Limb-Girdle Muscular Dystrophy, Type 2D
Conditions
Keywords
limb girdle muscular dystrophy, LGMD2D, alpha-sarcoglycan, gene transfer, adeno-associated virus
Brief summary
This is an open-label, dose escalation gene transfer therapy study evaluating the safety of SRP-9004 (patidistrogene bexoparvovec) via isolated limb infusion (ILI) administration in approximately 6 participants with LGMD2D.
Interventions
GENETICSRP-9004
Isolated Limb Infusion (ILI)
Sponsors
Nationwide Children's Hospital
Sarepta Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Cohort 1A must be adult and wheelchair-dependent; Cohorts 1B and 2 will be participants of age 7 or older. * Confirmed alpha-sarcoglycan deficiency or identified sarcoglycan alpha (SGCA) deoxyribonucleic acid (DNA) mutation. * Participants enrolled in Cohorts 1B or 2 must be able to walk independently, but must exhibit signs of lower extremity weakness (that is, a Gowers' sign, use a handrail for climbing stairs) and walk ≤80% of predicted distance on the 6 minute walk test (6MWT) based on normative data. Key
Exclusion criteria
* Active viral infection based on clinical observations. * The presence of SGCA mutations without weakness or loss of function. * Symptoms or signs of cardiomyopathy. * Serological evidence of human immunodeficiency virus (HIV), Hepatitis B, or C infection. * Diagnosis of (or ongoing treatment for) an autoimmune disease. * Participants with AAVrh74 or AAV8 binding antibody titers ≥ 1:50 as determined by enzyme-linked immunosorbent assay (ELISA) immunoassay. Other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs). | Up to 2 Years | An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug related. An AE was considered serious if, in the view of the investigator or sponsor, it resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Treatment-related Treatment Emergent Adverse Event (TEAE) is defined as an TEAE that was classified by the investigator as related to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of the Distance Walked in 6 Minutes (6MWT) | Baseline, Up to 2 Years | The 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course in 6 minutes (timed), and the distance walked (in meters) was recorded. |
Participant flow
Pre-assignment details
Participants with limb-girdle muscular dystrophy, type 2D (LGMD2D) were enrolled into 3 cohorts: Cohort 1A (non-ambulant adult participants), Cohort 1B (pediatric participants), and Cohort 2 (pediatric participants).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1A: SRP-9004 SRP-9004 was administered once by ILI to a single limb on Day 0. The administered dose was 1\*10\^12 vector genomes per kilogram body weight (vg/kg). Dose determined via supercoiled titer method. | 1 |
| Cohort 1B: SRP-9004 SRP-9004 was administered once by ILI to both limbs on Day 0. The participants received a total dose of 2\*10\^12 vg/kg split between the two extremities (1\*10\^12 vg/kg per limb). Dose determined via supercoiled titer method. | 3 |
| Cohort 2: SRP-9004 SRP-9004 was administered once by ILI to both limbs on Day 0. The participants received a total dose of 6\*10\^12 vg/kg split between the two extremities (3\*10\^12 vg/kg per limb). Dose determined via supercoiled titer method. | 2 |
| Total | 6 |
Baseline characteristics
| Characteristic | Cohort 1A: SRP-9004 | Cohort 1B: SRP-9004 | Cohort 2: SRP-9004 | Total |
|---|---|---|---|---|
| Age, Continuous | 49 Years | 10 Years STANDARD_DEVIATION 2.65 | 10 Years STANDARD_DEVIATION 2.83 | 16.5 Years STANDARD_DEVIATION 16.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 1 / 1 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 1 | 2 / 3 | 1 / 2 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs).
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug related. An AE was considered serious if, in the view of the investigator or sponsor, it resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Treatment-related Treatment Emergent Adverse Event (TEAE) is defined as an TEAE that was classified by the investigator as related to treatment.
Time frame: Up to 2 Years
Population: The FAS included all participants who received at least 1 administration of SRP-9004.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1A: SRP-9004 | Number of Participants With Adverse Events (AEs). | Treatment Related TEAEs | 1 Participants |
| Cohort 1A: SRP-9004 | Number of Participants With Adverse Events (AEs). | Serious Adverse Events | 0 Participants |
| Cohort 1A: SRP-9004 | Number of Participants With Adverse Events (AEs). | Adverse Events | 1 Participants |
| Cohort 1B: SRP-9004 | Number of Participants With Adverse Events (AEs). | Treatment Related TEAEs | 3 Participants |
| Cohort 1B: SRP-9004 | Number of Participants With Adverse Events (AEs). | Adverse Events | 3 Participants |
| Cohort 1B: SRP-9004 | Number of Participants With Adverse Events (AEs). | Serious Adverse Events | 2 Participants |
| Cohort 2: SRP-9004 | Number of Participants With Adverse Events (AEs). | Treatment Related TEAEs | 2 Participants |
| Cohort 2: SRP-9004 | Number of Participants With Adverse Events (AEs). | Serious Adverse Events | 1 Participants |
| Cohort 2: SRP-9004 | Number of Participants With Adverse Events (AEs). | Adverse Events | 2 Participants |
Secondary
Change From Baseline of the Distance Walked in 6 Minutes (6MWT)
The 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course in 6 minutes (timed), and the distance walked (in meters) was recorded.
Time frame: Baseline, Up to 2 Years
Population: The FAS included all participants who received at least 1 administration of SRP-9004. Here, Overall Number of Participants Analyzed signifies those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1A: SRP-9004 | Change From Baseline of the Distance Walked in 6 Minutes (6MWT) | NA Meters | — |
| Cohort 1B: SRP-9004 | Change From Baseline of the Distance Walked in 6 Minutes (6MWT) | -66.0 Meters | Standard Deviation 77.78 |
| Cohort 2: SRP-9004 | Change From Baseline of the Distance Walked in 6 Minutes (6MWT) | 29.0 Meters | — |