Clinical trial NCT05481879: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myotonic Dystrophy Type 1 (DM1)
Lead sponsor: Dyne Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-08-01
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 (144 weeks) in both multiple-ascending dose (MAD) and dose expansion cohorts.


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, 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.

Primary outcomes:
measure: MAD Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Through study completion, up to Week 193
measure: Dose Expansion Cohorts: Change From Baseline in Composite Alternative Splicing Index (CASI) in Skeletal Muscle Tissue up to Week 13
timeFrame: Baseline up to Week 13
Secondary outcomes:
measure: MAD Cohorts: Change From Baseline in CASI in Skeletal Muscle Tissue
timeFrame: Baseline up to Week 45
measure: MAD Cohorts: Change From Baseline in Dystrophia Myotonica Protein Kinase (DMPK) Ribonucleic Acid (RNA) Expression in Muscle Tissue
timeFrame: Baseline up to Week 45
measure: MAD Cohorts: Change From Baseline in Hand Grip Relaxation Time
timeFrame: Baseline up to Week 121
measure: MAD Cohorts: Change From Baseline in Myotonia as Measured by Video Hand Opening Time (vHOT)
timeFrame: Baseline up to Week 193
measure: MAD Cohorts: Change From Baseline in Quantitative Myometry Testing (QMT)
timeFrame: Baseline up to Week 193
measure: MAD Cohorts: Change From Baseline in 10-Meter Walk/Run Test (10-MWRT)
timeFrame: Baseline up to Week 193
measure: MAD Cohorts: Change From Baseline in Stair-Ascend/Descend Test
timeFrame: Baseline up to Week 121
measure: MAD Cohorts: Change From Baseline in 5 Times Sit to Stand (5×STS)
timeFrame: Baseline up to Week 193
measure: MAD Cohorts: Change From Baseline in 9-Hole Peg Test (9-HPT)
timeFrame: Baseline up to Week 193
measure: MAD Cohorts: Maximum Observed Plasma Drug Concentration (Cmax) of DYNE-101
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Time to Maximum Observed Plasma Concentration (tmax) of DYNE-101
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Plasma Concentration (AUCtlast) of DYNE-101
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC∞) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Apparent Terminal Elimination Rate Constant (λz) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Apparent Terminal Elimination Half-Life (t1/2) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Clearance (CL) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Volume of Distribution at the Terminal Phase (Vz) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Volume of Distribution at Steady State (Vss) of DYNE-101 in Plasma
timeFrame: Pre-dose, and at multiple timepoints up to Week 193
measure: MAD Cohorts: Antisense Oligonucleotide (ASO) Concentration of DYNE-101 in Muscle Tissue
timeFrame: Up to Week 45
measure: MAD Cohorts: Number of Participants With Antidrug Antibodies (ADAs)
timeFrame: Up to Week 193
measure: Dose Expansion Cohorts: Change From Baseline in Myotonia as Measured by vHOT up to Week 25
timeFrame: Baseline up to Week 25
measure: Dose Expansion Cohorts: Change From Baseline in 10-MWRT up to Week 25
timeFrame: Baseline up to Week 25
measure: Dose Expansion Cohorts: Change From Baseline in QMT up to Week 25
timeFrame: Baseline up to Week 25
measure: Dose Expansion Cohorts: Change From Baseline in 5×STS up to Week 25
timeFrame: Baseline up to Week 25
measure: Dose Expansion Cohorts: Change From Baseline in Myotonic Dystrophy Health Index (MDHI) Total Score up to Week 25
timeFrame: Baseline up to Week 25
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut de Myologie
city: Munich
country: Germany
facility: Ludwig Maximilians University, Munich - Friedrich Baur Institut
city: Milan
country: Italy
facility: Centro Clinico Nemo
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario A Gemelli-Rome
city: Nijmegen
country: Netherlands
facility: Radboud Medical Center
city: Auckland
country: New Zealand
facility: NZCR Auckland
city: London
country: United Kingdom
facility: University College London Hospitals
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: John Walton Muscular Dystrophy Research Centre
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
Study officials:
References: