Humanised IgG1 kappa fragment antibody targeting TFR1 conjugated to P125 oligonucleotide for Myotonic dystrophy type 1

Inclusion criteria

• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 3. Age of onset of DM1 muscle symptoms ≥ 12 years"}
• {"criterion_text":"- 4. Clinically apparent myotonia equivalent to hand opening time of at least 2 seconds in the opinion of the Investigator"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 7. Body mass index (BMI) < 35kg/m2"}
• {"criterion_text":"- 8. If being treated with testosterone, on a stable replacement dose for 30 days prior to screening"}
• {"criterion_text":"- Sex and Contraceptive/Barrier Requirements 9. Participants must agree to follow protocol-specified contraception guidance"}
• {"criterion_text":"- 10. Female participants must not be pregnant or breastfeeding"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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

• {"criterion_text":"- 1. 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 3. History of anaphylaxis"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 8. Recent history (within previous 12 months) of drug or alcohol abuse"}
• {"criterion_text":"- 9. Medical condition other than DM1 that would significantly impact ambulation or participation in functional assessments"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 11. 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"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 13. Use of anticoagulant such as warfarin or a direct oral anticoagulant (eg, dabigatran) due to the increased risk of bleeding"}
• {"criterion_text":"- 14. Current treatment with immunosuppressive therapy"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 17. Percent predicted forced vital capacity (FVC) < 50%"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 20. Inability to undergo venipuncture successfully or tolerate venous access"}
• {"criterion_text":"- 21. (Not listed in provided text)"}
• {"criterion_text":"- 22. (Not listed in provided text)"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)"}
• {"criterion_text":"- 26. Hematuria > 5 red blood cells per high power field (RBC/HPF) on urinalysis at Screening"}
• {"criterion_text":"- 27. Persistent systolic blood pressure < 90 mm Hg or signs or symptoms of hypotension or volume depletion/dehydration"}
• {"criterion_text":"- 28. Prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE)"}
• {"criterion_text":"- 29. Recent physical inactivity (eg, immobilization of ≥ 3 days)"}

Primary endpoints

• {"endpoint_text":"- Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), TEAEs considered related to study drug, and TEAEs leading to discontinuation from study drug and discontinuation from the study.","definition_or_measurement_approach":"Safety endpoints captured as standard pharmacovigilance reports: incidence and classification of TEAEs, TESAEs, relationship to study drug, and events leading to discontinuation (collected throughout dosing and follow-up according to protocol)."}
• {"endpoint_text":"- Dose Expansion Cohort: Change from baseline in myotonia as measured by vHOT (middle finger) at Week 25","definition_or_measurement_approach":"Efficacy endpoint measured as change from baseline in video hand opening time (vHOT) of the middle finger at Week 25 in the dose expansion cohort."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in CASI in skeletal muscle tissue Change from baseline in DMPK RNA expression in muscle tissue","definition_or_measurement_approach":"Molecular tissue endpoints: change from baseline in Composite Alternative Splicing Index (CASI) and DMPK RNA expression measured in skeletal muscle tissue samples (biopsy)."}
• {"endpoint_text":"- MAD Cohorts Change from baseline in hand grip relaxation time by a dynamometer Change from baseline in myotonia as measured by vHOT Change from baseline in Quantitative Myometry Testing (QMT) Change from baseline in 10-meter walk/run test (10-MWRT) Change from baseline in stair-ascend/descend test Change from baseline in 5 times sit to stand (5×STS) Change from baseline in 9-Hole Peg Test (9-HPT)","definition_or_measurement_approach":"Functional endpoints for MAD cohorts: change from baseline in dynamometer-measured hand grip relaxation time, vHOT myotonia measurements, QMT, 10-MWRT, stair ascend/descend, 5×STS, and 9-HPT, assessed at protocol-specified visits."}
• {"endpoint_text":"- Dose Expansion Cohort Change from baseline in CASI in skeletal muscle tissue at Week 25 Change from baseline in 10-MWRT at Week 25 Change from baseline in 5×STS at Week 25 Change from baseline in MDHI total score at Week 25 Change from baseline in 9-HPT at Week 25 Change from baseline in percent predicted hand grip strength at Week 25","definition_or_measurement_approach":"Dose expansion cohort functional and patient-reported endpoints: CASI in muscle tissue at Week 25 and multiple functional measures (10-MWRT, 5×STS, MDHI total score, 9-HPT, percent predicted hand grip strength) measured as change from baseline at Week 25."}
• {"endpoint_text":"- MAD Cohorts Plasma endpoints: Max observed plasma drug concentration Time to max observed plasma drug concentration Area under the plasma-drug concentration-time curve from time 0 to the last quantifiable concentration AUC extrapolated to time infinity Apparent terminal phase elimination rate constant and elimination half-life Plasma clearance Volume of distribution at the terminal phase, if appropriate and at steady state, if appropriate Muscle tissue endpoint: Tissue ASO concentration","definition_or_measurement_approach":"Pharmacokinetic endpoints: standard PK metrics in plasma (Cmax, Tmax, AUC0-last, AUCinf, elimination rate constant, half-life, clearance, Vd) and muscle tissue ASO concentration measurements."}
• {"endpoint_text":"- MAD Cohorts Incidence of antidrug antibodies (ADAs)","definition_or_measurement_approach":"Immunogenicity endpoint: incidence of anti-drug antibodies measured in plasma samples per schedule."}

Methods

• Country-specific recruitment arrangements documents and materials published (recruitment arrangements and patient brochures available for France, Netherlands, Italy, Germany)
• Patient recruitment materials produced/managed by Matthews Media Group Inc. (role: Patient recruitment material)
• GP letter used in Italy (K2_General Practitioner Letter_IT) and other country-specific recruitment leaflets/inserts (splicing-insert, participant data brochures)
• Site-based recruitment via participating neurology/muscle centres (listed trial sites and investigators)

Netherlands

Earliest CTIS Part Ii Submission Date

08-04-2024

Latest Decision Or Authorization Date

13-04-2026

Processing Time Days

735

Number Of Sites

1

Number Of Participants

19

France

Earliest CTIS Part Ii Submission Date

08-04-2024

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

736

Number Of Sites

2

Number Of Participants

23

Italy

Earliest CTIS Part Ii Submission Date

08-04-2024

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

736

Number Of Sites

2

Number Of Participants

43

Germany

Earliest CTIS Part Ii Submission Date

08-04-2024

Latest Decision Or Authorization Date

08-05-2026

Processing Time Days

760

Number Of Sites

3

Number Of Participants

18

Primary sponsor

Full Name

Dyne Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Pharmaceutical Product Development LLC

Responsibilities

Monitoring (Regulatory applications to CA and ethics committee), Investigator recruitment, Data management, Medical writing, Safety Management, Medical monitoring

Name

PPD Development LP

Responsibilities

Clinical operations/central lab role (as listed in sponsor duties)

Name

Syneos Health Inc.

Responsibilities

Investigator meeting planning

Name

Charles River Laboratories Inc.

Responsibilities

Immunogenicity/ADA assay

Name

PPD Global Central Labs

Responsibilities

Clinical chemistry, haematology, microbiology, bioanalytical detection of DYNE-101

Name

eResearchTechnology GmbH / Ersearchtechnology Inc. / Eresearchtechnology Inc.

Responsibilities

Central reading for ECG (cardiac safety) and e-data systems

Name

Suvoda LLC

Responsibilities

IVRS – treatment randomisation

Third parties

• {"country":"Germany","full_name":"Centogene GmbH","duties_or_roles":"DMPK gene repeat number analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Matthews Media Group Inc.","duties_or_roles":"Patient recruitment material","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Charles River Laboratories Inc.","duties_or_roles":"Immunogenecity/ADA assay","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Investigator meeting planner","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Central reading for ECG (cardiac safety)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Patient travel and patient reimbursement services","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Q2 Solutions - Innovation Labs","duties_or_roles":"Muscle DMPK and Splicing","organisation_type":"Health care"}
• {"country":"United States","full_name":"Athena Diagnostics Inc.","duties_or_roles":"DMPK gene repeat number analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Aeverl Medical","duties_or_roles":"Provider of the Quantitative Myometry Testing equipment and its calibration and maintenance","organisation_type":"Health care"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"Patient Reported Outcome licensing, validation, translation","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"AGADA Biosciences Inc.","duties_or_roles":"Muscle Biopsy Sample Management","organisation_type":"Health care"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"role code 5 (as listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Monitoring (Regulatory applications to CA and ethics committee), Investigator recruitment, Data management, Medical writing, Safety Management, Medical monitoring","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"E-data capture","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"eResearchTechnology GmbH","duties_or_roles":"Central reading for ECG (cardiac safety)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"IVRS – treatment randomisation","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Chillibean Limited","duties_or_roles":"Clinical Trial Video Services: Video file storage, Functional assessment videos, vHOT videos, Physio","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Clinical chemistry, Clinical haematology, Clinical microbiology, BioAnalytical detection of Intact DYNE-101 in blood, urine, muscle tissue.","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharma Start LLC","duties_or_roles":"Home nursing service provider","organisation_type":"Pharmaceutical company"}