AFFINITY DUCHENNE: RGX-202 Gene Therapy in Participants With Duchenne Muscular Dystrophy (DMD)

Phase 1

Recruiting

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Genetic: RGX-202

• Registration Number: NCT05693142
• Lead Sponsor: REGENXBIO Inc.

Brief Summary

RGX-202 is a gene therapy designed to deliver a transgene for a novel microdystrophin that includes functional elements of naturally-occurring dystrophin including the C-Terminal (CT) domain.

This is a multicenter, open-label dose evaluation clinical study to assess the safety, tolerability and clinical efficacy of a one-time intravenous (IV) dose of RGX-202 in participants with Duchenne.

Detailed Description

Duchenne muscular dystrophy (Duchenne) is a rare genetic disorder, caused by mutations in the gene responsible for making dystrophin, a protein of central importance for muscle cell structure and function. The absence of functional dystrophin protein in individuals with Duchenne results in cell damage during muscle contraction leading to cell death, inflammation, and fibrosis in muscle tissues, and ultimately progressive muscle weakness. RGX-202 is designed to use the AAV8 vector to deliver a transgene to muscle cells that encodes a novel microdystrophin that includes the functional elements of naturally occurring dystrophin including the C-Terminal (CT) domain. This is a Phase 1/2, multicenter, open-label, dose evaluation clinical study to assess the safety, tolerability, pharmacodynamics (microdystrophin protein levels), pharmacokinetics, and preliminary clinical efficacy of RGX-202 in 2 dose groups over 52 weeks when administered by one-time intravenous infusion (IV) in ambulatory male pediatric participants with Duchenne.

The first 2 participants (ages 4-11 years old) in the first dose group (Cohort 1) will be dosed with 1x10\^14 genome copies (GC)/kg body weight in a staggered fashion, at least 4 weeks apart, following increasing body weight: ≤25kg and ≤35kg. After an independent safety data review, 2 participants (ages 4-11 years old) in the second dose group (Cohort 2) will be dosed with 2x10\^14 GC/kg body weight in a staggered fashion, at least 4 weeks apart, following increasing body weight: ≤25kg and ≤35kg. After an independent safety data review, an expansion phase of Cohort 2 may allow for up to five additional participants (ages 4-11 years old) to be enrolled. A separate group (Cohort 1b) was added and expected to enroll in the first dose group, a single patient, 4-11 years old, with at-risk mutations (premature stop codon mutation in exons 12-17). An additional group was added for the second dose group (Cohort 2c) and expected to enroll up to five, 1-3-years-old participants, must be ≥ 10 kg at the time of screening. A total of up to 15 participants may be enrolled in the study with 3 participants receiving dose level 1 and up to 12 participants receiving dose level 2.

A comprehensive, short-term, prophylactic immunosuppression regimen will be administered during treatment to mitigate a potential immune response.

Study Timeline

• Study Start: 2023-01-04
• Study First Submitted: 2023-01-04
• Study First Submitted QC: 2023-01-12
• Study First Posted: 2023-01-20
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-19
• Last Update Posted: 2024-07-23
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 15

Inclusion Criteria

• DMD gene mutation in exons 18 and above, and a clinical picture consistent with typical DMD with the exception of a participant (Cohort 1b) with DMD gene mutation in exons 12-17.
• Participant is able to walk 100 meters independently without assistive devices. Cohort 2c participant must be able to walk 10 meters independently without assistive devices. Cohort 1b participant must be able to walk with or without assistive devices.
• Participant is able to complete the TTSTAND per protocol-specific criteria.
• Participant has been on a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks prior to obtaining the pharmacodynamic assessments, imaging assessments, patient-reported outcomes, and functional clinical outcome assessments within the Day -60 to Day -3 screening period. Cohort 2c participants must be consistently on or off a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks prior to obtaining the pharmacodynamic assessments, imaging assessments, patient-reported outcomes, and functional clinical outcomes assessments within the Day -60 to Day -3 screening period and the 12 month duration of the study.
• Clinical laboratory test results, including hepatic and renal function, are within the normal range during screening, or if abnormal, are not clinically significant, in the opinion of the investigator.
• Documentation is provided at screening visit for participant's adherence to the local country's vaccination schedule. The parent(s) or legal guardian(s) must be willing to have their child receive a meningococcal vaccine, if not already vaccinated.
• Participant and parent(s)/legal guardian(s) are willing and able to comply with scheduled visits, study intervention administration plan, and study procedures.

Read More

Exclusion Criteria

• Participant has any condition that would contraindicate treatment with immunosuppression.
• Participant has received ataluren (a protein restoration therapy) or an exon-skipping therapy for the treatment of DMD within 6 months of study entry or is unable to refrain from taking ataluren or exon-skipping therapy for a duration of 5 years from the time of RGX-202 administration.
• Participant has received any investigational or commercial gene therapy product over his lifetime.
• Participant is currently taking any other investigational intervention (other than corticosteroids) or has taken any other investigational intervention (other than corticosteroids) within 3 months prior to the scheduled Day 1 intervention. If the corticosteroid is 6 mg/kg/day vamorolone, the participant must be converted to daily prednisolone or prednisone for a period of 12 weeks starting the day before the scheduled Day 1 intervention before being allowed to resume vamorolone at the original dose, unless the investigator determines that this is not clinically indicated or possible.
• Participant has detectable AAV8 total binding antibodies in serum.
• Participant has impaired cardiac function defined as a left ventricular ejection fraction of < 55% on screening cardiac assessments (echocardiogram or MRI).
• Participant is not a good candidate for the study, in the opinion of the investigator.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
RGX-202 Dose 2	RGX-202	A single IV infusion of RGX-202 at a dose of 2x10\^14 GC/kg body weight
RGX-202 Dose 1	RGX-202	A single IV infusion of RGX-202 at a dose of 1×10\^14 GC/kg body weight

Primary Outcome Measures

Name	Time	Method
Safety measured by incidence of Adverse Events and Serious Adverse Events	52 weeks	Evaluate incidences of AEs and SAEs

Secondary Outcome Measures

Name	Time	Method
Efficacy measured by change in Functional Assessment	Multiple timepoints through 52 weeks	Change from baseline in motor skill acquisition as measured by the Peabody Developmental Motor Scale-Third Edition (PDMS-3).
Pharmacokinetics (PK)	Multiple timepoints through 52 weeks	Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in serum.
Microdystrophin protein expression	12 weeks	RGX-202 microdystrophin protein levels determined in muscle biopsy and the vector genome concentrations in muscle at assessed time points.
Vector Shedding	Multiple timepoints through 52 weeks	Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in urine.

Trial Locations

Locations (5)

Ann & Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

Children's Hospital of Richmond at Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

Stanford School of Medicine /Division of Neuromuscular Medicine; 🇺🇸 Palo Alto, California, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

The University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States