Evaluation of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of DYNE-101 in Myotonic Dystrophy Type 1 Patients
- Trial ID
- 2023-510353-42-00
- Sponsor
- Dyne Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of multiple intravenous doses of DYNE-101 in participants with **Myotonic Dystrophy Type 1** (DM1). This is clinically relevant as it aims to ensure that the treatment is safe for patients, which is a critical step before assessing its efficacy. Additionally, the study seeks to assess the effect of DYNE-101 on muscle tissue in the dose expansion cohort, which is important for understanding the potential therapeutic benefits of the treatment.
Secondary objectives include:
- Evaluating the effect of multiple intravenous doses of DYNE-101 on muscle tissue and changes in muscle parameters.
- Assessing plasma and muscle tissue pharmacokinetics (PK) following multiple doses.
- Evaluating the immunogenicity of the treatment.
- Assessing participant-reported and clinician-reported outcomes.
- Evaluating the safety and tolerability in the dose expansion cohort.
Participants
The clinical trial involves a total of **81 participants** diagnosed with **Myotonic Dystrophy Type 1** (DM1), confirmed by molecular genetics with a trinucleotide repeat size greater than 100. The study population includes both male and female subjects, aged between 18 and 65 years, with the age of onset of DM1 muscle symptoms being 12 years or older. Participants are required to have clinically apparent myotonia and specific hand grip and ankle dorsiflexion strength parameters. The trial population was selected based on their ability to perform certain physical tasks without assistive devices and a body mass index (BMI) of less than 35 kg/m². Participants must not be pregnant or breastfeeding and must adhere to protocol-specified contraception guidance. The study includes individuals who are part of a vulnerable population, and all participants are required to provide informed consent and demonstrate willingness and ability to comply with study procedures, including multiple needle muscle biopsy procedures.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, pharmacodynamics, efficacy, and pharmacokinetics of DYNE-101 in participants with **Myotonic Dystrophy Type 1**. This study is a randomized, placebo-controlled, multiple ascending dose trial. Participants will receive either DYNE-101 or a placebo, which is a commercially available 0.9% saline solution intended for intravenous use. The trial is structured to include both a Multiple Ascending Dose (MAD) cohort and a Dose Expansion cohort, with the primary objective of assessing the safety and tolerability of multiple intravenous doses of DYNE-101. The trial is expected to conclude by February 2030, with recruitment having commenced in March 2023.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of Myotonic Dystrophy Type 1, and specific functional assessments. The inclusion criteria require participants to be between 18 and 65 years old, with a confirmed diagnosis of the disease and specific muscle strength and functional capabilities. The study will include regular follow-up visits to monitor the participants' response to the treatment, assess any treatment-emergent adverse events, and evaluate changes in muscle tissue and function. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.
The expected duration of participant involvement in the trial is contingent upon the cohort assignment and the dosing schedule, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial will measure primary endpoints such as the number and proportion of participants with treatment-emergent adverse events and changes in muscle tissue at specified weeks. Secondary endpoints will include changes in muscle function and strength, as well as pharmacokinetic parameters. The trial is not classified as low intervention and is categorized as a Phase 1/2 study, focusing on both safety and preliminary efficacy outcomes.
Treatment
**DYNE-101** is the experimental medication being evaluated in this clinical trial. It is a **humanised IgG1 kappa fragment antibody** targeting **TFR1**, conjugated to **P125 oligonucleotide**. The pharmaceutical form of DYNE-101 is an **injection/infusion**, and it is administered via the **intravenous route**. The dosing schedule involves multiple ascending doses, although specific dosage amounts and frequency are not detailed in the provided data. DYNE-101 is of biological/biotechnological origin and is not classified as an Advanced Therapy Investigational Medicinal Product (ATIMP). The trial aims to assess the safety, tolerability, pharmacodynamics, efficacy, and pharmacokinetics of DYNE-101 in participants with **Myotonic Dystrophy Type 1** (DM1).
The study also includes a **placebo** control, which is a commercially available **0.9% (w/v) saline solution** intended for intravenous use. The placebo serves as a comparator treatment to evaluate the effects of DYNE-101 against a standard non-active treatment. The placebo is administered in the same manner as DYNE-101, ensuring that the route of administration is consistent across all study participants. The use of a placebo is critical in maintaining the integrity of the trial's randomized, placebo-controlled design.
Efficacy
The clinical trial aims to assess the efficacy of DYNE-101 in participants with **Myotonic Dystrophy Type 1** (DM1). Efficacy will be evaluated through a series of primary and secondary endpoints. For the Dose Expansion Cohort, the primary endpoint is the change from baseline in CASI (Clinical Assessment of Skeletal Muscle Involvement) in skeletal muscle tissue at Week 13. Secondary endpoints include changes from baseline in DMPK RNA expression in muscle tissue, myotonia as measured by vHOT (video Hand Opening Time), and various functional tests such as the 10-meter walk/run test (10-MWRT), stair ascend/descend test, and 5 times sit to stand (5×STS) at Week 25. Additionally, changes in hand grip strength, Quantitative Myometry Testing (QMT), and MDHI (Myotonic Dystrophy Health Index) total score will be assessed.
For the MAD (Multiple Ascending Dose) Cohorts, secondary endpoints include changes from baseline in hand grip relaxation time using a dynamometer, myotonia as measured by vHOT, and functional tests such as the 10-MWRT, stair ascend/descend test, and 5×STS. Plasma endpoints will also be evaluated, including maximum observed plasma drug concentration, time to maximum concentration, area under the plasma-drug concentration-time curve, and other pharmacokinetic parameters. The incidence of antidrug antibodies (ADAs) will be monitored as well. Efficacy assessments will be conducted at specified timepoints, including Week 13 and Week 25, using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 1. MAD Cohort: Age 18 to < 50 years, at the time of signing the informed consent., Dose Expansion Cohort: Age 18 to ≤ 65 years, at the time of signing the informed consent Type of Participant and Disease Characteristics 2. Diagnosis of DM1 confirmed by molecular genetics with trinucleotide repeat size > 100. Historical results from clinical testing are acceptable 3. Age of onset of DM1 muscle symptoms ≥ 12 years 4. Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds in the opinion of the Investigator 5. Hand grip strength and ankle dorsiflexion strength a. Hand grip strength averaged from both sides ≥ 20% and ≤ 80% (±5%) predicted for age, sex, and height at screening b. Ankle dorsiflexion strength averaged from both sides ≥ 20% and ≤80% (± 10%) predicted for age, sex, and height at screening Note: Two sets of functional assessments must be performed during the Screening Period. Participants must meet inclusion criterion #5 on both sets of functional assessments for study eligibility 6. 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. The use of submalleolar orthoses and inserts or supports that do not extend above the malleolus are permitted during testing 7. Body mass index (BMI) < 35kg/m2 8. If being treated with testosterone, on a stable replacement dose for 30 days prior to screening Sex and Contraceptive/Barrier Requirements 9. Participants must agree to follow protocol-specified contraception guidance 10. Female participants must not be pregnant or breastfeeding Informed Consent 11. Capable of giving signed informed consent in compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol Other Inclusions 12. Willingness and ability of participant to comply with and tolerate scheduled visits, dosing administration plan, and study assessments, including multiple needle muscle biopsy procedures over the duration of the study
Exclusion Criteria
- Previous or ongoing medical condition, medical history, physical findings, or laboratory abnormalities that in the opinion of the Investigator could affect safety, make it unlikely that dosing schedule and follow-up will be correctly completed, and/or impair the assessment and interpretation of study results 2. 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 course of the study 3. History of anaphylaxis 4. History of clinically significant liver disease or ongoing treatment for liver disease, or confirmed elevated alanine aminotransferase (ALT) > 3× upper limit of normal (ULN), at Screening. 5. History of clinically significant hematologic disease or have any of the following hematologic results at Screening: platelets or hemoglobin below the lower limit of normal for age and sex. 6. History of clinically significant kidney disease, ongoing treatment for kidney disease (treatment for hypertension is permitted) or estimated glomerular filtration rate (eGFR) < 60 mL/min as calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Cystatin C Equation at screening 7. Active malignancy or history within the last 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated 8. Recent history (within previous 12 months) of drug or alcohol abuse 9. Medical condition other than DM1 that would significantly impact ambulation or participation in functional assessments 10. Current insulin-dependent diabetes mellitus or uncontrolled diabetes mellitus, congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary artery disease, multiple sclerosis, or other serious medical illness
- Second- or third-degree heart block, symptomatic first-degree heart block, atrial flutter, atrial fibrillation, ventricular arrhythmias, pacemakers, implanted defibrillator, or is receiving medication for treatment of cardiac arrhythmia 12. Treatment with medications that can improve myotonia or clinical functional endpoints within a period of 5 half-lives of the medication prior to performing screening assessments. May include but not limited to mexiletine, phenytoin, carbamazepine, procainamide, disopyramide, ranolazine, flecainide, lamotrigine, nifedipine, acetazolamide, clomipramine, imipramine, amitriptyline, taurine, quinine, or metformin. 13. Use of anticoagulant such as warfarin or a direct oral anticoagulant (eg, dabigatran) due to the increased risk of bleeding 14. Current treatment with immunosuppressive therapy 15. Receipt of another investigational drug, biologic agent, or device within 5 half-lives (if known) of the agent, or within 4 months prior to the start of Screening, whichever is longer. Individuals previously treated with oligonucleotide therapies (including small interfering RNA [siRNA]) may be eligible if the last dose of the investigational drug was received ≥ 3 years ago 16. ECG with the corrected QT interval by Fridericia's Formula (QTcF) ≥450 ms in men and QTcF ≥ 460 ms in women, PR ≥ 240 ms, left bundlebranch block, or a conduction defect, which is clinically significant in the opinion of the Investigator 17. Percent predicted forced vital capacity (FVC) < 50% 18. 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 19. Inability, or impaired ability, to complete study procedures and/or complete the study, due to physical or cognitive impairment, in the judgment of the Investigator 20. Inability to undergo venipuncture successfully or tolerate venous access 23. 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. 24. Use of nephrotoxic medications within a period of 5 half-lives of the medication prior to performing screening assessments. May include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides (eg, gentamicin, streptomycin), bisphosphonates, and antiviral agents (eg, acyclovir, adefovir). Planned procedures that require contrast during the study are also exclusionary. 25. Acute kidney injury within 12 weeks prior to Screening, characterized by an increase in serum creatinine of 0.3 mg/dL within 48 hours, or of 1.5-fold within a week (Khwaja 2012) 26. Hematuria > 5 red blood cells per high power field (RBC/HPF) on urinalysis at Screening 27. Persistent systolic blood pressure < 90 mm Hg or signs or symptoms of hypotension or volume depletion/dehydration 28. Prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE) 29. Recent physical inactivity (eg, immobilization of ≥ 3 days)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 08 Mar 2023 | 23 |
 Germany | Not Recruiting | 08 Mar 2023 | 18 |
 Italy | Not Recruiting | 08 Mar 2023 | 43 |
 The Netherlands | Not Recruiting | 08 Mar 2023 | — |
| Netherlands | — | — | 19 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DYNE-101 | Test | INJECTION/INFUSION | INTRAVENOUS USE | — | — | PRD10159728 |
The placebo is commercially available 0.9% (w/v) saline solution intended for IV | Placebo | N/A | INTRAVENOUS USE | — | — | N/A |