Abstract Details

Title Safety, ß-sarcoglycan Expression and Functional Outcomes from Systemic Gene Transfer of rAAVrh74.MHCK7.SGCB in Patients with Limb-Girdle Muscular Dystrophy Type 2E (LGMD2E)

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S32 - Therapeutics of Genetic Neuromuscular Diseases (4:24 PM-4:32 PM)

Poster/Presentation
Number 003

Background

LGMD2E is caused by mutations in the β-sarcoglycan (SGCB) gene that result in loss of functional protein affecting other structural components of the dystrophin-associated protein complex. Clinically, LGMD2E usually manifests with progressive hip/shoulder muscle weakness and often includes cardiac involvement and elevated creatine kinase (CK). We designed a self-complementary (sc) rAAVrh74.MHCK7.hSGCB construct to restore functional SGCB to muscles.

Objective

To report initial findings of a Phase 1/2 clinical gene transfer trial of rAAVrh74.MHCK7.hSGCB in patients with limb-girdle muscular dystrophy type 2E (LGMD2E).

Design/Methods

In this first-in-human, single-center, open-label, systemic gene delivery, Phase 1/2 study (NCT03652259), 6 patients with LGMD2E received rAAVrh74.MHCK7.hSGCB in escalating doses. Eligible patients: age 4-15y, SGCB gene mutation (both alleles), no rAAVrh74 antibodies, >40% on 100-meter timed test. Cohort 1 (n=3) received single IV infusion of 5x10¹³ vg/kg rAAVrh74.MHCK7.hSGCB; Cohort 2 (n=3) received single IV infusion of 2x10¹⁴ vg/kg. For all patients, prednisone 1 mg/kg/day was initiated 1d before treatment (tapering after 30–60 days). Primary endpoint: safety. Secondary endpoint: change in SGCB expression from baseline to week 8. Other endpoints: CK decrease; functional endpoints (North Star Assessment of Limb-girdle Muscular Dystrophies [NSAD] and timed functional tests [100-meter walk/run, 10-meter walk/run, 4-Stair Climb, and Time to Rise]).

Results Systemic administration of rAAVrh74.MHCK7.hSGCB is well tolerated with no unexpected immunological responses observed. Results show efficient transduction and robust SGCB protein expression in all patients post-infusion, leading to re-constitution of the sarcoglycan complex and reductions in CK. Six months after rAAVrh74.MHCK7.hSGCB infusion, patients from both cohorts experienced improvements in functional measures compared with baseline. For Cohort 1, data up to 18 months post-infusion are available and demonstrate improvements in NSAD and timed tests maintained over baseline.

Conclusions

These data suggest the long-term efficacy of rAAVrh74.MHCK7.hSGCB gene transfer therapy, supporting advancement of the clinical development program.

Authors/Disclosures
Louise R. Rodino-Klapac (Sarepta Therapeutics) PRESENTER	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 F. Miller, PT	Dr. Miller has received personal compensation for serving as an employee of ATOM International. Dr. Miller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casimir.
Megan Iammarino, PT (Nationwide Children'S Hospital)	Dr. Iammarino has nothing to disclose.
Linda P. Lowes, PT PhD	The institution of Ms. Lowes has received research support from Sarepta Therapeutics.
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.