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

Purpose: 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.

Trial registration: ClinicalTrials.gov NCT02383511.

Conflict of interest statement

Competing Interests: This study was funded by Summit Therapeutics. JT and BT are employees of Summit Therapeutics. NR is employed by SHB Enterprises Limited. GL is employed by ParamStat Limited. NR and GL are paid consultants to Summit Therapeutics. KED is a shareholder in Summit Therapeutics. FM is involved as a Chief Investigator in a Summit Clinical trial of SMT C1100. He is also Chief Investigator of a Sarepta sponsored clinical trial; and Principal investigator of ISIS Pharmaceutics / Biogen; Roche; PTC and Prosensa/ Biomarin sponsored clinical trials. FM is a current member of the Pfizer Rare Disease Scientific Advisory Board and has provided ad hoc consultancies for Nicox; Italfarmaco; Ashaki, Summit Therapeutics, Roche and PTC Therapeutics. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study flow chart showing a multiple ascending dose design.

Fig 2

Individual plasma concentrations of SMT C1100 for each of four patients in Groups A (black line), B (red line) and C (blue line). Group A patients received a single 50 mg/kg dose on Day 1 and on the morning of Day 11, with 50 mg/kg bid on Days 2 to 10. Group B and Group C patients received a single 100 mg/kg dose on Day 1 and on the morning of Day 11, with 100 mg/kg bid (Group B) or 100 mg/kg tid (Group C) on Days 2 to 10.

Fig 3. Plot of the average reduction from baseline (estimate, square) of the following plasma markers: creatine phosphokinase (CPK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), gamma-glutamyl transferase (GGT), and albumen (ALB).

Upper and lower 95% confidence intervals for the following time points after dosing shown: Day 7, Day 12, and follow-up (3 days after completion of dosing).

Fig 4. Individual patient waterfall plots of gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), and alanine aminotransferase (ALT) showing changes from baseline after 10 days of dosing with SMT C1100.

Fig 5. Comparison of the average plasma levels of SMT C1100 from the 10 Duchenne muscular dystrophy pediatric patients (DMD fed) who had unexpectedly low exposure to SMT C1100 compared with the average plasma level of five healthy volunteers (HV) fasted prior to a single 200 mg/kg dose of SMT C1100.