Abstract Details

Title Safety, ß-Sarcoglycan Expression, and Functional Outcomes From Systemic Gene Transfer of rAAVrh74.MHCK7.hSGCB in LGMD2E/R4

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S23 - Therapeutics for Muscle Diseases (4:18 PM-4:30 PM)

Poster/Presentation
Number 005

Background Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by mutations in the β-sarcoglycan gene (SGCB), resulting in loss of SGCB protein and, subsequently, an absence of the dystrophin-associated protein complex (DAPC) at the sarcolemma. LGMD 2E/R4 manifests as progressive hip/shoulder muscle weakness.

Objective

To report the interim findings of an ongoing first-in-human, phase 1/2 trial (NCT03652259) evaluating SRP-9003, a self-complementary rAAVrh74.MHCK7.hSGCB construct designed to restore SGCB protein production.

Design/Methods Patients aged 4–15 years with SGCB mutation (both alleles) received 1 SRP-9003 IV infusion: Cohort 1 (n=3), 1.85×10¹³ vg/kg; Cohort 2 (n=3), 7.41×10¹³ vg/kg. Endpoints included safety (primary), SGCB protein expression (secondary), and function (North Star Assessment for Limb-girdle Type Muscular Dystrophies [NSAD], time to rise [TTR], 4-stair climb [4-sc], 100-meter timed test [100m], 10-meter timed test [10m]).

Results Previously reported results: Year 1 (Y1) for Cohort 2 and Year 2 (Y2) for Cohort 1 showed that as of January 2021, SRP-9003 was well tolerated; adverse events occurred early and were manageable. Immunofluorescence showed robust SGCB expression and correct sarcolemmal localization post treatment, leading to DAPC reconstitution, maintained to Y2 (Cohort 1). SRP-9003–treated patients showed functional improvements, maintained at Y2 in Cohort 1 (NSAD, +5.7 points; TTR, -0.6 s; 4-sc, -0.3 s; 100m, -2.8 s; 10m, -0.2 s) and Y1 in Cohort 2 (NSAD, +4 points; TTR, -1.1 s; 4-sc, -0.4 s; 100m, -7.9 s; 10m, -0.6 s). Post hoc analysis showed improved NSAD outcomes versus untreated natural history cohort (9.2-point difference, Y2; 95% CI, 3.2−15.1). An update with 3-year functional data for Cohort 1 and 2-year protein expression and functional data for Cohort 2 will be presented.

Conclusions These data suggest long-term efficacy of SRP-9003 therapy, supporting advancement of the clinical development program.

Authors/Disclosures
Jacob S. Elkins, MD PRESENTER	No disclosure on file
Louise R. Rodino-Klapac (Sarepta Therapeutics)	Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.
Eric Pozsgai	Eric Pozsgai has received personal compensation for serving as an employee of Sarepta Therapeutics. Eric Pozsgai has received stock or an ownership interest from Sarepta Therapeutics.
	No disclosure on file
Danielle A. Griffin	Ms. Griffin has stock in Sarepta Therapeutics. Ms. Griffin has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Kelly Lehman, MSN, CNP (Nationwide Children's Hospital- The Research Institute)	Ms. Lehman has nothing to disclose.
Kathleen Church	No disclosure on file
Natalie Reash (Nationwide Children's Hospital)	No disclosure on file
Megan Iammarino, PT (Nationwide Children'S Hospital)	Dr. Iammarino has nothing to disclose.
	No disclosure on file
Lindsay N. Alfano, PT (Nationwide Children'S Hospital)	Ms. Alfano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ATOM International, Ltd (Amicus Therapeutics, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics). Ms. Alfano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Novartis Gene Therapies. The institution of Ms. Alfano has received research support from Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Audentes Therapeutics/Astellas Gene Therapies. Ms. Alfano has received intellectual property interests from a discovery or technology relating to health care.
Linda P. Lowes, PT PhD	The institution of Ms. Lowes has received research support from Sarepta Therapeutics.
Erica Koenig	Erica Koenig has nothing to disclose.
Sarah B. Neuhaus, DO (Johns Hopkins Hospital)	Dr. Neuhaus has nothing to disclose.
	No disclosure on file
Jerry R. Mendell, MD, FAAN (The Research Institute at Nationwide Children's Hospital)	Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vertex. Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta Therapeutics . The institution of Dr. Mendell has received research support from Sarepta.