Phase 3 Multinational Study on the Safety and Efficacy of Bidridistrogene Xeboparvovec in Limb-Girdle Muscular Dystrophy Type 2E/R4 Patients
- Trial ID
- 2022-503112-17-00
- Protocol
- SRP-9003-301
- Sponsor
- Sarepta Therapeutics Inc.
Trial statistics
Objectives
The primary objective of this study is to evaluate the effect of **SRP-9003** on **β-sarcoglycan** (β-SG) expression at Day 60 post-dose. This is measured by immunofluorescence (IF) percent β-SG positive fibers (PβSGPF). The clinical relevance of this objective lies in its potential to demonstrate the therapeutic efficacy of SRP-9003 in increasing β-SG expression, which is crucial for improving muscle function in patients with Limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4) or β-sarcoglycanopathy.
Secondary objectives include: - Evaluating the effect of SRP-9003 on β-SG expression at Day 60 post-dose as measured by IF percent fluorescent expression (PFE) and Western of biopsied muscle tissue. - Assessing the effect of SRP-9003 on physical function through Month 60 in all cohorts, using the North Star Assessment for Dysferlinopathy (NSAD) score and Performance of Upper Limb (PUL) 2.0 score. - Evaluating the effect of SRP-9003 on timed function tests for subjects in Cohort 1 (ambulatory) through Month 60. - Assessing the safety of SRP-9003. - Evaluating the effect of SRP-9003 on creatine kinase (CK) level. - Assessing the effect of SRP-9003 on disease milestones, such as loss of ambulation (LOA).
Participants
The clinical trial involves a total of **7 participants** diagnosed with **limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4)**, also known as β-sarcoglycanopathy. The study population includes both male and female subjects, aged 4 years and older, encompassing both ambulatory and non-ambulatory individuals. Participants were selected based on specific criteria, including the ability to walk without assistive aid for ambulatory subjects and specific performance scores for non-ambulatory subjects. All participants possess either one homozygous or two heterozygous pathogenic β-SG DNA gene mutations. The trial includes individuals who are willing to comply with the study protocol and assessments, and those who have stable glucocorticoid doses for at least 12 weeks prior to the study. Both genders of childbearing potential are required to use highly effective contraception methods throughout the study duration. The trial population is considered vulnerable, and informed consent or assent, along with parental or guardian consent, is mandatory for participation.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and **efficacy** of SRP-9003 in subjects with **limb-girdle muscular dystrophy, type 2E/R4**. This is a Phase 3, open-label, multinational study. The trial will involve a systemic gene delivery approach, with the primary objective being to assess the effect of SRP-9003 on **β-sarcoglycan** expression at Day 60 post-dose, as measured by immunofluorescence. The study is expected to run until February 2030, with recruitment starting in May 2024.
Participants will be randomly assigned to receive either SRP-9003 via intravenous infusion or a control treatment. The trial will include several key visits: an initial screening visit to determine eligibility, followed by dosing visits, and multiple follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement in the trial. The expected duration of participant involvement is up to 60 months, with conditions for early termination including significant adverse events or non-compliance with the study protocol.
Inclusion criteria require participants to be at least 4 years old, with specific criteria for ambulatory and non-ambulatory subjects. Participants must have stable glucocorticoid doses and meet genetic criteria related to **β-sarcoglycan** mutations. Exclusion criteria are not specified in the provided data. The study will monitor primary and secondary endpoints, including changes in **β-sarcoglycan** expression and various physical function tests. Safety assessments will include the incidence of treatment-emergent adverse events and clinically significant laboratory abnormalities.
Treatment
The clinical trial involves the administration of **SRP-9003**, a gene therapy product, which is provided in a **vial for intravenous use**. The active substance in SRP-9003 is **bidridistrogene xeboparvovec**, also known as adeno-associated virus serotype rh74 containing the human sarcoglycan beta gene. This investigational product is administered via **intravenous infusion**. The maximum total dose is 74,100,000,000,000 dosage forms, with a treatment period extending up to 60 days. SRP-9003 is classified as an orphan drug and contains genetically modified organisms (GMOs). The primary objective of the trial is to evaluate the effect of SRP-9003 on β-sarcoglycan expression in subjects with Limb Girdle Muscular Dystrophy 2E/R4.
In addition to the experimental treatment, **PREDNISONE** is used as a non-experimental treatment in the study. Prednisone is administered in **tablet form** and is taken **orally**. The maximum daily dose is 60 mg, with a total treatment period of up to 12 days. Prednisone is a chemical substance with anti-inflammatory properties similar to other corticosteroids. It is not classified as an orphan drug and does not contain GMOs. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
Efficacy
The efficacy of SRP-9003 in the treatment of **Limb Girdle Muscular Dystrophy 2E/R4** will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the change from baseline in **β-sarcoglycan** (β-SG) expression at Day 60 post-dose, measured by immunofluorescence (IF) percent β-SG positive fibers (PβSGPF). Secondary endpoints include additional measures of β-SG expression changes at Day 60 using IF PFE and Western blot techniques. Furthermore, the study will evaluate changes from baseline through Month 60 in physical function scores, such as the North Star Assessment for Dysferlinopathy (NSAD) total score and the Performance of the Upper Limb (PUL) 2.0 total score.
For ambulatory subjects in Cohort 1, timed function tests will be conducted, including time to rise from the floor, time to complete the 10-meter walk/run (10MWR), time to ascend four steps, time to complete the 100-meter walk/run (100MWR), and the timed up and go test. The incidence of treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events (SAEs) will also be monitored. Clinically significant laboratory abnormalities, changes in electrocardiograms (ECGs), echocardiograms (ECHOs), and creatine kinase (CK) levels will be assessed. The time to change of disease milestones will be recorded to provide a comprehensive evaluation of the treatment's efficacy over the study period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Cohort 1, only ambulatory subjects - ≥ 4 years of age - Able to walk without assistive aid - 10MWR < 30 seconds - NSAD total score ≥ 25
- Cohort 2, only non-ambulatory subjects − ≥ 4 years of age − 10MWR ≥ 30 seconds or unable to perform − PUL 2.0 entry scale score ≥ 3
- Has AAVrh74 antibody titers < 1:400 (ie, not elevated) as determined by AAVrh74 Antibody ELISA.
- Is willing to provide informed consent. Alternatively, is willing to provide assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide informed consent for the subject to participate in the study.
- Willing and able to comply with the study protocol required assessments
- Possesses 1 homozygous or 2 heterozygous pathogenic and/or likely pathogenic β-SG DNA gene mutations as documented prior to Screening. Results to be confirmed by Sponsor at a CLIA/CAP/ISO15189 certified laboratory prior to dosing.
- Able to cooperate with muscle testing
- Male or female who are of childbearing potential must agree to use, through Month 24, a highly-effective method of contraception (Appendix 1)., Section 11.4.1.1). A woman is considered of childbearing potential (i.e., fertile) following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
- Stable dose equivalent of oral glucocorticoids for at least 12 weeks before Screening/Baseline and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the first year of the study
Exclusion Criteria
- Has a symptomatic infection (eg, upper respiratory tract infection, pneumonia, pyelonephritis, meningitis) within 4 weeks before study treatment infusion (in such case, enrollment may be postponed). If symptomatic infection occurs between Day -7 (±3d) baseline testing and infusion baseline Day 1, the baseline Day -7 (±3d) testing will need to be repeated.
- Has received a live virus vaccine within 4 weeks or an inactive vaccine (including a coronavirus disease vaccine) within 2 weeks of the Day 1 visit or expects to receive a vaccine during the first 3 months after Day 1.
- Has LVEF < 40% on the Screening/Baseline ECHO or clinical signs and/or symptoms of cardiomyopathy
- Has FVC ≤ 40% of predicted value at Screening/Baseline and/or requirement for nocturnal ventilation.
- Serological evidence of current, chronic, or active human immunodeficiency virus infection, or hepatitis B or C infection or active viral or bacterial infection based on clinical observations.
- Diagnosis of (or ongoing treatment for) an autoimmune disease and on active immunosuppressant treatment.
- Has abnormal laboratory values considered clinically significant by the Investigator upon medical review including but not limited to: − Gamma-glutamyl transferase upper limit normal (ULN) − Total bilirubin ULN. Note that elevations on total bilirubin due to Gilbert’s syndrome are not exclusionary. − White blood cell count − Platelets
- Presence of any other clinically significant illness or medical condition, including cardiac, hepatic, renal, hematologic, immunologic, neuromuscular (other than LGMD2E/R4), or behavioral disease, or infection or malignancy or concomitant illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for gene transfer or a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability.
- Orthopedic comorbidity, such as scoliosis or joint contractures in the upper or lower extremity that would significantly inhibit accurate motor function testing, in the opinion of the Investigator.
- Any contraindication to the use of glucocorticoids.
- Has hypersensitivity to any component of the study drug
- Major surgery within 3 months prior to Day 1 or planned surgery or procedure that would interfere with the conduct of the study for any time during this study
- Treatment with any of the following therapies according to the time frames specified • Any time: − Gene therapy − Cell based therapy (eg, stem cell transplantation) − Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), or any other form of gene editing • Within 3 months of Day 1: − Use of human growth factor • Within 6 months of the Screening/Baseline visit: Any investigational medication (other than glucocorticoids)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 31 May 2024 | 2 |
 Germany | Not Recruiting | 31 May 2024 | 2 |
 Italy | Not Recruiting | 31 May 2024 | 2 |
 Spain | Not Recruiting | 31 May 2024 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PREDNISONE | Other | — | ORAL | 60 | 12 | SUB10020MIG |
PREDNISONE | Other | — | ORAL | 60 | 12 | SUB10020MIG |
PREDNISONE | Other | — | ORAL | 60 | 12 | SUB10020MIG |
SRP-9003 | Test | VIAL FOR INTRAVENOUS USE | INTRAVENIOUS INFUSION | 74100000000000 | 60 | PRD10893265 |