title: 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.
abstract: OBJECTIVE
  SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage.
  
  
  METHODS
  This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A-C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study.
  
  
  RESULTS
  Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing.
  
  
  CONCLUSIONS
  SMT C1100 was well tolerated in pediatric DMD patients.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02383511.
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ricotti
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Spinty
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Roper
authors.affiliation: Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, United Kingdom.
authors.forename: Imelda
authors.initials: I
authors.lastname: Hughes
authors.affiliation: Summit Therapeutics, Abingdon, United Kingdom.
authors.forename: Bina
authors.initials: B
authors.lastname: Tejura
authors.affiliation: S.H.B. Enterprises Limited, Beaconsfield, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Robinson
authors.affiliation: ParamStat Limited, Ash, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, United Kingdom.
authors.forename: Kay
authors.initials: K
authors.lastname: Davies
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Summit Therapeutics, Abingdon, United Kingdom.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Tinsley
mesh_terms: D001583:Benzoxazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D049411:Utrophin / Q000378:metabolism*
chemical_list: D001583:Benzoxazoles; C000610115:SMT C1100; C483599:UTRN protein, human; D049411:Utrophin