Sarepta Therapeutics' Phase 3 Study for Limb-Girdle Muscular Dystrophy Gene Therapy SRP-9003 Begins Screening Activities

Sarepta Therapeutics has begun screening patients for EMERGENE, a phase 3 clinical trial (NCT identifier pending) that will evaluate SRP-9003 (bidridistrogene xeboparvovec), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat limb-girdle muscular dystrophy Type 2E (LGMD2E/R4, also known as beta sarcoglycanopathy).¹

The multinational, open-label EMERGENE study will seek to enroll 15 patients with LGMD2E/R4 in total. Patients may be ambulatory or nonambulatory, but must be at least 4 years of age or older. The trial, which will use commercially representative process gene therapy product material, will evaluate expression of beta-sarcoglycan, the disease-targeted protein, at 60 days posttreatment as its primary outcome measure. Additional end points will include assessments of functional outcomes and safety. EMERGENE will include a 6-month evaluation of natural history for each patient before treatment.

“We are pleased to share our continued progress in advancing SRP-9003, our investigational gene therapy candidate for LGMD2E, a rare form of LGMD with no treatments beyond symptom management,” Louise Rodino-Klapac, PhD, the executive vice president, chief scientific officer, and head of research and development at Sarepta Therapeutics, said in a statement.¹ “Early results from the SRP-9003 clinical development program demonstrated significant protein expression at both 12-weeks and 2 years after treatment as well as functional benefits including slowing progression of this disease, improving mobility, and enhancing the quality of life for individuals living with LGMD2E. In addition to its importance for the LGMD2E community, EMERGENE will inform the clinical development of other programs for LGMD in Sarepta’s pipeline while serving as a pathfinder for viable regulatory pathways to support the development of gene therapies to treat ultra rare diseases.”

SRP-9003 is composed of a full-length beta-sarcoglycan transgene transported by an AAVrh74 vector, which Sarepta notes has been designed for delivery to skeletal, diaphragm, and cardiac muscle. The gene therapy also makes use of the MHCK7 promoter with the intention of improving expression in the cells of the heart. SRP-9003 has previously been evaluated in a phase 1 clinical trial (NCT05876780) and a phase 1/2 clinical trial (NCT03652259).

Results from the phase 1/2 study were previously presented at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.² In a low-dose cohort with 2 years of follow-up, mean beta-sarcoglycan (beta-SG) expression was 54% by western blot in patients receiving SRP-9003, which was an increase from 36% at day 60. In a high-dose cohort, the 60-day beta-SG expression was 62%.

In addition to SRP-9003, Sarepta is also developing gene therapies for 5 other forms of LGMD, including LGMD2D, LGMD2C, LGMD2B, LGMD2L, and LGMD2A.¹ The company previously made history with the FDA approval of delandistrogene moxeparvovec (SRP-9001, marketed as Elevidys), its gene therapy for the treatment of Duchenne muscular dystrophy, in June 2023.³

Sarepta Therapeutics is 1 of several companies currently developing gene therapies for the treatment of forms of LGMD. Others include Atamyo Therapeutics, which is developing ATA-100 (previously referred to as GNT0006), an investigational AAV vector-based gene therapy intended to treat fukutin-related protein (FKRP) LGMD type 2I/R9 (LGMD2I/R9), and Asklepios BioPharmaceutical, which is developing atingAB-1003 (LION-101), an investigational AAV vector-based gene therapy also intended to treat FKRP LGMD2I/R9.^4,5 Atamyo is additionally developing ATA-200, an investigational AAV vector-based gene therapy for the treatment of γ-sarcoglycan-related LGMD Type 2C/R5 (LGMD2C/R5).⁶

REFERENCES
1. Sarepta Therapeutics initiates screening in EMERGENE, a phase 3 clinical study of SRP-9003 for the treatment of limb-girdle muscular dystrophy type 2E/R4. News release. Sarepta Therapeutics, Inc. January 16, 2024. Accessed January 29, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-initiates-screening-emergene-phase-3?_ga=2.7071793.2083102767.1706027313-1116878115.1706027313
2. Rodino-Klapac L. Safety, β-sarcoglycan Expression, and Functional Outcomes from Systemic Gene Transfer of rAAVrh74.MHCK7.SGCB in Limb-Girdle Muscular Dystrophy Type 2E. Presented at MDA Clinical and Scientific Conference 2021; March 15-18.
3. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. June 22, 2023. Accessed January 29, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene
4. ATA-200, AtamyoTherapeutics’ gene therapy to treat limb-girdle muscular dystrophy type 2C/R5, reaches key milestones with the filing of a clinical trial application in Europe and a non-dilutive financing from France 2030 program. News release. Atamyo Therapeutics. September 19, 2023. Accessed January 29, 2024. https://atamyo.com/press-releases/https-atamyo-com-wp-content-uploads-pr-sept-19-2023-ata-200-reaches-key-milestones-with-cta-in-europe-and-france2030-financing-pdf/
5. AskBio announces first patient dosed in phase 1 / phase 2 trial of AB-1003 gene therapy for limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9). News release. Asklepios BioPharmaceutical, Inc. August 3, 2023. Accessed January 29, 2024. https://www.askbio.com/askbio-announces-first-patient-dosed-in-phase-1-phase-2-lgmd2i-r9/
6. ATA-200, AtamyoTherapeutics’ gene therapy to treat limb-girdle muscular dystrophy type 2C/R5, reaches key milestones with the filing of a clinical trial application in Europe and a non-dilutive financing from France 2030 program. News release. Atamyo Therapeutics. September 19, 2023. Accessed January 29, 2024. https://atamyo.com/press-releases/https-atamyo-com-wp-content-uploads-pr-sept-19-2023-ata-200-reaches-key-milestones-with-cta-in-europe-and-france2030-financing-pdf/