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

PurposeSMT 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.MethodsThis 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.ResultsMost 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.ConclusionsSMT C1100 was well tolerated in pediatric DMD patients.Trial RegistrationClinicalTrials.gov NCT02383511

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…The use of SMT C1100 translated into improvement of muscle morphology and functionality, with utrophin detected also in heart and diaphragm in mdx mice [43]. A phase I clinical trial showed that SMT C1100 is safe and well tolerated [44]. Neuregulin 1/heregulin beta 1 (NRG1/HRGβ1) is a factor that controls the expression of utrophin at the NMJ, through the interaction with erbB/HER receptor and the utrophin A promoter, after GABPα/β activation by the ERK pathway [45].…”

Identification of serum protein biomarkers for utrophin based DMD therapy

“…Glucocorticoid treatment is the current standard of care which delays the loss of ambulation by 3-4 years 7,8 but shows no long treatment benefit and is often associated with debilitating side effects [9][10][11] . The urgency to seek a therapy for DMD has resulted in parallel efforts to develop exon skipping 12,13 , termination codon read through 14 , dystrophin gene replacement or editing therapies 15,16 and non-dystrophin strategies [17][18][19] such as utrophin modulation 20,21 . However, despite the recent accelerated approval of Exondys 51 (eteplirsen) in US, disappointing clinical trials results 22 and failure of approval from the FDA for Ataluren 23 and Kyndrisa 24 drugs rekindle discussions about clinical trials designs and endpoints.…”

Advances in the Treatment of Duchenne Muscular Dystrophy: New and Emerging Pharmacotherapies

“…In adult muscles, dystrophin is more prevalent than utrophin. Utrophin is localized to the neuromuscular and myotendinous junctions and upregulated only when a muscle is being repaired . The expression and prevalence of utrophin is increased in DMD but not to the extent that would decrease dystrophic symptoms .…”