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

Study Overview
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Brief Summary
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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 multiple-ascending dose (MAD) Placebo-Controlled Period (24 weeks), a Treatment Period (24 weeks) and a Long-Term Extension (LTE) Period (96 weeks).

Official Title
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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

Conditions
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Myotonic Dystrophy Type 1 (DM1)

Intervention / Treatment
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* Drug: DYNE-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Note: Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo-Controlled MAD Period: DYNE-101<br>Participants will be randomized to receive ascending doses of DYNE-101, once every 4 weeks (Q4W) or once every 8 weeks (Q8W) for up to 24 weeks. | Drug: DYNE-101<br>* Administered by IV infusion<br>|
| Placebo Comparator: Placebo-Controlled MAD Period: Placebo<br>Participants will be randomized to receive DYNE-101 matching placebo, Q4W or Q8W for up to 24 weeks. | Drug: Placebo<br>* Administered by IV infusion<br>|
| Experimental: Treatment Period: DYNE-101<br>Participants who receive DYNE-101 in Placebo-Controlled Period will continue to receive DYNE-101, Q4W or Q8W for up to 24 weeks. Participants who receive placebo in Placebo-Controlled Period will receive DYNE-101, Q4W or Q8W for up to 24 weeks. | Drug: DYNE-101<br>* Administered by IV infusion<br>Drug: Placebo<br>* Administered by IV infusion<br>|
| Experimental: Long-Term Extension Period: DYNE-101<br>Participants will receive DYNE-101, Q4W or Q8W for up to 96 weeks. | Drug: DYNE-101<br>* Administered by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Through study completion, up to Week 145 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Splicing Index in Skeletal Muscle Tissue |  | Baseline up to Week 97 | 
| Change From Baseline in Dystrophia Myotonica Protein Kinase (DMPK) Ribonucleic Acid (RNA) Expression in Muscle Tissue |  | Baseline up to Week 97 | 
| Change From Baseline in Hand Grip Relaxation Time |  | Baseline up to Week 145 | 
| Change From Baseline in Myotonia as Measured by Video Hand Opening Time (vHOT) |  | Baseline up to Week 145 | 
| Change From Baseline in Quantitative Myometry Testing (QMT) |  | Baseline up to Week 145 | 
| Change From Baseline in 10-Meter Walk/Run Test (10-MWRT) |  | Baseline up to Week 145 | 
| Change From Baseline in Stair-Ascend/Descend Test |  | Baseline up to Week 145 | 
| Change From Baseline in 5 Times Sit to Stand (5×STS) |  | Baseline up to Week 145 | 
| Change From Baseline in 9-Hole Peg Test (9-HPT) |  | Baseline up to Week 145 | 
| Maximum Observed Plasma Drug Concentration (Cmax) of DYNE-101 |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Time to Maximum Observed Plasma Concentration (tmax) of DYNE-101 |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Plasma Concentration (AUCtlast) of DYNE-101 |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Area Under the Concentration-time Curve Extrapolated to Infinity (AUC∞) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Apparent Terminal Elimination Rate Constant (λz) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Apparent Terminal Elimination Half-Life (t½) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Clearance (CL) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Volume of Distribution at Steady State (Vss) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Volume of Distribution at the Terminal Phase (Vz) of DYNE-101 in Plasma |  | Pre-dose, and at multiple timepoints up to Week 145 | 
| Antisense Oligonucleotide (ASO) Concentration of DYNE-101 in Muscle Tissue |  | Up to Week 97 | 
| Percentage of Participants With Antidrug Antibodies (ADAs) |  | Up to Week 145 |