Phase 1/2a for Safety, PK and PD of SQY51 in Paediatric and Adult Patients Duchenne Muscular Dystrophy

Study Overview
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Brief Summary
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This is a Phase 1/2a, monocentric, open label study to evaluate the safety, pharmacokinetics, and pharmacodynamics of SQY51 in patients with Duchenne muscular dystrophy

Detailed Description
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Avance1 is a Phase 1/2a, Monocentric, Open Label Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of SQY51 in 12 patients with a genetically confirmed diagnosis of Duchenne muscular dystrophy, This study will include i) 13-week Phase 1 Multiple Dose Escalation Phase, and a ii) 32-week Phase 2a. Twelve (12) patients ≥ 6 years, both ambulant and non-ambulant, will be sequentially enrolled in phase 1 and will receive escalating doses of SQY51 once every two weeks. In phase 2a, patients will be allocated in three cohorts in a non-randomized manner.

Official Title
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Phase 1/2a, Monocentric, Open Label Study to Evaluate the Safety, PK and PD of SQY51 in Paediatric and Adult Patients With a Genetically Confirmed Diagnosis of Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: Phase 1, SQY51
* Drug: Phase 2a, SQY51 (cohort 1)
* Drug: Phase 2a, SQY51 (cohort 2)
* Drug: Phase 2a, SQY51 (cohort 3)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA FOR PHASE 1: Boys of ≥6 years of age and ≥ 16 kg body weight. Ambulatory or non-ambulatory status, Patients and, if minor, their legal guardians, who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Diagnosed with Duchenne Muscular Dystrophy (DMD), genotypically confirmed with DMD mutations amenable to exon-51 skipping. Stable hepatic and renal function. Left ventricular ejection fraction (LVEF) at screening ≥40%. If clinically indicated, approved concomitant treatment within standards of care guidelines for DMD, such as antihypertensive, vasodilators, lipid lowering, thyroid replacement, vitamins, mineral substitution, gastric protectors, and nutritional supplements. Non-invasive mechanical ventilation is permissive if < 16 h/day. Being affiliated with a French social security. Informed consent form signed by the patient or, if minor, by the legal guardian(s). INCLUSION CRITERIA FOR PHASE 2a: Patients must have completed Phase 1 of the study. EXCLUSION CRITERIA FOR PHASE 1 AND 2a: Patient with any serious medical/surgical or psychiatric condition/illness/history that in the opinion of the investigator would jeopardize patient's safety or would interfere with the study assessments/results, including insufficient vaccination against infectious diseases as recommended by national guidelines, medical history of infection with Hepatitis B,C and HIV. Patient with any known allergies to products likely to be used in the study (e.g., antiseptics, anesthetics), known hypersensitivity to any of the ingredients, or excipients of the study drug). Patient who participated in other investigational study within the last three months, including those with investigational drugs that aim at restoring dystrophin expression such as other antisense oligomers. Patient that received gene therapy. Patient with intellectual disability or behavioral problem such that they cannot comply with the study procedure. Patient with advanced cardiomyopathy and LVEF < 40%. Patients with dysrhythmias and being treated for dysrhythmias. Patients with non-treated tachycardia. Patient for which orthopedic surgery is planned during the time of the study. Tracheostomized patients and dependent on invasive mechanical ventilation. Non-invasive mechanical ventilation ≥ 16 h/day. Predicted vital forced capacity < 20%. Medical history with more than two respiratory decompensations requiring hospitalization during the previous year. No respiratory decompensation in the four months preceding enrolment. Patients on medications that can restore dystrophin expression, tamoxifen and other drugs without indication for DMD or paediatric population. Abnormal laboratory values in the clinically significant range.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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Male

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: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Participants will receive single escalating doses of 2, 4, 6, 10, 16 and 25 mg/kg by intravenous infusion of SQY51 every 2 weeks. | Drug: Phase 1, SQY51<br>* SQY51 is administered by intravenous infusion.<br>|
| Experimental: Phase 2a - Treatment arm (Dose 1)<br>Non randomized participants will receive by IV dose 1 of SQY51 in 4 blocks of 4-weeks. | Drug: Phase 2a, SQY51 (cohort 1)<br>* SQY51 is administered by intravenous infusion at dose 1<br>|
| Experimental: Phase 2a - Treatment arm (Dose 2)<br>Non randomized participants will receive by IV dose 2 of SQY51 in 4 blocks of 4-weeks. | Drug: Phase 2a, SQY51 (cohort 2)<br>* SQY51 is administered by intravenous infusion at dose 2.<br>|
| Experimental: Phase 2a - Treatment arm (Dose 3)<br>Non randomized participants will receive by IV dose 3 of SQY51 in 4 blocks of 4-weeks. | Drug: Phase 2a, SQY51 (cohort 3)<br>* SQY51 is administered by intravenous infusion at dose 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs in all participants |  | From baseline up to week 49 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic plasma concentration of SQY51 (µg/ml) |  | From baseline up to week 49 | 
| Change from baseline in time to rise from floor, time to complete 1-min, 6-min and 10-min walk in ambulant patients as well as MFM and PUL scores in both ambulant and non-ambulant patients |  | From baseline up to week 49 | 
| Changes from baseline in skeletal muscle dystrophin expression |  | From baseline up to week 49 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne Muscular Dystrophy, Duchenne, Dystrophin, DMD, Exon skipping, Exon 51, ASO therapeutics, Tricyclo-DNA