Clinical trial NCT05693142: AFFINITY DUCHENNE: RGX-202 Gene Therapy in Participants With Duchenne Muscular Dystrophy (DMD)
Official title: A Phase 1/2/3 Open-label Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics, and Pharmacokinetics of Intravenous RGX-202 Gene Therapy in Males With Duchenne Muscular Dystrophy (DMD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Duchenne Muscular Dystrophy
Keywords: Gene therapy
DMD
Duchenne Muscular Dystrophy
Duchenne
Lead sponsor: REGENXBIO Inc.
Sponsor class: INDUSTRY
First posted: 2023-01-20
Enrollment: 65
Sex: MALE
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Dose Evaluation
Primary purpose: TREATMENT

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. 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.

Eligibility 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.
* 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.
* 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.
  * 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 Exclusion Criteria:

* Participant has any condition that would contraindicate treatment with immunosuppression.
* Participant has received givinostat within 3 months of study entry or 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 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.

Primary outcomes:
measure: Part 1 Safety measured by incidence of Adverse Events and Serious Adverse Events
timeFrame: 52 weeks
measure: Part 2 and 3 Pharmacodynamic
timeFrame: 12 weeks
Secondary outcomes:
measure: Time to Stand (TTSTAND)
timeFrame: 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3)
measure: Time to Walk/Run 10 meters (TTWR)
timeFrame: 52 Weeks (Part 1) and 104 Weeks (Part 2 &3)
measure: Time to Climb 4 Stairs (TTCLIMB)
timeFrame: 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3)
measure: North Star Ambulatory Assessment (NSAA)
timeFrame: 52 Weeks (Part 1) and; 52 and 104 Weeks (Part 2 &3)
measure: Peabody Developmental Motor Scale, Third Edition (PDMS-3); Body Control Subtest
timeFrame: 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3)
measure: Peabody Developmental Motor Scale, Third Edition (PDMS-3); Body Transport Subtest
timeFrame: 52 Weeks (Part 1); 52 and 104 Weeks (Part 2 &3)
measure: Part 2 and 3: Stride velocity 95th centile
timeFrame: 104 weeks
measure: Part 1 Microdystrophin protein expression
timeFrame: 12 weeks
measure: Part 1 Pharmacokinetics (PK)
timeFrame: 12 weeks (muscle) and 52 weeks (serum)
measure: Part 1 Vector Shedding
timeFrame: 52 weeks
measure: Part 2 and 3 Microdystrophin protein expression
timeFrame: 12 weeks
measure: Part 2 and 3 Safety measured by incidence of Adverse Events and Serious Adverse Events
timeFrame: 104 weeks
measure: Part 2 and 3 Pharmacokinetics (PK)
timeFrame: 12 weeks (muscle) 52 weeks (serum)
measure: Part 2 and 3 Vector Shedding
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Palo Alto
country: United States
facility: Stanford School of Medicine /Division of Neuromuscular Medicine
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Richmond
country: United States
facility: Children's Hospital of Richmond at Virginia Commonwealth University
state: Virginia
city: London
country: Canada
facility: Children's Hospital London Health Science Centre
state: Ontario
Study officials:
References: