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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dyne Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05], Diseases [C] - Nervous System Diseases [C10]

Trial duration

21 Feb 2022 → ongoing

Decision date (initial)

2024-04-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Dyne Therapeutics, Inc

External identifiers

EU CT number

2023-510353-42-00

EudraCT number

2022-000889-18

ClinicalTrials.gov

NCT05481879

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Safety, Dose response

MAD Cohorts: To evaluate the safety and tolerability of multiple IV doses of DYNE-101 administered to participants with DM1
Dose Expansion Cohort: To evaluate the effect of multiple intravenous doses of DYNE-101 administered to participants with DM1 on hand myotonia

Secondary objectives 2

1. MAD Cohorts: To evaluate the effect of multiple intravenous doses of DYNE-101 administered to participants with DM1 on muscle tissue To evaluate change in muscle parameters after multiple doses of DYNE-101 administered to particsssipants with DM1 To evaluate plasma and muscle tissue PK following multiple intravenous doses of DYNE-101 administered to participants with DM1 To evaluate the immunogenicity of multiple intravenous doses of DYNE-101 administered to participants with DM1
2. Dose Expansion Cohort: To evaluate the change in muscle parameters and participant-reported and clinician reported outcomes after multiple intravenous doses of DYNE-101 administered to participants with DM1 To evaluate plasma and muscle tissue PK following multiple intravenous doses of DYNE 101 administered to participants with DM1 To evaluate the immunogenicity of multiple intravenous doses of DYNE-101 administered to participants with DM1 To evaluate the safety and tolerability of multiple IV doses of DYNE 101 administered to participants with DM1

Conditions and MedDRA coding

Myotonic Dystrophy Type 1

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 2

1. 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 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
2. 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 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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.
2. Dose Expansion Cohort: Change from baseline in myotonia as measured by vHOT (middle finger) at Week 25

Secondary endpoints 5

1. Change from baseline in CASI in skeletal muscle tissue Change from baseline in DMPK RNA expression in muscle tissue
2. 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)
3. 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
4. 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
5. MAD Cohorts Incidence of antidrug antibodies (ADAs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dyne Therapeutics Inc.

Sponsor organisation

Dyne Therapeutics Inc.

Address

1560 Trapelo Road

City

Waltham

Postcode

02451-7306

Country

United States

Scientific contact point

Organisation

Dyne Therapeutics Inc.

Contact name

Dyne Clinical Trials

Public contact point

Organisation

Dyne Therapeutics Inc.

Contact name

Dyne Clinical Trials

Third parties 19

Locations

4 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 78 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications