Safety, tolerability, and pharmacokinetics of SMT c1100, a 2-arylbenzoxazole utrophin modulator, following single-and multiple-dose administration to pediatric patients with duchenne muscular dystrophy

PLoS ONE

Volumn 11, Issue 4, 2016, Pages

  Ricotti, Valeria ^a   Spinty, Stefan ^b   Roper, Helen ^c   Hughes, Imelda ^d   Tejura, Bina ^e   Robinson, Neil ^f   Layton, Gary ^g   Davies, Kay ^h   Muntoni, Francesco ^a   Tinsley, Jonathon ^e  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b ALDER HEY CHILDREN'S NHS FOUNDATION TRUST   (United Kingdom)

^c BIRMINGHAM HEARTLANDS HOSPITAL   (United Kingdom)

^d ROYAL MANCHESTER CHILDREN S HOSPITAL   (United Kingdom)

^e SUMMIT PLC   (United Kingdom)

^f SHB Enterprises Limited   (United Kingdom)

^g ParamStat Limited   (United Kingdom)

^h UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ANALGESIC AGENT; ASPARTATE AMINOTRANSFERASE; CREATINE KINASE; EZUTROMID; BENZOXAZOLE DERIVATIVE; UTRN PROTEIN, HUMAN; UTROPHIN;

ABDOMINAL PAIN; ABNORMAL BEHAVIOR; AREA UNDER THE CURVE; ARTICLE; CHILD; CLINICAL ARTICLE; CONSTIPATION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; COUGHING; DIARRHEA; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DUCHENNE MUSCULAR DYSTROPHY; DYSPEPSIA; ECZEMA; ERYTHEMA; FLATULENCE; GASTROINTESTINAL DISEASE; HEADACHE; HUMAN; LIMIT OF QUANTITATION; MALE; MAXIMUM PLASMA CONCENTRATION; MOOD DISORDER; MORNING DOSAGE; MULTICENTER STUDY; MUSCLE INJURY; OTALGIA; OUTCOME ASSESSMENT; PALLOR; PHASE 1 CLINICAL TRIAL; RASH; SINGLE DRUG DOSE; SKIN ALLERGY; TOOTH PAIN; UPPER ABDOMINAL PAIN; BLOOD; CLINICAL TRIAL; METABOLISM; MUSCULAR DYSTROPHY, DUCHENNE; PATHOLOGY; PRESCHOOL CHILD;

BENZOXAZOLES; CHILD; CHILD, PRESCHOOL; HUMANS; MALE; MUSCULAR DYSTROPHY, DUCHENNE; UTROPHIN;

EID: 84963622982     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0152840     Document Type: Article

References (14)

1. Emery AE. Population frequencies of inherited neuromuscular diseases-a world survey. Neuromuscul Disord. 1991; 1: 19-29. PMID: 1822774.
2. Van Deutekom JC, van Ommen GJ. Advances in Duchenne muscular dystrophy gene therapy. Nat Rev Genet 2003; 4: 774-784. PMID: 14526374.
3. Squire S, Raymackers JM, Vandebrouck C, Potter A, Tinsley J, Fischer R, et al. Prevention of pathology in mdx mice by expression of utrophin: Analysis using an inducible transgenic expression system. Hum Mol Genet 2002; 11: 3333-3344. PMID: 12471059.
4. Tinsley J, Deconinck N, Fisher R, Kahn D, Phelps S, Gillis JM, et al. Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat Med 1998; 4: 1441-1444. PMID: 9846586.
5. Chakkalakal JV, Stocksley MA, Harrison MA, Angus LM, Deschenes-Furry J, St-Pierre S, et al Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling. Proc Natl Acad Sci USA 2003; 100: 7791-7796. PMID: 12808150.
6. Dennis CL, Tinsley JM, Deconinck AE, Davies KE. Molecular and functional analysis of the utrophin promoter. Nucleic Acids Res 1996; 24: 1646-1652. PMID: 8649981.
7. Chancellor DR, Davies KE, De Moor O, Dorgan CR, Johnson PD, Lambert AG, et al. Discovery of 2- Arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy. J Med Chem 2011; 54: 3241-3250. doi:10.1021/jm200135z PMID: 21456623.
8. Tinsley JM, Fairclough RJ, Storer R, Wilkes FJ, Potter AC, Squire SE, et al. Daily treatment with SMTC1100, a novel small molecule utrophin upregulator, dramatically reduces the dystrophic symptoms in the mdx mouse. PLoS One 2011; 6: e19189doi:10.1371/journal.pone.0019189 PMID: 21573153.
9. Tinsley J, Robinson N, Davies KE. Safety, tolerability, and pharmacokinetics of SMT C1100, a 2-arylbenzoxazole utrophin modulator, following single- And multiple-dose administration to healthy male adult volunteers. J Clin Pharmacol 2015; 55: 698-707doi:10.1002/jcph.468 PMID: 25651188.
10. Milic Rasic V, Vojinovic D, Pesovic J, Mijalkovic G, Lukic V, Mladenovic J, et al. Intellectual ability in the Duchenne muscular dystrophy and dystrophin gene mutation location. Balkan J Med Genet 2014; 17: 25-36. doi:10.2478/bjmg-2014-0071 PMID: 25937795.
11. Ricotti V, Mandy WP, Scoto M, Pane M, Deconinck N, Messina S, et al. Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations. Dev Med Child Neurol 2016; 58: 77-84. doi:10.1111/dmcn.12922 PMID: 26365034.
12. Tanaka K, Takeshita K, Suganuma I, Kasagi S. Low serum cholic acid concentration of duchenne muscular dystrophy. Brain Devel 1983; 5: 511-513.
13. Finkel RS, Flanigan KM, Wong B, Bönnemann C, Sampson J, Sweeney HL, et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One 2013; 8: e81302. doi:10.1371/journal.pone.0081302PMID: 24349052.
14. Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): An exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 2014; 13: 987-996. doi:10.1016/S1474-4422(14)70195-4 PMID: 25209738.