Duchenne Muscular Dystrophy
Conditions
Keywords
Gene therapy, DMD, Duchenne Muscular Dystrophy, Duchenne
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 multicenter, phase I/II/III, open-label study to evaluate the safety, tolerability, pharmacodynamics (microdystrophin protein levels), pharmacokinetic, and clinical efficacy of RGX-202 when administered IV as one-time dose to ambulant male participants with Duchenne. Enrollment is complete for Parts 1, 2 and 3 of the study. A comprehensive, short-term, prophylactic immunosuppression regimen will be administered during treatment to mitigate a potential immune response. This study is being conducted in three sequential parts: a phase I/II study (Part 1), a phase 3 pivotal study (Part 2) and a confirmatory study (Part 3). Part 1 will study a one-time dose of RGX-202 (1x10\^14 or 2x10\^14 GC/kg) in up to 15 participants with Duchenne. In part 1, the primary objective is to evaluate the safety and tolerability of RGX-202 through 52 weeks. Part 2 (Pivotal Expansion) will study a single dose of RGX-202 (2x10\^14 GC/kg) in approximately 30 participants. After the last Part 2 participant is dosed, enrollment into the confirmatory study (Part 3) will be initiated. The target enrollment for the confirmatory study (Part 3) is approximately 30 participants. Participants will be assessed at various time points for 104 weeks after receiving RGX-202. All participants will be given the opportunity to enroll in a separate long-term follow-study in accordance with the US federal government guidelines for the safety follow-up of patients receiving gene therapy.
Interventions
GENETICRGX-202
RGX-202 is a recombinant AAV8 containing a transgene encoding a novel microdystrophin
Sponsors
REGENXBIO Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose Evaluation
Eligibility
Sex/Gender
MALE
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part 1 - Key Inclusion Criteria: * The participant's legal guardian(s) is (are) willing and able to provide written, signed informed consent prior to any study-related procedures; and, where applicable, the minor participant has provided written or verbal assent according to local requirements. * Is a male at least 4 years of age and less than 12 years of age at consent or 1 to \<4 years of age at the time of dosing and ≥ 10 kg at the time of screening. * Must meet any of the following 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. 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. * 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. Part 2 and 3 Inclusion Criteria: * The participant's legal guardian(s) is (are) willing and able to provide written, signed informed consent prior to any study-related procedures; and, where applicable, the minor participant has provided written or verbal assent according to local requirements. * DMD gene mutation with any mutation except for those with deletions or point mutations in exons 8, 9 and/or 10. * Participant is able to complete the TTSTAND per protocol-specific criteria. * 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. * Is a male at least 1 year of age and ≥ 10 kg at the time of screening. * Sexually active participants must be willing to use a medically accepted method of contraception from the time of the screening visit through 5 years after RGX-202 administration. * Participants 1 to \<4 years of age must meet the following criteria: * is able to walk 10 meters independently without assistive devices. * must be consistently on or off a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks and the 24-month duration of the study. * Participants 4 years and older must meet the following criteria: * are able to walk 100 meters independently without assistive devices. * have been on a stable dose of systemic glucocorticoids according to the standard of care for at least 12 weeks and remain on a stable dose for the 24-month duration of the study. * have a NSAA total score ≥16. Part 1
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 your corticosteroid is vamorolone, the participant will be asked to temporarily convert his daily dosing to prednisolone/prednisone during a short period of time around RGX-202 administration. He will be allowed to revert back to his baseline vamorolone regimen at the original per kilogram dose at which he entered the study and should remain on this for 24 months unless the investigator determines that this is not clinically indicated or possible. * 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. Part 2 and 3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 Safety measured by incidence of Adverse Events and Serious Adverse Events | 52 weeks | Evaluate incidences of AEs and SAEs |
| Part 2 and 3 Pharmacodynamic | 12 weeks | Proportion of participants whose RGX-202 microdystrophin protein expression determined in their muscle biopsy is ≥ 10% relative to dystrophin level in non-DMD participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Stand (TTSTAND) | 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3) | Values will include time (seconds) and velocity (tasks/second) |
| Time to Walk/Run 10 meters (TTWR) | 52 Weeks (Part 1) and 104 Weeks (Part 2 &3) | Values will include time (seconds) and velocity (meters/second) |
| Time to Climb 4 Stairs (TTCLIMB) | 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3) | Values will include time (seconds) and velocity (tasks/second) |
| North Star Ambulatory Assessment (NSAA) | 52 Weeks (Part 1) and; 52 and 104 Weeks (Part 2 &3) | Performance-based assessment of muscle strength and function using a 17-item scale, with all items rated 0,1, or 2, with higher score indicating better performance. The NSAA total score is the sum of the 17 items, ranging from 0 to 34. NSAA linearized score ranges from 0 to 100. |
| Peabody Developmental Motor Scale, Third Edition (PDMS-3); Body Control Subtest | 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3) | The PDMS-3 is a norm-referenced developmental assessment that measures motor skills of young children. The Body Control subtest measures the child's ability to maintain balance and postural reactions in a variety of positions. Motor skills appropriate for the child's developmental level are administered and rated 0, 1, or 2, with higher score indicating better performance. Body Control subtest total raw scores range from 0 to 112. Age equivalent and scaled scores will also be generated. PDMS-3 Body Control subtests is included for participants age \<4 at screening. |
| Peabody Developmental Motor Scale, Third Edition (PDMS-3); Body Transport Subtest | 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3) | The PDMS-3 is a norm-referenced developmental assessment that measures motor skills of young children. The Body Transport subtest measures the child's ability to move from one place to another, including walking, running, jumping forward, and skipping. Motor skills appropriate for the child's developmental level are administered and rated 0, 1, or 2, with higher score indicating better performance. Body Transport subtest total raw score ranges from 0 to 63. Age equivalent and scaled scores will also be generated. PDMS-3 Body Control subtests is included for participants age \<4 at screening. |
| Part 2 and 3: Stride velocity 95th centile | 104 weeks | Assessment of peak ambulatory performance captured by wearable activity monitoring device. For velocity measures, higher values indicate greater function. |
| Part 1 Microdystrophin protein expression | 12 weeks | RGX-202 microdystrophin protein levels determined in muscle biopsy. |
| Part 1 Pharmacokinetics (PK) | 12 weeks (muscle) and 52 weeks (serum) | Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in muscle and serum. |
| Part 1 Vector Shedding | 52 weeks | Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in urine. |
| Part 2 and 3 Microdystrophin protein expression | 12 weeks | RGX-202 microdystrophin protein levels determined in muscle biopsy. |
| Part 2 and 3 Safety measured by incidence of Adverse Events and Serious Adverse Events | 104 weeks | Evaluate incidences of AEs and SAEs |
| Part 2 and 3 Pharmacokinetics (PK) | 12 weeks (muscle) 52 weeks (serum) | Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in muscle and serum. |
| Part 2 and 3 Vector Shedding | 52 weeks | Vector genome concentrations as measured by polymerase chain reaction \[PCR\] to RGX-202 deoxyribonucleic acid \[DNA\] in urine, feces, and saliva. |
Countries
Canada, United States
Outcome results
None listed