Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies

NCT04033159 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: DYN101-C101
• Study Type: interventional
• Target: 14
• Locations: 6 countries
• Sites: 8

Brief Summary

There are no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)/preliminary efficacy of a new medicine called DYN101 in patients ≥ 16 years of age with CNM caused by mutations in Dynamin2 (DNM2) or Myotubularin1 (MTM1). The trial will consist of a consent, a screening period, a run-in period (if applicable), a Single dose treatment part (SAD) with 4 weeks of follow-up after the drug administration and a washout period of at least 12 weeks (followed by follow-up phone calls), a Multiple dose treatment part (MAD) of 12 weeks of weekly dosing, and a Multiple dose extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. During this time, multiple test will be performed in order to better understand how the drug is distributed and then later removed from the body and whether there any signs of an effect. As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their disease.

Conditions

Centronuclear Myopathy

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Drug-related Treatment Emergent Adverse Events (TEAEs)

  Number of participants with drug-related TEAEs during the study period.

  Baseline until Study termination, up to 28 months

Study Arms (3)

cohort 1

EXPERIMENTAL

DYN101 in a low dose (1.5 mg/kg), (unless the independent data monitoring committee \[IDMC\] advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).

Drug: DYN101

cohort 2

EXPERIMENTAL

DYN101 in a middle dose (4.5 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).

Drug: DYN101

cohort 3

EXPERIMENTAL

DYN101 in a high dose (9 mg/kg), (unless the IDMC advises otherwise). In each cohort, there will be 3-4 subjects with a mutation in DNM2 (subcohort a) and 2-3 subjects with a mutation in MTM1 (subcohort b).

Drug: DYN101

Interventions

DYN101 DRUG

DYN101, is a constrained ethyl gapmer ASO directed against human DNM2 RNA

Also known as: there is no other intervention name

cohort 1; cohort 2; cohort 3

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged ≥ 16 years on the date of signing the main Informed Consent Form (ICF).
• Have a documented mutation in DNM2 or MTM1.
• Have a symptomatic CNM in the opinion of the investigator, at least mild to moderately affected, i.e. showing clinical symptoms in at least 2 of the relevant 4 domains that will be investigated in this trial (respiratory, muscle strength, muscle function, and dysphagia), and be ambulatory, i.e. being able to walk 10 steps, if needed with support/assisted. If a subject is non-ambulatory but highly functioning in the view of the investigator, he/she may be included following discussion with the sponsor.
• \. Have an understanding, ability, and willingness to fully comply with visit frequency, trial procedures and restrictions, including contraceptive requirements.
• \. Able to provide written, signed and dated informed consent/assent to participate in the trial. Parental consent (one or both parents) and an assent for subjects \< 18 years may be required per local legislation.

You may not qualify if:

• Clinically significant liver disease.
• Clinically significant renal disease.
• Presence of significant co-morbidities or conditions other than CNM or clinically significant (CS) findings during screening of medical history, physical examination, laboratory testing, vital signs or ECG recording for which, in the opinion of the investigator and the medical monitor, participation would not be in the best interest of the subject (e.g. compromise the safety or well-being) or that could prevent, limit, or confound the protocol-specified assessments (e.g. taking a muscle biopsy).
• For female subjects of child-bearing potential: pregnant or breastfeeding, or planning to become pregnant during the trial.
• Current or past abuse of alcohol or recreational/narcotic drugs (with the exception of caffeine and nicotine), which in the investigator's opinion would compromise the subject's safety and/or compliance with the trial procedures.
• Currently enrolled in any interventional trial or scheduled to participate in such a trial whilst participating in this trial. Subjects are allowed to participate in registry studies.
• Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the IMP or procedures.
• Intake of any disallowed therapies as noted in Section 5.5 within 12 weeks before the planned first IMP administration.
• Known or suspected intolerance or hypersensitivity to IMP ingredients or closely-related compounds, or history of a significant allergic reaction to IMP ingredients as determined by the investigator, such as anaphylaxis requiring hospitalization.
• Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully understand the protocol requirements and complete all study required procedures.

Sponsors & Collaborators

• Dynacure: lead

Study Sites (8)

Antwerp University Hospital (UZA)

Edegem, Belgium

Location

Rigshospitalet, Copenhagen Neuromuscular Center, Neurocentret

Copenhagen, Denmark

Location

Institut de Myologie

Paris, France

Location

universitätsklinikum Essen, Kinderklinik I, Sozialpädiatrisches Zentrum

Essen, Germany

Location

Friedrich Baur Institut - Neurologische Klinik LMV, Klinikum Innenstadt

München, Germany

Location

Radboud University Medical Centre

Nijmegen, Netherlands

Location

MRC centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery

London, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, United Kingdom

Location

Related Links

• Background info published in Nature on: "Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice."

MeSH Terms

Conditions

Myopathies, Structural, Congenital

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Results Point of Contact

• Title: Dynacure
• Organization: Dynacure

info@dynacure.com

+33 3 74 95 20 50

Study Officials

• Chris Freitag, MD

  Dynacure

  STUDY DIRECTOR

• N.C. Voermans, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Trial consisting of pre-screening consent, screening period, run-in period (if applicable), SAD part with 4 weeks follow-up after IMP and washout period of ≥ 12 weeks, MAD part of 12 weeks and MAD extension part of 12 weeks. All subjects to participate in SAD, MAD, and MAD extension unless they withdraw. Subjects to receive DYN101 in a low (1.5 mg/kg), middle (4.5 mg/kg) or high (9 mg/kg) dose in Cohorts 1, 2 and 3 respectively, and remain on assigned dose throughout the trial (unless IDMC advises otherwise). Each cohort will have 3-4 subjects with a DNM2 mutation and 2-3 subjects with a MTM1 mutation. Cohorts will enroll in a sequential staggered approach with an interval of ≥7 days between dosing of the first and the next subject in a cohort (after Medical Monitor 48hr safety data review).

Study Record Dates

• First Submitted: June 12, 2019
• First Posted: July 25, 2019
• Study Start: January 9, 2020
• Primary Completion: June 22, 2022
• Study Completion: June 22, 2022
• Last Updated: June 27, 2023
• Results First Posted: June 27, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); FR (1); NL (1); DE (2); DK (1); GB (2)