The administration of trophinetide has an AUC of about 755 μg·h / mL to about 1300 μg·h / mL in the subject 0-12,ss 12. The method according to any one of items 1 to 11, (Item 13) The administration of trophinetide is agonizing in the subject with a vasopressin-dependent increase in blood cholesterol level of at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, AUC of at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg·h / mL 0-12,ss 12. The method according to any one of items 1 to 11, (Item 14) The administration of trophinetide to the subject results in a C of about 100 to about 200 μg / mL in the subject. max,ss 14. The method according to any one of items 1 to 13, (Item 15) and / or administering to the subject a C of at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL in the subject. max,ss 14. The method according to any one of items 1 to 13, (Item 16) 16. The method of any one of items 1 to 15, wherein the trophinetide is administered to the subject in a single dose per day. (Item 17) 16. The method according to any one of items 1 to 15, wherein the trophinetide is administered to the subject in multiple doses per day that together amount to the daily dose. (Item 18) Item 18. The method of item 17, wherein the trophinetide is administered to the subject in two doses per day that total the daily dose. (Item 19) 19. The method according to any one of items 1 to 18, wherein the trophinetide is administered as a pharmaceutical composition comprising the trophinetide and a pharmaceutically acceptable carrier. (Item 20) 20. The method of claim 19, wherein the pharmaceutically acceptable carrier comprises water. (Item 21) 21. The method according to items 19 to 20, wherein the pharmaceutical composition is a solution. (Item 22) 22. The method of claim 21, wherein the concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL in the solution. (Item 23) 23. The method of claim 22, wherein the concentration of trophinetide in the solution is about 0.2 g / mL in the solution. (Item 24) 24. The method according to any one of items 1 to 23, wherein the trophinetide is orally administered to the subject. (Item 25) 25. The method according to any one of items 1 to 24, wherein the subject is a human. (Item 26) 26. The method of claim 25, wherein the subject is a female. (Item 27) 27. The method according to any one of items 1 to 26, wherein the subject is between about 18 months and about 20 years old. (Item 28) 28. The method according to any one of items 1 to 27, wherein the subject has an MECP2 mutation. (Item 29) 29. The method according to any one of items 1 to 28, wherein the Rett syndrome is atypical Rett syndrome. (Item 30) 29. The method according to any one of items 1 to 28, wherein the Rett syndrome is classic / typical Rett syndrome. (Item 31) 1. Trofinetide for use in the treatment of Rett syndrome in a subject, said trophinetide comprising: a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) a daily dose of 10.1 to 14.0 g if the subject weighs 12.0 to 20.0 kg; c) a daily dose of 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg; d) a daily dose of 18.1 to 22.0 g if the subject weighs 35.1 to 50.0 kg; or e) The trophinetide administered in a daily dose of 22.1 to 26 g when the subject weighs 50.1 to 150 kg. (Item 32) 32. Trofinetide for use according to Item 31, wherein the subject weighs 8 to 11.9 kg. (Item 33) 33. Trofinetide for use according to item 32, wherein the trophinetide is administered to the subject in a daily dose of 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or 10 g. (Item 34) Item 32. Trofinetide for use according to Item 31, wherein the subject has a body weight of 12.0 to 20.0 kg. (Item 35) 35. Trofinetide for use according to item 34, wherein the trophinetide is administered to the subject in a daily dose of 11 g, about 12 g, about 13 g, or 14 g. (Item 36) Item 32. Trofinetide for use according to Item 31, wherein the subject has a body weight of 20.1 to 35.0 kg. (Item 37) 37. Trofinetide for use according to item 36, wherein the trophinetide is administered to the subject in a daily dose of 15 g, about 16 g, about 17 g, or 18 g. (Item 38) Item 32. Trofinetide for use according to Item 31, wherein the subject has a body weight of 35.1 to 50.0 kg. (Item 39) 39. Trofinetide for use according to item 38, wherein the trophinetide is administered to the subject in a daily dose of 19 g, about 20 g, about 21 g, or 22 g. (Item 40) Item 32. Trofinetide for use according to Item 31, wherein the subject weighs 50.1 to 100 kg. (Item 41) 41. Trofinetide for use according to item 40, wherein the trophinetide is administered to the subject in a daily dose of 23 g, about 24 g, about 25 g, or 26 g. (Item 42) The administration of trophinetide has an AUC of about 755 μg·h / mL to about 1300 μg·h / mL in the subject 0-12,ss 42. Trofinetide for use according to any one of items 31 to 41, which results in (Item 43) The administration of trophinetide is agonizing in the subject with a vasopressin-dependent increase in blood cholesterol level of at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, AUC of at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg·h / mL 0-12,ss 42. Trofinetide for use according to any one of items 31 to 41, which results in (Item 44) The administration of trophinetide to the subject results in a C of about 100 to about 200 μg / mL in the subject. max,ss 44. Trofinetide for use according to any one of items 31 to 43, which results in (Item 45) and / or administering to the subject a C of at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL in the subject. max,ss 44. Trofinetide for use according to any one of items 31 to 43, which results in (Item 46) 46. ​​Trofinetide for use according to any one of items 31 to 45, wherein the trofinetide is administered to the subject in a single dose per day. (Item 47) Item 48: Trofinetide for use according to any one of Items 31 to 45, wherein the trophinetide is administered to the subject in multiple doses per day that total the daily dose. Item 48. Trofinetide for use according to item 47, wherein the trophinetide is administered to the subject in two doses per day that together amount to the daily dose. (Item 49) 49. Trofinetide for use according to any one of items 31 to 48, wherein said trophinetide is administered as a pharmaceutical composition comprising said trophinetide and a pharmaceutically acceptable carrier. (Item 50) Item 50. Trofinetide for use according to item 49, wherein the pharmaceutically acceptable carrier comprises water. (Item 51) 51. Trofinetide for use according to items 49 to 50, wherein the pharmaceutical composition is a solution. (Item 52) 52. Trofinetide for use according to item 51, wherein the concentration of said trophinetide in said solution is about 0.05 g / mL to 0.7 g / mL in said solution. (Item 53) 53. Trofinetide for use according to item 52, wherein the concentration of trophinetide in the solution is about 0.2 g / mL in the solution. (Item 54) 54. Trofinetide for use according to any one of items 31 to 53, wherein the trophinetide is administered orally to the subject. (Item 55) 55. Trofinetide for use according to any one of items 31 to 54, wherein the subject is a human. (Item 56) Item 56. Trofinetide for use according to item 55, wherein the subject is a female. (Item 57) 57. Trofinetide for use according to any one of items 31 to 56, wherein the subject is between about 18 months and about 20 years old. (Item 58) 58. Trofinetide for use according to any one of items 31 to 57, wherein the subject has an MECP2 mutation. (Item 59) 59. Trofinetide for use according to any one of items 31 to 58, wherein the Rett syndrome is atypical Rett syndrome. (Item 60) 59. Trofinetide for use according to any one of items 31 to 58, wherein the Rett syndrome is classic / typical Rett syndrome. (Item 61) 1. Use of trophinetide for the manufacture of a medicament for treating Rett syndrome in a subject, wherein said trophinetide comprises: a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) a daily dose of 10.1 to 14.0 g if the subject weighs 12.0 to 20.0 kg; c) a daily dose of 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg; d) a daily dose of 18.1 to 22.0 g if the subject weighs 35.1 to 50.0 kg; or e) The use, wherein the subject weighs 50.1 to 150 kg and is administered a daily dose of 22.1 to 26 g. (Item 62) Item 62. The use according to item 61, wherein the subject weighs 8 to 11.9 kg. (Item 63) 63. The use of item 62, wherein the trophinetide is administered to the subject in a daily dose of 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or 10 g. (Item 64) Item 62. The use according to Item 61, wherein the subject weighs 12.0 to 20.0 kg. (Item 65) 65. The use of item 64, wherein the trophinetide is administered to the subject in a daily dose of 11 g, about 12 g, about 13 g, or 14 g. (Item 66) Item 62. The use according to Item 61, wherein the subject weighs 20.1 to 35.0 kg. (Item 67) 67. The use of item 66, wherein the trophinetide is administered to the subject in a daily dose of 15 g, about 16 g, about 17 g, or 18 g. (Item 68) Item 62. The use according to Item 61, wherein the subject weighs 35.1 to 50.0 kg. (Item 69) 69. The use of item 68, wherein the trophinetide is administered to the subject in a daily dose of 19 g, about 20 g, about 21 g, or 22 g. (Item 70) Item 62. The use according to Item 61, wherein the subject weighs 50.1 to 100 kg. (Item 71) 71. The use of item 70, wherein the trophinetide is administered to the subject in a daily dose of 23, about 24, about 25, or 26 g. (Item 72) The administration of trophinetide has an AUC of about 755 μg·h / mL to about 1300 μg·h / mL in the subject 0-12,ss Use according to any one of items 61 to 71, resulting in (Item 73) The administration of trophinetide is agonizing in the subject with a vasopressin-dependent increase in blood cholesterol level of at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, AUC of at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg·h / mL 0-12,ss Use according to any one of items 61 to 71, resulting in (Item 74) The administration of trophinetide to the subject results in a C of about 100 to about 200 μg / mL in the subject. max,ss Use according to any one of items 61 to 73, resulting in (Item 75) and / or administering to the subject a C of at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL in the subject. max,ss Use according to any one of items 61 to 73, resulting in (Item 76) 76. Trofinetide for use according to any one of items 61 to 75, wherein the trofinetide is administered to the subject in a single dose per day. (Item 77) 76. The use according to any one of items 61 to 75, wherein the trophinetide is administered to the subject in multiple doses per day that together amount to the daily dose. (Item 78) Item 78. The use of item 77, wherein the trophinetide is administered to the subject in two doses per day that together amount to the daily dose. (Item 79) 79. The use according to any one of items 61 to 78, wherein the trophinetide is administered as a pharmaceutical composition comprising the trophinetide and a pharmaceutically acceptable carrier. (Item 80) 80. The use according to item 79, wherein the pharmaceutically acceptable carrier comprises water. (Item 81) 81. The use according to items 79 to 80, wherein the pharmaceutical composition is a solution. (Item 82) Item 82. The use according to item 81, wherein the concentration of the trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL in the solution. (Item 83) 83. The use according to item 82, wherein the concentration of trophinetide in the solution is about 0.2 g / mL in the solution. (Item 84) 84. The use according to any one of items 61 to 83, wherein the trophinetide is administered orally to the subject. (Item 85) 85. The use according to any one of items 61 to 84, wherein the subject is a human. (Item 86) Item 86. The use of item 85, wherein the subject is a female. (Item 87) 87. The use according to any one of items 61 to 86, wherein the subject is between about 18 months and about 20 years old. (Item 88) The use according to any one of Items 61 to 87, wherein the subject has an MECP2 mutation. (Item 89) 89. The use according to any one of items 61 to 88, wherein the Rett syndrome is atypical Rett syndrome. (Item 90) 89. The use according to any one of items 61 to 88, wherein the Rett syndrome is classic / typical Rett syndrome. (Item 91) 1. A method of treating Rett syndrome in a subject in need thereof, comprising administering to said subject an AUC of about 755 μg·h / mL to about 1300 μg·h / mL. 0-12,ss (Item 92) The method comprises administering to the subject a daily amount of trophinetide that provides: AUC of about 800 μg·h / mL to about 1000 μg·h / mL in the subject 0-12,ss 92. The method of claim 91, comprising administering to the subject a daily dose of trophinetide providing: (Item 93) 1. A method of treating Rett Syndrome in a subject in need thereof, comprising administering to the subject at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 990 μg·h / mL, at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1090 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1190 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μg·h / mL, at least about 1280 μg·h / mL, at least about 1290 μg·h / mL, at least about 1300 μg·h / mL, at least about 1310 μg·h / mL, at least about 1 or an AUC of at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg·h / mL. 0-12,ssThe method comprises administering to the subject a daily amount of trophinetide that provides: (Item 94) 94. The method according to any one of items 91 to 93, wherein the subject weighs about 12 kg to about 20 kg. (Item 95) 95. The method according to any one of items 91 to 94, wherein the daily dose of trophinetide is about 12 g. (Item 96) 94. The method according to any one of items 91 to 93, wherein the subject weighs about 20.1 kg to about 35 kg. (Item 97) 97. The method of any one of items 91 to 93 or 96, wherein the daily dose of trophinetide is about 16 g. (Item 98) 94. The method according to any one of items 91 to 93, wherein the subject weighs about 35.1 kg to about 50 kg. (Item 99) 99. The method of any one of items 91-93 or 88, wherein the daily dose of trophinetide is about 20 g. (Item 100) 94. The method according to any one of items 91 to 93, wherein the subject weighs about 50.1 kg to about 100 kg. (Item 101) 101. The method according to items 91 to 93 or 100, wherein the daily dose of trophinetide is about 24 g. (Item 102) 102. The method of any one of items 91 to 101, wherein the trophinetide is administered to the subject in a single dose per day. (Item 103) 102. The method of any one of items 91 to 101, wherein the trophinetide is administered to the subject in multiple doses per day that add up to the daily dose. (Item 104) Item 104. The method of item 103, wherein the trophinetide is administered to the subject in two doses per day that total the daily dose. (Item 105) 105. The method of any one of items 91 to 104, wherein the trophinetide is administered as a pharmaceutical composition comprising the trophinetide and a pharmaceutically acceptable carrier. (Item 106) 106. The method of claim 105, wherein the pharmaceutically acceptable carrier comprises water. (Item 107) 107. The method of claim 105 or 106, wherein the pharmaceutical composition is a solution. (Item 108) Item 108. The method of claim 107, wherein the concentration of the trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. (Item 109) Item 109. The method of item 108, wherein the concentration of trophinetide is about 0.2 g / mL in the solution. (Item 110) 109. The method of any one of items 91 to 109, wherein the trophinetide is administered orally to the subject. (Item 111) 111. The method according to any one of items 91 to 110, wherein the subject is a human. (Item 112) Item 112. The method of item 111, wherein the subject is a female. (Item 113) 13. The method according to any one of items 1 to 112, wherein the subject is between about 18 months and about 20 years old. (Item 114) 14. The method of any one of items 91 to 113, wherein the subject has an MECP2 mutation. (Item 115) 115. The method according to any one of items 91 to 114, wherein the Rett syndrome is atypical Rett syndrome. (Item 116) 115. The method according to any one of items 91 to 114, wherein the Rett syndrome is classic / typical Rett syndrome. (Item 117) 31. The method of any one of items 5 or 12-30, wherein the trophinetide is administered to the subject in a daily dose of about 12 g. (Item 118) 31. The method of any one of items 7 or 12-30, wherein the trophinetide is administered to the subject in a daily dose of about 16 g. (Item 119) 31. The method of any one of items 9 or 12-30, wherein the trophinetide is administered to the subject in a daily dose of about 20 g. (Item 120) 31. The method of any one of items 11 to 30, wherein the trophinetide is administered to the subject in a daily dose of about 24 g. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows a graph of the clearance (Cl) of trofinetide after administration in adolescents and adults with RTT compared to healthy volunteers (three combined data sets) as a function of body weight. [Figure 2] 1 shows a graph of the clearance (Cl) of trofinetide after administration in children and adolescents with RTT as a function of body weight. [Figure 3] Figure 1 shows a graph of the central volume of distribution (Vc) of the central compartment of trofinetide after administration in adolescents and adults with RTT compared to healthy volunteers (3 combined data sets) as a function of body weight. [Figure 4] 1 shows a graph of the volume of distribution (Vc) of the central compartment of trofinetide after administration in children and adolescents with RTT as a function of body weight. [Figure 5] Graphs showing the relationship between the percentage change from treatment baseline in RSBQ total score (RBTOT) and trophinetide AUCss at Visit 28 (Visit 5, Figure 5A; Visit 6, Figure 5B; Visit 7, Figure 5C; Visit 8, Figure 5D). [Figure 6] 1 is a graph showing the relationship between percentage change from treatment baseline in RSBQ total score (RBTOT) and trofinetide cumulative AUC0-x during active trofinetide administration. [Figure 7] 1 is a bar graph showing the distribution of AUC results for the 200 mg / kg dose group in previous trofinetide studies in children and adolescents. [Figure 8] 1 is a graph showing the simulated AUC profile of a 200 mg / kg trofinetide dose at a consistent dose of 10,000 mg BID. [Figure 9] A graphical summary of the timing of assessments and assessors. [Figure 10] 1 is a graph showing the predicted probability of CGI-I score in the range of Day 42 Cmax values ​​from 0 to 600 μg / mL. [Figure 11] 1 is a graph showing predicted change in RSBQ score versus AUC0-12 at day 42 of treatment with trofinetide. [Figure 12] 1 is a box plot summarizing predicted Day 14 AUC0-12 values ​​for each weight band following the estimated dosing regimen of trofinetide.

[0017] [Mode for Carrying Out the Invention] Reference will now be made in detail to certain embodiments of the invention. The invention is described in conjunction with the described embodiments. However, such description is not intended to limit the invention to those embodiments. Rather, the invention is defined by the appended claims. It is intended to cover all alternatives, modifications, and equivalents that may fall within the invention. .

[0018] Before describing the present teachings in detail, it is to be understood that the disclosure is not limited to particular compositions or process steps. It is to be understood that the present invention is not limited to the above and may therefore vary. When used, the singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Please note that plural references are included unless otherwise specified.

[0019] "Or" is used in the inclusive sense, i.e. "and / or" unless the context otherwise requires. It is used in the same sense as "or".

[0020] Numeric ranges include the numbers that define the range. Measurements and measurable values ​​are those associated with a measurement. It is understood that these are approximations that take into account significant figures and errors.

[0021] Also, "comprise", "comprises", "contains" containing, containing, contains "containing", "include", "incl udes," "included," and "including" The use of is not intended to be limiting. Both the general and detailed descriptions set forth above are for illustrative purposes only. It should be understood that the teachings are exemplary and explanatory and are not limiting.

[0022] Unless otherwise specifically noted in the above specification, descriptions that describe various components as "comprising" The embodiments herein may also be described as "consisting of" or "essentially consisting of" the listed components. and embodiments of the specification that describe various components as "consisting of" Also, it is intended that the invention "comprises" or "consists essentially of" the listed components. Embodiments of the specification that are illustrated and described as "consisting essentially of" various components also refer to the It is contemplated to "consist of" or "include" the elements listed (and interchangeably (The term "gender" does not apply to the use of these terms in the claims.)

[0023] As used herein, the term "trophinetide" refers to glycyl-L-2-methyl- Tyrprolyl-L-glutamate: [ka] or "G-2-MePE", "H-Gly-MePro-Glu-OH", or "Gly-MePro-Glu-OH" (wherein each stereocenter is in the S configuration), or It refers to its pharmaceutically acceptable salts. The IUPAC name for trophinetide is (2S)-2-[ [(2S)-1-(2-aminoacetyl)-2-methylpyrrolidine-2-carbonyl]a It is methylaminopentanedioic acid.

[0024] In one embodiment, the term trophinetide refers to a compound of formula I, i.e., is a neutral species.

[0025] In another embodiment, the term trophinetide refers to a pharmaceutically acceptable salt of the compound of formula I. It refers to salt.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to a compound that is physiologically acceptable in a subject. refers to any acceptable salt of formula I, for example, a salt obtained by reaction with an acid or base. Clinically acceptable salts include metal salts such as sodium salts, potassium salts, and cesium salts; calcium salts; alkaline earth metal salts such as ammonium salts and magnesium salts, triethylamine salts, pyridine salts, Choline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Organic amine salts such as N,N'-dibenzylethylenediamine salts, hydrochlorides, hydrobromides, Inorganic acid salts such as phosphates, sulfates, citrates, lactates, tartrates, maleates, Salts, mandelates, acetates, dichloroacetates, trifluoroacetates, oxalates, Organic acid salts such as sulfonates, methanesulfonates, benzenesulfonates, p-toluenesulfonates sulfonates, such as phosphates; as well as alginates, aspartates (aspargates) nate), salts of amino acids such as glutamate.

[0027] Acid addition salts can be prepared by dissolving a solution of Formula I in an acid solution containing an acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, or citric acid. , tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and other pharmaceutically acceptable non-toxic acids. The base salt can be formed by mixing a solution of Formula I with a solution of sodium hydroxide. Pharmacologically acceptable non-toxic salts such as ethanol, potassium hydroxide, choline hydroxide, sodium carbonate, etc. The polymer may be formed by mixing with a solution of the base.

[0028] As used herein, "or a combination thereof" means "or a combination thereof" or "or a combination thereof"; ion thereof" and "or combination thereof" The term "(ions thereof)" refers to any and all of the terms that precede it. Refers to all permutations and combinations. For example, "A, B, C, or any combination thereof" " means A, B, C, AB, AC, BC, or ABC, and where order is important in certain contexts. If necessary, BA, CA, CB, ACB, CBA, BCA, BAC, or CAB Following this example, BB, AAA, AAB, BBC, AAABC A group containing one or more repeated items or terms, such as CCC, CBBAAA, CABABB, etc. Those skilled in the art will typically understand that any combination is expressly included unless it is clear from the context. It will be understood that there is no limit to the number of items or terms that can be combined.

[0029] Unless otherwise defined herein, scientific and technical terms used herein are In case of any potential ambiguity, the meanings given herein are those that are commonly understood by those skilled in the art. The definitions provided take precedence over any dictionary or foreign definitions unless the context requires otherwise. Unless otherwise specified, singular terms include the plural and plural terms include the singular. Let's say.

[0030] The section headings used herein are for organizational purposes only and do not limit the desired subject matter. Any document incorporated by reference is In the event of a conflict with any term defined herein, the present specification will control. Although described in conjunction with embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings are intended to be illustrative and not restrictive, as will be appreciated by those skilled in the art. It includes alternatives, modifications and equivalents.

[0031] As used herein, the "body weight" or "body mass" of a subject "Weight" is the mass of the subject. Weight may be determined by a physician during a medical visit. In some embodiments, body weight is determined on the day or one day before starting trophinetide administration. In some embodiments, the subject has not fasted until the day before weighing.

[0032] As used herein, "treating" or "treating" Rett Syndrome "Treatment" includes (a) preventing disease, i.e., may be susceptible to a syndrome but have not yet experienced one or more symptoms of that syndrome Does not cause the development of clinical symptoms of Rett syndrome in subjects who do not have or show (b) inhibiting the disease, i.e., causing it to develop more slowly; preventing or alleviating the onset of one or more symptoms of a disease or syndrome; Reducing and / or preventing the progression of symptoms or alleviating the disease, i.e. This includes causing regression of the disease or its clinical symptoms.

[0033] In some embodiments, the efficacy of the treatment method is assessed by the Rett Syndrome Behavioral Questionnaire (RSBQ). , Rett Syndrome-Clinic Area Specific Concerns ian Domain Specific Concerns) (RTT-DSC), and and / or Clinical Global Impression-Improvement (CGI-I) et al.,”Double-blind,randomized,placebo -controlled study of trophinetide in pedi atric Rett syndrome,”Neurology 2019,92(1 6), e1912-e1925). The RSGQ total score is based on the RTT impairments already known. It is a 45-item caregiver-completed rating scale assessing a wide range of neurobehavioral symptoms. The SBQ is a validated questionnaire developed to assess the behavioral and emotional characteristics of RTT. The RSBQ correlates with function and quality of life and is associated with various age and genetic variations in RTT. The scale contains 45 items, 39 of which are Items are grouped into eight subscales, the ratings of which reflect the severity and frequency of symptoms. The eight subscales include general mood, breathing problems, hand movements, facial movements, and rocking. These included: blank face, nighttime activity, fear / anxiety, and walking / stopping. The time frame for controlled clinical trials may suitably be 12 weeks. The effectiveness of the method is assessed by the rating scale in Table 1 and may be combined with other measures. , timing of assessment of exemplary endpoints for determining efficacy and exemplary skills of assessors Provide a room.

[0034] The RTT-DSC measures hand use, gait, seizures, autonomic features, behavior, attention, and social interaction. A clinician-completed questionnaire assessing the fluency and severity of language / communication concerns. Concerns were identified on an individual basis at baseline. Severity is assessed by measuring the number of centimeters on the 10-cm VAS line. Each concern is scored and reported as a percentage of the line. The AS score is calculated as the sum of the scores for the eight concerns.

[0035] The CGI-I scale uses standardized rubrics specific to clinical features of RTT. The degree to which an individual's disease has improved or worsened compared to their baseline condition is scored. It is an assessment completed by a clinician about whether [Table 1] JPEG2025148461000005.jpg206147

[0036] One aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof Trofinetide was administered to the subjects a) If the subject has a body weight in the range of 8 to 12 kg, 4 to 12 g, for example 4 to 8 g daily amount, b) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; c) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , d) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 18 to 22 g ,or e) If the subject weighs more than 50 kg, administer a daily dose of 22 to 26 g. It is a method including: Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) If the subject has a body weight in the range of 8 to 12 kg, 4 to 12 g, for example 4 to 8 g daily amount, b) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; c) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , d) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 18 to 22 g , e) If the subject weighs more than 50 kg and less than or equal to 100 kg, 22 to 26 g per day Amount, or f) If the subject weighs more than 100 kg, administer a daily dose of 46 to 50 g. The method includes:

[0037] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; b) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , c) 18-22g daily dose if the subject weighs more than 35kg and less than or equal to 50kg The method comprises administering

[0038] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) If the subject weighs between 8 and 12 kg, 8 ± x g or 6 ± x g daily amount, b) a daily dose of 12±xg if the subject has a weight in the range of 12-20 kg; c) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; d) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; or e) If the subject weighs more than 50 kg, the daily dose should be 24 ± 1 g. fruit, x is 1, 2, 3, 4, 5, or 6, and optionally the daily dose is at least 3 g and optionally, the daily dose is at least 4 g.

[0039] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of 12±xg if the subject has a body weight in the range of 12-20 kg; b) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; c) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; or d) If the subject weighs more than 50 kg, the daily dose should be 24 ± x g. fruit, x is 1, 2, 3, 4, 5, or 6.

[0040] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) If the subject weighs between 8 and 12 kg, 8 ± x g or 6 ± x g daily amount, b) a daily dose of 12±xg if the subject has a weight in the range of 12-20 kg; c) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; d) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; e) If the subject weighs more than 50 kg and less than or equal to 100 kg, a daily dose of 24 ± x g ,or f) If the subject weighs more than 100 kg, administer a daily dose of 48 ± x g. Including, x is 1, 2, 3, 4, 5, or 6, and optionally the daily dose is at least 3 g and optionally, the daily dose is at least 4 g.

[0041] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of 12±xg if the subject has a body weight in the range of 12-20 kg; b) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; or c) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 20 ± x g administering x is 1, 2, 3, 4, 5, or 6.

[0042] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. the subject having a body weight w, d is d max Below and d min That's all, and d min and d max are respectively expressed as ( (I) and (II) are calculated according to the method: d min =w / 3750+6g (I) d max =w / 3750+12g (II).

[0043] In formulas (I) and (II), the unit of body weight w is 6 g in formula (I) and 10 g in formula (II). As long as the y-intercept value of 12g in Exemplary values ​​according to this method include: [Table 2]

[0044] Another aspect of the present disclosure is a method for treating Rett Syndrome in a person in need thereof. the method comprising administering trophinetide to a subject having a steroid hormone receptor agonist, wherein the trophinetide is administered to a subject having a steroid hormone receptor agonist ... 50th percentile AUC in g·h / mL 0-12 twice daily in an amount sufficient to In some embodiments, the 50th percentile AUC 0-1 2 is at least or about 888 μg h / mL. Finetide has a 75th percentile AUC of at least 950 μg·h / mL 0-12 It is administered twice daily in an amount sufficient to produce

[0045] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. and administering trophinetide to a subject, wherein the trophinetide is administered for at least 80 minutes. 80th percentile AUC of 0 μg·h / mL 0-12 Enough to provide a daily dose It is administered twice.

[0046] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. and administering trofinetide to a subject having at least 75% or more of the trophinetide. 25th percentile AUC at 5 μg·h / mL 0-12 Enough to provide a daily dose It is administered twice.

[0047] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. and administering trophinetide to a subject, wherein the subject is over 12 kg, such as 8 to 12 kg. and weighing less than 100 g, and trophinetide is administered at a daily dose of 4 to 12 g, such as 4 to 8 g. This is the way it is done.

[0048] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. The method comprises administering trophinetide to a subject having a body weight in the range of 12 to 20 kg. The method has a weight, and trophinetide is administered at a daily dose of 10 to 14 g.

[0049] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. The method comprises administering trophinetide to a subject weighing more than 20 kg and less than or equal to 35 kg. and trophinetide is administered at a daily dose of 14 to 18 g.

[0050] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. The method comprises administering trophinetide to a subject weighing more than 35 kg and less than 50 kg. and trophinetide is administered at a daily dose of 18 to 22 g.

[0051] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. the subject having a body weight of more than 50 kg, Trofinetide is administered at a daily dose of 22 to 26 g.

[0052] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) a daily dose of about 16 g if the subject weighs more than 20 kg and less than or equal to 35 kg; c) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of approximately 20 g, or or d) if the subject weighs more than 50 kg, administering a daily dose of about 24 g. , method.

[0053] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) If the subject weighs more than 20 kg and less than or equal to 35 kg, a daily dose of approximately 16 g, or or c) If the subject weighs more than 35 kg and less than or equal to 50 kg, administer a daily dose of approximately 20 g. It is a method that includes providing

[0054] Another aspect disclosed herein is a method for treating Rett Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of steroids. Trofinetide was administered to the subjects a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) a daily dose of about 16 g if the subject weighs more than 20 kg and less than or equal to 35 kg; c) a daily dose of about 20 g if the subject weighs more than 35 kg and less than or equal to 50 kg; d) a daily dose of about 24 g if the subject weighs more than 50 kg and less than or equal to 100 kg; or e) If the subject weighs more than 100 kg, administer a daily dose of approximately 48 g. Hmm, that's the method.

[0055] In some embodiments, the subject has a weight in the range of 12 to 20 kg. In embodiments, the subject weighs more than 20 kg and less than or equal to 35 kg. In some embodiments, the subject has a body weight of more than 35 kg and less than or equal to 50 kg. In some embodiments, the subject has a body weight that is greater than 50 kg. 0kg, 50-75kg, 50-70kg, 50-65kg, or 50-60kg body In some embodiments, the subject weighs more than 100 kg, and optionally , and weight is less than 150 kg.

[0056] In some embodiments, the daily amount of trophinetide administered is about 6 g. In some embodiments, the daily amount of trophinetide administered is about 8 g. In an embodiment, the daily amount of trophinetide administered is in the range of 6 to 8 g. In some embodiments, the daily amount of trophinetide administered is about 12 g. In some embodiments, the daily dose is about 16 g. In some embodiments, the daily dose is about 24 g. In this case, the daily dose of trophinetide administered is approximately 48 g.

[0057] In some embodiments, trophinetide is administered in a single dose per day. In some embodiments, trophinetide is administered in multiple doses per day that add up to the daily dose. The doses may be administered in doses, e.g., two, three, or four times daily, totaling the daily dose. In some embodiments, trophinetide is administered in a total of 100 mg / day. In some embodiments, trophinetide is administered in two doses, one in the morning and one in the afternoon. In some embodiments, the interval between doses is at least 8 hours. In some embodiments, the subject receives a steroid hormone-lowering agent (SEQ ID NO: 1) for 1 hour before administration of trophinetide. and no food for 1 hour after administration. In some embodiments, the dose is administered within 10 minutes. and / or followed by providing water to the subject, e.g., in a volume of about 250 mL. Provide.

[0058] In some embodiments, trophinetide is a pharmaceutically acceptable salt of trophinetide. It is administered as a pharmaceutical composition containing a carrier. Any of the well-known techniques and excipients may be used. and may be used as understood in the art, e.g., Remington: Science and Practice of Pharmacy,Twenty- See first Ed., (Pharmaceutical Press, 2005) In some embodiments, the pharmaceutically acceptable carrier is purified water. In embodiments of the present invention, the pharmaceutical composition may further contain a preservative, a flavoring agent, a coloring agent, a time-release controlling agent, a surfactant, , diluents, buffers, stabilizers, antioxidants, antifoaming agents, or bulking agents, or mixtures thereof In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the pharmaceutical composition contains a sweetener (e.g., maltitol and / or sucralose), flavoring agents (e.g., strawberry flavor), preservatives agents (e.g., methylparaben salts such as sodium methylparaben, or propylparaben) propylparaben salts such as benzalkonium sodium, or combinations thereof), and colorants ( For example, FD&C Red #40). In this embodiment, trophinetide is present in a solution of 0.05 to 0.6 g / mL, 0.1 to 0.4 g / mL, g / mL, or in the range of 0.15 to 0.3 g / mL, or less than 0.7 g / mL. In some embodiments, trophinetide has a concentration of about 0.2 g / mL in solution. do.

[0059] The pharmaceutical compositions disclosed herein may be administered by any suitable mode of administration. In some embodiments, trophinetide is administered orally. Trofinetide is administered via a gastrostomy tube or via the G-port of a gastrojejunostomy tube. In some embodiments, trophinetide is administered intravenously.

[0060] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a female. In some embodiments, the subject is between 18 months and 60 years old. In some embodiments, the subject is 20 years old or younger ( In some embodiments, the subject is between 5 and 20 years old. In some embodiments, the subject is between 5 and 10 years old, between 11 and 15 years old, or between 16 and 20 years old. In some embodiments, the subject is 2 to 5 years old. The subjects are over 20 years old.

[0061] Accordingly, the following embodiments are provided: Embodiment 1 is a method for treating Rett Syndrome. A method for administering trophinetide to a subject in need thereof, a) If the subject has a body weight in the range of 8 to 12 kg, 4 to 12 g, for example 4 to 8 g daily amount, b) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; c) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , d) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 18 to 22 g ,or e) If the subject weighs more than 50 kg, administer a daily dose of 22 to 26 g. It is a method including:

[0062] Embodiment 2 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) If the subject weighs between 8 and 12 kg, 8 ± x g or 6 ± x g daily amount, b) a daily dose of 12±xg if the subject has a weight in the range of 12-20 kg; c) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; d) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; or e) If the subject weighs more than 50 kg, the daily dose should be 24 ± 1 g. fruit, x is 1, 2, 3, 4, 5, or 6, and optionally the daily dose is at least 3 g and optionally, the daily dose is at least 4 g.

[0063] Embodiment 3 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; b) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , c) 18-22g daily dose if the subject weighs more than 35kg and less than or equal to 50kg ,or d) If the subject weighs more than 50 kg, the daily dose should be 22-26 g. It is a method including:

[0064] Embodiment 4 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) a daily dose of 12±xg if the subject has a body weight in the range of 12-20 kg; b) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; c) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; or d) If the subject weighs more than 50 kg, the daily dose should be 24 ± x g. fruit, x is 1, 2, 3, 4, 5, or 6.

[0065] Embodiment 5 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) If the subject has a body weight in the range of 8 to 12 kg, 4 to 12 g, for example 4 to 8 g daily amount, b) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; c) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg , d) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 18 to 22 g , e) If the subject weighs more than 50 kg and less than or equal to 100 kg, 22 to 26 g per day Amount, or f) If the subject weighs more than 100 kg, administer a daily dose of 46 to 50 g. The method includes:

[0066] Embodiment 6 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) If the subject weighs between 8 and 12 kg, 8 ± x g or 6 ± x g daily amount, b) a daily dose of 12±xg if the subject has a weight in the range of 12-20 kg; c) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; d) a daily dose of 20±xg if the subject weighs more than 35 kg and less than or equal to 50 kg; e) If the subject weighs more than 50 kg and less than or equal to 100 kg, a daily dose of 24 ± x g ,or f) If the subject weighs more than 100 kg, administer a daily dose of 48 ± x g. Including, x is 1, 2, 3, 4, 5, or 6, and optionally the daily dose is at least 3 g and optionally, the daily dose is at least 4 g.

[0067] Embodiment 7 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) a daily dose of 10 to 14 g if the subject has a body weight in the range of 12 to 20 kg; b) 14-18g daily dose if the subject weighs more than 20kg and less than or equal to 35kg ,or c) 18-22g daily dose if the subject weighs more than 35kg and less than or equal to 50kg The method comprises administering

[0068] Embodiment 8 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. Finetide, a) a daily dose of 12±xg if the subject has a body weight in the range of 12-20 kg; b) a daily dose of 16±xg if the subject weighs more than 20 kg and less than or equal to 35 kg; or c) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of 20 ± x g administering x is 1, 2, 3, 4, 5, or 6.

[0069] Embodiment 9 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a thrombin-containing compound. administering finetide at a daily dose d, wherein the subject has a body weight w, and d is d max Below Down and d min That's all, and d min and d max are represented by formula (I) and (II), respectively. It is calculated according to the following method: d min =w / 3750+6g (I) d max =w / 3750+12g (II).

[0070] Embodiment 10 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof and administering finetide, wherein the concentration of finetide is at least 790 μg·h / mL. AUC 0-12 The method is a method in which the therapeutic agent is administered twice daily in an amount sufficient to provide

[0071] Embodiment 11 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof and administering finetide, wherein the concentration of finetide is at least 800 μg·h / mL. AUC 0-12 The method is a method in which the therapeutic agent is administered twice daily in an amount sufficient to provide

[0072] Embodiment 12 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof and administering finetide, wherein the concentration of finetide is at least 755 μg·h / mL. AUC 0-12 The method is a method in which the therapeutic agent is administered twice daily in an amount sufficient to provide

[0073] Embodiment 13 is any of the preceding embodiments, wherein the subject has a body weight in the range of 12 to 20 kg. This is one of the methods.

[0074] Embodiment 14 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof The method comprises administering finetide to a subject having a body weight in the range of 12 to 20 kg and a trough. This method involves administering 10 to 14 g of methicillin per day.

[0075] Embodiment 15 is the method of any one of the preceding embodiments, wherein the daily dose is about 12 g. is.

[0076] Embodiment 16 is a method according to any one of embodiments 1 to 3, wherein the subject has a body weight of more than 20 kg and less than or equal to 35 kg. 12. The method according to claim 12,

[0077] Embodiment 17 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof administering finetide, wherein the subject has a body weight of more than 20 kg and less than or equal to 35 kg; Trofinetide is administered at a daily dose of 14 to 18 g.

[0078] Embodiment 18 is any of embodiments 1-12, 16, or 17, wherein the daily dose is about 16 g. This is the method described.

[0079] Embodiment 19 is a method according to any one of embodiments 1 to 5, wherein the subject has a body weight of more than 35 kg and less than or equal to 50 kg. 12. The method according to claim 12,

[0080] Embodiment 20 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof administering finetide, wherein the subject has a body weight of more than 35 kg and less than or equal to 50 kg; Trofinetide is administered at a daily dose of 18 to 22 g.

[0081] Embodiment 21 is any of embodiments 1 to 12, 19, or 20, wherein the daily dose is about 20 g. This is the method described.

[0082] Embodiment 22 is a method according to embodiments 1 to 3 or 5 to 8, wherein the subject has a body weight greater than 50 kg. 8. The method according to claim 8.

[0083] Embodiment 23 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof and administering trophinetide to the subject, wherein the subject has a body weight of more than 50 kg and trophinetide is administered to the subject. , administered at a daily dose of 22 to 26 g, and optionally, the body weight is 100 kg or less. be.

[0084] In embodiment 24, the subject is 50 to 80 kg, 50 to 75 kg, 50 to 70 kg, 50 to 65 kg, or 50-60 kg, or the method described in 23.

[0085] Embodiment 25 is any of embodiments 1-6, 9-12, or 22, wherein the daily dose is about 24 g. The method according to any one of claims 1 to 24.

[0086] Embodiment 26 is a method for treating a subject having a body weight of more than 100 kg, and optionally a body weight of less than 150 kg. 13. The method of any one of embodiments 5, 6, or 9-12, wherein the amount of water in the water is 1000 mg or less.

[0087] Embodiment 27 is the method of embodiment 26, wherein the daily dose is about 48 g.

[0088] Embodiment 28 is the method of any of embodiments 1, 2, 5, or 6, wherein the subject has a body weight in the range of 8 to 12 kg. or 6. A method according to any one of claims 1 to 6.

[0089] In embodiment 29, the daily dose is about 6 g or about 8 g, or a value in the range of 6-8 g. 29. The method of claim 28.

[0090] Embodiment 30 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a Rofinetide, a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) a daily dose of about 16 g if the subject weighs more than 20 kg and less than or equal to 35 kg; c) If the subject weighs more than 35 kg and less than or equal to 50 kg, a daily dose of approximately 20 g, or or d) if the subject weighs more than 50 kg, administering a daily dose of about 24 g. , method.

[0091] Embodiment 31 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a Rofinetide, a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) If the subject weighs more than 20 kg and less than or equal to 35 kg, a daily dose of approximately 16 g, or or c) If the subject weighs more than 35 kg and less than or equal to 50 kg, administer a daily dose of approximately 20 g. It is a method that includes providing

[0092] Embodiment 32 is a method of treating Rett Syndrome, comprising administering to a subject in need thereof a Rofinetide, a) a daily dose of about 12 g if the subject has a body weight in the range of 12 to 20 kg; b) a daily dose of about 16 g if the subject weighs more than 20 kg and less than or equal to 35 kg; c) a daily dose of about 20 g if the subject weighs more than 35 kg and less than or equal to 50 kg; d) a daily dose of about 24 g if the subject weighs more than 50 kg and less than or equal to 100 kg; or e) If the subject weighs more than 100 kg, administer a daily dose of approximately 48 g. Hmm, that's the method.

[0093] In embodiment 33, trophinetide is administered twice daily at a dose of 790 to 1000 μg h / day. AUC of at least 790 μg h / mL, such as the mL range 0-12 and arbitrarily selected The ranges are 790-950 μg·h / mL, 800-1000 μg·h / mL, or The method of any one of the preceding embodiments, wherein the concentration is 800 to 950 μg h / mL. do.

[0094] In embodiment 34, trophinetide is administered twice daily at a dose of 790 to 1000 μg h / day. AUC in mL range 0-12 Optionally, the range is 790-950 μg h / mL, 800–1000 μg·h / mL, or 800–950 μg·h / mL 2. The method of any one of the preceding embodiments.

[0095] Embodiment 35 is a method in which trophinetide is administered twice daily in an amount of 800 to 1300 μg. AUC in the g·h / mL range 0~12 Optionally, the range is 800 to 120 0 μg·h / mL, 1000–1300 μg·h / mL, or 100–1200 μg· 10. The method of any one of the preceding embodiments, wherein the saturation concentration is 1000 mg / mL.

[0096] Embodiment 36 is a method in which trophinetide is administered in multiple doses per day, totaling the daily dose. The method of any one of the preceding embodiments, wherein the

[0097] Embodiment 37 is a combination of embodiments 1 to 3, in which trophinetide is administered in a single dose per day. 9 or any one of the methods described in 13 to 32.

[0098] Embodiment 38 is a regimen in which trophinetide is administered in two doses per day, totalling the daily dose. 38. The method of embodiment 37, wherein the patient is administered

[0099] Embodiment 39 is a pharmaceutical composition in which trophinetide comprises trophinetide and a pharmaceutically acceptable carrier. 12. The method of any one of the preceding embodiments, wherein the compound is administered as a pharmaceutical composition comprising the compound.

[0100] Embodiment 40 is a pharmaceutical composition according to embodiment 3, wherein the pharmaceutical composition is a solution, optionally an aqueous solution. 9.

[0101] Embodiment 41 is a method for treating ulcerative colitis, in which trophinetide is present in a concentration of 0.05 to 0.7 g / mL in solution, 0.05 to 0 Concentrations ranging from 0.6g / mL, 0.1-0.4g / mL, or 0.15-0.3g / mL 41. The method of embodiment 40, comprising:

[0102] Embodiment 42 is an embodiment in which trophinetide has a concentration of about 0.2 g / mL in solution. This is the method described in embodiment 41.

[0103] Embodiment 43 is the method of any one of the preceding embodiments, wherein trophinetide is administered orally. This is the method described above.

[0104] Embodiment 44 is a method in which trophinetide is administered via a gastrostomy tube or a gastrojejunostomy tube 43. The method of any one of embodiments 1-42, wherein the administration is via a G port.

[0105] Embodiment 45 is the method of any one of the preceding embodiments, wherein the subject is a mammal. is.

[0106] Embodiment 46 is the method of any one of the preceding embodiments, wherein the subject is a human. do.

[0107] Embodiment 47 is the method of any one of the preceding embodiments, wherein the subject is a female. do.

[0108] Embodiment 48 is any one of the preceding embodiments, wherein the subject is between 18 months and 60 years of age. This is the method described.

[0109] Embodiment 49 is a method for treating a subject who is 5 to 20 years old, and optionally a subject who is 5 to 10 years old, 11 years old, or 20 years old. 49. The method of embodiment 48, wherein the patient is aged 16 to 20 years.

[0110] Embodiment 50 is the method of any one of the preceding embodiments, wherein the subject has an MECP2 mutation. This is the method described above.

[0111] Embodiment 51 is a method in which the Rett syndrome is atypical or classic / typical Rett syndrome. 10. The method of any one of the preceding embodiments.

[0112] Embodiment 52 is any of the preceding embodiments, in which the Rett syndrome is classic / typical Rett syndrome. The method according to any one of the above.

[0113] The following embodiments are also provided:

[0114] Embodiment I. Methods of Treating Rett Syndrome in a Subject in Need of Treatment A method comprising administering a therapeutically effective amount of trophinetide to a patient in need thereof. a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g daily amount, c) 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg daily amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g daily dose, or e) a daily dose of 22.1 to 26 g if the subject weighs 50.1 to 150 kg The method comprising administering to the subject

[0115] Embodiment II. The method of embodiment I, wherein the subject weighs between 8 and 11.9 kg. .

[0116] Embodiment III. The trophinetide is 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or 10 g daily dose, e.g., about 6 g, e.g., 6 g daily dose, The method of embodiment II, wherein

[0117] Embodiment IV. The method of embodiment I, wherein the subject weighs between 12.0 and 20.0 kg. How to do it.

[0118] Embodiment V. The trophinetide is administered in an amount of 11 g, about 12 g, about 13 g, or 14 g, e.g., For example, a daily dose of about 12 g, e.g., 12 g, is administered to the subject. How to do it.

[0119] Embodiment VI. The method of embodiment I, wherein the subject weighs between 20.1 and 35.0 kg. How to do it.

[0120] Embodiment VII. The trophinetide is 15 g, about 16 g, about 17 g, or 18 g The method of claim VI, wherein the subject is administered a daily dose of, for example, about 16 g, e.g., 16 g. How to post.

[0121] Embodiment VIII. The method of embodiment I, wherein the subject weighs between 35.1 and 50.0 kg. The method described.

[0122] Embodiment IX. The trophinetide is 19 g, about 20 g, about 21 g, or 22 g, For example, a daily dose of about 20 g, e.g., 20 g, is administered to the subject. The method described below.

[0123] Embodiment X. The subject of embodiment I, wherein the subject weighs between 50.1 and 100 kg. Law.

[0124] Embodiment XI. The trophinetide is 23 g, about 24 g, about 25 g, or 26 g, For example, a daily dose of about 24 g, e.g., 24 g, is administered to the subject. How to do it.

[0125] Embodiment XII. The administration of said trophinetide is about 755 μg· h / mL to approximately 1300 μg h / mL, e.g., 755 μg h / mL to 1300 μg h / mL, 790μg·h / mL~1000μg·h / mL, 790μg·h / mL~9 50μg·h / mL, 800μg·h / mL~1000μg·h / mL, 800μg·h / mL~950μg·h / mL, 800μg·h / mL~1200μg·h / mL, 10 00μg·h / mL to 1300μg·h / mL, or 1000μg·h / mL to 120 AUC of 0 μg·h / mL 0-12,ss Any one of embodiments I-XI, resulting in The method described below.

[0126] Embodiment XIII. The administration of said trophinetide provides at least about 100 mg / kg of trophinetide in said subject. 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg· h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, a little at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 8 80 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1 020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μ g·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL, a little at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 124 0 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg·h / mL, e.g., at least 755 μg·h / mL, at least 780 μg·h / mL, at least 790 μg·h / mL, at least 800 μg·h / mL, at least at least 820 μg·h / mL, at least 840 μg·h / mL, at least 860 μg·h / mL, at least 880 μg·h / mL, at least 900 μg·h / mL, at least at least 920 μg·h / mL, at least 940 μg·h / mL, at least 960 μg·h / mL, at least 980 μg·h / mL, at least 1000 μg·h / mL, at least At least 1020 μg·h / mL, at least 1040 μg·h / mL, at least 1060 μg·h / mL, at least 1080 μg·h / mL, at least 1100 μg·h / m L, at least 1120 μg·h / mL, at least 1140 μg·h / mL, at least at least 1160 μg·h / mL, at least 1180 μg·h / mL, at least 1200 μ g·h / mL, at least 1220 μg·h / mL, at least 1240 μg·h / mL , an AU of at least 1260 μg·h / mL, or at least 1280 μg·h / mL C 0-12,ss The method of any one of embodiments I to XI, wherein

[0127] Embodiment XIV. The administration of said trophinetide to said subject results in about 10 days in said subject. 100 μg / mL to about 200 μg / mL, for example, 100 μg / mL to 200 μg / mL C max,ss The method of any one of embodiments I to XIII, wherein

[0128] Embodiment XV. The administration of said trophinetide to said subject results in at least one of the following: at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 1 50 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL μg / mL, e.g., at least 100 μg / mL, at least 110 μg / mL, at least 120 μg / mL, at least 130 μg / mL, at least 140 μg / mL, At least 150 μg / mL, at least 160 μg / mL, at least 170 μg / m L, at least 180 μg / mL, at least 190 μg / mL, or at least 20 C of 0 μg / mL max,ss any one of embodiments I to XIII, How to do it.

[0129] Embodiment XVI. The trophinetide is administered to the subject in a single dose per day , the method according to any one of embodiments I to XV.

[0130] Embodiment XVII. The trophinetide is administered in a daily dose of multiple doses totaling the daily dose. The method of any one of embodiments I-XV, wherein several doses are administered to the subject.

[0131] Embodiment XVIII. The trophinetide is administered per day, totaling the daily dose The method of embodiment XVII, wherein two doses are administered to the subject.

[0132] Embodiment XIX. The trophinetide is a mixture of the trophinetide and a pharmaceutically acceptable salt thereof

[0033] The method of any one of embodiments I to XVIII, wherein the compound is administered as a pharmaceutical composition comprising a carrier. How to do it.

[0133] Embodiment XX. The method of embodiment XIX, wherein the pharmaceutically acceptable carrier comprises water. Law.

[0134] Embodiment XXI. The method of embodiment XX, wherein the pharmaceutical composition is a solution.

[0135] Embodiment XXII. The concentration of the trophinetide in the solution is about 0.05 g / mL to 0. The method of embodiment XXI, wherein the concentration is 0.7 g / mL.

[0136] Embodiment XXIII. The concentration of trophinetide is about 0.2 g / mL in the solution. The method of embodiment XXII, wherein

[0137] Embodiment XXIV. The trophinetide is administered orally to the subject. XXIII.

[0138] Embodiment XXV. The method of any one of Embodiments I-XXIV, wherein the subject is a human. How to post.

[0139] Embodiment XXVI. The method of embodiment XXV, wherein said subject is female.

[0140] Embodiment XXVII. The subject is about 18 months to 20 years old, e.g., 2 to 5 years old. The method according to any one of embodiments I to XXVI.

[0141] Embodiment XXVIII. The subject has an MECP2 mutation. 1. The method according to any one of claims 1 to 10.

[0142] Embodiment XXIX. The Rett syndrome is atypical Rett syndrome. The method according to any one of claims XVIII.

[0143] Embodiment XXX. The Rett syndrome is classic / typical Rett syndrome. The method according to any one of I to XXVIII.

[0144] Embodiment XXXI. Trofinetide for use in treating Rett syndrome in a subject wherein the trophinetide is a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g daily amount, c) 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg daily amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g daily dose, or e) a daily dose of 22.1 to 26 g if the subject weighs 50.1 to 150 kg The trophinetide is administered at

[0145] Embodiment XXXII. The subject weighs between 8 and 11.9 kg. Trofinetide for the use described in 1.

[0146] Embodiment XXXIII. The trophinetide is administered in an amount of 4 g, about 5 g, about 6 g, about 7 g, about 8 g, or XXXII, wherein the subject is administered a daily dose of about 9 g, about 9 g, or 10 g. Trofinetide for use in:

[0147] Embodiment XXXIV. The subject weighs 12.0 to 20.0 kg. Trofinetide for use in XXI.

[0148] Embodiment XXXV. The trophinetide is administered in an amount of 11 g, about 12 g, about 13 g, or about 14 g. trophinetide for use in embodiment XXXIV, wherein the compound is administered to said subject in a daily dose of 0.05g. .

[0149] Embodiment XXXVI. The subject weighs 20.1 to 35.0 kg. Trofinetide for use as described in XXI.

[0150] Embodiment XXXVII. The trophinetide is 15 g, about 16 g, about 17 g, or A trocarcinoma for use according to embodiment XXXVI, administered to said subject in a daily dose of 18 g. Finetide.

[0151] Embodiment XXXVIII. The subject weighs between 35.1 and 50.0 kg. Trofinetide for use according to form XXXI.

[0152] Embodiment XXXIX. The trophinetide is 19 g, about 20 g, about 21 g, or 2 The subject is administered a daily dose of 2 g for use according to embodiment XXXVIII. Rofinetide.

[0153] Embodiment XL. The method of embodiment XXXI, wherein the subject weighs between 50.1 and 100 kg. Trofinetide for the described uses.

[0154] Embodiment XLI. The trophinetide is 23 g, about 24 g, about 25 g, or 26 g The use according to embodiment XL, wherein trophinetide is administered to said subject in a daily dose of

[0155] Embodiment XLII. The administration of said trophinetide is about 755 μg in said subject h / mL to about 1300 μg h / mL, for example, about 800 μg h / mL to about 1000 μ AUC in g·h / mL 0-12,ss Any of embodiments XXXI to XLI, resulting in Trofinetide for the use described in 1.

[0156] Embodiment XLIII. The administration of said trophinetide provides at least About 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg ·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg· h / mL, at least about 940 μg h / mL, at least about 960 μg h / mL, a little at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 12 40 μg·h / mL, at least about 1260 μg·h / mL, or at least about 128 AUC of 0 μg·h / mL 0-12,ss Any of embodiments XXXI to XLI Trofinetide for use as described in any one of the preceding claims.

[0157] Embodiment XLIV. The administration of said trophinetide to said subject comprises administering to said subject C of approximately 100 to approximately 200 μg / mL max,ss Embodiments XXXI to XLI Trofinetide for use according to any one of claims 11 to 14.

[0158] Embodiment XLV. The administration of said trophinetide to said subject results in at least one of: at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 20 C of 0 μg / mL max,ss any one of embodiments XXXI to XLIII, Trofinetide for the use described in one of the claims.

[0159] Embodiment XLVI. The trophinetide is administered to the subject in a single dose per day. Trofinetide for use according to any one of embodiments XXXI to XLV.

[0160] Embodiment XLVII. The trophinetide is administered per day, totaling the daily dose As described in any one of embodiments XXXI-XLV, wherein multiple doses are administered to the subject. Trofinetide for use in:

[0161] Embodiment XLVIII. The trophinetide is administered in a dose totaling the daily dose per day. The trocarcinoma for use according to embodiment XLVIII, wherein the trocarcinoma is administered to the subject in two doses, each dose being a single dose. Finetide.

[0162] Embodiment XLIX. The trophinetide is a compound selected from the group consisting of trophinetide and a pharmaceutically acceptable salt thereof. Any of embodiments XXXI-XLVIII, wherein the compound is administered as a pharmaceutical composition comprising a carrier comprising Trofinetide for the use described in 1.

[0163] Embodiment L. The use of embodiment XLIX, wherein the pharmaceutically acceptable carrier comprises water. The drug trophinetide.

[0164] Embodiment LI. The method of embodiment L, wherein the pharmaceutical composition is a solution. Chid.

[0165] EMBODIMENT LI I. The concentration of said trophinetide in said solution is from about 0.05 g / mL to 0. The trophinetide for use according to embodiment LI, wherein the trophinetide is 7 g / mL.

[0166] Embodiment LIII. The concentration of trophinetide is about 0.2 g / mL in the solution. Trofinetide for use according to embodiment LII.

[0167] Embodiment LIV. The trophinetide is administered orally to the subject. Trofinetide for use according to any one of I to LIII.

[0168] Embodiment LV. Any one of Embodiments XXXI-LIV, wherein the subject is a human. Trofinetide for the described uses.

[0169] Embodiment LVI. The method of embodiment LV, wherein the subject is a female. Inetid.

[0170] Embodiment LVII. The subject is about 18 months to 20 years old, e.g., 2 to 5 years old. Trofinetide for use according to any one of Forms XXXI to LVI.

[0171] Embodiment LVIII. The subject has an MECP2 mutation. Trofinetide for use according to any one of claims 11 to 14.

[0172] Embodiment LIX. The Rett syndrome is atypical Rett syndrome. Trofinetide for use according to any one of claims 1 to 8.

[0173] Embodiment LX. The Rett syndrome is classic / typical Rett syndrome. Trofinetide for use according to any one of claims XXI to LVIII.

[0174] Embodiment LXI. A method for manufacturing a medicament for treating Rett Syndrome in a subject. Use of rofinetide, wherein said rofinetide is a) a daily dose of 4 to 10.0 g if the subject weighs 8 to 11.9 kg; b) If the subject weighs 12.0 to 20.0 kg, 10.1 to 14.0 g daily amount, c) 14.1 to 18.0 g if the subject weighs 20.1 to 35.0 kg daily amount, d) If the subject weighs 35.1 to 50.0 kg, 18.1 to 22.0 g daily dose, or e) a daily dose of 22.1 to 26 g if the subject weighs 50.1 to 150 kg The above-mentioned use, wherein the administration is carried out in a dose of 100 mg / kg or less.

[0175] Embodiment LXII. The method of embodiment LXI, wherein the subject weighs between 8 and 11.9 kg. Use of the above.

[0176] Embodiment LXIII. The trophinetide is 4 g, about 5 g, about 6 g, about 7 g, about 8 g The use of embodiment LXII, wherein the subject is administered a daily dose of about 9 g, 10 g, or 15 g. For.

[0177] Embodiment LXIV. The subject weighs 12.0 to 20.0 kg. Use as described in I.

[0178] Embodiment LXV. The trophinetide is 11 g, about 12 g, about 13 g, or 14 g The use of embodiment LXIV, wherein the subject is administered a daily dose of

[0179] Embodiment LXVI. The subject weighs 20.1 to 35.0 kg. Use as described in I.

[0180] Embodiment LXVII. The trophinetide is 15 g, about 16 g, about 17 g, or 1 The use of embodiment LXVI, wherein a daily dose of 8 g is administered to the subject.

[0181] Embodiment LXVIII. The subject weighs between 35.1 and 50.0 kg. Use as described in LXI.

[0182] Embodiment LXIX. The trophinetide is 19 g, about 20 g, about 21 g, or 22 g The use of embodiment LXVIII, wherein the subject is administered a daily dose of 0.1 mg / kg or more.

[0183] Embodiment LXX. The method of embodiment LXI, wherein the subject weighs 50.1 to 100 kg. Use as described.

[0184] Embodiment LXXI. The trophinetide is administered in an amount of 23 g, about 24 g, about 25 g, or about 26 g. The use of embodiment LXX, wherein the subject is administered a daily dose of 0.1 mg / kg or more.

[0185] Embodiment LXXII. The administration of said trophinetide achieves a blood glucose level of about 755 μg in said subject. g·h / mL to about 1300 μg·h / mL, for example, about 800 μg·h / mL to about 1000 AUC in μg·h / mL 0-12,ss Any of embodiments LXI to LXXI or the use described in one of the preceding paragraphs.

[0186] Embodiment LXXIII. The administration of said trophinetide produces at least at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL g·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL , at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least About 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg ·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 106 0 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg· h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL , at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, or at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1 240 μg·h / mL, at least about 1260 μg·h / mL, or at least about 12 AUC of 80 μg·h / mL 0-12,ss Any of embodiments LXI to LXXI Use as described in any one of the following:

[0187] Embodiment LXXIV. The administration of said trophinetide to said subject results in said subject C of about 100 to about 200 μg / mL max,ss Embodiments LXI to LXX III. The use according to any one of the preceding paragraphs.

[0188] Embodiment LXXV. The administration of trophinetide to the subject comprises administering to the subject At least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL g / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 2 C of 00 μg / mL max,ss The use of any of the embodiments LXI to LXXIII For.

[0189] Embodiment LXXVI. The trophinetide is administered to the subject in a single dose per day. Trofinetide for use according to any one of embodiments LXI to LXXV.

[0190] Embodiment LXXVII. The trophinetide is administered in a dose that totals the daily dose. The method of any one of embodiments LXI to LXXV, wherein the method is administered to the subject in multiple doses of Use of the above.

[0191] Embodiment LXXVIII. The trophinetide is administered in a dose totaling the daily dose and The use of embodiment LXXVII, wherein two doses comprising the above-mentioned compound are administered to said subject.

[0192] Embodiment LXXIX. The trophinetide is a compound selected from the group consisting of trophinetide and a pharmaceutically acceptable salt thereof. Any of embodiments LXI to LXXVIII, wherein the compound is administered as a pharmaceutical composition comprising a carrier or the use described in one of the preceding paragraphs.

[0193] Embodiment LXXX. The method of embodiment LXXIX, wherein the pharmaceutically acceptable carrier comprises water. Use as described.

[0194] Embodiment LXXXI. The use of embodiment LXXIX, wherein the pharmaceutical composition is a solution. For.

[0195] Embodiment LXXXII. The concentration of the trophinetide is about 0.05 g / mL in the solution. The use according to embodiment LXXXI, wherein the HCl concentration is 0.7 g / mL or less.

[0196] Embodiment LXXXIII. The concentration of trophinetide in the solution is about 0.2 g / The use according to embodiment LXXXII, wherein the total amount of erythrocytes per 1000 mg / mL is 100 mg / mL.

[0197] Embodiment LXXXIV. The trophinetide is administered orally to the subject Use according to any one of LXI to LXXXIII.

[0198] Embodiment LXXXV. Any of Embodiments LXI-LXXXIV, wherein the subject is a human. Use as described in any one of the following:

[0199] Embodiment LXXXVI. The use of embodiment LXXXV, wherein the subject is female.

[0200] Embodiment LXXXVII. The subject is about 18 months to about 20 years old, e.g., 2 to 5 years old. The use according to any one of embodiments LXI to LXXXVI.

[0201] Embodiment LXXXVIII. The subject has an MECP2 mutation. The use according to any one of paragraphs LXXXVII.

[0202] Embodiment LXXXIX. The Rett syndrome is atypical Rett syndrome. The use according to any one of XI to LXXXVIII.

[0203] Embodiment XC. The Rett syndrome is classic / typical Rett syndrome. The use according to any one of LXI to LXXXVIII.

[0204] Embodiment XCI. Treating Rett Syndrome in a Human Subject in Need of Treatment A method for treating a patient with trophinetide, comprising administering a therapeutically effective amount of trophinetide to a patient in a range of about 500 mg / kg to about 1, 250 mg / kg daily to the subject, wherein the subject is about 15 months of age. The method, wherein the age is about 6 years.

[0205] Embodiment XCII. A method comprising administering to said subject a daily dose of about 500 mg / kg. The method according to embodiment XCI.

[0206] Embodiment XCIII. Comprising administering to the subject a daily dose of about 600 mg / kg. The method of embodiment XCI.

[0207] Embodiment XCIV. A method comprising administering to said subject a daily dose of about 700 mg / kg. The method according to embodiment XCI.

[0208] Embodiment XCV. An embodiment comprising administering to said subject a daily dose of about 800 mg / kg. Method according to form XCI.

[0209] Embodiment XCVI. A method comprising administering to said subject a daily dose of about 900 mg / kg. The method according to embodiment XCI.

[0210] Embodiment XCVII. A method comprising administering to the subject a daily dose of about 1,000 mg / kg. The method of embodiment XCI.

[0211] Embodiment XCVIII. A daily dose of about 1,100 mg / kg is administered to the subject. The method of embodiment XCI, comprising:

[0212] Embodiment XCIX. Comprising administering to the subject a daily dose of about 1,200 mg / kg. , the method of embodiment XCI.

[0213] Embodiment C. The administration of trophinetide is about 755 μg h / day in the subject. mL to about 1300 μg h / mL, e.g., about 800 μg h / mL to about 1000 μg h AUC in / mL 0-12,ss In any one of embodiments XCI to XCIX, The method described.

[0214] Embodiment CI. The administration of said trophinetide provides at least about 75 days of gestational age in said subject. 5 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, or at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / m L, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 102 0 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg· h / mL, at least about 1080 μg h / mL, at least about 1100 μg h / mL , at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, or at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1 200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μ g·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg AUC in h / mL 0-12,ss Any one of embodiments XCI to XCIX, resulting in The method described in the first paragraph.

[0215] Embodiment CII. The administration of said trophinetide to said subject provides about 100 mg / kg of trophinetide in said subject. C of 100 to approximately 200 μg / mL max,ss Any of embodiments XCI to CI resulting in The method according to any one of the following:

[0216] Embodiment CIII. The administration of trophinetide to the subject comprises administering to the subject At least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL g / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 2 C of 00 μg / mL max,ss 10. The method of claim 1, wherein the method further comprises: How to post.

[0217] Embodiment CIV. The trophinetide is administered to the subject in a single dose per day , The method of any one of embodiments XCI to CIII.

[0218] Embodiment CV. The trophinetide is administered multiple times per day, totaling the daily dose. The method of any one of embodiments XCI-CIV, wherein the subject is administered a dose of

[0219] Embodiment CVI. The trophinetide is administered two times per day, totaling the daily dose. The method of embodiment CV, wherein the subject is administered a dose of

[0220] Embodiment CVII. The trophinetide is a compound selected from the group consisting of trophinetide and a pharmaceutically acceptable salt thereof. The compound according to any one of embodiments XCI to CVI, wherein the compound is administered as a pharmaceutical composition comprising a carrier comprising How to post.

[0221] Embodiment CVIII. The composition of Embodiment CVII, wherein the pharmaceutically acceptable carrier comprises water. The method described.

[0222] Embodiment CIX. The method of embodiment CVIII, wherein the pharmaceutical composition is a solution.

[0223] Embodiment CX. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. The method of embodiment CIX, wherein the saturation is 0.05 to 0.1 g / mL.

[0224] Embodiment CXI. The concentration of said trophinetide is about 0.2 g / mL in said solution. The method of embodiment CX,

[0225] Embodiment CXII. The trophinetide is administered orally to the subject. The method according to any one of I to CXI.

[0226] Embodiment CXIII. Any of Embodiments XCI-CXII, wherein the subject is female. The method described in one.

[0227] Embodiment CXIV. The subject has an MECP2 mutation. 1. The method according to any one of claims 1 to 10.

[0228] Embodiment CXV. The Rett syndrome is atypical Rett syndrome. CXIV.

[0229] Embodiment CXVI. The Rett syndrome is classic / typical Rett syndrome. The method of any one of Forms XCI-CXIV.

[0230] Embodiment CXVII. Any of Embodiments XCI-CXVI, wherein the subject is about 2 years old. or one of the methods described above.

[0231] Embodiment CXVIII. The method of any of Embodiments XCI-CXVI, wherein the subject is about 3 years old. The method according to any one of the following:

[0232] Embodiment CXIX. Any of Embodiments XCI-CXVI, wherein the subject is about 4 years old. The method described in one.

[0233] Embodiment CXX. Any one of Embodiments XCI-CXVI, wherein the subject is about 5 years old. The method described in the first paragraph.

[0234] Embodiment CXXI. Trophine for use in treating Rett syndrome in a human subject trophinetide, wherein the trophinetide is about 500 mg / kg to about 1,250 mg / kg. The trophinetide is administered in a daily dose and the subject is between about 15 months and about 6 years old.

[0235] Embodiment CXXII. comprising administering to the subject a daily dose of about 500 mg / kg. Trofinetide for use according to embodiment CXXI.

[0236] Embodiment CXXIII. Comprising administering to the subject a daily dose of about 600 mg / kg , Trofinetide for use according to embodiment CXXI.

[0237] Embodiment CXXIV. comprising administering to the subject a daily dose of about 700 mg / kg. Trofinetide for use according to embodiment CXXI.

[0238] Embodiment CXXV. A method comprising administering to the subject a daily dose of about 800 mg / kg. Trofinetide for use according to embodiment CXXI.

[0239] Embodiment CXXVI. Comprising administering to the subject a daily dose of about 900 mg / kg. Trofinetide for use according to embodiment CXXI.

[0240] Embodiment CXXVII. A daily dose of about 1,000 mg / kg is administered to the subject. Trofinetide for use according to embodiment CXXI, comprising

[0241] Embodiment CXXVIII. Administering to the subject a daily dose of about 1,100 mg / kg Trofinetide for use according to embodiment CXXI, comprising:

[0242] Embodiment CXXIX. trophinetide for use according to embodiment CXXI.

[0243] Embodiment CXXX. The administration of trophinetide is about 755 μg in the subject h / mL to about 1300 μg h / mL, for example, about 800 μg h / mL to about 1000 μ AUC in g·h / mL 0-12,ss Any of embodiments CXXI ​​to CXXIX Trofinetide for use as described in any one of the preceding claims.

[0244] Embodiment CXXXI. The administration of trophinetide in the subject About 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg ·h / mL, at least about 800 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg· h / mL, at least about 940 μg h / mL, at least about 960 μg h / mL, a little at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 12 40 μg·h / mL, at least about 1260 μg·h / mL, or at least about 128 AUC of 0 μg·h / mL 0-12,ss In the embodiments CXXI ​​to CXXIX, Trofinetide for the use according to any one of the preceding items.

[0245] Embodiment CXXXII. The administration of said trophinetide to said subject results in said subject C of about 100 to about 200 μg / mL max,ss Embodiments CXXI ​​to C Trofinetide for use according to any one of paragraphs XXXI.

[0246] Embodiment CXXXIII. The administration of the trophinetide to the subject provides the subject with at least about 100 μg / mL, at least about 110 μg / mL, at least about 1 20 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least C of about 200 μg / mL max,ss Any of embodiments CXXI ​​to CXXXI, Trofinetide for use as described in any one of the preceding items.

[0247] Embodiment CXXXIV. The trophinetide is administered to the subject in a single dose per day. A trough for use according to any one of embodiments CXXI ​​to CXXXIII. Inetid.

[0248] Embodiment CXXXV. The trophinetide is administered per day, totaling the daily dose. Any one of embodiments CXXI-CXXXIV, wherein multiple doses are administered to the subject. Trofinetide for the use described in 1.

[0249] Embodiment CXXXVI. The trophinetide is administered in a dose totaling the daily dose per day. The method of claim 1, wherein the thrombin time is 20 ms and the thrombin time is 20 ms, the thrombin time is 20 ms and the thrombin time is 20 ms. Finetide.

[0250] Embodiment CXXXVII. The trophinetide is a compound selected from the group consisting of trophinetide and pharmaceutically acceptable salts thereof. Any of embodiments CXXI-CXXXVI is administered as a pharmaceutical composition comprising an acceptable carrier. Trofinetide for use as described in any one of the preceding items.

[0251] Embodiment CXXXVIII. Embodiment CX wherein the pharmaceutically acceptable carrier comprises water. Trofinetide for use as described in XXVII.

[0252] Embodiment CXXXIX. The pharmaceutical composition of embodiment CXXXVIII, wherein the pharmaceutical composition is a solution. Trofinetide for the described uses.

[0253] Embodiment CXL. The concentration of said trophinetide in said solution is from about 0.05 g / mL to 0. The trophinetide for use according to embodiment CXXXIX, wherein the trophinetide is 7 g / mL.

[0254] Embodiment CXLI. The concentration of trophinetide is about 0.2 g / mL in the solution. In one embodiment, trophinetide for use in CXL.

[0255] Embodiment CXLII. The trophinetide is administered orally to the subject. Trofinetide for use according to any one of XXI to CXLI.

[0256] Embodiment CXLIII. Any of Embodiments CXXI-CXLII, wherein the subject is female. Trofinetide for use as described in any one of the preceding items.

[0257] Embodiment CXLIV. Embodiments CXXI-CX. Trofinetide for use as described in any one of claims LIII.

[0258] Embodiment CXLV. The Rett syndrome is atypical Rett syndrome. Trofinetide for use as described in any one of I to CXLIV.

[0259] Embodiment CXLVI. The Rett syndrome is classic / typical Rett syndrome. Trofinetide for use according to any one of embodiments CXXI ​​to CXLIV.

[0260] Embodiment CXLVII. The method of any one of Embodiments CXXI-CXLVI, wherein the subject is about 2 years old. Trofinetide for the use according to any one of the preceding items.

[0261] Embodiment CXLVIII. The subject is about 3 years old. Trofinetide for use according to any one of the preceding items.

[0262] Embodiment CXLIX. Any of Embodiments CXXI-CXLVI, wherein the subject is about 4 years old. Trofinetide for use as described in any one of the preceding items.

[0263] Embodiment CL. Any of Embodiments CXXL-CXLVI, wherein the subject is about 5 years old. Trofinetide for the use described in 1.

[0264] Embodiment CLI. For manufacturing a medicament for treating Rett Syndrome in a human subject The use of trophinetide, wherein the trophinetide is administered in an amount of about 500 mg / kg to about 1, 250 mg / kg daily, and the subject is between about 15 months and about 6 years old. use.

[0265] Embodiment CLII. A method comprising administering to said subject a daily dose of about 500 mg / kg. Use according to embodiment CLI.

[0266] Embodiment CLII. comprising administering to the subject a daily dose of about 600 mg / kg. The use according to embodiment CLI.

[0267] Embodiment CLIV. A method comprising administering to said subject a daily dose of about 700 mg / kg. Use according to embodiment CLI.

[0268] Embodiment CLV. An embodiment comprising administering to said subject a daily dose of about 800 mg / kg. Use as described in Form CLI.

[0269] Embodiment CLVI. A method comprising administering to said subject a daily dose of about 900 mg / kg. Use according to embodiment CLI.

[0270] Embodiment CLVII. A method comprising administering to said subject a daily dose of about 1,000 mg / kg. Included are the uses described in embodiment CLI.

[0271] Embodiment CLVIII. A daily dose of about 1,100 mg / kg is administered to the subject. trophinetide for use as described in embodiment CLI.

[0272] Embodiment CLIX. Comprising administering to the subject a daily dose of about 1,200 mg / kg , the use described in embodiment CLI.

[0273] Embodiment CLX. The administration of said trophinetide is about 755 μg· h / mL to about 1300 μg h / mL, for example, about 800 μg h / mL to about 1000 μg AUC in h / mL 0-12,ss Any one of embodiments CLI to CLIX The use described in one.

[0274] Embodiment CLXI. The administration of said trophinetide provides at least about 100 mg / kg of trophinetide in said subject. 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg· h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, a little at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 8 80 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1 020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μ g·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL, a little at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 124 0 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 AUC in μg·h / mL 0-12,ss Any of the embodiments CLI to CLIX or the use described in one of the preceding paragraphs.

[0275] Embodiment CLXII. The administration of said trophinetide to said subject results in said subject C of about 100 to about 200 μg / mL max,ss The embodiments CLI to CLX 1. The use according to any one of claims 1 to 10.

[0276] Embodiment CLXIII. The administration of said trophinetide to said subject provides at least about 100 μg / mL, at least about 110 μg / mL, at least about 12 0 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, or at least At least about 150 μg / mL, at least about 160 μg / mL, and at least about 170 μg / mL L, at least about 180 μg / mL, at least about 190 μg / mL, or at least C of approximately 200 μg / mL max,ss Any of embodiments CLI to CLXI Use as described in one.

[0277] Embodiment CLXIV. The trophinetide is administered to the subject in a single dose per day. The use according to any one of embodiments CLI to CLXIII.

[0278] Embodiment CLXV. The trophinetide is administered daily in a number of doses that add up to the daily dose. Administered to the subject in several doses, Use of.

[0279] Embodiment CLXVI. The trophinetide is administered per day, totaling the daily dose The use of embodiment CLXV, wherein two doses are administered to the subject.

[0280] Embodiment CLXVII. The trophinetide is a compound selected from the group consisting of trophinetide and pharmaceutically acceptable salts thereof Any of embodiments CLI to CLXVI, wherein the compound is administered as a pharmaceutical composition comprising a carrier Use as described in one.

[0281] Embodiment CLXVIII. The pharmaceutically acceptable carrier comprises water. Use as described in VII.

[0282] Embodiment CLXIX. Described in embodiment CLXVIII, wherein the pharmaceutical composition is a solution. Use of.

[0283] Embodiment CLXX. The concentration of the trophinetide in the solution is from about 0.05 g / mL to 0. The use described in embodiment CLXIX, wherein the HCl concentration is 0.7 g / mL.

[0284] Embodiment CLXXI. The concentration of the trophinetide is about 0.2 g / mL in the solution. The use described in embodiment CLXX.

[0285] Embodiment CLXXII. The trophinetide is administered orally to the subject Use as described in any one of CLI to CLXXLI.

[0286] Embodiment CLXXIII. The method of any one of Embodiments CLI-CLXXII, wherein the subject is a female. Use as described in any one of the above.

[0287] Embodiment CLXXIV. The subject has an MECP2 mutation. XXIII.

[0288] Embodiment CLXXV. The Rett syndrome is atypical Rett syndrome. The use according to any one of I to CLXXIV.

[0289] Embodiment CLXXVI. The Rett syndrome is classic / typical Rett syndrome. The use according to any one of embodiments CLI to CLXXIV.

[0290] Embodiment CLXXVII. Embodiments CLI-CLXXVII wherein the subject is about 2 years old. 1. The use according to any one of the preceding claims.

[0291] Embodiment CLXXVIII. Embodiments CLI-CLXXV. 1. The use according to any one of claims 1 to 10.

[0292] Embodiment CLXXIX. The method of any one of Embodiments CLI to CLXXVI, wherein the subject is about 4 years old. Use as described in any one of the above.

[0293] Embodiment CLXXX. Any of Embodiments CLI-CLXXVI, wherein the subject is about 5 years old. Use as described in any one of the following:

[0294] Embodiment CLXXXI. The administration of said trophinetide produces at least For example, 755 μg·h / mL to 1300 μg ·h / mL, e.g., 780μg·h / mL to 1300μg·h / mL, e.g., 790μg h / mL~1300μg h / mL, e.g., 800μg h / mL~1300μg h / mL, e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg·h / mL~1300μg·h / mL, e.g., 860μg·h / mL~1300μg·h / m L, e.g., 880 μg·h / mL to 1300 μg·h / mL, e.g., 900 μg·h / m L to 1300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, For example, 940 μg·h / mL to 1300 μg·h / mL, for example, 960 μg·h / mL to 1300μg·h / mL, e.g., 980μg·h / mL to 1300μg·h / mL, e.g., For example, 1000μg·h / mL to 1300μg·h / mL, for example, 1020μg·h / mL to 1300μg·h / mL, e.g., 1040μg·h / mL to 1300μg·h / mL, e.g. For example, 1060μg·h / mL to 1300μg·h / mL, e.g., 1080μg·h / mL ~1300μg·h / mL, e.g., 1100μg·h / mL~1300μg·h / mL, For example, 1120 μg·h / mL to 1300 μg·h / mL, for example, 1140 μg·h / m L to 1300 μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL , e.g., 1180μg·h / mL to 1300μg·h / mL, e.g., 1200μg·h / mL to 1300 μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / m L, e.g., 1240 μg·h / mL to 1300 μg·h / mL, e.g., 1260 μg·h / mL to 1300 μg·h / mL, or e.g., 1280 μg·h / mL to 1300 μg AUC in h / mL 0-12,ss Embodiments I to XI or XIV to XXX The use according to any one of the preceding claims. However, the AUC of 755 μg·h / mL to 1300 μg·h / mL was observed in the subjects. 0-12 ,ss The method of embodiment CLXXXI, resulting in

[0295] Embodiment CLXXXIII. The administration of trophinetide is AUC from 0 μg·h / mL to 1300 μg·h / mL 0-12,ss bring about, implementation The method according to clause CLXXXII.

[0296] Embodiment CLXXXIV. The administration of trophinetide is AUC of μg·h / mL to 1300 μg·h / mL 0-12,ss In an embodiment, The method according to claim CLXXXIII.

[0297] Embodiment CLXXXV. The administration of said trophinetide produces at least For example, 755 μg·h / mL to 1300 μg ·h / mL, e.g., 780μg·h / mL to 1300μg·h / mL, e.g., 790μg h / mL~1300μg h / mL, e.g., 800μg h / mL~1300μg h / mL, e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg·h / mL~1300μg·h / mL, e.g., 860μg·h / mL~1300μg·h / m L, e.g., 880 μg·h / mL to 1300 μg·h / mL, e.g., 900 μg·h / m L to 1300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, For example, 940 μg·h / mL to 1300 μg·h / mL, for example, 960 μg·h / mL to 1300μg·h / mL, e.g., 980μg·h / mL to 1300μg·h / mL, e.g., For example, 1000μg·h / mL to 1300μg·h / mL, for example, 1020μg·h / mL to 1300μg·h / mL, e.g., 1040μg·h / mL to 1300μg·h / mL, e.g. For example, 1060μg·h / mL to 1300μg·h / mL, e.g., 1080μg·h / mL ~1300μg·h / mL, e.g., 1100μg·h / mL~1300μg·h / mL, For example, 1120 μg·h / mL to 1300 μg·h / mL, for example, 1140 μg·h / m L to 1300 μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL , e.g., 1180μg·h / mL to 1300μg·h / mL, e.g., 1200μg·h / mL to 1300 μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / m L, e.g., 1240 μg·h / mL to 1300 μg·h / mL, e.g., 1260 μg·h / mL to 1300 μg·h / mL, or e.g., 1280 μg·h / mL to 1300 μg AUC in h / mL 0-12,ss Embodiments XXXI to XLI or XLI Trofinetide for use according to any one of V to LX.

[0298] Embodiment CLXXXVI. The administration of trophinetide in the subject AUC of μg·h / mL to 1300 μg·h / mL 0-12,ss In an embodiment, Trofinetide for use in CLXXXV.

[0299] Embodiment CLXXXVII. The administration of said trophinetide is in said subject AUC from 0 μg·h / mL to 1300 μg·h / mL 0-12,ss bring about, implementation Trofinetide for use as described in form CLXXXVI.

[0300] Embodiment CLXXXVIII. The administration of trophinetide is AUC of 90 μg·h / mL to 1300 μg·h / mL 0-12,ss bring about, carry out Trofinetide for use according to Form CLXXXVII.

[0301] Embodiment CLXXXIX. The administration of said trophinetide provides at least In the subject, for example, 755 μg·h / mL to 1300 μ g·h / mL, e.g., 780μg·h / mL to 1300μg·h / mL, e.g., 790μ g·h / mL to 1300μg·h / mL, e.g., 800μg·h / mL to 1300μg· h / mL, e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg· h / mL~1300μg·h / mL, e.g., 860μg·h / mL~1300μg·h / mL, e.g., 880 μg·h / mL to 1300 μg·h / mL, e.g., 900 μg·h / mL to 1300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL , for example, 940 μg·h / mL to 1300 μg·h / mL, for example, 960 μg·h / mL ~1300μg·h / mL, e.g. 980μg·h / mL~1300μg·h / mL, e.g. For example, 1000μg·h / mL to 1300μg·h / mL, e.g., 1020μg·h / mL ~1300μg·h / mL, e.g., 1040μg·h / mL~1300μg·h / mL, For example, 1060 μg·h / mL to 1300 μg·h / mL, for example, 1080 μg·h / m L to 1300 μg·h / mL, e.g., 1100 μg·h / mL to 1300 μg·h / mL , e.g., 1120μg·h / mL to 1300μg·h / mL, e.g., 1140μg·h / mL to 1300 μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / m L, e.g., 1180 μg·h / mL to 1300 μg·h / mL, e.g., 1200 μg·h / mL~1300μg·h / mL, e.g., 1220μg·h / mL~1300μg·h / mL, e.g., 1240 μg·h / mL to 1300 μg·h / mL, e.g., 1260 μg· h / mL to 1300 μg·h / mL, or e.g., 1280 μg·h / mL to 1300 μ AUC in g·h / mL 0-12,ss Embodiments LXI to LXXI or LX The use according to any one of XIV to XC.

[0302] Embodiment CXC. The administration of trophinetide is 755 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss Embodiment CLXX Use as described in XIX.

[0303] Embodiment CXCI. The administration of trophinetide in the subject is 780 μg· AUC of h / mL to 1300 μg·h / mL 0-12,ss , in accordance with embodiment CXC. Use as described in.

[0304] Embodiment CXCII. The administration of trophinetide in the subject is 790 μg AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss , embodiment CX Use as described in CI.

[0305] Embodiment CXCIII. The administration of said trophinetide produces at least For example, 755 μg·h / mL to 1300 μg ·h / mL, e.g., 780μg·h / mL to 1300μg·h / mL, e.g., 790μg h / mL~1300μg h / mL, e.g., 800μg h / mL~1300μg h / mL, e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg·h / mL~1300μg·h / mL, e.g., 860μg·h / mL~1300μg·h / m L, e.g., 880 μg·h / mL to 1300 μg·h / mL, e.g., 900 μg·h / m L to 1300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, For example, 940 μg·h / mL to 1300 μg·h / mL, for example, 960 μg·h / mL to 1300μg·h / mL, e.g., 980μg·h / mL to 1300μg·h / mL, e.g., For example, 1000μg·h / mL to 1300μg·h / mL, for example, 1020μg·h / mL to 1300μg·h / mL, e.g., 1040μg·h / mL to 1300μg·h / mL, e.g. For example, 1060μg·h / mL to 1300μg·h / mL, e.g., 1080μg·h / mL ~1300μg·h / mL, e.g., 1100μg·h / mL~1300μg·h / mL, For example, 1120 μg·h / mL to 1300 μg·h / mL, for example, 1140 μg·h / m L to 1300 μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL , e.g., 1180μg·h / mL to 1300μg·h / mL, e.g., 1200μg·h / mL to 1300 μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / m L, e.g., 1240 μg·h / mL to 1300 μg·h / mL, e.g., 1260 μg·h / mL to 1300 μg·h / mL, or e.g., 1280 μg·h / mL to 1300 μg AUC in h / mL 0-12,ss Embodiments XCI to XCIV or CII -CXX.

[0306] Embodiment CXCIV. The administration of trophinetide is 755 μg or more in the subject. AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss , embodiment CX Use as described in CIII.

[0307] Embodiment CXCV. The administration of trophinetide in the subject is 780 μg· AUC of h / mL to 1300 μg·h / mL 0-12,ss , in accordance with embodiment CXC. Use as described in IV.

[0308] Embodiment CXCVI. The administration of trophinetide is 790 μg or more in the subject. AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss , embodiment CX Use as stated in CV.

[0309] Embodiment CXCVII. The administration of said trophinetide produces at least For example, 755 μg·h / mL to 1300 μg ·h / mL, e.g., 780μg·h / mL to 1300μg·h / mL, e.g., 790μg h / mL~1300μg h / mL, e.g., 800μg h / mL~1300μg h / mL, e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg·h / mL~1300μg·h / mL, e.g., 860μg·h / mL~1300μg·h / m L, e.g., 880 μg·h / mL to 1300 μg·h / mL, e.g., 900 μg·h / m L to 1300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, For example, 940 μg·h / mL to 1300 μg·h / mL, for example, 960 μg·h / mL to 1300μg·h / mL, e.g., 980μg·h / mL to 1300μg·h / mL, e.g., For example, 1000μg·h / mL to 1300μg·h / mL, for example, 1020μg·h / mL to 1300μg·h / mL, e.g., 1040μg·h / mL to 1300μg·h / mL, e.g. For example, 1060μg·h / mL to 1300μg·h / mL, e.g., 1080μg·h / mL ~1300μg·h / mL, e.g., 1100μg·h / mL~1300μg·h / mL, For example, 1120 μg·h / mL to 1300 μg·h / mL, for example, 1140 μg·h / m L to 1300 μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL , e.g., 1180μg·h / mL to 1300μg·h / mL, e.g., 1200μg·h / mL to 1300 μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / m L, e.g., 1240 μg·h / mL to 1300 μg·h / mL, e.g., 1260 μg·h / mL to 1300 μg·h / mL, or e.g., 1280 μg·h / mL to 1300 μg AUC in h / mL 0-12,ss Embodiments CXXI ​​to CXXIX or C Trofinetide for use according to any one of XXXII to CL.

[0310] Embodiment CXCVIII. The administration of trophinetide in the subject AUC of μg·h / mL to 1300 μg·h / mL 0-12,ss In an embodiment, Trofinetide for use as described in CXCVII.

[0311] Embodiment CXCIX. The administration of trophinetide is 780 μg or more in the subject AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss , embodiment CX Trofinetide for use as described in CVIII.

[0312] Embodiment CC. The administration of trophinetide is 790 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss Embodiment CXCIX Trofinetide for the use described in 1.

[0313] Embodiment CCI. The administration of said trophinetide provides at least 75 days of treatment in said subject. 5 μg·h / mL, for example, 755 μg·h / mL to 1300 μg·h / mL in the subject mL, e.g., 780 μg·h / mL to 1300 μg·h / mL, e.g., 790 μg·h / mL to 1300 μg·h / mL, e.g., 800 μg·h / mL to 1300 μg·h / mL , e.g., 820 μg·h / mL to 1300 μg·h / mL, e.g., 840 μg·h / mL ~1300μg·h / mL, e.g. 860μg·h / mL~1300μg·h / mL, e.g. For example, 880 μg·h / mL to 1300 μg·h / mL, for example, 900 μg·h / mL to 1 300 μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g. 940μg·h / mL to 1300μg·h / mL, e.g., 960μg·h / mL to 130 0 μg·h / mL, e.g., 980 μg·h / mL to 1300 μg·h / mL, e.g., 10 00μg·h / mL~1300μg·h / mL, e.g., 1020μg·h / mL~130 0 μg·h / mL, e.g., 1040 μg·h / mL to 1300 μg·h / mL, e.g., 1 060μg·h / mL~1300μg·h / mL, e.g., 1080μg·h / mL~13 00μg·h / mL, e.g., 1100μg·h / mL to 1300μg·h / mL, e.g. 1120μg·h / mL to 1300μg·h / mL, e.g., 1140μg·h / mL to 1 300μg·h / mL, e.g., 1160μg·h / mL to 1300μg·h / mL, e.g., For example, 1180 μg·h / mL to 1300 μg·h / mL, for example, 1200 μg·h / mL to 1300μg·h / mL, e.g., 1220μg·h / mL to 1300μg·h / mL, e.g. For example, 1240μg·h / mL to 1300μg·h / mL, e.g., 1260μg·h / mL ~1300μg·h / mL, or e.g. 1280μg·h / mL~1300μg·h / AUC in mL 0-12,ss In embodiments CLI to CLIX or CLXII to CLXXX.

[0314] Embodiment CCII. The administration of trophinetide in the subject is 755 μg· AUC of h / mL to 1300 μg·h / mL 0-12,ss , resulting in embodiment CCI Use as described in.

[0315] Embodiment CCIII. The administration of trophinetide is 780 μg or more in the subject. AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss , resulting in embodiment CC Use as described in II.

[0316] Embodiment CCIV. The administration of trophinetide in the subject is 790 μg· AUC of h / mL to 1300 μg·h / mL 0-12,ss , resulting in embodiment CCI Use as described in II.

[0317] Embodiment CCV. The administration of said trophinetide to said subject results in at least one of: at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject L, e.g., 110 μg / mL to 300 μg / mL, e.g., 120 μg / mL to 300 μg / mL, for example, 130μg / mL to 300μg / mL, for example, 140μg / mL to 300 μg / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / mL to 3 00μg / mL, for example 170μg / mL to 300μg / mL, for example 180μg / mL ~300μg / mL, e.g., 190μg / mL~300μg / mL, e.g., 200μg / mL to 300 μg / mL, for example, 210 μg / mL to 300 μg / mL, for example, 220 μ g / mL to 300 μg / mL, for example, 230 μg / mL to 300 μg / mL, for example, 24 0 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example 260μg / mL~300μg / mL, e.g. 270μg / mL~300μg / mL, e.g. For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μg / mL C max,ss Embodiments I to XIII, XVI to XXX, or C A method according to any one of LXXXI to CLXXXIV.

[0318] Embodiment CCVI. The administration of trophinetide to the subject comprises administering to the subject at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject mL, e.g., 110 μg / mL to 300 μg / mL, e.g., 120 μg / mL to 300 μ g / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 30 0 μg / mL, e.g., 150 μg / mL to 300 μg / mL, e.g., 160 μg / mL to 300 μg / mL, for example, 170 μg / mL to 300 μg / mL, for example, 180 μg / m L to 300 μg / mL, e.g., 190 μg / mL to 300 μg / mL, e.g., 200 μg / mL to 300μg / mL, for example 210μg / mL to 300μg / mL, for example 220 μg / mL to 300 μg / mL, for example, 230 μg / mL to 300 μg / mL, for example, 2 40μg / mL~300μg / mL, e.g. 250μg / mL~300μg / mL, e.g. For example, 260 μg / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL, For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μ C in g / mL max,ss Embodiments XXXI to XLIII, XLVI to LX or a trophozoite for use according to any one of CLXXXV to CLXXXVIII Inetid.

[0319] Embodiment CCVII. The administration of said trophinetide to said subject results in said subject at least 100 μg / mL in the subject, for example 100 μg / mL to 300 μg / mL, for example, 110μg / mL to 300μg / mL, for example, 120μg / mL to 300 μg / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 3 00μg / mL, for example 150μg / mL to 300μg / mL, for example 160μg / mL ~300μg / mL, e.g., 170μg / mL~300μg / mL, e.g., 180μg / mL to 300 μg / mL, for example 190 μg / mL to 300 μg / mL, for example 200 μ g / mL to 300 μg / mL, for example, 210 μg / mL to 300 μg / mL, for example, 22 0 μg / mL to 300 μg / mL, for example, 230 μg / mL to 300 μg / mL, for example 240μg / mL~300μg / mL, e.g. 250μg / mL~300μg / mL, e.g. For example, 260 μg / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL , for example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 C in μg / mL max,ss Embodiments LXI to LXXIII, LXXVI to XC, or the use described in any one of CLXXXIX to CXCI.

[0320] Embodiment CCVIII. The administration of said trophinetide to said subject comprises administering to said subject at least 100 μg / mL in the subject, for example 100 μg / mL to 300 μg / mL in the subject g / mL, for example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 30 0 μg / mL, e.g., 130 μg / mL to 300 μg / mL, e.g., 140 μg / mL to 300 μg / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / m L to 300 μg / mL, e.g., 170 μg / mL to 300 μg / mL, e.g., 180 μg / mL to 300μg / mL, for example 190μg / mL to 300μg / mL, for example 200 μg / mL to 300 μg / mL, for example, 210 μg / mL to 300 μg / mL, for example, 2 20μg / mL~300μg / mL, e.g. 230μg / mL~300μg / mL, e.g. For example, 240 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, For example, 260 μg / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / m L, for example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 30 C of 0 μg / mL max,ss Embodiments XCI to CI, CIV to CXX, or or a method according to any one of CXCIII to CXCVI.

[0321] Embodiment CCIX. The administration of said trophinetide to said subject comprises administering to said subject at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject mL, e.g., 110 μg / mL to 300 μg / mL, e.g., 120 μg / mL to 300 μ g / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 30 0 μg / mL, e.g., 150 μg / mL to 300 μg / mL, e.g., 160 μg / mL to 300 μg / mL, for example, 170 μg / mL to 300 μg / mL, for example, 180 μg / m L to 300 μg / mL, e.g., 190 μg / mL to 300 μg / mL, e.g., 200 μg / mL to 300μg / mL, for example 210μg / mL to 300μg / mL, for example 220 μg / mL to 300 μg / mL, for example, 230 μg / mL to 300 μg / mL, for example, 2 40μg / mL~300μg / mL, e.g. 250μg / mL~300μg / mL, e.g. For example, 260 μg / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL, For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μ C in g / mL max,ss In embodiments CXXI ​​to CXXXI, CXXXIV to CL, or trophinetide for use as described in any one of CXCVII to CC.

[0322] Embodiment CCX. The administration of said trophinetide to said subject results in at least one of: at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject L, e.g., 110 μg / mL to 300 μg / mL, e.g., 120 μg / mL to 300 μg / mL, for example, 130μg / mL to 300μg / mL, for example, 140μg / mL to 300 μg / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / mL to 3 00μg / mL, for example 170μg / mL to 300μg / mL, for example 180μg / mL ~300μg / mL, e.g., 190μg / mL~300μg / mL, e.g., 200μg / mL to 300 μg / mL, for example, 210 μg / mL to 300 μg / mL, for example, 220 μ g / mL to 300 μg / mL, for example, 230 μg / mL to 300 μg / mL, for example, 24 0 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example 260μg / mL~300μg / mL, e.g. 270μg / mL~300μg / mL, e.g. For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μg / mL C max,ss Embodiments CLI to CLXI, CLXIV to CLXX X, or the use described in any one of CCI to CCIV.

[0323] The following embodiments are also provided:

[0324] Embodiment 1. Method of treating Rett syndrome in a subject in need thereof a method for determining a blood glucose level in the subject from about 755 μg·h / mL to about 1300 μg·h / mL, e.g., For example, AUC of 755 μg·h / mL to 1300 μg·h / mL 0-12,ss provide The method comprising administering a daily dose of the trophinetide to the subject.

[0325] Embodiment 2. About 800 μg h / mL to about 1000 μg h / mL in the subject; For example, AUC of 800 μg·h / mL to 1000 μg·h / mL 0-12,ss Provide 2. The method of claim 1, comprising administering to the subject a daily amount of trophinetide equivalent to method.

[0326] Embodiment 3. Method of treating Rett syndrome in a subject in need thereof 20. The method of claim 19, wherein the subject has a blood glucose level of at least about 755 μg·h / mL, at least about 780 μg·h / mL, or μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg·h / m L, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL g·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL , at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1020 μg·h / mL, at least about 104 0 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg· h / mL, at least about 1100 μg h / mL, at least about 1120 μg h / mL , at least about 1140 μg·h / mL, at least about 1160 μg·h / mL, or less at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1 220 μg·h / mL, at least about 1240 μg·h / mL, at least about 1260 μ g·h / mL, or an AUC of at least about 1280 μg·h / mL 0-12,ss Offer The method comprises administering to the subject a daily dose of trophinetide that provides

[0327] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the subject weighs about 12 kg to about 20 kg. The method according to any one of the preceding claims.

[0328] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the daily dose of trophinetide is about 12 g. The method according to any one of the preceding claims.

[0329] Embodiment 6. The method of any one of embodiments 1 to 3, wherein the subject weighs between about 20.1 kg and about 35 kg. 10. The method according to claim 9, wherein

[0330] Embodiment 7. The daily dose of trophinetide according to any of the preceding embodiments 1, 2, or 3 is about 16 g. 7. The method according to any one of claims 3 or 6.

[0331] Embodiment 8. The method of any one of embodiments 1 to 3, wherein the subject weighs between about 35.1 kg and about 50 kg. 10. The method according to claim 9, wherein

[0332] Embodiment 9. The daily dose of trophinetide according to any of the preceding embodiments, wherein the daily dose is about 20 g. 9. The method according to any one of claims 3 or 8.

[0333] Embodiment 10. The subject weighs about 50.1 kg to about 100 kg. A method according to any one of claims 1 to 3.

[0334] Embodiment 11. The daily dose of trophinetide is about 24 g, as in embodiments 1 and 2. 10. The method according to any one of claims 1 to 4, 3, or 10.

[0335] Embodiment 12. The trophinetide is administered to the subject in a single dose per day. 12. The method according to any one of embodiments 1 to 11.

[0336] Embodiment 13. The trophinetide is administered multiple times per day, totaling the daily dose. 12. The method of any one of embodiments 1-11, wherein the subject is administered a dose of

[0337] Embodiment 14. The trophinetide is administered twice daily, totaling the daily dose. 14. The method of embodiment 13, wherein the subject is administered a dose of

[0338] Embodiment 15. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. 15. The method of any one of embodiments 1-14, wherein the compound is administered as a pharmaceutical composition comprising the compound.

[0339] Embodiment 16. The method of embodiment 15, wherein the pharmaceutically acceptable carrier comprises water. .

[0340] Embodiment 17. The method of embodiment 16, wherein the pharmaceutical composition is a solution.

[0341] Embodiment 18. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. 18. The method of embodiment 17, wherein the saturation is 0.05 mg / mL.

[0342] Embodiment 19. The concentration of trophinetide is about 0.2 g / mL in the solution. 19. The method of embodiment 18.

[0343] Embodiment 20. The trophinetide is administered orally to the subject. 10. The method according to claim 9, wherein

[0344] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the subject is a human. Law.

[0345] Embodiment 22. The method of embodiment 21, wherein the subject is a female.

[0346] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the subject is between about 18 months and about 20 years old. The method according to any one of the following:

[0347] Embodiment 24. Any one of embodiments 1 to 23, wherein the subject has an MECP2 mutation. The method described in the first paragraph.

[0348] Embodiment 25. The method of any one of embodiments 1 to 22, wherein the Rett syndrome is atypical Rett syndrome. The method according to any one of the preceding claims.

[0349] Embodiment 26. The Rett syndrome is classic / typical Rett syndrome. 25. The method according to any one of 1 to 24.

[0350] Embodiment 27. A method for treating Rett syndrome in a subject, comprising administering to a subject a therapeutically effective amount of trophine. The trophinetide is administered in a concentration of about 755 μg h / mL to about 1300 μg h / mL. AUC of L 0-12,ss The trophinetate is administered to the subject in a daily amount that provides Do.

[0351] Embodiment 28. The trophinetide is administered in a dose range of about 800 μg h / mL to about 1000 μg h AUC in / mL 0-12,ss administering to the subject a daily amount of said trophinetide providing Trofinetide for use according to embodiment 27.

[0352] Embodiment 29. Trofinetide for use in treating Rett syndrome in a subject. Thus, the trophinetide is at least about 755 μg·h / mL in the subject, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 8 00 μg·h / mL, at least about 820 μg·h / mL, at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 94 0 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg h / mL, at least about 1020 μg h / mL, a little at least about 1040 μg·h / mL, at least about 1060 μg·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 112 0 μg·h / mL, at least about 1140 μg·h / mL, at least about 1160 μg· h / mL, at least about 1180 μg h / mL, at least about 1200 μg h / mL , at least about 1220 μg·h / mL, at least about 1240 μg·h / mL, or less AUC0 of about 1260 μg·h / mL or at least about 1280 μg·h / mL -12,ss The trophinetide is administered to the subject in a daily amount providing

[0353] Embodiment 30. The method of any of embodiments 27 to 22, wherein the subject weighs between about 12 kg and about 20 kg. 9. Trofinetide for use according to any one of claims 9 to 9.

[0354] Embodiment 31. The daily dose of trophinetide is about 12 g. 30. Trofinetide for use as described in any one of claims 1 to 30.

[0355] Embodiment 32. The subject weighs about 20.1 kg to about 35 kg. Trofinetide for use according to any one of claims 1 to 29.

[0356] Embodiment 33. The daily dose of trophinetide is about 16 g, as described in embodiments 27 to 29. 29 or 32. Trofinetide for use according to any one of the preceding claims.

[0357] Embodiment 34. The subject weighs about 35.1 kg to about 50 kg. Trofinetide for use according to any one of claims 1 to 29.

[0358] Embodiment 35. The daily dose of trophinetide is about 20 g. 29 or 34. Trofinetide for use as described in any one of the above.

[0359] Embodiment 36. The subject weighs between about 50.1 kg and about 100 kg. Trofinetide for use according to any one of items 7 to 29.

[0360] Embodiment 37. The daily dose of trophinetide is about 24 g. 29 or 36. Trofinetide for use as described in any one of 29 or 36.

[0361] Embodiment 38. The trophinetide is administered to the subject in a single dose per day. Trofinetide for use according to any one of embodiments 27 to 37.

[0362] Embodiment 39. The trophinetide is administered multiple times per day, totaling the daily dose. For the use according to any one of embodiments 27 to 37, wherein the subject is administered at a dose of Trofinetide.

[0363] Embodiment 40. The trophinetide is administered twice daily, totaling the daily dose. The trophinetide for use according to embodiment 39, wherein the trophinetide is administered to the subject at a dose of

[0364] Embodiment 41. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 27 to 40, wherein the use is administered as a pharmaceutical composition comprising the body Trofinetide for.

[0365] Embodiment 42. The use of embodiment 41, wherein the pharmaceutically acceptable carrier comprises water. Trofinetide for.

[0366] Embodiment 43. The method for use according to embodiment 42, wherein the pharmaceutical composition is a solution. Rofinetide.

[0367] Embodiment 44. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. Trofinetide for use according to embodiment 43, wherein the trophinetide concentration is 100 mg / mL.

[0368] Embodiment 45. The concentration of trophinetide is about 0.2 g / mL in the solution. , Trofinetide for use according to embodiment 44.

[0369] Embodiment 46. The trophinetide is administered orally to the subject. 5. Trofinetide for use according to any one of claims 1 to 5.

[0370] Embodiment 47. The method of any one of embodiments 27 to 46, wherein the subject is a human. Trofinetide for use.

[0371] Embodiment 48. A method for the use of embodiment 47, wherein the subject is a woman. Nechid.

[0372] Embodiment 49. The method of any of embodiments 27 to 48, wherein the subject is about 18 months to about 20 years old. Trofinetide for use as described in any one of the preceding items.

[0373] Embodiment 50. Any of embodiments 27 to 49, wherein the subject has an MECP2 mutation. Trofinetide for the use described in 1.

[0374] Embodiment 51. The Rett syndrome is atypical Rett syndrome. Trofinetide for use according to any one of the preceding items.

[0375] Embodiment 52. The Rett syndrome is classic / typical Rett syndrome. Trofinetide for use according to any one of 27 to 50.

[0376] Embodiment 53. A method for producing a medicament for treating Rett Syndrome in a subject. Use of finetide, wherein the finetide is administered in a concentration of about 755 μg·h / mL to about 130 μg·h / mL. AUC of 0 μg·h / mL 0-12,ss and administering to said subject a daily amount providing Used.

[0377] Embodiment 54. An AUC of about 800 μg h / mL to about 1000 μg h / mL 0-12 ,ss administering to the subject a daily amount of said trophinetide providing Use of state 53.

[0378] Embodiment 55. A method for producing a medicament for treating Rett Syndrome in a subject. 1. Use of finetide, wherein said finetide is effective in achieving at least about 75% CI in said subject. 5 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg·h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, or at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 880 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / m L, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 102 0 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μg· h / mL, at least about 1080 μg h / mL, at least about 1100 μg h / mL , at least about 1120 μg·h / mL, at least about 1140 μg·h / mL, or at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1 200 μg·h / mL, at least about 1220 μg·h / mL, at least about 1240 μ g·h / mL, at least about 1260 μg·h / mL, or at least about 1280 μg AUC in h / mL 0-12,ss said use being administered to said subject in a daily amount providing .

[0379] Embodiment 56. The method of any of embodiments 53 to 5, wherein the subject weighs between about 12 kg and about 20 kg. 5. The use according to any one of the preceding items.

[0380] Embodiment 57. The daily dose of trophinetide is about 12 g. 56. The use according to any one of claims 1 to 56.

[0381] Embodiment 58. Embodiment 53. The subject weighs between about 20.1 kg and about 35 kg. 55. The use according to any one of claims 1 to 55.

[0382] Embodiment 59. The daily dose of trophinetide is about 16 g, as described in embodiments 53 to 59. 55 or 58. The use according to any one of paragraphs 55 or 58.

[0383] Embodiment 60. The subject weighs about 35.1 kg to about 50 kg. 55. The use according to any one of claims 1 to 55.

[0384] Embodiment 61. The daily dose of trophinetide is about 20 g. 55 or 60.

[0385] Embodiment 62. The subject weighs about 50.1 kg to about 100 kg. 3 to 55.

[0386] Embodiment 63. The daily dose of trophinetide is about 24 g. 55 or 62.

[0387] Embodiment 64. The trophinetide is administered to the subject in a single dose per day. Use according to any one of embodiments 53 to 63.

[0388] Embodiment 65. The trophinetide is administered multiple times per day, totaling the daily dose. The use according to any one of embodiments 53 to 63, wherein the subject is administered a dose of

[0389] Embodiment 66. The trophinetide is administered twice daily, totaling the daily dose. The use of embodiment 65, wherein the subject is administered a dose of

[0390] Embodiment 67. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 53 to 66, wherein the use is administered as a pharmaceutical composition comprising the body .

[0391] Embodiment 68. The use of embodiment 67, wherein the pharmaceutically acceptable carrier comprises water. .

[0392] Embodiment 69. The use of embodiment 68, wherein the pharmaceutical composition is a solution.

[0393] Embodiment 70. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. The use of embodiment 69, wherein the saturation is 0.05 mg / mL.

[0394] Embodiment 71. The concentration of trophinetide is about 0.2 g / mL in the solution. , the use according to embodiment 70.

[0395] Embodiment 72. The trophinetide is administered orally to the subject. 1. The use according to any one of claims 1 to 1.

[0396] Embodiment 73. The method of any one of embodiments 53 to 72, wherein the subject is a human. use.

[0397] Embodiment 74. The use of embodiment 73, wherein the subject is a woman.

[0398] Embodiment 75. The method of any of embodiments 53-74, wherein the subject is about 18 months to about 20 years old. Use as described in any one of the following:

[0399] Embodiment 76. Any of embodiments 53 to 75, wherein the subject has an MECP2 mutation. Use as described in one.

[0400] Embodiment 77. The Rett syndrome is atypical Rett syndrome. 1. The use according to any one of the preceding claims.

[0401] Embodiment 78. The Rett syndrome is classic / typical Rett syndrome. 53 to 76. The use according to any one of claims 53 to 76.

[0402] Embodiment 79. The administration of trophinetide achieves at least 755 mg / kg / day in the subject. μg·h / mL, e.g., 755μg·h / mL to 1300μg·h / mL, e.g., 780 μg·h / mL to 1300μg·h / mL, e.g., 790μg·h / mL to 1300μg ·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μg ·h / mL~1300μg·h / mL, e.g. 840μg·h / mL~1300μg·h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg·h / mL~1300μg·h / mL, e.g., 900μg·h / mL~1300μg·h / m L, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / m L to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL, For example, 980μg·h / mL to 1300μg·h / mL, for example, 1000μg·h / mL ~1300μg·h / mL, e.g., 1020μg·h / mL~1300μg·h / mL, For example, 1040 μg·h / mL to 1300 μg·h / mL, for example, 1060 μg·h / m L to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / mL , e.g., 1100μg·h / mL to 1300μg·h / mL, e.g., 1120μg·h / mL to 1300 μg·h / mL, e.g., 1140 μg·h / mL to 1300 μg·h / m L, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg·h / mL~1300μg·h / mL, e.g., 1200μg·h / mL~1300μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg· h / mL to 1300μg h / mL, e.g., 1260μg h / mL to 1300μg h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0-1 2,ss 27. The method of any one of embodiments 3 to 26, wherein

[0403] Embodiment 80. The administration of trophinetide is 755 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 79. How to do it.

[0404] Embodiment 81. The administration of trophinetide is 780 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 80. How to do it.

[0405] Embodiment 82. The administration of trophinetide is 790 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 81. How to do it.

[0406] Embodiment 83. The administration of trophinetide achieves at least 755 mg / kg / day in the subject. μg·h / mL, e.g., 755μg·h / mL to 1300μg·h / mL, e.g., 780 μg·h / mL to 1300μg·h / mL, e.g., 790μg·h / mL to 1300μg ·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μg ·h / mL~1300μg·h / mL, e.g. 840μg·h / mL~1300μg·h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg·h / mL~1300μg·h / mL, e.g., 900μg·h / mL~1300μg·h / m L, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / m L to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL, For example, 980μg·h / mL to 1300μg·h / mL, for example, 1000μg·h / mL ~1300μg·h / mL, e.g., 1020μg·h / mL~1300μg·h / mL, For example, 1040 μg·h / mL to 1300 μg·h / mL, for example, 1060 μg·h / m L to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / mL , e.g., 1100μg·h / mL to 1300μg·h / mL, e.g., 1120μg·h / mL to 1300 μg·h / mL, e.g., 1140 μg·h / mL to 1300 μg·h / m L, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg·h / mL~1300μg·h / mL, e.g., 1200μg·h / mL~1300μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg· h / mL to 1300μg h / mL, e.g., 1260μg h / mL to 1300μg h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0-1 2,ss trophies for use according to any one of embodiments 29 to 52, Nechid.

[0407] Embodiment 84. The administration of trophinetide is 755 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 83. Trofinetide for use in:

[0408] Embodiment 85. The administration of trophinetide is 780 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 84. Trofinetide for use in:

[0409] Embodiment 86. The administration of trophinetide is 790 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 85. Trofinetide for use in:

[0410] Embodiment 87. The administration of trophinetide achieves at least 755 mg / kg / day in the subject. μg·h / mL, e.g., 755μg·h / mL to 1300μg·h / mL, e.g., 780 μg·h / mL to 1300μg·h / mL, e.g., 790μg·h / mL to 1300μg ·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μg ·h / mL~1300μg·h / mL, e.g. 840μg·h / mL~1300μg·h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg·h / mL~1300μg·h / mL, e.g., 900μg·h / mL~1300μg·h / m L, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / m L to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL, For example, 980μg·h / mL to 1300μg·h / mL, for example, 1000μg·h / mL ~1300μg·h / mL, e.g., 1020μg·h / mL~1300μg·h / mL, For example, 1040 μg·h / mL to 1300 μg·h / mL, for example, 1060 μg·h / m L to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / mL , e.g., 1100μg·h / mL to 1300μg·h / mL, e.g., 1120μg·h / mL to 1300 μg·h / mL, e.g., 1140 μg·h / mL to 1300 μg·h / m L, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg·h / mL~1300μg·h / mL, e.g., 1200μg·h / mL~1300μg·h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg· h / mL to 1300μg h / mL, e.g., 1260μg h / mL to 1300μg h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0-1 2,ss The use according to any one of embodiments 55 to 78, resulting in

[0411] Embodiment 88. The administration of trophinetide is 755 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 88. The method of claim 87, Use of.

[0412] Embodiment 89. The administration of trophinetide is 780 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 88. Use of.

[0413] Embodiment 90. The administration of trophinetide is 790 μg h / day in the subject. AUC of mL ~ 1300 μg·h / mL 0-12,ss 89. Use of.

[0414] The following embodiments are also provided:

[0415] Embodiment 1. Method of treating Rett syndrome in a subject in need thereof The method of claim 1, wherein the subject has a C of about 100 μg / mL to about 300 μg / mL. max,s s The method comprises administering to the subject a daily amount of trophinetide that provides:

[0416] Embodiment 2. A C of about 100 μg / mL to about 200 μg / mL in the subject max, ss 2. The method of claim 1, comprising administering to said subject a daily dose of trophinetide providing The method described.

[0417] Embodiment 3. Method of treating Rett syndrome in a subject in need thereof 10. The method of claim 1, wherein the subject has a blood glucose level of at least about 100 μg / mL, at least about 110 μg / mL, / mL, at least about 120 μg / mL, at least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or a C of at least about 200 μg / mL max,ss Provides a daily dose of fatty tuna The method comprising administering finetide to the subject.

[0418] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the subject weighs about 12 kg to about 20 kg. The method according to any one of the preceding claims.

[0419] Embodiment 5. The method of any one of embodiments 1 to 4, wherein the daily dose of trophinetide is about 12 g. The method according to any one of the preceding claims.

[0420] Embodiment 6. The method of any one of embodiments 1 to 3, wherein the subject weighs between about 20.1 kg and about 35 kg. 10. The method according to claim 9, wherein

[0421] Embodiment 7. The daily dose of trophinetide according to any of the preceding embodiments 1, 2, or 3 is about 16 g. 3 or 6.

[0422] Embodiment 8. The method of any one of embodiments 1 to 3, wherein the subject weighs between about 35.1 kg and about 50 kg. 10. The method according to claim 9, wherein

[0423] Embodiment 9. The daily dose of trophinetide according to any of the preceding embodiments, wherein the daily dose is about 20 g. 3 or 8.

[0424] Embodiment 10. The subject weighs about 50.1 kg to about 100 kg. 32. A method according to any one of claims 1 to 32.

[0425] Embodiment 11. The daily dose of trophinetide is about 24 g, as in embodiments 1 and 2. , 3, or 10.

[0426] Embodiment 12. The trophinetide is administered to the subject in a single dose per day. 12. The method according to any one of embodiments 1 to 11.

[0427] Embodiment 13. The trophinetide is administered multiple times per day, totaling the daily dose. 12. The method of any one of embodiments 1-11, wherein the subject is administered a dose of

[0428] Embodiment 14. The trophinetide is administered twice daily, totaling the daily dose. 14. The method of embodiment 13, wherein the subject is administered a dose of

[0429] Embodiment 15. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. 15. The method of any one of embodiments 1-14, wherein the compound is administered as a pharmaceutical composition comprising the compound.

[0430] Embodiment 16. The method of embodiment 15, wherein the pharmaceutically acceptable carrier comprises water. .

[0431] Embodiment 17. The method of embodiment 16, wherein the pharmaceutical composition is a solution.

[0432] Embodiment 18. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. 18. The method of embodiment 17, wherein the saturation is 0.05 mg / mL.

[0433] Embodiment 19. The concentration of trophinetide is about 0.2 g / mL in the solution. 19. The method of embodiment 18.

[0434] Embodiment 20. The trophinetide is administered orally to the subject. 10. The method according to claim 9, wherein

[0435] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the subject is a human. Law.

[0436] Embodiment 22. The method of embodiment 21, wherein the subject is a female.

[0437] Embodiment 23. The method of any one of embodiments 1 to 22, wherein the subject is between about 18 months and about 20 years old. The method according to any one of the following:

[0438] Embodiment 24. Any one of embodiments 1 to 23, wherein the subject has an MECP2 mutation. The method described in the first paragraph.

[0439] Embodiment 25. The method of any one of embodiments 1 to 22, wherein the Rett syndrome is atypical Rett syndrome. The method according to any one of the preceding claims.

[0440] Embodiment 26. The Rett syndrome is classic / typical Rett syndrome. 25. The method according to any one of 1 to 24.

[0441] Embodiment 27. Trofinetide for use in treating Rett syndrome in a subject. Therefore, the trophinetide is administered to the subject at a concentration of about 100 μg / mL to about 300 μg / mL. C of L max,ss The trophinetide is administered to the subject in a daily amount providing

[0442] Embodiment 28. The trophinetide is administered in the subject at a concentration of from about 100 μg / mL to about 20 μg / mL. C of 0 μg / mL max,ss administering to the subject a daily amount of said trophinetide providing Trofinetide for use according to embodiment 27.

[0443] Embodiment 29. Trofinetide for use in treating Rett syndrome in a subject. Thus, the trophinetide is at least about 100 μg / mL, at least at least about 110 μg / mL, at least about 120 μg / mL, and at least about 130 μg / mL L, at least about 140 μg / mL, at least about 150 μg / mL, at least about 16 0 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, or C of about 190 μg / mL, or at least about 200 μg / mL max,ss Provide The trophinetide is administered to the subject in a daily amount equal to or greater than 100 mg / kg of trophinetide.

[0444] Embodiment 30. The method of any of embodiments 27 to 22, wherein the subject weighs between about 12 kg and about 20 kg. 9. Trofinetide for use according to any one of claims 9 to 9.

[0445] Embodiment 31. The daily dose of trophinetide is about 12 g. 30. Trofinetide for use as described in any one of claims 1 to 30.

[0446] Embodiment 32. The subject weighs about 20.1 kg to about 35 kg. Trofinetide for use according to any one of claims 1 to 29.

[0447] Embodiment 33. The daily dose of trophinetide is about 16 g, as described in embodiments 27 to 29. 29 or 32. Trofinetide for use according to any one of the preceding claims.

[0448] Embodiment 34. The subject weighs about 35.1 kg to about 50 kg. Trofinetide for use according to any one of claims 1 to 29.

[0449] Embodiment 35. The daily dose of trophinetide is about 20 g. 29 or 34. Trofinetide for use as described in any one of the above.

[0450] Embodiment 36. The subject weighs between about 50.1 kg and about 100 kg. Trofinetide for use according to any one of items 7 to 29.

[0451] Embodiment 37. The daily dose of trophinetide is about 24 g. 29 or 36. Trofinetide for use as described in any one of 29 or 36.

[0452] Embodiment 38. The trophinetide is administered to the subject in a single dose per day. Trofinetide for use according to any one of embodiments 27 to 37.

[0453] Embodiment 39. The trophinetide is administered multiple times per day, totaling the daily dose. For the use according to any one of embodiments 27 to 37, wherein the subject is administered at a dose of Trofinetide.

[0454] Embodiment 40. The trophinetide is administered twice daily, totaling the daily dose. The trophinetide for use according to embodiment 39, wherein the trophinetide is administered to the subject at a dose of

[0455] Embodiment 41. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 27 to 40, wherein the use is administered as a pharmaceutical composition comprising the body Trofinetide for.

[0456] Embodiment 42. The use of embodiment 41, wherein the pharmaceutically acceptable carrier comprises water. Trofinetide for.

[0457] Embodiment 43. The method for use according to embodiment 42, wherein the pharmaceutical composition is a solution. Rofinetide.

[0458] Embodiment 44. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. Trofinetide for use according to embodiment 43, wherein the trophinetide concentration is 100 mg / mL.

[0459] Embodiment 45. The concentration of trophinetide is about 0.2 g / mL in the solution. , Trofinetide for use according to embodiment 44.

[0460] Embodiment 46. The trophinetide is administered orally to the subject. 5. Trofinetide for use according to any one of claims 1 to 5.

[0461] Embodiment 47. The method of any one of embodiments 27 to 46, wherein the subject is a human. Trofinetide for use.

[0462] Embodiment 48. A method for the use of embodiment 47, wherein the subject is a woman. Nechid.

[0463] Embodiment 49. The method of any of embodiments 27 to 48, wherein the subject is about 18 months to about 20 years old. Trofinetide for use as described in any one of the preceding items.

[0464] Embodiment 50. Any of embodiments 27 to 49, wherein the subject has an MECP2 mutation. Trofinetide for the use described in 1.

[0465] Embodiment 51. The Rett syndrome is atypical Rett syndrome. Trofinetide for use according to any one of the preceding items.

[0466] Embodiment 52. The Rett syndrome is classic / typical Rett syndrome. Trofinetide for use according to any one of 27 to 50.

[0467] Embodiment 53. A method for producing a medicament for treating Rett Syndrome in a subject. 1. Use of finetide, wherein the finetide is administered to the subject at a dose of about 100 μg / m L ~ approximately 300 μg / mL C max,ss and administering to said subject a daily amount that results in Used.

[0468] Embodiment 54. A C of about 100 μg / mL to about 200 μg / mL in the subject max ,ss administering to the subject a daily amount of said trophinetide providing 53. The use according to claim 53.

[0469] Embodiment 55. A method for producing a medicament for treating Rett Syndrome in a subject. 1. Use of finetide, wherein said finetide is administered to said subject to at least about 10 0 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, or at least about 130 μg / mL, at least about 140 μg / mL, and at least about 150 μg / mL L, at least about 160 μg / mL, at least about 170 μg / mL, at least about 18 0 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL C max,ss The method of claim 1, wherein the composition is administered to the subject in a daily amount providing

[0470] Embodiment 56. The method of any of embodiments 53 to 5, wherein the subject weighs between about 12 kg and about 20 kg. 5. The use according to any one of the preceding items.

[0471] Embodiment 57. The daily dose of trophinetide is about 12 g. 56. The use according to any one of claims 1 to 56.

[0472] Embodiment 58. Embodiment 53. The subject weighs between about 20.1 kg and about 35 kg. 55. The use according to any one of claims 1 to 55.

[0473] Embodiment 59. The daily dose of trophinetide is about 16 g, as described in embodiments 53 to 59. 55 or 58. The use according to any one of paragraphs 55 or 58.

[0474] Embodiment 60. The subject weighs about 35.1 kg to about 50 kg. 55. The use according to any one of claims 1 to 55.

[0475] Embodiment 61. The daily dose of trophinetide is about 20 g. 55 or 60.

[0476] Embodiment 62. The subject weighs about 50.1 kg to about 100 kg. 3 to 55.

[0477] Embodiment 63. The daily dose of trophinetide is about 24 g. 55 or 62.

[0478] Embodiment 64. The trophinetide is administered to the subject in a single dose per day. Use according to any one of embodiments 53 to 63.

[0479] Embodiment 65. The trophinetide is administered multiple times per day, totaling the daily dose. The use according to any one of embodiments 53 to 63, wherein the subject is administered a dose of

[0480] Embodiment 66. The trophinetide is administered twice daily, totaling the daily dose. The use of embodiment 65, wherein the subject is administered a dose of

[0481] Embodiment 67. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 53 to 66, wherein the use is administered as a pharmaceutical composition comprising the body .

[0482] Embodiment 68. The use of embodiment 67, wherein the pharmaceutically acceptable carrier comprises water. .

[0483] Embodiment 69. The use of embodiment 68, wherein the pharmaceutical composition is a solution.

[0484] Embodiment 70. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. The use of embodiment 69, wherein the saturation is 0.05 mg / mL.

[0485] Embodiment 71. The concentration of trophinetide is about 0.2 g / mL in the solution. , the use according to embodiment 70.

[0486] Embodiment 72. The trophinetide is administered orally to the subject. 1. The use according to any one of claims 1 to 1.

[0487] Embodiment 73. The method of any one of embodiments 53 to 72, wherein the subject is a human. use.

[0488] Embodiment 74. The use of embodiment 73, wherein the subject is a woman.

[0489] Embodiment 75. The method of any of embodiments 53-74, wherein the subject is about 18 months to about 20 years old. Use as described in any one of the following:

[0490] Embodiment 76. Any of embodiments 53 to 75, wherein the subject has an MECP2 mutation. Use as described in one.

[0491] Embodiment 77. The Rett syndrome is atypical Rett syndrome. 1. The use according to any one of the preceding claims.

[0492] Embodiment 78. The Rett syndrome is classic / typical Rett syndrome. 53 to 76. The use according to any one of claims 53 to 76.

[0493] Embodiment 79. The administration of trophinetide to the subject results in at least one of the following: At most 100 μg / mL, for example, 100 μg / mL to 300 μg / mL in the subject , for example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μ g / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / mL to 30 0 μg / mL, e.g., 170 μg / mL to 300 μg / mL, e.g., 180 μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / m L to 300 μg / mL, e.g., 210 μg / mL to 300 μg / mL, e.g., 220 μg / mL to 300μg / mL, for example 230μg / mL to 300μg / mL, for example 240 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 2 60μg / mL~300μg / mL, e.g. 270μg / mL~300μg / mL, e.g. For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μg / mL C in mL max,ss 27. The method of any one of embodiments 3 to 26, wherein

[0494] Embodiment 80. The administration of trophinetide to the subject results in at least one of the following: At most 100 μg / mL, for example, 100 μg / mL to 300 μg / mL in the subject , for example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μ g / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / mL to 30 0 μg / mL, e.g., 170 μg / mL to 300 μg / mL, e.g., 180 μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / m L to 300 μg / mL, e.g., 210 μg / mL to 300 μg / mL, e.g., 220 μg / mL to 300μg / mL, for example 230μg / mL to 300μg / mL, for example 240 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 2 60μg / mL~300μg / mL, e.g. 270μg / mL~300μg / mL, e.g. For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μg / mL C in mL max,ss For use according to any one of embodiments 29 to 52, The drug trophinetide.

[0495] Embodiment 81. The administration of trophinetide to the subject results in at least one of the following: At most 100 μg / mL, for example, 100 μg / mL to 300 μg / mL in the subject , for example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, for example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μ g / mL, for example, 150 μg / mL to 300 μg / mL, for example, 160 μg / mL to 30 0 μg / mL, e.g., 170 μg / mL to 300 μg / mL, e.g., 180 μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / m L to 300 μg / mL, e.g., 210 μg / mL to 300 μg / mL, e.g., 220 μg / mL to 300μg / mL, for example 230μg / mL to 300μg / mL, for example 240 μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 2 60μg / mL~300μg / mL, e.g. 270μg / mL~300μg / mL, e.g. For example, 280 μg / mL to 300 μg / mL, or for example, 290 μg / mL to 300 μg / mL C in mL max,ss The use according to any one of embodiments 55 to 78, resulting in

[0496] The following embodiments are also provided:

[0497] Embodiment 1. Method of treating Rett syndrome in a subject in need thereof 1. A method for treating a rheumatoid arthritis, comprising administering to said subject a therapeutically effective amount of trophinetide; (i) A total daily dose of about 1 g to about 4 g of trophinetide is administered within the first 7±1 days of treatment period A. administered to the subject over a period of three days; (ii) A total daily dose of about 4 g to about 6 g of trophinetide is administered during the next 14 days of treatment period B. administered to the subject for a period of ±3 days; (iii) A total daily dose of about 6 g to about 8 g of trophinetide is administered in the next 2 days of treatment period C. administered to said subject for 8±3 days; and (iv) a total daily dose of about 8 g to about 10 g of trophinetide is administered after completion of treatment period C administered to the subject at The object is (a) is under 4 years of age at the time Treatment Period A begins; and / or (b) The method has a body weight of about 9 kg to about 12 kg at the start of the treatment period A. Law.

[0498] Embodiment 2. A total daily dose of about 1 g of trophinetide is administered daily for 7±3 days of treatment period A. 2. The method of embodiment 1, wherein the subject is administered a period of time.

[0499] Embodiment 3. A total daily dose of about 2 g of trophinetide is administered daily for 7±3 days of treatment period A. 2. The method of embodiment 1, wherein the subject is administered a period of time.

[0500] Embodiment 4. A total daily dose of about 3 g of the trophinetide is administered daily for 7±3 days of treatment period A. 2. The method of embodiment 1, wherein the subject is administered a period of time.

[0501] Embodiment 5. A total daily dose of about 4 g of trophinetide is administered daily for 7±3 days of treatment period A. 2. The method of embodiment 1, wherein the subject is administered a period of time.

[0502] Embodiment 6. The total daily dose of about 4 g of trophinetide is 14±3 mg / day during treatment period B. The method of any one of embodiments 1 to 5, wherein the subject is administered for days.

[0503] Embodiment 7. The total daily dose of about 5 g of trophinetide is 14±3 mg / day during treatment period B. The method of any one of embodiments 1 to 5, wherein the subject is administered for days.

[0504] Embodiment 8. The total daily dose of about 6 g of trophinetide is 14±3 mg / day during treatment period B. The method of any one of embodiments 1 to 5, wherein the subject is administered for days.

[0505] Embodiment 9. The total daily dose of about 6 g of trophinetide is 28±3 mg / day during treatment period C. The method of any one of embodiments 1 to 8, wherein the subject is administered for days.

[0506] Embodiment 10. About 7 g of the trophinetide is administered over 28±3 days of the treatment period C. The method of any one of embodiments 1 to 8, wherein the subject is administered

[0507] Embodiment 11. The total daily dose of about 8 g of trophinetide is 28 ± 10 mg / day during treatment period C. 9. The method of any one of embodiments 1-8, wherein the compound is administered to the subject for three days.

[0508] Embodiment 12. A total daily dose of about 8 g of trophinetide is administered after completion of treatment period C. 12. The method of any one of embodiments 1 to 11, wherein the subject is administered

[0509] Embodiment 13. A total daily dose of about 9 g of the trophinetide is administered after completion of treatment period C. 12. The method of any one of embodiments 1 to 11, wherein the subject is administered

[0510] Embodiment 14. A total daily dose of about 10 g of the trophinetide is administered by the end of treatment period C. The method of any one of embodiments 1 to 11, wherein the method is subsequently administered to the subject.

[0511] Embodiment 15. The subject does not experience any treatment-emergent adverse events, as described in any of embodiments 1 to 1. 4. The method according to any one of claims 1 to 4.

[0512] Embodiment 16. The trophinetide is administered to the subject in a single dose per day. 16. The method according to any one of embodiments 1 to 15.

[0513] Embodiment 17. The trophinetide is administered multiple times per day, totaling the daily dose. 16. The method of any one of embodiments 1-15, wherein the subject is administered a dose of

[0514] Embodiment 18. The trophinetide is administered twice daily, totaling the daily dose. 18. The method of embodiment 17, wherein the subject is administered a dose of

[0515] Embodiment 19. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. 19. The method of any one of embodiments 1-18, wherein the compound is administered as a pharmaceutical composition comprising the compound.

[0516] Embodiment 20. The method of embodiment 19, wherein the pharmaceutically acceptable carrier comprises water. .

[0517] Embodiment 21. The method of embodiment 20, wherein the pharmaceutical composition is a solution.

[0518] Embodiment 22. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. 22. The method of embodiment 21, wherein the saturation is 0.05 mg / mL.

[0519] Embodiment 23. The concentration of trophinetide is about 0.2 g / mL in the solution. 23. The method of embodiment 22.

[0520] Embodiment 24. The trophinetide is administered orally to the subject. 10. The method according to claim 9, wherein

[0521] Embodiment 25. The trophinetide is administered to the subject by gastrostomy (G) tube. 24. The method according to any one of embodiments 1 to 23, wherein

[0522] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the subject is a human. Law.

[0523] Embodiment 27. The method of embodiment 26, wherein the subject is a female.

[0524] Embodiment 28. Any one of embodiments 1 to 27, wherein the subject has an MECP2 mutation. The method described in the first paragraph.

[0525] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the Rett syndrome is atypical Rett syndrome. The method according to any one of the preceding claims.

[0526] Embodiment 30. The Rett syndrome is classic / typical Rett syndrome. 29. The method according to any one of 1 to 28.

[0527] Embodiment 31. A method for treating Rett syndrome in a subject, comprising administering to a subject a therapeutically effective amount of trophine. It is a (i) A total daily dose of about 1 g to about 4 g of trophinetide is administered within the first 7±1 days of treatment period A. administered to the subject over a period of three days; (ii) A total daily dose of about 4 g to about 6 g of trophinetide is administered during the next 14 days of treatment period B. administered to the subject for a period of ±3 days; (iii) A total daily dose of about 6 g to about 8 g of trophinetide is administered in the next 2 days of treatment period C. administered to said subject for 8±3 days; and (iv) a total daily dose of about 8 g to about 10 g of trophinetide is administered after completion of treatment period C administered to the subject at The object is (a) is under 4 years of age at the time Treatment Period A begins; and / or (b) The trochanter having a body weight of about 9 kg to about 12 kg at the start of the treatment period A. Finetide.

[0528] Embodiment 32. The total daily dose of about 1 g of trophinetide is 7±3 mg / day during treatment period A. 32. The method of claim 31, wherein the trophinetide is administered to the subject for a period of days. Do.

[0529] Embodiment 33. The total daily dose of about 2 g of trophinetide is 7±3 mg / day during treatment period A. 32. The method of claim 31, wherein the trophinetide is administered to the subject for a period of days. Do.

[0530] Embodiment 34. The total daily dose of about 3 g of trophinetide is 7±3 mg / day during treatment period A. 32. The method of claim 31, wherein the trophinetide is administered to the subject for a period of days. Do.

[0531] Embodiment 35. The total daily dose of about 4 g of trophinetide is 7±3 mg / day during treatment period A. 32. The method of claim 31, wherein the trophinetide is administered to the subject for a period of days. Do.

[0532] Embodiment 36. The total daily dose of about 4 g of trophinetide is 14 ± 10 mg / day during treatment period B. The use of any one of embodiments 31 to 35, wherein the use is administered to the subject over a period of 3 days. Trofinetide for use.

[0533] Embodiment 37. The total daily dose of about 5 g of trophinetide is 14±10 mg / day during treatment period B. The use of any one of embodiments 31 to 35, wherein the use is administered to the subject over a period of 3 days. Trofinetide for use.

[0534] Embodiment 38. The total daily dose of about 6 g of trophinetide is 14 ± 10 mg / day during treatment period B. The use according to any one of embodiments 31 to 35, wherein the use is administered to the subject over a period of 3 days. Trofinetide for use.

[0535] Embodiment 39. The total daily dose of about 6 g of trophinetide is 28 ± 10 mg / day during treatment period C. The use of any one of embodiments 31 to 38, wherein the use is administered to the subject over a period of 3 days. Trofinetide for use.

[0536] Embodiment 40. About 7 g of the trophinetide is administered over 28±3 days of the treatment period C. The method for use according to any one of embodiments 31 to 38, wherein the method is administered to the subject in the form of Rofinetide.

[0537] Embodiment 41. The total daily dose of about 8 g of trophinetide is 28 ± 10 mg / day during treatment period C. The use of any one of embodiments 31 to 38, wherein the use is administered to the subject over a period of 3 days. Trofinetide for use.

[0538] Embodiment 42. A total daily dose of about 8 g of trophinetide is administered after completion of treatment period C. 42. The method of claim 31, wherein the thrombin time is 10 minutes or more and the thrombin time is 10 minutes or more. Finetide.

[0539] Embodiment 43. A total daily dose of about 9 g of the trophinetide is administered after completion of treatment period C. 42. The method of claim 31, wherein the thrombin time is 10 minutes or more and the thrombin time is 10 minutes or more. Finetide.

[0540] Embodiment 44. A total daily dose of about 10 g of trophinetide is administered by the end of treatment period C. A method for use according to any one of embodiments 31 to 41, which is subsequently administered to said subject. Rofinetide.

[0541] Embodiment 45. The subject does not experience any treatment-emergent adverse events. 44. Trofinetide for use according to any one of claims 1 to 44.

[0542] Embodiment 46. The trophinetide is administered to the subject in a single dose per day. Trofinetide for use according to any one of embodiments 31 to 45.

[0543] Embodiment 47. The trophinetide is administered multiple times per day, totaling the daily dose. For the use according to any one of embodiments 31 to 45, wherein the subject is administered at a dose of Trofinetide.

[0544] Embodiment 48. The trophinetide is administered twice daily, totaling the daily dose. 48. Trofinetide for use according to embodiment 47, wherein the compound is administered to the subject in a dose of

[0545] Embodiment 49. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 31 to 48, wherein the use is administered as a pharmaceutical composition comprising the body Trofinetide for.

[0546] Embodiment 50. The use of embodiment 49, wherein the pharmaceutically acceptable carrier comprises water. Trofinetide for.

[0547] Embodiment 51. The method for use according to embodiment 50, wherein the pharmaceutical composition is a solution. Rofinetide.

[0548] Embodiment 52. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. Trofinetide for use according to embodiment 51, wherein the troponin level is 100 mg / mL.

[0549] Embodiment 53. The concentration of trophinetide is about 0.2 g / mL in the solution. , Trofinetide for use according to embodiment 52.

[0550] Embodiment 54. The trophinetide is administered orally to the subject. 3. Trofinetide for use according to any one of claims 1 to 3.

[0551] Embodiment 55. The trophinetide is administered to the subject by gastrostomy (G) tube. Trofinetide for use according to any one of embodiments 31 to 53.

[0552] Embodiment 56. The method of any one of embodiments 31 to 55, wherein the subject is a human. Trofinetide for use.

[0553] Embodiment 57. A method for the use of embodiment 56, wherein the subject is a woman. Nechid.

[0554] Embodiment 58. Any of Embodiments 31 to 57, wherein the subject has an MECP2 mutation. Trofinetide for the use described in 1.

[0555] Embodiment 59. The Rett syndrome is atypical Rett syndrome. Trofinetide for use according to any one of the preceding items.

[0556] Embodiment 60. The Rett syndrome is classic / typical Rett syndrome. Trofinetide for use according to any one of items 31 to 58.

[0557] Embodiment 61. A method for producing a medicament for treating Rett syndrome in a subject. Use of finetide, (i) A total daily dose of about 1 g to about 4 g of trophinetide is administered within the first 7±1 days of treatment period A. administered to the subject over a period of three days; (ii) A total daily dose of about 4 g to about 6 g of trophinetide is administered during the next 14 days of treatment period B. administered to the subject for a period of ±3 days; (iii) A total daily dose of about 6 g to about 8 g of trophinetide is administered in the next 2 days of treatment period C. administered to said subject for 8±3 days; and (iv) A total daily dose of about 8 g to about 10 g of trophinetide is administered at the end of the treatment period C. and administering the same to the subject after completion of the procedure. The object is (a) is under 4 years of age at the time Treatment Period A begins; and / or (b) The patient has a body weight of about 9 kg to about 12 kg at the start of the treatment period A. .

[0558] Embodiment 62. The total daily dose of about 1 g of trophinetide is 7±3 mg / day during treatment period A. The use of embodiment 61, wherein the compound is administered to the subject for days.

[0559] Embodiment 63. The total daily dose of about 2 g of trophinetide is 7±3 mg / day during treatment period A. The use of embodiment 61, wherein the compound is administered to the subject for days.

[0560] Embodiment 64. The total daily dose of about 3 g of trophinetide is 7±3 mg / day during treatment period A. The use of embodiment 61, wherein the compound is administered to the subject for days.

[0561] Embodiment 65. The total daily dose of about 4 g of trophinetide is 7±3 mg / day during treatment period A. The use of embodiment 61, wherein the compound is administered to the subject for days.

[0562] Embodiment 66. The total daily dose of about 4 g of trophinetide is 14 ± 10 mg / day during treatment period B. The use according to any one of embodiments 61 to 65, wherein the use is administered to the subject over a period of 3 days. For.

[0563] Embodiment 67. The total daily dose of about 5 g of trophinetide is 14 ± 10 mg / day during treatment period B. The use according to any one of embodiments 61 to 65, wherein the use is administered to the subject over a period of 3 days. For.

[0564] Embodiment 68. The total daily dose of about 6 g of trophinetide is 14 ± 10 mg / day during treatment period B. The use according to any one of embodiments 61 to 65, wherein the use is administered to the subject over a period of 3 days. For.

[0565] Embodiment 69. The total daily dose of about 6 g of trophinetide is 28 ± 10 mg / day during treatment period C. The use according to any one of embodiments 61 to 68, wherein the use is administered to the subject over a period of 3 days. For.

[0566] Embodiment 70. About 7 g of the trophinetide is administered over 28±3 days of the treatment period C. The use according to any one of embodiments 61 to 68, wherein the compound is administered to the subject in the form of a compound selected from the group consisting of acetaminophen, benzodiazepine ...

[0567] Embodiment 71. The total daily dose of about 8 g of trophinetide is 28 ± 10 mg / day during treatment period C. The use according to any one of embodiments 61 to 68, wherein the use is administered to the subject over a period of 3 days. For.

[0568] Embodiment 72. A total daily dose of about 8 g of the trophinetide is administered after completion of treatment period C. The use according to any one of embodiments 61 to 71, wherein the subject is administered

[0569] Embodiment 73. A total daily dose of about 9 g of the trophinetide is administered after completion of treatment period C. The use according to any one of embodiments 61 to 71, wherein the subject is administered

[0570] Embodiment 74. A total daily dose of about 10 g of trophinetide is administered by the end of treatment period C. The use according to any one of embodiments 61 to 71, wherein the compound is subsequently administered to the subject.

[0571] Embodiment 75. The subject does not experience any treatment-emergent adverse events. 74. The use according to any one of claims 1 to 74.

[0572] Embodiment 76. The trophinetide is administered to the subject in a single dose per day. Use according to any one of embodiments 61 to 75.

[0573] Embodiment 77. The trophinetide is administered multiple times per day, totaling the daily dose. The use according to any one of embodiments 61 to 75, wherein the subject is administered a dose of

[0574] Embodiment 78. The trophinetide is administered twice daily, totaling the daily dose. The use of embodiment 77, wherein the subject is administered a dose of

[0575] Embodiment 79. The trophinetide is a compound comprising the trophinetide and a pharmaceutically acceptable carrier. The use according to any one of embodiments 61 to 78, wherein the use is administered as a pharmaceutical composition comprising the body .

[0576] Embodiment 80. The use of embodiment 79, wherein the pharmaceutically acceptable carrier comprises water. .

[0577] Embodiment 81. The use of embodiment 80, wherein the pharmaceutical composition is a solution.

[0578] Embodiment 82. The concentration of trophinetide in the solution is about 0.05 g / mL to 0.7 g / mL. The use according to embodiment 81, wherein the saturation is 0.05 mg / mL.

[0579] Embodiment 83. The concentration of trophinetide is about 0.2 g / mL in the solution. , the use according to embodiment 52.

[0580] Embodiment 84. The trophinetide is administered orally to the subject. 3. The use according to any one of the preceding items.

[0581] Embodiment 85. The trophinetide is administered to the subject by gastrostomy (G) tube. The use according to any one of embodiments 61 to 83,

[0582] Embodiment 86. The method of any one of embodiments 61 to 85, wherein the subject is a human. use.

[0583] Embodiment 87. The use of embodiment 86, wherein the subject is a woman.

[0584] Embodiment 88. Any of embodiments 61 to 87, wherein the subject has an MECP2 mutation. Use as described in one.

[0585] Embodiment 89. The Rett syndrome is atypical Rett syndrome. 1. The use according to any one of the preceding claims.

[0586] Embodiment 90. The Rett syndrome is classic / typical Rett syndrome. 61 to 88. The use according to any one of the preceding items.

[0587] Embodiment 91. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 755 μg·h / mL to about 1 AUC of 300 μg·h / mL 0-12,ss Any of embodiments 1 to 30, The method described in one.

[0588] Embodiment 92. The method of administering trophinetide to the subject after completion of the treatment period C. AUC at a total daily dose of approximately 800 μg·h / mL to approximately 1000 μg·h / mL 0-12, ss 92. The method of embodiment 91, wherein

[0589] Embodiment 93. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg· h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, a little at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 8 80 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1 020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μ g·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL, a little at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 124 0 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 AUC in μg·h / mL 0-12,ss In any one of embodiments 1 to 30, The method described.

[0590] Embodiment 94. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 755 μg·h / mL to about 1 AUC of 300 μg·h / mL 0-12,ss Any of embodiments 31 to 60 1. Trofinetide for use as described in any one of the preceding paragraphs.

[0591] Embodiment 95. The method of administering trophinetide to the subject after completion of the treatment period C. AUC at a total daily dose of approximately 800 μg·h / mL to approximately 1000 μg·h / mL 0-12, ss Trofinetide for use according to embodiment 94, resulting in

[0592] Embodiment 96. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg· h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, a little at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 8 80 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1 020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μ g·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL, a little at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 124 0 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 AUC in μg·h / mL 0-12,ss Any one of embodiments 31 to 60, Trofinetide for the use described in 1.

[0593] Embodiment 97. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 755 μg·h / mL to about 1 AUC of 300 μg·h / mL 0-12,ss Any of embodiments 61 to 90 or the use described in one of the preceding paragraphs.

[0594] Embodiment 98. The method of administering trophinetide to the subject after completion of the treatment period C. AUC at a total daily dose of approximately 800 μg·h / mL to approximately 1000 μg·h / mL 0-12, ss Trofinetide for use according to embodiment 97, resulting in

[0595] Embodiment 99. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 755 μg·h / mL, at least about 780 μg·h / mL, at least about 790 μg· h / mL, at least about 800 μg h / mL, at least about 820 μg h / mL, a little at least about 840 μg·h / mL, at least about 860 μg·h / mL, at least about 8 80 μg·h / mL, at least about 900 μg·h / mL, at least about 920 μg·h / mL, at least about 940 μg·h / mL, at least about 960 μg·h / mL, at least about 980 μg·h / mL, at least about 1000 μg·h / mL, at least about 1 020 μg·h / mL, at least about 1040 μg·h / mL, at least about 1060 μ g·h / mL, at least about 1080 μg·h / mL, at least about 1100 μg·h / mL, at least about 1120 μg h / mL, at least about 1140 μg h / mL, a little at least about 1160 μg·h / mL, at least about 1180 μg·h / mL, at least about 1200 μg·h / mL, at least about 1220 μg·h / mL, at least about 124 0 μg·h / mL, at least about 1260 μg·h / mL, or at least about 1280 AUC in μg·h / mL 0-12,ss Any one of embodiments 61 to 90, Trofinetide for the use described in 1.

[0596] Embodiment 100. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 100 μg / day in the subject. g / mL to approximately 300 μg / mL C max,ss Any of embodiments 1 to 30 or one of the methods described above.

[0597] Embodiment 101. The trophinetide administered to the subject after completion of the treatment period C. The total daily dose of the compound is about 100 μg / mL to about 200 μg / mL in the subject. max ,ss 101. The method of embodiment 100, wherein

[0598] Embodiment 102. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, At least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL g / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL C in mL max,ss 31. The method of any one of embodiments 1 to 30, wherein

[0599] Embodiment 103. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 100 μg / day in the subject. g / mL to approximately 300 μg / mL C max,ss Any of embodiments 31 to 60 Trofinetide for use as described in any one of the preceding claims.

[0600] Embodiment 104. The trophinetide administered to the subject after completion of the treatment period C. The total daily dose of the compound is about 100 μg / mL to about 200 μg / mL in the subject. max ,ss Trofinetide for use according to embodiment 103, resulting in

[0601] Embodiment 105. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, At least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL g / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL C in mL max,ss For the use according to any one of embodiments 31 to 60, The drug trophinetide.

[0602] Embodiment 106. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is about 100 μg / day in the subject. g / mL to approximately 300 μg / mL C max,ss Any of embodiments 61 to 90 Use as described in any one of the following:

[0603] Embodiment 107. The trophinetide administered to the subject after completion of the treatment period C. The total daily dose of the compound is about 100 μg / mL to about 200 μg / mL in the subject. max ,ss The use according to embodiment 106, resulting in

[0604] Embodiment 108. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least about 100 μg / mL, at least about 110 μg / mL, at least about 120 μg / mL, At least about 130 μg / mL, at least about 140 μg / mL, at least about 150 μg / mL g / mL, at least about 160 μg / mL, at least about 170 μg / mL, at least about 180 μg / mL, at least about 190 μg / mL, or at least about 200 μg / mL C in mL max,ss The use according to any one of embodiments 61 to 90, resulting in

[0605] Embodiment 109. The administration of trophinetide achieves at least 75 days of gestational age in the subject. 5 μg·h / mL, e.g., 755 μg·h / mL to 1300 μg·h / mL, e.g., 78 0μg·h / mL~1300μg·h / mL, e.g., 790μg·h / mL~1300μ g·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μ g·h / mL to 1300μg·h / mL, e.g., 840μg·h / mL to 1300μg· h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg· h / mL~1300μg·h / mL, e.g. 900μg·h / mL~1300μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / mL to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL , e.g., 980 μg·h / mL to 1300 μg·h / mL, e.g., 1000 μg·h / m L to 1300 μg·h / mL, e.g., 1020 μg·h / mL to 1300 μg·h / mL , e.g., 1040μg·h / mL to 1300μg·h / mL, e.g., 1060μg·h / mL to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / m L, e.g., 1100 μg·h / mL to 1300 μg·h / mL, e.g., 1120 μg·h / mL~1300μg·h / mL, e.g., 1140μg·h / mL~1300μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg· h / mL to 1300μg h / mL, e.g., 1200μg h / mL to 1300μg h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg ·h / mL~1300μg·h / mL, e.g., 1260μg·h / mL~1300μg· h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0- 12,ss 94. The method of embodiment 93, wherein

[0606] Embodiment 110. The administration of trophinetide is 755 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 109, Use as described.

[0607] Embodiment 111. The administration of trophinetide is 780 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 110, Use as described.

[0608] Embodiment 112. The administration of trophinetide is 790 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 111, Use as described.

[0609] Embodiment 113. The administration of trophinetide achieves at least 75 days of gestational age in the subject. 5 μg·h / mL, e.g., 755 μg·h / mL to 1300 μg·h / mL, e.g., 78 0μg·h / mL~1300μg·h / mL, e.g., 790μg·h / mL~1300μ g·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μ g·h / mL to 1300μg·h / mL, e.g., 840μg·h / mL to 1300μg· h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg· h / mL~1300μg·h / mL, e.g. 900μg·h / mL~1300μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / mL to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL , e.g., 980 μg·h / mL to 1300 μg·h / mL, e.g., 1000 μg·h / m L to 1300 μg·h / mL, e.g., 1020 μg·h / mL to 1300 μg·h / mL , e.g., 1040μg·h / mL to 1300μg·h / mL, e.g., 1060μg·h / mL to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / m L, e.g., 1100 μg·h / mL to 1300 μg·h / mL, e.g., 1120 μg·h / mL~1300μg·h / mL, e.g., 1140μg·h / mL~1300μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg· h / mL to 1300μg h / mL, e.g., 1200μg h / mL to 1300μg h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg ·h / mL~1300μg·h / mL, e.g., 1260μg·h / mL~1300μg· h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0- 12,ss Trofinetide for use according to embodiment 96, resulting in

[0610] Embodiment 114. The administration of trophinetide is 755 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 113, Trofinetide for the described uses.

[0611] Embodiment 115. The administration of trophinetide is 780 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 114, Trofinetide for the described uses.

[0612] Embodiment 116. The administration of trophinetide is 790 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 115, Trofinetide for the described uses.

[0613] Embodiment 117. The administration of trophinetide provides at least 75 days of treatment in the subject. 5 μg·h / mL, e.g., 755 μg·h / mL to 1300 μg·h / mL, e.g., 78 0μg·h / mL~1300μg·h / mL, e.g., 790μg·h / mL~1300μ g·h / mL, e.g., 800μg·h / mL to 1300μg·h / mL, e.g., 820μ g·h / mL to 1300μg·h / mL, e.g., 840μg·h / mL to 1300μg· h / mL, e.g., 860 μg·h / mL to 1300 μg·h / mL, e.g., 880 μg· h / mL~1300μg·h / mL, e.g. 900μg·h / mL~1300μg·h / mL, e.g., 920 μg·h / mL to 1300 μg·h / mL, e.g., 940 μg·h / mL to 1300 μg·h / mL, e.g., 960 μg·h / mL to 1300 μg·h / mL , e.g., 980 μg·h / mL to 1300 μg·h / mL, e.g., 1000 μg·h / m L to 1300 μg·h / mL, e.g., 1020 μg·h / mL to 1300 μg·h / mL , e.g., 1040μg·h / mL to 1300μg·h / mL, e.g., 1060μg·h / mL to 1300 μg·h / mL, e.g., 1080 μg·h / mL to 1300 μg·h / m L, e.g., 1100 μg·h / mL to 1300 μg·h / mL, e.g., 1120 μg·h / mL~1300μg·h / mL, e.g., 1140μg·h / mL~1300μg·h / mL, e.g., 1160 μg·h / mL to 1300 μg·h / mL, e.g., 1180 μg· h / mL to 1300μg h / mL, e.g., 1200μg h / mL to 1300μg h / mL, e.g., 1220 μg·h / mL to 1300 μg·h / mL, e.g., 1240 μg ·h / mL~1300μg·h / mL, e.g., 1260μg·h / mL~1300μg· h / mL, or an AUC of, for example, 1280 μg·h / mL to 1300 μg·h / mL 0- 12,ss The use according to embodiment 99, resulting in

[0614] Embodiment 118. The administration of trophinetide is 755 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 117, Use as described.

[0615] Embodiment 119. The administration of trophinetide is 780 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 118, Use as described.

[0616] Embodiment 120. The administration of trophinetide is 790 μg h AUC of 1300 μg h / mL to 1300 μg h / mL 0-12,ss In embodiment 119, Use as described.

[0617] Embodiment 121. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject, e.g. For example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, For example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μg / m L, e.g., 150 μg / mL to 300 μg / mL, e.g., 160 μg / mL to 300 μg / mL, for example, 170μg / mL to 300μg / mL, for example, 180μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / mL to 3 00μg / mL, for example 210μg / mL to 300μg / mL, for example 220μg / mL ~300μg / mL, e.g., 230μg / mL~300μg / mL, e.g., 240μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 260 μ g / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL, for example, 28 0 μg / mL to 300 μg / mL, or, for example, 290 μg / mL to 300 μg / mL C max,ss 103. The method of embodiment 102, wherein

[0618] Embodiment 122. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject, e.g. For example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, For example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μg / m L, e.g., 150 μg / mL to 300 μg / mL, e.g., 160 μg / mL to 300 μg / mL, for example, 170μg / mL to 300μg / mL, for example, 180μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / mL to 3 00μg / mL, for example 210μg / mL to 300μg / mL, for example 220μg / mL ~300μg / mL, e.g., 230μg / mL~300μg / mL, e.g., 240μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 260 μ g / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL, for example, 28 0 μg / mL to 300 μg / mL, or, for example, 290 μg / mL to 300 μg / mL C max,ss Trofinetide for use according to embodiment 105, resulting in

[0619] Embodiment 123. After completion of the treatment period A, the treatment period B, or the treatment period C, The total daily dose of trophinetide administered to the subject is at least 100 μg / mL, for example 100 μg / mL to 300 μg / mL in the subject, e.g. For example, 110 μg / mL to 300 μg / mL, for example, 120 μg / mL to 300 μg / mL, For example, 130 μg / mL to 300 μg / mL, for example, 140 μg / mL to 300 μg / m L, e.g., 150 μg / mL to 300 μg / mL, e.g., 160 μg / mL to 300 μg / mL, for example, 170μg / mL to 300μg / mL, for example, 180μg / mL to 300 μg / mL, for example, 190 μg / mL to 300 μg / mL, for example, 200 μg / mL to 3 00μg / mL, for example 210μg / mL to 300μg / mL, for example 220μg / mL ~300μg / mL, e.g., 230μg / mL~300μg / mL, e.g., 240μg / mL to 300 μg / mL, for example, 250 μg / mL to 300 μg / mL, for example, 260 μ g / mL to 300 μg / mL, for example, 270 μg / mL to 300 μg / mL, for example, 28 0 μg / mL to 300 μg / mL, or, for example, 290 μg / mL to 300 μg / mL C max,ss The use according to embodiment 108, resulting in

[0620] Subjects with Rett syndrome (unless otherwise indicated, this term includes Rett-like syndrome and Rett syndrome) (used in the broadest sense, including variants in BBH syndrome) are involved in the expression of MECP2, ACTL 6B, AGAP6, ANKRD31, ARHGEF10L, ATP8B1, BTBD9, CACNA1I, CDKL5, CHD4, CHRNA5, CTNNB1, EEF1A2, EIF2B2, EIF4G1, FAM151A, FAT3, FOXG1, GABBR2, GABRD, GRAMD1A, GRIN1, GRIN2B, HAP1, HCN1, HDA C1, HTT, IMPDH2, IQGAP3, IQSEC2, IZUMO4, JMJD1 C, KCNA2, KCNJ10, KCNQ2, KIF1A, LAMB2, LRRC40, MEF2C, MGRN1, NCOR2, PDLIM7, PPT1, PWP2, RHOBT B2, SAFB2, SATB2, SCG2, SCN1A, SCN2A, SCN8A, SD HA, SEMA6B, SHANK3, SHROOM4, SLC2A1, SLC35A2, SLC39A13, SLC6A1, SMARCA1, SMC1A, SRRM3, STXB P1, SYNE2, SYNGAP1, TAF1B, TBLXR1, TCF4, TRRAP , VASH2, WDR45, XAB2, ZFX, ZNF238, ZNF620, and ZS They have been found to have mutations in any of a number of genes, including CAN12. , Ehrhart, F. et al., “Current Developments in the Genetics of Rett and Rett-Like Sy ndrome,”Curr Opin Psychiatry 31, no.2(Mar 2018):103-08,dx.doi.org / 10.1097 / YCO.000 0000000000389, Iwama,K.,et al.,”Genetic L andscape of Rett Syndrome-Like Phenotype s Revealed by Whole Exome Sequencing,”J Med Genet(Mar 6 2019):jmedgenet-2018-105 775,dx.doi.org / 10.1136 / jmedgenet-2018-10 5775, and Wang, J., et al., “Rett and Rett-Lik. e Syndrome:Expanding the Genetic Spectru m to Kif1a and Grin1 Gene,”Mol Genet Gen omic Med(Sep 11 2019):e968,dx.doi.org / 10 See .1002 / mgg3.968. Thus, in some embodiments, The mutants may contain mutations associated with Rett syndrome, e.g., in any of the genes listed above. In some embodiments, the subject has an MECP2 mutation. In embodiments, the subject has a nonsense mutation, a missense mutation, a C-terminal truncation, a deletion, an R168X mutation, or a mutation in the nucleotide sequence of interest. , R270X, R255X, T158M, R306C, and R106W In some embodiments, the subject has an ECP2 mutation. 255X, T158M, and R306C. In some embodiments, the subject is selected from R168X, R270X, R255X, and T158M. In some embodiments, the subject has a selected MECP2 mutation. 270X, and R255X. In some cases, the subject has an MECP2 mutation selected from R168X and R270X. In some embodiments, the subject has an R168X MECP2 mutation. In this study, the target genes were ACTL6B, AGAP6, ANKRD31, ARHGEF10L, and A TP8B1, BTBD9, CACNA1I, CDKL5, CHD4, CHRNA5, CT NNB1, EEF1A2, EIF2B2, EIF4G1, FAM151A, FAT3, F OXG1, GABBR2, GABRD, GRAMD1A, GRIN1, GRIN2B, H AP1, HCN1, HDAC1, HTT, IMPDH2, IQGAP3, IQSEC2, IZUMO4, JMJD1C, KCNA2, KCNJ10, KCNQ2, KIF1A, L AMB2, LRRC40, MEF2C, MGRN1, NCOR2, PDLIM7, PPT 1, PWP2, RHOBTB2, SAFB2, SATB2, SCG2, SCN1A, SC N2A, SCN8A, SDHA, SEMA6B, SHANK3, SHROOM4, SLC 2A1, SLC35A2, SLC39A13, SLC6A1, SMARCA1, SMC1 A, SRRM3, STXBP1, SYNE2, SYNGAP1, TAF1B, TBLXR 1, TCF4, TRRAP, VASH2, WDR45, XAB2, ZFX, ZNF238 , ZNF620, or ZSCAN12 mutations.

[0621] As used herein, the administration of trophinetide to a subject in need of treatment for Rett syndrome is "Subject in need thereof" in the context of a method of treating Rett syndrome, including administering The authors describe the following: classic / typical Rett syndrome, atypical Rett syndrome, and possible "possibly", "probably", "probably" e) or "probably" Rett syndrome, "possible" (possible), "possibly", "probably" "probable" or "probably" atypical Rett syndrome group, "Rett-like syndrome," one or more symptoms of Rett syndrome, mutations associated with Rett syndrome (e.g., any of the mutations discussed above, or nonsense mutations, C-terminal truncations, deletions , R168X, R270X, R255X, T158M, R306C, or R106W It has been observed in subjects with MECP2 mutations, which are the cause of death, and / or Rett syndrome. The subject has a mutation.

[0622] As used herein, the term "therapeutically effective amount" refers to a therapeutically effective amount in a subject in need thereof. resulting in improvement of one or more symptoms of Rett syndrome or slowing the progression of Rett syndrome Trofinetide is administered in an amount sufficient to prevent or cause regression of Rett syndrome. For example, a therapeutically effective amount is an amount that elicits a therapeutic response, e.g., reduces the severity of Rett syndrome in a subject. The progression of the disease is reduced by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about This refers to the amount of trophinetide that delays the onset of inflammatory bowel disease by 95%, or at least about 100% or more.

[0623] As used herein, the term "about" includes the stated numerical value plus or minus 10%. Therefore, "about 10" means 9 to 11.

[0624] In some embodiments, Rett syndrome is atypical or classic / typical Rett syndrome. In some embodiments, the Rett syndrome is classic / typical Rett syndrome. In some embodiments, Rett Syndrome is a "possible" " or "possibly" Rett syndrome. In some cases, Rett syndrome is classified as "possible" or "probable" In some embodiments, Rett syndrome is atypical Rett syndrome. The phenomenon is called "probable" or "probable" In some embodiments, Rett syndrome is a "likely" disorder. "probable" or "probably" atypical Rett syndrome It is a group.

[0625] In some embodiments, a subject with classic / typical Rett syndrome has one of the following clinical features: All of the parameters are present: partial or complete loss of learned intentional manual skills, Partial or complete loss of acquired speech, gait abnormalities (e.g., gait disturbance (apraxia) or absence of ambulatory ability), and stereotypic hand movements (e.g., hand wringing / grasping, clapping / grasping) Involuntary clapping, mouthing, and hand washing / rubbing ). Acquired language loss is based on the most acquired speech skills and may be a separate or more It is not strictly based on the acquisition of higher language skills. Individuals who have acquired the ability to speak and then subsequently lose this ability will experience a loss of the language they have acquired. is deemed to have

[0626] In some embodiments, the subject with classic / typical Rett syndrome optionally , indicating one or more supporting criteria selected from the following: breathing disorder upon awakening, awakening bruxism, sleep pattern disorders, abnormal muscle tone, peripheral vasomotor disorders, spinal Curvature / kyphosis, growth retardation, small, cold hands and feet, inappropriate laughter and / or frequent, sharp shouting reduced pain response, and engaged eye communication (e.g., Pointing (eye pointing).

[0627] In some embodiments, the subject with classic / typical Rett syndrome is 6 months of age or older. During the supported by clinical evidence such as neurological or ophthalmological examination and MRI / CT scans have no impairments that cause markedly abnormal psychomotor development. In some embodiments, the injury may be a trauma (e.g., prenatal or postnatal), a neurometabolic disease, or is brain damage that occurs after a severe infection. Gross abnormalities include the loss of normal functions (head control habits) This means that the development of cognitive impairment (e.g., cognitive impairment, swallowing, and social smiling) is not met. During the first 6 months of life, mild generalized hypotonia or other previously reported subtle developmental changes were observed. It is common and does not constitute a severe abnormality in psychomotor development during the first 6 months of life.

[0628] In some embodiments, a subject with atypical Rett syndrome exhibits: 1) Partial or complete loss of acquired intentional manual skills, acquired speech skills Partial or complete loss of gait, abnormalities in walking (e.g., impaired walking (apraxia) or absence of the ability to walk) and stereotypic hand movements (e.g., hand squeezing / grasping, clapping / claps, mouth squeezing, etc.). 2) selected from the following: mouthing, and the involuntary act of washing / rubbing hands one or three clinical parameters, and 2) breathing problems upon awakening, bruxism upon awakening, disturbances in sleep patterns, Abnormal muscle tone, peripheral vasomotor disorders, scoliosis / kyphosis, growth retardation, small, cold hands and feet inappropriate laughter and / or loud, sharp cries, decreased pain response, and eagerness At least five selected from visual communication (e.g., pointing with eyes) Two supporting criteria.

[0629] If an individual has or has ever had any of the listed clinical features: It counts as a supporting criterion. Many of these characteristics are age-dependent and may be present at certain ages. Therefore, the diagnosis of atypical RTT is more common in older people than in younger people. It may be easier to

[0630] In some embodiments, the subject with atypical Rett syndrome undergoes a regression period and at least Young patients who have at least two clinical parameters but do not meet the requirements for at least five supporting criteria Individuals under 5 years of age (e.g., 18 months to 5 years of age) with a "likely atypical RTT" A diagnosis of idiopathic encephalopathy may be made. Individuals in this category should be reevaluated as they get older. , the diagnosis needs to be revised accordingly.

[0631] In some embodiments, the subject with Rett syndrome has an MECP2 mutation and The rhesus has not been lost (e.g., before any clear evidence of regression), but otherwise Clinical features suggestive of a syndrome, e.g., gait abnormalities (e.g., impaired gait (apraxia) or ability lack of coordination), and stereotypic hand movements (e.g., hand squeezing / grasping, clapping / smacking) involuntary actions such as biting, mouthing, and hand washing / rubbing, Breathing problems when awake, bruxism when awake, disturbed sleep patterns, abnormal muscles Tension, peripheral vasomotor disorders, scoliosis / kyphosis, growth retardation, small, cold hands and feet, inadequate Laughing and / or loud, sharp cries, decreased pain response, and eager eye contact Children under 3 years of age who have one or more of the following communication skills (e.g., pointing with their eyes) In such cases, Rett syndrome is a "possible" atypical Rett syndrome. Such subjects should be reassessed every 6 to 12 months for evidence of regression. be.

[0632] In some embodiments, subjects with Rett Syndrome experience a period of regression followed by recovery or It is in a stabilization period.

[0633] In some embodiments, the subject with Rett-like syndrome is atypical Rett syndrome or Any combination of the clinical features discussed above that does not fully meet the criteria for typical Rett syndrome Some clinical features of RTT, such as the combination of Two or three of the following: motor retardation, stereotypic hand movements, loss of hand use, and speech impairment; or Showing four. [Example]

[0634] Example 1: Pharmacokinetic analysis of trofinetide from a phase 2 study In a previous phase 2 trial of Rett syndrome (Glaze et al., 2019), Inetide demonstrated linear pharmacokinetics over the dose range tested in pediatric RTT patients. These pharmacokinetic results were previously obtained in healthy subjects and adolescent and adult RTT patients. From a drug metabolism perspective, no accumulation, metabolic inhibition, or induction was observed during treatment. In subjects treated with 50 mg / kg BID, the median C max is 17.7μ g / mL, and the median AUC( 0-12ss ) was 139.4 μg / mL·h. In subjects treated with 100 mg / kg BID, the median C max is 52.6 μg / mL Yes, median AUC( 0-12ss ) was 338.6 μg / mL·h. 200 mg In subjects treated with 100 mg / kg BID, the median C max The median was 82.2 μg / mL. Value AUC( 0-12ss ) was 505.1 μg / mL·h. period(T 1 / 2 The geometric mean of ) varied from 5.3 to 6.1 hours across the three dose groups. Ta.

[0635] Further analysis provided by the present disclosure is shown in Figure 1 (Adolescents and Adults vs. Healthy Volunteers) ) and Figure 2 (children and adolescents), there was no significant effect of body weight on clearance. 3 (adolescents and adults vs. healthy volunteers) and FIG. 4 (children and adolescents). These results indicate that acetaminophen had a significant effect on the volume of distribution in the central compartment. The drug was administered at a dose level of 200 mg / kg BID in children and adolescents. The exposure range was below the expected exposure range for this dose level.

[0636] Minimum target exposure levels of orally administered trofinetide at different body weights in the pediatric population To characterize the dose levels required to achieve We developed a new system.

[0637] Although lower than the expected exposure range, the 200 mg / kg BID dose was clinically significant. showed evidence of efficacy, and exploratory analyses suggested a positive PK / PD relationship. Systemic exposure and RSBQ Correlations were observed between changes in RTT-DSC, and CGI-I, with higher exposures (steady-state Improvements were observed at higher cumulative exposures and in the condition AUC (AUCss). , percentage change in RSBQ total score from treatment baseline and by visit (Fig. 5) and the correlation between trophinetide AUCss during the active administration period (Figure 6). Ta.

[0638] Therefore, higher levels of exposure at the 200 mg / kg BID dose level were effective. and therefore was considered to be an appropriate target exposure level. The 90-100% observed in pediatric / adolescent studies for a nominal dose of 200 mg / kg BID AUC quantiles of % exposure (AUC 0-12 ) and a maximum of 800 μg / mL h It was developed to provide a small target exposure in the 90-100% quantile of the study. As shown in Figure 7, the AUC (0-12) was included. Using weight bands, a greater proportion of subjects is expected to achieve target drug exposure .

[0639] As can be seen in Table 2 below, five dosing scenarios were investigated in the Phase 3 study. Each of these scenarios involves one or more subject weight ranges that collectively encompass 15–70 kg. The indicated BID dose levels were assigned to each weight range.

[0640] Using population pharmacokinetic and simulation-based techniques, weight combinations were compared with AU C 0-12 The planned exposure, represented by For each weight / dose level combination, subjects were given 5, 25, and 5 Exposures to the 0th, 75th, and 95th percentiles were planned. Under normal conditions, for example, after 42 days of administration, AUC 0-12 Measure.

[0641] Scenario 1 uses a single weight band to measure the weight of a patient weighing less than 45 kg, as shown in Figure 8. Partial target AUC 0-12 It was planned to stay within the range of

[0642] Scenario 4 uses four weight bands to examine the overlap with the target exposure range for each weight band, and The exposure multiplication calculation included a 50th percentile. In scenario 4, the highest planned 50% exposure in the four weight ranges was chosen. The centile exposure was 882 h·ng / mL, and this value was used for the multiple exposure calculation. [Table 3]

[0643] Dose simulation modeling revealed that 6000mg BID and 8000mg BID , 10,000 mg BID, or 12,000 mg BID fixed doses. The weight-dose range model at this level was established to provide exposure within the target range at body weights of 12 to 100 kg. It was shown that this resulted in many subjects receiving the treatment (Table 3). [Table 4]

[0644] Example 2: Clinical trial protocol using the dosing specified herein. Protocol Title Trofinetide for the Treatment of Girls and Women with Rett Syndrome A randomized, double-blind, placebo-controlled, parallel-group study

[0645] Name of the test drug: Trofinetide oral solution Rett syndrome is a devastating disorder for which there is still no treatment other than symptomatic treatment. There is a significant unmet medical need. In two trials of trophinetide, trophinetide was well tolerated. As mentioned above, the dose of 200 mg / kg BID was sufficient even in a relatively small study. A benefit was observed compared to placebo. Treatment with α-glucan has a statistically significant advantage over placebo in a well-respected trial The objective is to evaluate whether the

[0646] Therefore, this study confirms the efficacy of trofinetide administration found in two phase 2 studies. The study was designed to assess whether this effect is confirmed in a larger population of children, adolescents, and young adults. It is calculated.

[0647] This study was conducted in women only, and with confirmed mutations in the typical RTT and MECP2 genes. The effect of the registrants was examined only in subjects who had the RTT plateau. Subjects with atypical RTT, documented The exclusion of subjects without disease-causing MECP2 mutations and male subjects may result in a more homogeneous study. This allows for a research population and, hopefully, the trojan horses in this relatively small population sample. Reduced variability allowing for observation of differences between treatment with finetide and placebo This is based on research design considerations.

[0648] The upper limit of the accepted age range is 15 years, compared with 15 years in most recent phase 2 trials. The age limit was raised to 20. School districts in the United States generally provide services up to the age of 20 or 21. Because service availability beyond that age is inconsistent across the United States, The age range is mostly no more than 20 years old.

[0649] This study compares the efficacy and safety of a single trofinetide treatment arm with placebo treatment. Based on the results of previous trophinetide treatment trials, 200 mg / kg BI However, underweight subjects had a lower risk of developing HIV than heavier subjects. A trend towards predictive exposure was observed. The identification of body weight as a covariate was particularly relevant for blue When other groups with different years or demographic characteristics are considered, similar distribution characteristics are observed. This has been frequently observed with drugs (Jusko et al. 1982, Kers ting et al. 2012, Piana et al. 2014). A best practice approach to address this is to use dosing models that consider the effect of body weight on exposure. The development of a minimum target for oral trofinetide at different weights in the pediatric population. To characterize the dose levels required to achieve exposure levels, the 100 mg / kg bw ... A dose-level model was developed to simulate the dose-level effects. The ring is available for fixing 6g BID, 8g BID, 10g BID, or 12g BID. The model has a four-level weight-dosing band with doses targeted at body weights from 12 kg to 100 kg. It was shown to result in an optimal proportion of subjects with exposure within the range (Table 3 above).

[0650] This study was a multicenter, randomized, double-blind, randomized, randomized, placebo-controlled ... This study will be conducted as a placebo-controlled, parallel-group study. One active treatment group will be compared with a placebo group. 15 years, and 16-20 years) and baseline RSBQ severity (total score less than 35, and A minimum of 12 subjects will be required for each age group. Treatment allocation must be randomized. The sponsor, subjects, caregivers, and investigators must The study participants will be blinded to the intended outcome. The duration of participation for each study subject will be approximately 19 weeks. The facility will participate in this study.

[0651] The test has three periods: ●Screening period: up to 3 weeks Double-blind treatment period: 12 weeks Safety follow-up period: 30 days

[0652] The study completion date was the date when the final subject completed the protocol-defined final evaluations at all sites. Individual subjects completed the study on the protocol-defined final assessment date. "Protocol-defined final evaluation" includes a follow-up visit or contact Note that the slowest of the two is included.

[0653] Main purpose Oral trophinetide versus placebo treatment in girls and women with Rett syndrome Examine the effectiveness of treatment

[0654] Multi-primary endpoints Rett Syndrome Behavior Questionnaire (RSBQ) total score - from baseline to week 12 change Clinical Global Impression-Improvement (CGI-I) score at 12 weeks. Key secondary objective Oral trophies for communication skills in girls and women with Rett syndrome Examining the efficacy of netide versus placebo treatment

[0655] Key secondary endpoints Change from baseline to week 12: ●Communicative and Symbolic Behavior Scale Developmental Profile ation and Symbolic Behavior Scales Devel Competent Profile™ Infant-Toddler Checklist - Social Composites Core (CSBS-DP-IT Social)

[0656] Other secondary objectives Oral trophinetide versus prothrombin on overall quality of life in girls and women with Rett syndrome Examining the benefits of placebo treatment Oral trophinetide versus placebo in girls and women with Rett syndrome for: To investigate the effectiveness of treatment with: ○Hand functions Walking and other gross motor skills Ability to communicate choices and preferences Ability to communicate verbally Oral trophoblasts for comprehensive assessment of disease severity in girls and women with Rett syndrome To examine the efficacy of treatment with netide versus placebo Oral trofinetide for caregiver burden in girls and women with Rett syndrome Examine the benefits of treatment versus placebo Oral trofinetide versus placebo on the impact of disability on children's and families' daily lives Explore the benefits of treatment with

[0657] Other secondary endpoints Change from baseline to week 12: Impact of Childhood Neurological Disorders Scale (ICND) overall quality of life assessment Rett Syndrome Clinician-Assessed Hand Function (RTT-HF) Assessment of Ambulation and Gross Motor Skills (RTT-AMB) Assessment of Rett Syndrome Clinician's Ability to Communicate Choices (RTT-COMC) Rett Syndrome Clinician-Assisted Verbal Communication Assessment (RTT-VCOM) Clinical Global Impression-Severity (CGI-S) Rett Syndrome Caregiver Burden Inventory (RTT-CBI) total score (items 1-24) Impact of Childhood Neurological Disorders Scale (ICND) total score safety purpose Safety of oral trophinetide versus placebo treatment in girls and women with Rett syndrome To check safety and tolerability

[0658] Safety evaluation items Treatment-emergent adverse events (TEAEs) Serious adverse events (SAEs) Discontinuation due to adverse events Potentially clinically important changes in other safety assessments

[0659] Pharmacokinetic Objectives The pharmacokinetics (PK) of trophinetide was characterized in girls and women with Rett syndrome. Sexual evaluation - Safety and efficacy endpoints were used to assess the efficacy and safety of steroids in girls and women with Rett syndrome. Evaluate the pharmacokinetic / pharmacodynamic (PK / PD) relationships

[0660] Pharmacokinetic endpoints Whole blood concentrations of trophinetide and potential metabolites ● Trofinetide PK parameters using a population PK approach ● Appropriate PK / PD analysis PK / PD using analytical methods

[0661] Number of testing facilities Approximately 18 centers will participate in the study.

[0662] Planned number of targets 184 subjects are expected to be randomized (at least 12 subjects across three age ranges). (randomized at ages 5-10, 11-15, and 16-20 years), per treatment group A total of 92 subjects were included.

[0663] Test article, dose, and administration Subjects will receive oral trophinetide or placebo for up to 12 weeks. Doses are based on subject weight at baseline as outlined below. (Doses administered via a gastrojejunostomy (GJ) tube may be administered via a GJ tube. (It must be administered via a syringe.) [Table 5]

[0664] Test Design This was a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The study compared one active treatment arm receiving weight-range doses of trofinetide with a placebo group The subjects were age groups (5-10 years old, 11-15 years old, and 16-20 years old) and baseline Stratified according to RSBQ severity (total score <35 and total score ≥35). The sponsor, subjects, caregivers, and investigators will be blinded to treatment assignment. can be.

[0665] The test has three periods: ●Screening period: up to 3 weeks Double-blind treatment period: 12 weeks Safety follow-up period: 30 days

[0666] Screening period (maximum 3 weeks) During the screening period, subjects will be assessed for eligibility. However, only subjects who do not meet the exclusion criteria are eligible for the study. Subjects must not discontinue prohibited medication for the purpose of enrolling in this study. should be discontinued only if deemed clinically appropriate and in consultation with the treating physician. Subjects are evaluated for a diagnosis of Rett syndrome. Additionally, subjects with evidence of MECP2 mutations are evaluated. If records are insufficient, genetic typing should be considered as part of the study. Caregivers will begin keeping a semi-structured caregiver diary during the screening period.

[0667] Double-blind treatment period (12 weeks) The baseline visit (Visit 2) is the time when screening procedures are completed and subjects are deemed eligible for the study. At Visit 2, if eligibility is confirmed, subjects will , versus trofinetide oral solution or a matching placebo Randomization will be 1:1. Dose will be based on body weight as outlined in Table 4. The dose will be determined after all baseline assessments are completed or if the study investigator determines otherwise on that day. If it is determined that this is too late, the vaccine will be administered at the study site the following day. An ECG should be performed 2-3 hours after the first dose and completion of the ECG is considered day 1. PK samples will be collected at the end of the study. If QTcF duration is ≥ 500 ms after randomization or An increase of 60 ms or more was observed compared to the mean QTcF interval at baseline (before administration). If this occurs, the study drug should be discontinued.

[0668] The drug is administered twice a day, once in the morning and once in the evening. In addition to the study medication dispensed at the site at the baseline visit, Ship study medication directly to subjects or visiting nurses. Study medication shipping, returns, and accountability are , in accordance with a drug distribution plan. Each facility also has a drug distribution plan for subjects. The home delivery confirmation will be made by a visiting nurse at the home. , and return to clinic for evaluation at week 12 / early termination (ET).

[0669] Safety follow-up period (30 days) Subjects who do not continue in the open-label extension study will be evaluated for safety 30 days after the last dose of study drug. Receive a follow-up call to

[0670] Exam period Individual study subjects will participate for a maximum of 3 weeks of screening and 12 weeks of treatment. The trial will last approximately 19 weeks, consisting of a 30-day safety follow-up period. Defined as the date the last subject completed the final protocol-defined assessment at all sites.

[0671] Main inclusion and exclusion criteria To be eligible for this study, subjects must meet all inclusion criteria and all exclusion criteria. It is not necessary to meet the standards.

[0672] Inclusion criteria: 1. Informed consent is required before any study procedures are performed as follows: : a. For minor subjects: Written informed consent must be obtained from the legal guardian (LA). Subjects will be asked to provide written consent if deemed possible by the investigator. The informed consent process is conducted by the patient. In accordance with Institutional Review Board (IRB) or Ethics Committee (EC) policies and applicable local laws. This is what happens. b. For subjects who are not minors: If deemed possible by the investigator If the subject agrees, written informed consent will be obtained from the LAR or the subject. If a subject is deemed unable to provide consent, the subject may be If it is deemed necessary, written or oral consent is required. The process of obtaining the certificate will be conducted in accordance with IRB or EC policy and applicable local law. It can be done. c. The subject's caregiver will also be informed of the subject's participation in the study prior to participating in any study procedures. Informed consent must be provided. 2. Female subjects must be between 5 and 20 years old (inclusive) at the time of screening. 3.Weight is 12 kg or more at the time of screening 4. Ability to swallow study medication provided as a liquid solution or via gastrostomy Can be administered through a tube 5. Eligible caregivers have sufficient language skills to complete the caregiver assessment in the language in which the study assessment will be delivered. Possess language skills

[0673] diagnosis 6. Classic / typical Rett syndrome (RTT) 7. Have a documented disease-causing mutation in the MECP2 gene 8. Post-regression at screening, defined as: Screening Within 6 months of No loss or deterioration of physical and mental health (including independence in walking / standing) b. No loss or deterioration of hand function within 6 months of screening c. Speech (babbling, making words, or There is no loss or deterioration of speech, language, or previously developed communicative vocalizations and d. Within 6 months of screening, have you experienced any changes in your non-verbal communication skills or social skills (eye contact, using one's body to indicate communicative intent, social attention) No loss or deterioration of 9. At screening, a score of 10 to 36 (inclusive) on the Rett Syndrome Clinical Severity Scale ) severe evaluation 10. Have a CGI-S score of 4 or greater at screening and baseline and

[0674] Combination therapy 11. Subject is not taking anticonvulsants or any other psychotropic medication (including cannabinoids) If you are taking or have taken: a. Treatment regimen is stable for at least 4 weeks prior to baseline and dose changes are not required. have no current plans to do so, or b. If medication is discontinued more than 2 weeks or 5 half-lives prior to baseline (whichever occurs first) (or longer) 12. Subject is not taking any other medications (including antibiotics, pain relievers, and laxatives) for chronic illness. If you take or have taken any other medication (not including steroids) daily: a. Drug treatment regimen is stable for at least 4 weeks prior to baseline and doses are There are no current plans to change it, or b. If medication was discontinued more than 2 weeks or 5 half-lives before baseline The subject must have discontinued non-pharmacological physical therapy (e.g., ketogenic therapy) If you are or have been on a diet or vagus nerve stimulation: a. Treatment regimen is stable for at least 4 weeks prior to baseline and no change in treatment is required that you have no current plans to do so, or b. If treatment was discontinued, it must have been discontinued at least 2 weeks prior to baseline. 14. The subject is educational therapy, behavioral therapy, physical therapy, occupational therapy, or speech-language-hearing therapy. If you are receiving or have received non-pharmacological treatment: a. Treatment regimen is stable for at least 4 weeks prior to baseline and no change in treatment is required No current plans to attend (Note: Due to school schedules or otherwise seasonal (changes in treatment regimen related to the b. If treatment was discontinued, it must have been discontinued at least 2 weeks prior to baseline.

[0675] Seizures 15. Have or have had a stable seizure pattern within 8 weeks of screening What I didn't do

[0676] Possibility of childbirth 16. Subjects of childbearing potential must not be sexually active during the study period and for at least 30 days thereafter. If the subject is sexually active or intends to become sexually active during the study, If this occurs, the subject must complete two clinically tolerated Contraceptive methods used (e.g., oral, intrauterine device [IUD], diaphragm + spermicide, injectable) Subjects must be pregnant or have a history of breastfeeding. must not be breastfeeding.

[0677] Exclusion criteria: Combination therapy 1. Have been treated with growth hormone within 12 weeks of baseline 2. Have been treated with IGF-1 within 12 weeks of baseline 3. Treated with insulin within 12 weeks of baseline

[0678] Medical conditions other than Rett syndrome 4. Currently have clinically significant cardiovascular disease, endocrine disease (hypothyroidism or thyroid dysfunction) hypertension, type 1 diabetes mellitus, or uncontrolled type 2 diabetes mellitus), kidney disease, liver disease, have a respiratory or gastrointestinal disease (such as celiac disease or inflammatory bowel disease); is scheduled for major surgery during the study 5. Have a history or current history of cerebrovascular disease or brain trauma 6. Have a significant uncorrected visual impairment or a significant uncorrected hearing impairment Harmful 7. Have a history or current history of malignant tumors

[0679] Laboratory tests, vital signs, and electrocardiograms 8. Clinically significant abnormal laboratory values ​​at screening. Laboratory tests , may be repeated during the screening period with the consent of the medical monitor. 9. Have serum potassium below the normal range for the subject at screening (median (The laboratory will determine the serum potassium level.) Serum potassium was measured during the screening period with the consent of the medical monitor. It can be repeated throughout. 10. Having hemoglobin A1C (HbA1c) > 7.0% at screening and 11. Thyroid-stimulating hormone (TSH) levels outside the normal range for the subject at screening (Central laboratory) 12. Clinically significant abnormalities in vital signs at screening or baseline There is 13. Have one of the following: a. QTcF interval >450 ms at screening or baseline (pre-dose) Being b. History of risk factors for torsades de pointes (heart failure or long QT syndrome) family history, etc.) c. A clinically significant increase in the risk of QT prolongation in a subject A history of significant QT prolongation 14. Any other ECG-related abnormalities at screening or baseline (pre-dose) Clinically significant findings 15. Have a positive pregnancy test at screening

[0680] Other criteria 16. Patients with significant sensitivity or allergic reaction to trophinetide or its excipients to have 17. Participation in another interventional clinical trial within 30 days prior to screening 18. Any participant who is deemed unsuitable for the study by the investigator or medical monitor for any reason. to be judged to be

[0681] Pharmacokinetic evaluation PK blood samples were collected at the baseline visit (both pre-dose and approximately 2-3 hours post-dose), and trophinetide concentration measurements at Visits 3, 4, and 5 / Early Termination (ET). At the baseline visit (Visit 2), approximately 2-3 hours after dosing, The second PK sample taken should be taken as soon as possible after the post-dose ECG is taken. PK samples at Visits 3, 4, and 5 will be collected at one of the following time intervals: You need: 2 to 3 hours after administration 3 to 7 hours after administration 7 to 11 hours after administration

[0682] During the study, the subjects were administered the steroids at different time intervals (2-3 hours after administration, 3-7 hours after administration, and 7 hours after administration). PK samples will be collected at Visits 3, 4, and 5, one each of the following visits (after ~11 hours): If samples are taken at equal time intervals during the visit, Every effort should be made to collect samples at different times within the specified time interval. Pharmacokinetic samples should also be collected, if possible, at any ET visit or immediately following any SAE. Collected at a later visit or immediately after any AE leading to discontinuation.

[0683] All PK samples (scheduled and unscheduled) will be The dates and times of the last three doses of the drug, the dates and times of the meals closest to those doses, and the test The date and time of sample collection should be recorded. Any SAEs experienced or AEs leading to discontinuation For samples collected from subjects who experienced an SAE or AE, the last dose of study drug prior to the SAE or AE The date and time should also be recorded.

[0684] Optional biomarker analysis Participation in efforts to identify biomarkers is an optional component of the study. Separate informed consent for the identification of biomarkers of response to rofinetide Subjects receiving the drug will have blood drawn at baseline (pre-dose) and Visit 5 / ET. Liquid samples are used to analyze RNA transcripts (transcriptomics), proteins (proteomics), and metabolites (metabolomics) in trophinetide-treated and placebo-treated subjects It is used to examine the differences between responders and non-responders in both subjects.

[0685] Sample Size Calculation Sample size calculations were based on a family of two hypothesis tests at an overall two-sided significance level of 0.05. The study was conducted to assess multiple primary endpoints. The total sample size of 174 evaluable subjects in proportions was 100% with the following treatment differences (SD) in Phase 2: Provide at least 90% power for a family of hypothesis tests, assuming they are inferred from test data. The mean change from baseline to week 12 in the RSBQ total score was estimated to be for the mean CGI-I score at week 12, it was -4.4(8), and for the mean CGI-I score at week 12, it was -0. 5(0.7).

[0686] A sample size of 174 evaluable subjects was used for each individual hypothesis test within the family. , providing at least 95% power at a two-sided significance level of 0.05. If the hypothesis test was shown to be statistically significant at 0.05, trofinetide was Based on data from a phase 2 study, RSBQ total score and CGI-I score were significantly superior to those of the control group. The correlation with the core is low, and therefore the measurements are assumed to be independent. The overall power to detect a treatment difference for both primary endpoints was at least 90% (0.952 By adjusting for an expected discontinuation rate of up to 5%, approximately 184 subjects were included in the trophine study. Patients will be randomized in a 1:1 ratio to receive either tidomethyl-p-thiazol-2-one or placebo.

[0687] statistical methods Analysis Set The following populations are defined and used in the analysis:

[0688] Safety Analysis Group The safety analysis population was comprised of all randomized patients who received at least one dose of study drug. The safety analysis population will be analyzed according to the treatment actually received.

[0689] Largest Analysis Set (FAS) FAS received at least one dose of study drug and completed a baseline study on the RSBQ total score. have both a baseline value and at least one post-baseline value, or All randomized patients with at least one post-baseline value for the I score The FAS consisted of subjects assigned to the treatment, regardless of the treatment they actually received. Analyze.

[0690] Per-protocol (PP) analysis population The PP analysis population was free of any significant protocol violations that could affect the interpretation of efficacy data The PP analysis population will consist of subjects from the FAS. The PP analysis population will be defined prior to unblinding of the study. The groups are analyzed according to the treatment they actually received.

[0691] Pharmacokinetic (PK) analysis population The PK analysis population will consist of at least one safety group with measurable trophinetide whole blood concentrations. The sexual analysis group consisted of subjects.

[0692] Descriptive statistics Unless otherwise stated, all statistical tests yield 95% (two-sided) confidence intervals. The study will be two-sided using a 5% significance level. Both co-primary endpoints will be statistically significant. Trofinetide is superior to placebo if it is shown to be The results include the data value, mean, standard error of the mean, median, standard deviation, minimum, and maximum. For each categorical outcome, the number of subjects in each category is reported. The number and percentage of elephants are reported.

[0693] A tiered approach was used to control for multiple endpoints (multiple primary and secondary). do.

[0694] Primary analysis Co-primary efficacy endpoints were analyzed using mixed models for repeated measures (MMRM). Use an unstructured covariance matrix and use the Kenward-Roger approximation to find the denominator. Treatment comparisons are based on least squares mean differences at 12 weeks.

[0695] For the change from baseline in the RSBQ total score, the MMRM model was based on treatment group, Age group (5–10 years, 11–15 years, and 16–20 years), visit, baseline RSBQ Total score and baseline RSBQ total score by treatment group and visit This includes the effect on the interaction of

[0696] For CGI-I scores, the MMRM model was based on treatment group, age group (5–10 years, 11– 15 years and 16-20 years), visit, baseline RSBQ severity (total score less than 35) and total score of 35 or more), baseline CGI-S score, and treatment visit Includes effects on the interaction of baseline CGI-S score by treatment group and visit.

[0697] To assess the impact of missing data, we used the missing non-random assumption. Conduct sensitivity analyses, including analyses.

[0698] Secondary analyses Key secondary endpoints were assessed by treatment group, age group (5-10 years, 11-20 years) using the MMRM method. Ages 16-20, 15-15, and 16-20 years, visit, baseline RSBQ severity (total score <35) and a total score of 35 or greater), baseline CSBS-DP-IT social score, and treatment group by visit and baseline CSBS-DP-IT social scores by visit. The effect of the two variables on the interaction is analyzed using an unstructured covariance matrix. De Roger's approximation was used to adjust the denominator degrees of freedom. Treatment comparisons were performed at 12 weeks. Based on the least squares mean difference between

[0699] For other secondary endpoints assessed at multiple post-baseline visits, baseline Changes from were measured using MMRM analyses similar to those described above for coprimary endpoints. The MMRM model was performed based on treatment group, age group (5-10 years, 11-15 years, and 16-18 years). Ages 20 years and older), visit, baseline RSBQ severity (total score less than 35 and ≥ 35) Total score), baseline score, and treatment group by visit and baseline by visit Includes effects on in-score interactions.

[0700] Other secondary assessments assessed at a single post-baseline visit (i.e., Week 12 only) For each item, change from baseline was assessed using an analysis of covariance (ANCOVA) model. Treatment group, age group (5-10 years, 11-15 years, and 16-20 years), baseline RSBQ severity (total score less than 35 and total score ≥ 35), and baseline The impact on the score is analyzed.

[0701] Safety analysis Safety results will be summarized by treatment group using descriptive statistics. Again, no formal statistical testing was performed. Adverse events were classified according to the Medical Dictionary for Regulatory Affairs (MedD). Treatment-emergent adverse events (TEAEs) are classified into standard terms using the RA. TEAEs leading to discontinuation, TEAEs related to study drug, TEAEs by maximum severity, and fatal All TEAEs, serious adverse events (SAEs), and SAEs related to the study drug will be summarized. Clinical laboratory tests, including ECG, vital signs, and weight, and changes from baseline Descriptive statistics of parameters are tabulated by time point. According to the guidelines, the incidence of subjects with prolonged QTc interval and QTc interval changes was Conduct a category analysis.

[0702] Pharmacokinetic analysis Pharmacokinetic (PK) and efficacy (PD) measurements were performed at the pre-dose baseline (week 0) visit. At the baseline (week 0) visit after administration, and at weeks 2, 6, and 12 after administration. At week 1 / EOT, all subjects will be collected.

[0703] Data on whole blood concentrations of trophinetide and its potential metabolites are listed and descriptive statistics are provided. When data permit, population PK and PK / PD analyses will be performed to assess safety and efficacy. Measured efficacy parameters were used to characterize the PK profile and exposure-response relationship of trofinetide. Trofinetide whole blood concentration data will be collected at the end of the study and used in clinical data collection. The study will remain blinded until the unblinding of the study site occurs.

[0704] Screening period (maximum 3 weeks) During the screening period, subjects will be evaluated for eligibility for the study. Only subjects who meet the inclusion criteria and do not meet the exclusion criteria will be eligible for the study. Subjects must not discontinue prohibited medication for the purpose of enrolling them in this study. Discontinue only if it is deemed clinically appropriate to do so in consultation with your treating physician. Subjects should be evaluated for a diagnosis of Rett syndrome. There must be documented records. If records are insufficient, the genetic material must be included as part of the study. Typing may be performed.

[0705] Caregivers will begin keeping a semi-structured caregiver diary during the screening period.

[0706] Double-blind treatment period (12 weeks) The baseline visit (Visit 2) is the time when screening procedures are completed and subjects are deemed eligible for the study. At Visit 2, if eligibility is confirmed, subjects will , randomized 1:1 to trophinetide oral solution or a matching dose of placebo Doses are based on the subject's weight at baseline, as outlined in Table 3 above. The dose may be administered via a gastrostomy (G) tube (as opposed to a gastrojejunostomy (GJ) tube). (Doses administered via a G-port should be administered via a G-port.)

[0707] The first dose of study medication was administered after all baseline assessments were completed or after the study physician If the nurse determines that it is too late to administer the vaccine that day, it will be administered at the trial facility the following day. The day this is administered is considered Day 1 of administration. An ECG should be performed 2-3 hours after the first administration. Upon completion of the ECG, a PK sample will be taken.

[0708] The drug is administered twice a day, once in the morning and once in the evening. should not eat.

[0709] In addition to the study medication dispensed at the facility at the baseline visit, additional study medication was administered to the subject or visit. Ship directly to the patient nurse. Study drug shipments, returns, and accountability are governed by the Drug Distribution Plan. Each facility also has a drug distribution plan for subjects. The confirmation will be carried out by a visiting nurse during a home visit.

[0710] Subjects will return to the clinic for evaluation at weeks 2, 6, and 12 / early termination (ET). Back. Administer trophinetide and concomitant medications 2 days before and on the morning of the clinic visit. The date and time of meals should be recorded in the caregiver's diary.

[0711] Safety follow-up period (30 days) Subjects who complete the treatment period of the study and decide not to continue in the open-label study or who are withdrawn from the open-label study Subjects who are ineligible for the study or who discontinue the study early will be followed by a 30-day safety Complete a follow-up telephone call. The telephone call includes an assessment of concomitant medications and treatments, and This includes evaluation of AEs.

[0712] Subject eligibility and discontinuation criteria To be eligible for this study, subjects must meet all inclusion criteria and all exclusion criteria. It must not meet external criteria.

[0713] Inclusion criteria To be eligible for study participation, subjects must meet all of the following inclusion criteria: 1. Informed consent is required before any study procedures are performed as follows: : a. For minor subjects: Written informed consent must be obtained from the legal guardian (LA). Subjects will be asked to provide written consent if deemed possible by the investigator. The informed consent process is conducted by the patient. In accordance with Institutional Review Board (IRB) or Ethics Committee (EC) policies and applicable local laws. This is what happens. b. For subjects who are not minors: If deemed possible by the investigator If the subject agrees, written informed consent will be obtained from the LAR or the subject. If a subject is deemed unable to provide consent, the subject may be If it is deemed necessary, written or oral consent is required. The process of obtaining the certificate will be conducted in accordance with IRB or EC policy and applicable local law. It can be done. c. The subject's caregiver will also be informed of the subject's participation in the study prior to participating in any study procedures. Informed consent must be provided. 2. Female subjects must be between 5 and 20 years old (inclusive) at the time of screening. 3.Weight is 12 kg or more at the time of screening 4. Ability to swallow study medication provided as a liquid solution or via gastrostomy Can be administered through a tube 5. Eligible caregivers have sufficient language skills to complete the caregiver assessment in the language in which the study assessment will be delivered. Possess language skills

[0714] diagnosis 6. Classic / typical Rett syndrome (RTT) 7. Have a documented disease-causing mutation in the MECP2 gene 8. Post-regression at screening, as defined as: a. Abdominal ambulation (gait) No loss or deterioration of motor skills (including motor coordination and independence in walking / standing) b. No loss or deterioration of hand function within 6 months of screening c. Speech (babbling, making words, or There is no loss or deterioration of speech, language, or previously developed communicative vocalizations and d.Dysfunction in nonverbal communication skills or social skills within 6 months of screening skills (including eye contact, using the body to indicate communicative intent, and social attention) No loss or deterioration of 9. Rett Syndrome Clinical Severity Scale score of 10-36 (inclusive) at screening Having a reputation 10. Have a CGI-S score of 4 or greater at screening and baseline and

[0715] Combination therapy 11. Subject is not taking anticonvulsants or any other psychotropic medication (including cannabinoids) If you are taking or have taken: a. Treatment regimen is stable for at least 4 weeks prior to baseline and dose changes are not required. have no current plans to do so, or b. If medication is discontinued more than 2 weeks or 5 half-lives prior to baseline (whichever occurs first) (or longer) 12. Subject is not taking any other medications (including antibiotics, pain relievers, and laxatives) for chronic illness. If you take or have taken any other medication (not including steroids) daily: a. Drug treatment regimen is stable for at least 4 weeks prior to baseline and doses are There are no current plans to change it, or b. If medication is discontinued more than 2 weeks or 5 half-lives prior to baseline (whichever occurs first) (or longer) 13. Subject is not receiving non-pharmacological physical treatment (e.g., ketogenic diet or vagus nerve stimulation) If you are receiving or have received: a. Treatment regimen is stable for at least 4 weeks prior to baseline and no change in treatment is required have no current plans to do so, or b. If treatment was discontinued, it must have been discontinued at least 2 weeks prior to baseline. 14. The subject is educational therapy, behavioral therapy, physical therapy, occupational therapy, or speech-language-hearing therapy. If you are receiving or have received non-pharmacological treatment: a. Treatment regimen is stable for at least 4 weeks prior to baseline and no change in treatment is required No current plans to attend (Note: Due to school schedules or otherwise seasonal (changes in treatment regimen related to the b. If treatment was discontinued, it must have been discontinued at least 2 weeks prior to baseline.

[0716] Seizures 15. Have or have had a stable seizure pattern within 8 weeks of screening What I didn't do

[0717] Possibility of childbirth 16. Subjects of childbearing potential must not be sexually active during the study period and for at least 30 days thereafter. If the subject is sexually active or intends to become sexually active during the study, If this occurs, the subject must complete two clinically tolerated Contraceptive methods used (e.g., oral, intrauterine device [IUD], diaphragm + spermicide, injectable) Subjects must be pregnant or have a history of breastfeeding. must not be breastfeeding.

[0718] Exclusion criteria To be eligible for the study, subjects must not meet any of the following exclusion criteria: .

[0719] Combination therapy 1. Have been treated with growth hormone within 12 weeks of baseline 2. Have been treated with IGF-1 within 12 weeks of baseline 3. Treated with insulin within 12 weeks of baseline

[0720] Medical conditions other than Rett syndrome 4. Currently have clinically significant cardiovascular disease, endocrine disease (hypothyroidism or thyroid dysfunction) hypertension, type 1 diabetes mellitus, or uncontrolled type 2 diabetes mellitus), kidney disease, liver disease, have a respiratory or gastrointestinal disease (such as celiac disease or inflammatory bowel disease); is scheduled for major surgery during the study 5. Have a history or current history of cerebrovascular disease or brain trauma 6. Have a significant uncorrected visual impairment or a significant uncorrected hearing impairment Harmful 7. Have a history or current history of malignant tumors

[0721] Laboratory tests, vital signs, and electrocardiograms 8. Clinically significant abnormal laboratory values ​​at screening. Laboratory tests , may be repeated during the screening period with the consent of the medical monitor. 9. Have serum potassium below the normal range for the subject at screening (median (The laboratory will determine the serum potassium level.) Serum potassium was measured during the screening period with the consent of the medical monitor. It can be repeated throughout. 10.Having hemoglobin A1C (HbA1c) greater than 7% at screening 11. Thyroid-stimulating hormone (TSH) levels outside the normal range for the subject at screening (Central laboratory) 12. Clinically significant abnormalities in vital signs at screening or baseline There is 13. Have one of the following: a. QTcF interval 450 ms at screening or baseline (pre-dose) Being super b. History of risk factors for torsades de pointes (heart failure or long QT syndrome) family history, etc.) c. A clinically significant increase in the risk of QT prolongation in a subject A history of significant QT prolongation 14. Any other ECG-related abnormalities at screening or baseline (pre-dose) Clinically significant findings 15. Have a positive pregnancy test at screening

[0722] Other criteria 16. Patients with significant sensitivity or allergic reaction to trophinetide or its excipients to have 17. Participation in another interventional clinical trial within 30 days prior to screening 18. Any participant who is deemed unsuitable for the study by the investigator or medical monitor for any reason. to be judged to be

[0723] Subject's withdrawal of consent Subjects and legally authorized persons consenting on their behalf in accordance with the Declaration of Helsinki and other applicable regulations. The agent may, for any reason, at any time without affecting the subject's future medical care. also has the right to cancel the exam.

[0724] If the subject (or LAR) requests or decides to withdraw consent, the ET or safety Observations up to the date of withdrawal, including assessments specified in the sex follow-up (if applicable) You must make every reasonable effort to complete and report the matter as thoroughly as possible. do.

[0725] Subject withdrawal or study discontinuation Subjects may be tested for a number of reasons, including but not limited to those listed below. Can be discontinued: Adverse events ●Death - Increase in QTcF interval after baseline (defined below) Lack of effectiveness No follow-up ● Non-compliance with test drugs ●Doctor's judgment Pregnancy Protocol deviations ● Completion of the test by the test sponsor Use of prohibited drugs ●Other

[0726] The Sponsor reserves the right to cancel the study at any time for any reason. Reasons include, but are not limited to: The occurrence of an AE not currently known in terms of nature, severity, and duration, or a known AE Unexpected occurrence of AE • Medical, ethical, or business reasons that affect the continued conduct of the trial. Regulatory authorities also have the right to terminate the conduct of a trial in their region for any reason. do.

[0727] Post-baseline QTcF interval stop criteria QTcF duration ≥ 500 ms after randomization or baseline (pre-dose) If an increase of 60 ms or more compared to the mean QTcF interval is observed, the study drug should be discontinued. There is a need.

[0728] Handling of subject discontinuation during treatment The subject withdraws consent to be contacted for this study (or the LAR withdraws consent on the subject's behalf) If a subject discontinues early for any reason, except for those who have withdrawn consent (e.g., Visit 5 / Early), All necessary steps are taken to complete the Exit (ET) and Safety Follow-Up (outlined in Table S-2). All information should be provided in the appropriate electronic case report form (eCRF). It will be reported on the page.

[0729] If a subject discontinues the study due to an AE, the subject will be continued until the AE has resolved or the investigator Any measures to follow the subject until the AE is determined to be long-term or stable are taken. Reasonable attempts should be made to continue safety follow-up. , SAEs should continue to be reported as described in Section 7.3.2. All SAEs will be considered for long-term or long-term follow-up until such events are resolved or the investigator determines that the event is not a long-term or long-term outcome. will continue to be followed until it is deemed stable.

[0730] Pharmacokinetic samples should be collected at any ET visit, even if unscheduled, if possible. was also collected at the visit immediately following any SAE or at the visit following any AE leading to discontinuation. do.

[0731] Subjects lost to follow-up If the subject does not attend a scheduled visit (except for safety follow-up calls) and the study site If the elephant or caregiver could not be contacted, the subject was considered lost to follow-up. It is considered.

[0732] All reasonable efforts must be made to contact the caregiver, and these efforts must include documentation A minimum of three recorded phone calls (each made at a different time of day), and if necessary This includes certified mail or the local equivalent to the caregiver's last known mailing address. All contact attempts must be documented in the source document.

[0733] Medical history and concomitant medications Use within 8 weeks prior to baseline, safety follow-up visit, or completion of ET Record all medications taken.

[0734] To ensure appropriate combination therapy is administered, Subjects will not be given any medications (unless they are receiving treatment) without prior consultation with the investigator. It is essential to instruct caregivers not to give

[0735] The investigator may prescribe appropriate medications to treat AEs. If so, the sponsor and investigator or designee shall consider the continued existence of such subject in the trial. The Board will consult to determine whether it is appropriate to

[0736] Any treatment regimens that are seasonally related due to school schedules or otherwise Maintain a stable regimen of concomitant medications, understanding that there will be some changes Every effort should be made to allow non-drug based therapies throughout the course of the trial. A special case is a drug that has diarrhea as an acute side effect, which requires monitoring. The recommended daily intake of 100mg of sucralose should be adjusted as needed if diarrhea occurs. Treatment should also be monitored.

[0737] Permitted and Prohibited Substances The prohibited substances are IGF-1, growth hormone, and insulin. Concomitant drug use is prohibited. Follow-up is required between Visit 2 and Visit 5 / ET. Drugs that can prolong the QT interval are prohibited. Although not prohibited, they should be used with caution. Any use should be discussed with the medical monitor.

[0738] Any questions regarding the use of drugs or concomitant medications that may interfere with the conduct of the study Any such changes should be reviewed and / or discussed with the medical monitor.

[0739] If possible, concomitant psychotropic medications should be maintained at stable doses throughout the study. Any non-pharmacological physical treatment regimen that has a CNS effect (e.g., ketogenic The blood pressure (e.g., blood sugar, blood sugar level, or vagus nerve stimulation) should remain stable throughout the study, if possible. Treatment for constipation can be modified as needed.

[0740] Subjects requiring current treatment with prohibited substances will be excluded from the study.

[0741] Subjects who have previously taken prohibited substances during the study will be excluded from the study unless: Can be: Prohibited substances have been discontinued, and • Exclusion from the study poses an unacceptable medical risk to the subject.

[0742] Justification for allowing a subject to continue in the study must include a medical This will be conducted and documented by the Sponsor / Medical Monitor with input from the investigator. If the subject is allowed to remain in the study, this will be reported as a major protocol deviation. and will not be reported as a waiver.

[0743] Test drug Description of the study drug The study drug was trofinetide oral solution or a counterbalanced dose of trofinetide oral solution. The dose is based on body weight as outlined in Table 4. Trofinetide is administered orally. It is provided in a ready-to-use aqueous solution for administration. The dose is administered orally or through a G-tube. (The dose administered by GJ tube is administered via the G port.) (It is necessary to

[0744] Formulation, appearance, and packaging The test sponsor used 500 mL high-density polyethylene (HDPE) containers with child-resistant lids. Trofinetide as a ready-to-use strawberry flavored aqueous liquid in a plastic bottle A matching dose of placebo will be provided for the oral solution and trophinetide oral solution.

[0745] Trofinetide oral solution is a clear red solution containing 1 gram of trofinetide in each 5 mL dose. Trofinetide oral solution is also available containing purified water, maltitol, and other inactive ingredients. , strawberry flavor, sucralose, sodium methylparaben, sodium propylparaben and FD&C Red #40.

[0746] The placebo solution did not contain trophinetide active pharmaceutical ingredient (API) but consisted of purified water, vinegar, and Acid, caramel colorant, citric acid, lemon flavor, maltitol, methylparaben sodium Sodium, Natural Quinine Flavor, Sodium Propylparaben, FD&C Red #40, Contains strawberry flavor, sucralose, xanthan gum, and D&C Yellow #10.

[0747] Trofinetide and matching placebo were manufactured under current good manufacturing practices. can be.

[0748] During the treatment period, study medication will be administered to ensure that subjects have an adequate supply of study medication between study visits. Distributed in amounts sufficient to

[0749] Product Storage and Stability The study drug will be shipped refrigerated at a temperature of 2°C to 8°C (36°F to 46°F) and will remain at this temperature. It needs to be stored. Do not freeze.

[0750] Dosing and Administration The first dose of study medication was administered after all baseline assessments were completed or after the study physician If the nurse determines that it is too late to administer the vaccine that day, it will be administered at the trial facility the following day. The day this is administered is considered Day 1 of administration. An ECG should be performed 2-3 hours after the first administration. Upon completion of the ECG, a PK sample will be taken.

[0751] Dosage is based on the subject's weight at baseline (see Table 41). Weight changes will remain the same for each subject throughout the study. In addition to the study medication provided, additional study medication will be shipped directly to the subject or visiting nurse. Shipping, returns, and accountability are governed by a drug distribution plan. Each facility also Have a drug distribution plan. Any delivery to the target's home will be verified by a visiting nurse during a home visit. cormorant.

[0752] The dose may be taken orally or via a gastrostomy tube. The drug must be administered via a gastric port. Subjects must be instructed to Subjects receiving continuous tube feeding should not eat. If possible, feed the animals for administration of the test drug 1 hour before and 1 hour after dose administration. The provision of the service may be suspended.

[0753] The dose may be taken over 10 minutes with a follow-up of 250 mL of water. Dosage is twice a day, once in the morning and once in the afternoon or evening. The interval between doses should be at least must also be 8 hours.

[0754] How subjects are assigned to treatment groups At Visit 2, eligible subjects who met the inclusion criteria and did not meet the exclusion criteria were randomly selected 1:1 Patients will be randomized to receive either trofinetide or placebo.

[0755] Blinding Treatment assignments were shared with all study subjects, caregivers, investigators, assessors, site personnel, and The study will be blinded to the study sponsor and the study organization. Potential for unexpected serious adverse reactions (SUSARs) If an outbreak is suspected, please follow current health authority guidance and contact affected individuals for reporting purposes. Treatment assignment unblinded to the sponsor's safety and / or regulatory control group Further details regarding unblinding procedures in medical emergencies are provided in Section 9.9. It is being done.

[0756] Study Drug Compliance If a subject misses a dose of study medication, they should not take an additional dose the next day. .

[0757] Overdose Overdose occurs when a patient intentionally or intentionally administers treatment at a dose higher than the maximum recommended dose per protocol. Even if no toxic effects are observed, this is still considered a All overdose events should be reported in the protocol. This is seen as a deviation from the norm.

[0758] Test Procedure Test-specific procedures are detailed below.

[0759] Screening Assessment Confirmed diagnosis of Rett syndrome and MECP2 mutation The institution must determine whether the subject meets criteria for typical / classic Rett syndrome and has the M Ensure there is documentation of the ECP2 gene mutation. Genotyping is performed by an American pathologist. Association (CAP), or Clinical Laboratory Improvement Act / Amendments (CLIA) or equivalent This should be done in a laboratory certified by the organization. If mutation documentation is not adequate, Genomic testing for ECP2 gene mutations can be performed as part of the screening.

[0760] The documented mutations are listed in the MECP2 mutation database RettBASE (mecp2. chw.edu.au / cgibin / mecp2 / search / search.cg i?form=combined)(Krishnaraj et al.2017) Therefore, there is a need for a link between the mutation and Rett syndrome. If you have any questions, you should consult your medical monitor. Documented in the source document and eCRF.

[0761] Medical history, including history of Rett syndrome, and demographics A complete medical history, including a history of symptoms associated with Rett syndrome, was performed at screening and All current medical conditions and past major medical events and conditions will be documented. For subjects already receiving treatment for SK, a major medical condition or The source document for an event (e.g., surgery) is a summary document from the medical record (as required by the clinician). For subjects who are not part of the clinical site practice, The team will obtain abstracted medical records from other providers in preparation for the screening visit. You need to get it.

[0762] Rett Syndrome Clinical Severity Scale (RTT-CSS) RTT-CSS is a national initiative of the NIH-sponsored Rare Diseases Project. sored Natural History of Rare Diseases P It has been evaluated in over 1200 RTT children, adolescents, and adults enrolled in the RTT project. This scale is consistent with the genotype / phenotype correlations reported in RTT and epilepsy studies. It has been used as a measure of severity, as reported by Glaze et al. 0), Neu-2566-RET of trofinetide in adolescents and adults with RTT In the T-001 study, it was evaluated as an outcome measure. This measure was developed by Amir et al. (2000) and Monros et al. (2001). was done.

[0763] The RTT-CSS is a clinician-completed scale that measures the severity of RTT core symptoms. The CSS consists of 13 items, three of which are used at the time of evaluation, i.e. During the study visit, clinical history or resting characteristics (age of onset of regression, age of onset of stereotypy, head growth) were assessed. ) and 10 of these items measure current function (physical growth, independent sitting, agility, hand use, Scoliosis, language, non-verbal communication, respiratory dysfunction, autonomic symptoms, and seizures All items were assessed by the investigator or the competent authority during the clinical interview and examination. The qualification designee will score the qualification using either a 4-point or 5-point Likert scale. Individual subscale scores and a total score are calculated.

[0764] RTT-CSS is administered only at screening.

[0765] Efficacy evaluation All assessments are performed in a standardized manner. Measures completed by trained clinicians are Caregiver-completed assessments are reviewed by study personnel and completed by the caregiver. Parents receive standardized training and guidance on how to complete the measurements. To the extent possible, the same caregiver informant or clinician rater (as applicable) will be used during a single subject visit. Every effort should be made to maintain the

[0766] Rett Syndrome Behavioral Questionnaire (RSBQ) The Rett Syndrome Behavior Questionnaire (RSBQ) is a questionnaire that examines a wide range of behaviors known to be impaired in RTT. Mount is a 45-item caregiver-completed rating scale assessing a range of neurobehavioral symptoms. RSBQ was administered in a phase 2 trial, Neu-2566-RETT- It is a validated instrument used in 2012 and other observational and interventional trials of RTT. (Glaze et al. 2019, Khwaja et al. 2014, O'L eary et al. 2018). The RSBQ correlates with function and quality of life, It has been characterized and validated across a range of ages and genetic variations in TT (Cianf aglione et al.2015,2016, Robertson et al. 2006, Barnes et al. 2015). This scale contains 45 items. Thirty-nine items were grouped into eight subscales, and the ratings reflected the severity and frequency of symptoms. Caregivers can rate items as "0" (not true) or "1" (somewhat or sometimes true). The eight subscales are rated as either "0" (very true) or "2" (very true). Included: 1. General mood 2. Respiratory problems 3.Hand movements 4. Facial Movement 5. Body rocking / Emotionless face 6.Nighttime behavior 7.Fear / Anxiety 8. Walking / Standing

[0767] The RSBQ was administered at screening, baseline (Visit 2), and Visits 3, 4, and 5. Administered at 5 / ET. Whenever possible, the caregiver assessor will remain the same throughout the study. At the start of the study, all caregiver raters received standardized training on how to complete the scale. You must complete the training.

[0768] Clinical Global Impression-Improvement (CGI-I) and Clinical Global Impression-Severity (CGI-S) The CGI-I scale will be administered at Visit 3, Visit 4, and Visit 5 / ET. Completion of this scale The goal is for the clinician to assess how much the target disease has improved or worsened compared to the baseline state. The 7-point scale ranges from 1 = very significant improvement, 2 = significant improvement, and 3 = minimal improvement. 4 = no change, 5 = minimal deterioration, 6 = significant deterioration, 7 = very significant deterioration It is used.

[0769] CGI-S assessments were conducted at screening, baseline, and at visits 3, 4, and 6. and Visit 5 / ET. The CGI-S is based on the clinician's experience with subjects with the same diagnosis. In comparison, a 7-point scale requires the clinician to assess the severity of the subject's illness at the time of evaluation. Considering the total clinical experience, subjects were evaluated based on the severity of their illness at the time of evaluation. 1, normal, no illness at all; 2, borderline illness; 3, mild illness; 4 5, markedly ill; 6, severely ill ) illness; or 7, extreme illness. In this study, the illnesses evaluated were Rett syndrome in general. In accordance with best practice, the CGI-S and CGI-I assessments in this study are based on the main symptom. The study will be evaluated in the same manner as in the Phase 2 trial, using RTT-specific anchors in the region (Neul et al. 2015, Busner and Targum 2007, Glaze et al. 2017, Glaze et al. 2019).

[0770] Communicative and Symbolic Behavior Scale Developmental Profile for Infants and Toddlers (CSBS- DP-IT) Checklist Communicative and Symbolic Behavior Scales-Developmental Profile™ (CSBS -DP) is a tool for assessing communication and pre-linguistic skills in young children aged 12-24 months. It is a standardized screening scale for assessing l.2002), can be used in older children with developmental delays (Anagno stou et al. 2015, Urbanowicz et al. 2016). C The SBS-DP includes a battery of three separate measures: the Infant-Toddler Checklist; , follow-up caregiver questionnaires, and behavioral samples. Only the SBS-DP-IT checklist is used.

[0771] Considering the limited communication abilities of individuals with Rett syndrome, The CSBS-DP-IT checklist was evaluated, and a subset of items was assessed for ages 8-19. have been found to be appropriate for assessing the communication skills of individuals with SI. The CSBS-DP-IT was published (Urbanowicz et al. 2016). A compound related to trophinetide was shown to be effective in children aged 2 to 10 years with Rett syndrome. Mecasermin (recombinant human IGF-1) was evaluated in a phase 2 trial (O'Leary (2018). The study included a social composite score that could be calculated. The first 16 items were completed. The CSBS-DP-IT was significantly more effective than the placebo treatment group. There was evidence of benefit in subjects in the dynamic treatment group (O'Leary et al. 2018) The CSBS-DP social composite score has also been correlated with change in behavioral intervention trials in other developmental disorders. have shown evidence of sensitivity to Anagnostou et al. 2015 ).

[0772] The CSBS-DP-IT checklist is a 24-item rating scale completed by caregivers. Each item has a frequency rating of three levels: "Not yet," "Sometimes," and "Often." The score is based on three composite scores assessing seven skill areas: 1) Social Complexity (including emotions and gaze, communication speed and function, and gestures) ), 2) speech complexes (including sounds and words), and 3) symbolic complexes (comprehending and using objects). (including the

[0773] All 24 items on the Infant-Toddler Checklist are completed by the caregiver. Item 24 Questions after ("Do you have any concerns about your child's development?") are considered incomplete and At each administration, study staff will review the instructions and scoring rubric with the caregiver. The social composite raw score is composed of items 1-13 and is used for key secondary outcomes. The CSBS-DP-IT checklist was administered at baseline, Visit 3, Visit 4, and Visit 5. This will be done at Question 5 / ET.

[0774] Impact of Childhood Neurological Disability Scale (ICND) The Impact of Child Neurological Disorders Scale (ICND) measures the child's condition currently and in the past 3 months. It was developed to assess the impact of the study on the daily lives of patients and their families (Camfield et al. al. 2003). Parents or other caregivers are asked to rate their views on 11 aspects of the child's or family's life. The impact of the four conditions or health problems was rated as "large," "somewhat," "almost none," or "not at all." The four conditions or health problems are rated as 1) unrelated, 2) not related, or 3) not applicable. mind, impulses, or mood; 2) thinking and memory abilities; 3) neurological or physical limitations; and 4) epilepsy.

[0775] The caregiver then assesses the subject's overall quality of life by responding to the following: "Please rate your child's overall "quality of life" on the following scale: Best Please circle the number that best represents your rating. The options are 1 ("poor") to 6 ("excellent"). Assessments will be performed at baseline and Visit 5 / ET.

[0776] Rett Syndrome Clinician-Rated Hand Function Scale (RTT-HF) Assessment of hand function by Rett syndrome clinicians includes functional goals (reaching and grasping objects, about the subject's ability to use their hands for purposes such as eating, drawing, etc. This is a clinical assessment completed by a clinician. The ratings are on an 8-point Likert scale (0-7), with 0 being indicates normal function and 7 indicates the most severe impairment.

[0777] This evaluation was based on the RTT-DSC method used in the Neu-2566-RETT-002 study. The Hand Use Rating is a further development of the Hand Use Rating. This will be done at Sline, Visit 3, Visit 4, and Visit 5 / ET.

[0778] Rett Syndrome Clinician-Rated Ambulation and Gross Motor Skills Scale (RTT-AMB) Assessment of gait and gross motor skills by a Rett syndrome clinician included the ability of the subject to sit, stand, and and clinician-completed assessments of ability to ambulate (e.g., walk, run, climb stairs). Clinical assessment. The assessment was performed on an 8-point Likert scale (0-7), with 0 indicating normal function. This rating was used in the Neu-2566-RETT-002 trial. This is a further development of the RTT-DSC gait assessment used in [1]. Assessments were performed at baseline, This will be done at Visit 3, Visit 4, and Visit 5 / ET.

[0779] Rett Syndrome Clinician's Ability to Communicate Choices (RTT-COMC) Assessment of ability to communicate choices by Rett syndrome clinicians may involve eye contact or gestures. Ability to communicate subject choices or preferences, which may include the use of non-verbal means such as gestures It is a clinician-completed clinical assessment of strength.

[0780] Ratings were made on an 8-point Likert scale (0–7), with 0 indicating normal function and 7 indicating the most severe. This assessment was performed using the R This is a further development of the TT-DSC language / communication assessment. These visits are conducted at Visit 1, Visit 2, Visit 3, Visit 4, and Visit 5 / ET.

[0781] Rett Syndrome Clinician Rating Scale for Verbal Communication (RTT-VCOM) Verbal communication assessment by Rett syndrome clinicians should be performed to assess the patient's ability to communicate in the target language. A clinician-completed clinical assessment of communication skills (e.g., words and phrases) be.

[0782] Ratings were made on an 8-point Likert scale (0–7), with 0 indicating normal function and 7 indicating the most severe. This assessment was performed using the R This is a further development of the TT-DSC language / communication assessment. These visits are conducted at Visit 1, Visit 2, Visit 3, Visit 4, and Visit 5 / ET.

[0783] Rett Syndrome Caregiver Burden Inventory (RTT-CBI) The RTT-CBI is a caregiver burden inventory designed for Alzheimer's disease. Based on the results of the study (e et al. 2017, Novak and Guest 1989), This is a syndrome-specific, caregiver-completed questionnaire. This scale...

Claims

[Claim 1] The invention described in this specification.

Images