Research Using an Investigational Treatment for CNM (Unite-CNM)
Research type
Research Study
Full title
A Phase 1/2 trial on the safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of DYN101 in patients ≥ 16 years of age with centronuclear myopathies caused by mutations in DNM2 or MTM1.
IRAS ID
263607
Contact name
Rosaline Quinlivan
Contact email
Sponsor organisation
Dynacure SAS
Eudract number
2018-004089-33
Duration of Study in the UK
1 years, 7 months, 28 days
Research summary
Summary of Research
Centronuclear myopathies (CNMs) are a group of severe, debilitating, non-dystrophic, congenital myopathies, for which no effective therapy is currently available. CNMs are characterized by muscle weakness, fiber atrophy, predominance of type I fibers, and increased centralization of nuclei not secondary to muscle regeneration.
The aim of the study is to investigate the study drug: DYN101, in patients ≥ 16 years of age with a rare muscle disease group called the centronuclear myopathies caused by genetic changes in DNM2 or MTM1 for the drug's safety, tolerability, how the body processes the drug as well as interactions of the drug with the body and preliminary effects of the drug.
The study will consist of a pre-screening, screening, treatment and washout period, for a period of 25 weeks.
Subjects will receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg) or high (9 mg/kg) dose level in Cohorts 1, 2 and 3, respectively, and will remain on the assigned dose level throughout the trial (unless the IDMC advises otherwise). In each cohort, there will be 3 subjects with a mutation in DNM2 (subcohort a) and 3 subjects with a mutation in MTM1 (subcohort b).
Summary of Results
This was a first-in-human, Phase 1/2, open-label, multicenter trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of DYN101 after single ascending dose (SAD) and multiple ascending dose (MAD) in subjects ≥16 years of age with CNMs caused by mutations in DNM2 or MTM1.
The current clinical study DYN101-C101 was originally designed to test the safety, tolerability and efficacy of DYN101 and to examine the pharmacokinetic behavior of 3 different doses (low: 1.5 mg/kg, mid: 4.5 mg/kg and high: 9 mg/kg). Overall, 26 subjects were screened. Of these, 12 (46.2%) subjects failed screening. A total of 14 subjects were enrolled and treated: 6 subjects in Cohort 1 (3 subjects with a mutation in DNM2 and 3 subjects with a mutation in MTM1) received 1.5 mg/kg dose first as unique dose then few months later on a weekly basis, and 8 subjects in Cohort 2 (5 subjects with a mutation in DNM2 and 3 subjects with a mutation in MTM1) received 4.5 mg/kg dose as unique dose only.
There were no signs of clinical efficacy observed in this study. None of the subjects completed the study in either Cohort. Overall, the majority of subjects (9 subjects [64.3%]) had at least one pre-therapy adverse Event (AE) in the SAD Cohort. All subjects (14 subjects [100.0%]) experienced at least one AE during treatment (TEAE), and 11 subjects (78.6%; 5 subjects [62.5%] in SAD Cohort and 6 subjects [100.0%] in MAD Cohort) experienced TEAEs related to the treatment.
Due to safety concerns the weight-based dosing was changed from actual body weight to ideal body weight dosing and then the study was terminated early, leading to reduced information on PK.
Overall Conclusions:
DYN101 at repeated doses of 1.5 mg/kg was not well tolerated in CNM patients
DYN101 at repeated doses of 1.5 mg/kg did not show any clinical efficacy in CNM patients.REC name
London - City & East Research Ethics Committee
REC reference
19/LO/0911
Date of REC Opinion
26 Jul 2019
REC opinion
Further Information Favourable Opinion