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

• ClinicalTrials.gov Identifier: NCT04033159
• Recruitment Status: Terminated
• First Posted: July 25, 2019
• Results First Posted: June 27, 2023
• Last Update Posted: June 27, 2023
• Sponsor: Dynacure
• Information provided by (Responsible Party): Dynacure

Tracking Information

• First Submitted Date: June 12, 2019
• First Posted Date: July 25, 2019
• Results First Submitted Date: March 23, 2023
• Results First Posted Date: June 27, 2023
• Last Update Posted Date: June 27, 2023
• Actual Study Start Date: January 9, 2020
• Actual Primary Completion Date: June 22, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2023)

Number of Participants With Drug-related Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline until Study termination, up to 28 months ]

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

Original Primary Outcome Measures (submitted: July 24, 2019)

incidence of drug-related Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline until Week 25 ]

Incidence of drug-related, treatment-emergent AEs during the study period (through to Week 25).

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies
• Official 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.

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.

Detailed Description

There are currently no available treatments aside from supportive care for patients with Centronuclear myopathy (CNM). This trial will assess the safety, tolerability, PK and PD/preliminary efficacy of DYN101 in patients ≥ 16 years of age with CNM caused by mutations in DNM2 or MTM1.

DYN101 is a synthetically manufactured constrained ethyl gapmer antisense oligonucleotide (ASO) directed against DNM2 pre-messenger ribonucleic acid (mRNA). DYN101 will be provided as a sterile concentrated solution for reconstitution into an infusion solution for intravenous (IV) administration, and will be diluted into a 0.9% sodium chloride solution before administration.

The trial will consist of a pre-screening consent, a screening period, a run-in period (if applicable), a SAD part with 4 weeks of follow-up after investigational medicinal product (IMP) administration and a washout period of at least 12 weeks (followed by follow-up phone calls until the MAD part starts), a MAD part of 12 weeks, and a MAD extension part of 12 weeks. All subjects will participate in the SAD, MAD, and MAD extension parts, unless they withdraw. End-of-treatment assessments will be performed after 24 weeks of MAD treatment have been completed, i.e. at the Week 25 visit. Subjects will be followed up on adverse events (AEs) and concomitant medications 3 months after the last IMP administration.

An interim analysis will be performed when all subjects in cohort 1 and 2 have completed 12 weeks of MAD treatment. The primary analysis will be performed when all subjects in all cohorts have completed 12 weeks of MAD treatment or discontinued earlier. The final analysis will be performed when all subjects have completed 24 weeks of MAD treatment (12 weeks in the MAD part + 12 weeks in the MAD extension part; Week 25 visit) or discontinued earlier.

As this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their pathology, and the knowledge that they contribute to RNA-targeted therapy for CNM patients carrying MTM1 and DNM2 mutations.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

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).

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Centronuclear Myopathy

Intervention

Drug: DYN101

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

Other Name: there is no other intervention name

Study Arms

• Experimental: cohort 1
  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).
  Intervention: Drug: DYN101
• Experimental: cohort 2
  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).
  Intervention: Drug: DYN101
• Experimental: cohort 3
  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).
  Intervention: Drug: DYN101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 2, 2023): 14
• Original Estimated Enrollment (submitted: July 24, 2019): 18
• Actual Study Completion Date: June 22, 2022
• Actual Primary Completion Date: June 22, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Male or female aged ≥ 16 years on the date of signing the main Informed Consent Form (ICF).
2. Have a documented mutation in DNM2 or MTM1.
3. 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.

5. Have an understanding, ability, and willingness to fully comply with visit frequency, trial procedures and restrictions, including contraceptive requirements.

6. 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.

Exclusion Criteria:

1. Clinically significant liver disease.
2. Clinically significant renal disease.
3. 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).
4. For female subjects of child-bearing potential: pregnant or breastfeeding, or planning to become pregnant during the trial.
5. 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.
6. 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.
7. 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.
8. Intake of any disallowed therapies as noted in Section 5.5 within 12 weeks before the planned first IMP administration.
9. 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.
10. Legally incapacitated or have limited legal capacity. Lack of mental capacity to fully understand the protocol requirements and complete all study required procedures.

Note: Retesting of subjects should always be discussed with the sponsor and/or medical monitor. Retesting of laboratory values that lead to exclusion will be allowed once using an unscheduled visit during the screening period to assess eligibility. This visit should be at least 2 weeks later than the original screening visit.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Denmark, France, Germany, Netherlands, United Kingdom
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT04033159
• Other Study ID Numbers: DYN101-C101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Dynacure
• Original Responsible Party: Same as current
• Current Study Sponsor: Dynacure
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chris Freitag, MD; Dynacure
• Principal Investigator: N.C. Voermans, MD, PhD; Radboud University Medical Center

• PRS Account: Dynacure
• Verification Date: June 2023