Safety, Tolerability, Pharmacodynamic, Efficacy, and Pharmacokinetic Study of DYNE-101 in Participants With Myotonic Dystrophy Type 1

Official title

A Randomized, Placebo-Controlled, Multiple Ascending Dose Study Assessing Safety, Tolerability, Pharmacodynamics, Efficacy, and Pharmacokinetics of DYNE-101 Administered to Participants With Myotonic Dystrophy Type 1

Overview

The primary purpose of the study is to evaluate the safety and tolerability of multiple intravenous (IV) doses of DYNE-101 administered to participants with Myotonic Dystrophy Type 1 (DM1). The study consists of 4 periods: A Screening Period (up to 8 weeks), a Placebo-Controlled Period (24 weeks), a Treatment Period (24 weeks) and a Long-Term Extension (LTE) Period (168 weeks) in both multiple-ascending dose (MAD) and dose expansion cohorts.

Interventions

• Drug DYNE-101
  Administered by IV infusion
• Drug Placebo
  Administered by IV infusion

Primary outcome measures

• MAD Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Time frame: Through study completion, up to Week 217]
• Dose Expansion Cohorts: Change From Baseline in Myotonia as Measured by Video Hand Opening Time (vHOT) [Time frame: Baseline up to Week 25]

Secondary outcome measures (12)

• MAD Cohorts: Change From Baseline in Composite Alternative Splicing Index (CASI) in Skeletal Muscle Tissue [Time frame: Baseline up to Week 45]
• MAD Cohorts: Change From Baseline in Dystrophia Myotonica Protein Kinase (DMPK) Ribonucleic Acid (RNA) Expression in Muscle Tissue [Time frame: Baseline up to Week 45]
• MAD Cohorts: Change From Baseline in Hand Grip Relaxation Time [Time frame: Baseline up to Week 121]
• MAD Cohorts: Change From Baseline in Myotonia as Measured by vHOT [Time frame: Baseline up to Week 193]
• MAD Cohorts: Change From Baseline in Quantitative Myometry Testing (QMT) [Time frame: Baseline up to Week 193]
• MAD Cohorts: Change From Baseline in 10-Meter Walk/Run Test (10-MWRT) [Time frame: Baseline up to Week 193]
• MAD Cohorts: Change From Baseline in Stair-Ascend/Descend Test [Time frame: Baseline up to Week 121]
• MAD Cohorts: Change From Baseline in 5 Times Sit to Stand (5×STS) [Time frame: Baseline up to Week 193]
• MAD Cohorts: Change From Baseline in 9-Hole Peg Test (9-HPT) [Time frame: Baseline up to Week 193]
• MAD Cohorts: Maximum Observed Plasma Drug Concentration (Cmax) of DYNE-101 [Time frame: Pre-dose, and at multiple timepoints up to Week 217]
• MAD Cohorts: Time to Maximum Observed Plasma Concentration (tmax) of DYNE-101 [Time frame: Pre-dose, and at multiple timepoints up to Week 217]
• MAD Cohorts: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Plasma Concentration (AUCtlast) of DYNE-101 [Time frame: Pre-dose, and at multiple timepoints up to Week 217]

Eligibility criteria

Inclusion criteria

• Diagnosis of DM1 with trinucleotide repeat size >100.
• Age of onset of DM1 muscle symptoms ≥12 years.
• Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds in the opinion of the Investigator.
• Hand grip strength and ankle dorsiflexion strength.
• Able to complete 10-MWRT, stair ascend/descend (MAD cohorts only), and 5×STS at screening without the use of assistive devices such as canes, walkers, or orthoses.

Exclusion criteria

• History of major surgical procedure within 12 weeks prior to the start of investigative product administration or an expectation of a major surgical procedure (eg, implantation of cardiac defibrillator) during the study.
• History of anaphylaxis.
• Medical condition other than DM1 that would significantly impact ambulation or participation in functional assessments.
• Treatment with medications that can improve myotonia within a period of 5 half-lives of the medication prior to performing screening assessments.
• Electrocardiogram (ECG) with the corrected QT interval by Fridericia's Formula (QTcF) ≥450 milliseconds (ms) in men and QTcF ≥460 ms in women, PR ≥240 ms, left bundle-branch block, or a conduction defect, which is clinically significant in the opinion of the Investigator.
• Percent predicted forced vital capacity (FVC) <50%.
• History of tibialis anterior biopsy within 3 months of Day 1 or planning to undergo tibialis anterior biopsies during study period for reasons unrelated to the study.
• Participant has a history of suicide attempt, suicidal behavior, or has any suicidal ideation within 6 months prior to Screening that meets criteria at a level of 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) or who, in the opinion of the Investigator, is at significant risk to commit suicide.
• Use of glucagon-like peptide 1 (GLP-1) agonist medications including semaglutide, dulaglutide, liraglutide, exenatide, or tirzepatide within a period of 5 half-lives of the medication prior to performing screening assessments.
• Significant weight loss during study participation may impact weight-based dosing, performance on muscle function assessments, and pharmacodynamic (PD) biomarkers.

Note: Other inclusion and exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 8 centers

• Stanford University — Stanford
• University of Florida College of Medicine — Gainesville
• Indiana University School of Medicine — Indianapolis
• University of Iowa — Iowa City
• Washington University in St. Louis — St Louis
• University of Rochester Medical Center — Rochester
• Neurology Rare Disease Center — Denton
• Virginia Commonwealth University (VCU) — Richmond

United Kingdom · 3 centers

• University College London Hospitals — London
• John Walton Muscular Dystrophy Research Centre — Newcastle upon Tyne
• Salford Royal Hospital — Salford

France · 2 centers

• CHU de Nantes — Nantes
• Institut de Myologie — Paris

Germany · 2 centers

• Charité - Universitätsmedizin Berlin — Berlin
• Ludwig Maximilians University, Munich - Friedrich Baur Institut — Munich

Italy · 2 centers

• Centro Clinico Nemo — Milan
• Fondazione Policlinico Universitario A Gemelli-Rome — Rome

Australia · 1 center

• St. Vincent's Hospital — Fitzroy

Netherlands · 1 center

• Radboud Medical Center — Nijmegen

New Zealand · 1 center

• NZCR Auckland — Auckland

Identifiers

NCT: NCT05481879 · DYNE101-DM1-201 · 2023-510353-42-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗