Open-label, Phase 3 Gene Delivery Study with SRP-9003 in LGMD 2E/R4 Subjects

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sarepta Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

16 Oct 2024 → ongoing

Decision date (initial)

2024-06-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Sarepta Therapeutics, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the effect of SRP-9003 on β-sarcoglycan (β-SG) expression at Day 60 post-dose as measured by immunofluorescence (IF) percent β-SG positive fibers (PβSGPF) for subjects in Cohort 1 (ambulatory subjects)

Secondary objectives 7

1. To evaluate the effect of SRP-9003 on β-SG expression at Day 60 post-dose as measured by IF percent fluorescent intensity (PFI) and Western assay of biopsied muscle tissue for subjects in Cohorts 1 (ambulatory subjects) and 2 (non ambulatory subjects)
2. To evaluate the effect of SRP-9003 on β-sarcoglycan (β-SG) expression at Day 60 post-dose as measured by immunofluorescence (IF) percent β-SG positive fibers (PβSGPF) for subjects in Cohort 2 (non-ambulatory subjects)
3. To evaluate the effect of SRP-9003 on physical function through Month 60 in all cohorts, as assessed by: − North Star Assessment for Dysferlinopathy (NSAD) score − Performance of Upper Limb (PUL) 2.0 score
4. To evaluate the effect of SRP-9003 timed function tests for subjects in Cohort 1 (ambulatory subject) through Month 60
5. To evaluate the safety of SRP-9003
6. To evaluate the effect of SRP-9003 on creatine kinase (CK) level
7. To evaluate the effect of SRP-9003 on disease milestones (eg, loss of ambulation [LOA])

Conditions and MedDRA coding

Limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4) or β-sarcoglycanopathy

Study design 5 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Cohort 1, only ambulatory subjects - ≥ 4 years of age - Able to walk without assistive aid - 10MWR < 30 seconds - NSAD total score ≥ 25
2. Cohort 2, only non-ambulatory subjects − ≥ 4 years of age − 10MWR ≥ 30 seconds or unable to perform − PUL 2.0 entry scale score ≥ 3
3. Has AAVrh74 antibody titers < 1:400 (ie, not elevated) as determined by AAVrh74 Antibody ELISA.
4. 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.
5. Willing and able to comply with the study protocol required assessments
6. 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.
7. Able to cooperate with muscle testing
8. 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.
9. 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 13

1. 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.
2. 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.
3. Has LVEF < 40% on the Screening/Baseline ECHO or clinical signs and/or symptoms of cardiomyopathy
4. Has FVC ≤ 40% of predicted value at Screening/Baseline and/or requirement for nocturnal ventilation.
5. 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.
6. Diagnosis of (or ongoing treatment for) an autoimmune disease and on active immunosuppressant treatment.
7. 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
8. 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.
9. 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.
10. Any contraindication to the use of glucocorticoids.
11. Has hypersensitivity to any component of the study drug
12. 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
13. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline in β-SG expression at Day 60 post-dose as measured by IF PβSGPF for subjects in Cohort 1 (ambulatory subjects)

Secondary endpoints 13

1. Change from Baseline in β-SG expression at Day 60 post-dose as measured by IF PβSGPF for subjects in Cohort 1 (ambulatory subjects)
2. Change from Baseline in β-SG expression at Day 60 post-dose for subjects in Cohorts 1 (ambulatory subjects) and 2 (non-ambulatory subjects) as measured by IF PFI
3. Change from Baseline in β-SG expression at Day 60 post-dose as measured by Western
4. Change from Baseline in β-SG expression at Day 60 post-dose as measured by IF PβSGPF for subjects in Cohort 2 (non-ambulatory subjects)
5. Change from Baseline through Month 60 in the following physical function for subjects in Cohorts 1(ambulatory subject) and 2 (non-ambulatory subject) − NSAD total score − PUL 2.0 total score
6. Change from Baseline through Month 60 in the following timed function tests for subjects in Cohort 1 (ambulatory subject): − Time to rise from the floor − Time to complete the 10MWR − Time to ascend 4 steps − Time to complete the 100MWR − Timed up and go
7. Incidence of TEAEs
8. Incidence of adverse events of special interest
9. Incidence of treatment-emergent SAEs
10. Incidence of clinically significant laboratory abnormalities
11. Clinically significant changes in ECGs, ECHOs
12. Change from Baseline through Month 60 in CK level
13. Time to change of disease milestones

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sarepta Therapeutics Inc.

Sponsor organisation

Sarepta Therapeutics Inc.

Address

215 1st Street

City

Cambridge

Postcode

02142-1213

Country

United States

Scientific contact point

Organisation

Sarepta Therapeutics Inc.

Contact name

Patient Recruitment

Public contact point

Organisation

Sarepta Therapeutics Inc.

Contact name

Patient Recruitment

Third parties 21

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 282 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications