Use of trofinetide in rett syndrome

Abstract

The present invention discloses a method for treating Rett syndrome comprising administering trafentidine to an individual in need, wherein a dose is provided that reduces or avoids, for example, underexposure in low-weight individuals and / or provides other benefits.

Description

[Technical Field] The present invention provides a method for treating Rett syndrome, comprising administering trofinetide to an individual in need. [Previous Technology] Rett syndrome (RTT) is a severe and debilitating neurodevelopmental disorder for which there is currently no approved treatment. Its incidence is reported to be 1 in 10,000–15,000 female live births (Bienvenu et al., "The incidence of Rett syndrome in France," Pediatr. Neurol. 2006, 34(5), 372–375; Neul et al., "Rett syndrome: revised diagnostic criteria and nomenclature," Ann. Neurol. 2010, 68(6), 944–950). Although the vast majority of RTT patients are female, males meeting the criteria for RTT have also been identified (Neul et al., "The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2," Am. J. Genet. B. Neuropsychiatr. Genet. 2019, 180(1), 55–67). Rett syndrome includes "normal" and "abnormal" forms, sometimes referred to as "typical" and "variant" RTT, respectively. Abnormal RTT usually involves some, but not all, of the criteria required for the diagnosis of normal RTT, which are discussed in more detail below. In patients with typical Rett syndrome (RTT), psychomotor development appears normal during the first six months of life, but shortly thereafter, failure to reach normal developmental milestones is observed, followed by a developmental regression phase in which normal use of hand and verbal language is lost, and ambulation is lost or impaired (Samaco and Neul, "Complexities of Rett syndrome and MeCP2," J. Neurosci. 2011, 31(22), 7951-7959). In many, but not all, individuals with RTT, the developmental regression phase is accompanied by temporary autistic features (Lee et al., "Early development and regression in Rett syndrome," Clin. Genet. 2013, 84(6), 572-576; Neul et al., "Developmental delay in Rett syndrome: data from the natural history study," J. Neurodevelop. Dis. 2014, 6(20), 1-9). The loss of social skills stabilizes or reverses after the regression stage, and some individuals with RTT demonstrate social intentions through eye contact (Young et al., "The diagnosis of autism in a female: could it be Rett syndrome? Eur. J. Pediatr. 2008, 167(6), 661-669; Djukic and McDermott, "Social preferences in Rett syndrome", Pediatr. Neurol. 2012, 46(4), 240-242; Urbanowicz et al., "An exploration of the use of eye gaze and gestures in females with Rett syndrome", J. Speech Lang. Hear. Res. 2016, 59(6), 1373-1383).Despite this, social interaction and communication remain limited (Mount et al., "Features of autism in Rett syndrome and severe mental retardation," 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 Rett syndrome," Am. J. Med. Genet. 2015, 167A(2), 354-362; Rose et al., "Rett syndrome: an eye-tracking study of attention and recognition memory," Dev. Med. Child Neurol. 2013, 55(4), 364-371; Kaufmann et al., "Social impairments in Rett syndrome: characteristics and relationship to clinical severity," J. Intellect. Disabil. Res. 2012, 56(3), 233-247; Woodyatt and Ozanne, "A Longitudinal study of cognitive skills and communication behaviors in children with Rett syndrome," J. Intellect. Disabil. Res. 1993, 37(Pt r), 419-435).The intellectual impairment in Rett syndrome appears to be profound; however, due to the fact that most individuals are affected by severe communication and motor deficits, it is difficult to accurately measure the degree of cognitive impairment (Byiers and Symons, "Issues in estimating developmental level and cognitive function in Rett syndrome", Hodapp, RM (ed.), International Review of Research in Intellectual and Developmental Disabilities, Waltham, MA: Elsevier; 2012, 43, 147-185; Clarkson et al., "Adapting the Mullen Scales of Early Learning for a standardized measure of cognition in children with Rett syndrome", Intellect. Dev. Disabil. 2017, 55(6), 419-431). Epilepsy is common but not a diagnostic criterion. Commonly observed symptoms include awake breathing disruption, scoliosis, and an interest in social interaction (intense eye contact) (Neul 2010, see above; Percy et al., "Profiling scoliosis in Rett syndrome", Pediatr. Res. 2010, 67(4), 436-439). Gastrointestinal symptoms, including constipation and difficulty chewing and swallowing, have been observed in most patients with Rett syndrome (Motil et al., "Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome," J. Pediatr. Gastroenterol. Nutr. 2012, 55(3, 292-298). Mood swings, screaming, and uncontrollable crying are common behaviors in children and adolescents with Rett syndrome (Mount et al., "Behavioural and emotional features in Rett syndrome," Disabil. Rehabil. 2001, 23(3-4), 129-138; Mount et al., "The Rett Syndrome Behaviour Questionnaire (RSBQ): Refining the behavioural phenotype of Rett syndrome," J. Child Psychol. Psychiatry 2002, 43(8), 1099-1110; Robertson et al., "The association between behavior and genotype in Rett syndrome using the Australian Rett syndrome database," Am. J. Med. Genet. 2006, 141B(2), 177-183; Cianfaglione et al., "A national survey of Rett syndrome: behavioral characteristics," J. Neurodev. Disord. 2015, 7(1), 11).These impairments can further exacerbate other symptoms and disrupt daily life activities, 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; Perry et al., "Brief report: cognitive and adaptive functioning in 28 girls with Rett syndrome," J. Autism Dev. Disord. 1991, 21(4), 551-556; Thompson and Iwata, "A descriptive analysis of social consequences following problem behavior," J. Appl. Behav. Anal. 2001, 34(2), 169-178; Iemmi et al., "Positive behavioural support for children and adolescents with intellectual disabilities whose behavior challenges: an exploration of the economic case," J. Intellect. Disabil. 2015, 20(3)). (281-295). Spontaneous manifestations of abnormalities in cardiac and respiratory function and peripheral circulation are considered to originate primarily from the CNS. RTT is also characterized by impaired growth affecting the brain and other organ systems. Loss of purposeful hand use is commonly observed in individuals with RTT during degenerative episodes, and at least 30% remain without any type of purposeful hand use (Downs et al., “Level of purposeful hand function as a marker of clinical severity in Rett syndrome,” Dev. Med. Child Neurol. 2010, 52(9), 817-823). Individuals with some purposeful hand movements had varying levels of ability to reach and grasp objects. The ability to self-feed was observed in 25–43% of individuals (Cass et al., “Findings from a multidisciplinary clinical case series of females with Rett syndrome,” Dev. Med. Child Neurol. 2003, 45, 325–337; S14-19; Downs et al. 2011). A less favorable standard of hand function is associated with both age and severity of impaired mobility (Downs et al., “Longitudinal hand function in Rett syndrome,” J. Child Neurol. 2011, 26(3), 334–340). In adults, there is a late stage of motor deterioration characterized by deteriorating muscle hypotonia, stiffness, and in some cases, deterioration of walking ability and Parkinson's symptoms. The annual mortality rate of affected individuals is between 1% and 2%, with 25% of all deaths characterized as sudden and unanticipated deaths (Kerr et al., “Rett syndrome: analysis of deaths in the British survey,” Eur. Child Adolesc. Psychiatry 1997, 6 Suppl. 1, 71–74; Samaco and Neul 2011 above). Women with RTT can survive into their fifties and occasionally longer (Samaco and Neul 2011 , see above). There are no approved medications for the treatment of Rett syndrome. Current treatment options focus on managing individual patient symptoms, and even in this regard, the results are often unsatisfactory and have limited efficacy in improving function. As a result, the burden on patients' families and other caregivers is significant (Palacios-Ceña et al., "Living an obstacle course: A qualitative study examining the experiences of caregivers of children with Rett syndrome," Int. J. Environ. Res. Public Health 2018, 16(1), 41). In 96% to 98% of patients diagnosed with typical RTT, the disease is caused by an X-linked mutation in the MECP2 gene (Percy et al., "When Rett syndrome is due to genes other that MECP2", Transl. Sci. Rare Dis. 2018, 3(1), 49-53). MECP2 encodes methyl-CpG binding protein 2 (MeCP2), which regulates gene expression by binding to methylated CpG dinucleotides, primarily through activation and also through transcriptional repression (Ip et al., "Rett syndrome: insights into genetic, molecular and circuit mechanisms," 2018, 19(6), 368-382; Neul et al., "Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome," Neurology 2008, 70(16), 1313-1321; Kriaucionis et al., "DNA methylation and Rett syndrome," Hum. Mol. Genet. 2003, 12 Special Issue No. 2, R221-227; Hite et al., "Recent advances in MeCP2 structure and function," Biochem. Cell Biol. 2009, 87(1)). 219-227). The activity of the MeCP2 protein is reduced in both neurons and stellate cells (Yasui et al., "MeCP2 modulates gene expression pathways in astrocytes," Mol. Autism 2013, 4(1), 3). This protein is crucial for the nervous system, especially for brain development. Mutations reduce protein production or cause inaccurate protein production. Without sufficient amounts of the working protein, the brain cannot develop normally, resulting in Rett syndrome.Eight MECP2 mutations constitute the majority of Rett syndrome cases, and the location and type of mutations affect the development and severity of syndrome symptoms. Among them, MECP2T158M and MECP2R106W mutations are the most common (Amir et al., "Rett syndrome is caused by mutations in X-linked MECP2", Nature Genetics 1999, 23(2), 185-188; Percy et al., "Rett syndrome: North American database", J. Child Neurol. 2007, 22(12), 1338-1341). Trifentidine is a synthetic analog of glycine-proline-glutamate (GPE), a peptide naturally found in the brain. GPE is the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1) protein. The structure of trifentidine is shown below. [Figure] Following oral administration, trofentidine crosses the blood-brain barrier. In the brain, it is believed to normalize the reduced bioavailability of IGF-1 and GPE, and possess anti-inflammatory effects on pathologically activated glial cells. Both conditions contribute to defects in synaptic development and functional maturation of synaptic plasticity, which is fundamental to its broad-spectrum effects on RTT. Mechanistically, it is hypothesized that trafentidine reduces neuroinflammation, decreases microglial cell activation and astrogenesis, normalizes protein synthesis and dendritic morphology, and restores homeostasis of excitatory and inhibitory neuronal signal transduction (Lu et al., "Glycyl-L-2-methylprolyl-L-glutamic acid, a glypromate analog, attenuates brain ischemia-induced non-convulsive seizures in rats," J. Cerebr. Blood Flow & Metab. 2009, 29, 1924-1932; Wei et al., "Glycyl-L-2-methylprolyl-L-glutamic acid treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats," J. Neuroinflammation 2009, 6, 19; Deacon et al., "NNZ-2566, a novel analog of (1-3) IGF-1, as a potential therapeutic agent for fragile X syndrome, Neuromol. Med. 2015, 17, 1). GPE treatment in MeCP2 mutant mice reversed Rett syndrome-like symptoms (Tropea et al., "Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice," Proc. Natl. Acad. Sci. USA 2009, 106, 2029-2034). Therefore, trafentidine represents an opportunity to treat Rett syndrome. Such treatments can affect brain structure and function, such as dendritic length and branching, and long-term potentiation, and are expected to induce a wide range of improvement in RTT symptoms. Pharmacokinetic data were available from previous clinical trials of trofinetide in healthy individuals and in individuals with Rett syndrome (the first in adolescents and adults, and the second in children and adolescents) (Oosterholt et al., "Population pharmacokinetics of NNZ-2566 in healthy subjects," Eur. J. Pharm. Sci. 2017, 15, 109S, S98-107; Glaze et al., "A double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome," Neurology 2019, 92(16), e1912-1925). However, in interventional clinical trials, a significant proportion of individuals did not achieve the expected level of exposure to trofinetide. [Summary of the Invention] As discussed in detail herein, analysis of results from human clinical studies indicates that lower-than-expected trafentidine exposure is associated with lower body weight in pediatric individuals. The methods disclosed in this invention involve various dosing regimens aimed at mitigating this problem and / or increasing trafentidine exposure levels in individuals, providing additional benefits, or at least providing applicable options for the public. Specifically, the applicant has unexpectedly discovered that high doses of trafentidine can be safely administered to lower body weight pediatric individuals for the treatment of Rett syndrome. In one embodiment, the present invention provides a method for treating Rett syndrome in an individual of need, the method comprising administering to the individual a therapeutically effective amount of trafentidine, the daily dose being: a) 4 to 10.0 g if the individual weighs between 8 and 11.9 kg; b) 10.1 to 14.0 g if the individual weighs between 12.0 and 20.0 kg; c) 14.1 to 18.0 g if the individual weighs between 20.1 and 35.0 kg; d) 18.1 to 22.0 g if the individual weighs between 35.1 and 50.0 kg; or e) 22.1 to 26 g if the individual weighs between 50.1 and 150 kg. In another embodiment, the present invention provides trafentidine for treating Rett syndrome in an individual, wherein trafentidine is administered in the following daily doses: a) 4 to 10.0 g if the individual weighs between 8 and 11.9 kg; b) 10.1 to 14.0 g if the individual weighs between 12.0 and 20.0 kg; c) 14.1 to 18.0 g if the individual weighs between 20.1 and 35.0 kg; d) 18.1 to 22.0 g if the individual weighs between 35.1 and 50.0 kg; or e) 22.1 to 26 g if the individual weighs between 50.1 and 150 kg. In another embodiment, the present invention provides the use of trafentidine in the manufacture of a pharmaceutical product for treating Rett syndrome in an individual, wherein trafentidine is administered in the following daily doses: a) 4 to 10.0 g if the individual weighs between 8 and 11.9 kg; b) 10.1 to 14.0 g if the individual weighs between 12.0 and 20.0 kg; c) 14.1 to 18.0 g if the individual weighs between 20.1 and 35.0 kg; d) 18.1 to 22.0 g if the individual weighs between 35.1 and 50.0 kg; or e) 22.1 to 26 g if the individual weighs between 50.1 and 150 kg.

Implementation Method

Claims

1. The use of trofinetide in the manufacture of a pharmaceutical product for the treatment of Rett syndrome in patients, wherein trofinetide is administered to the following patient populations at the following daily doses: a) about 10 g for patients weighing between 8 and 11.9 kg; b) about 12 g for patients weighing between 12 and 20 kg; c) about 16 g for patients weighing greater than 20 kg and less than or equal to 35 kg; d) about 20 g for patients weighing greater than 35 kg and less than or equal to 50 kg; and e) about 24 g for patients weighing greater than 50 kg.

2. As requested in claim 1, wherein administration of trafentidine in the patient produces an AUC0-12, ss of approximately 755 μg•h / mL to approximately 1300 μg•h / mL.

3. As requested in claim 1, wherein administration of trafentidine to the patient produces a Cmax, ss of approximately 100 µg / mL to approximately 200 µg / mL in the patient.

4. As requested in item 1, trafentidine shall be administered to the patient daily in two doses totaling the daily dose.

5. As claimed in claim 1, wherein trafentidine shall be administered in the form of a pharmaceutical composition comprising trafentidine and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises water, the pharmaceutical composition is a solution, and the concentration of trafentidine in the solution is approximately 0.2 g / mL.

6. As requested in item 1, wherein the patient has a MECP2 mutation.

7. As requested in claim 1, wherein the Rett syndrome is atypical Rett syndrome.

8. As requested in claim 1, wherein the Rett syndrome is classic / typical Rett syndrome.

9. As requested in item 1, trafentidine shall be administered to the patient daily in three doses totaling the daily dose.

10. As requested in claim 5, wherein the pharmaceutical composition is administered to the patient once in the morning and once in the evening.

11. As claimed in claim 5, wherein the solution is administered orally.

12. As claimed in claim 5, wherein the solution is administered via a gastrostomy tube.

13. As requested in claim 5, wherein the solution is administered via the G port of the gastrojejunal tube.

14. As claimed in claim 5, wherein the solution further comprises maltitol, sodium methylparaben, and sodium propylparaben.

15. For the purposes of claim 1, trafentidine shall be administered to the patient in the following daily doses: a) about 10 g for patients weighing between 8 and 11.9 kg; b) about 12 g for patients weighing between 12 and 20 kg; c) about 16 g for patients weighing more than 20 kg and less than or equal to 35 kg; d) about 20 g for patients weighing more than 35 kg and less than or equal to 50 kg; and e) about 24 g for patients weighing more than 50 kg and less than or equal to 100 kg.

16. As requested in paragraph 15, wherein trafentidine is administered to the patient daily in two doses totaling the daily dose.

17. As claimed in claim 16, wherein trafentidine shall be administered orally, via a gastrostomy tube, or via a G-port of a gastrojejunal tube in the form of a pharmaceutical composition comprising trafentidine and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises water, the pharmaceutical composition is a solution, and the concentration of trafentidine in the solution is about 0.2 g / mL.

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