SRP-9003 rAAVr74.MCK.SCGB Gene Therapy for Limb Girdle Dystrophy (Sarepta Therapeutics): Clinical Study Update

Sarepta Therapeutics: SRP-9003 rAAVr74.MCK.SCGB Gene Therapy for Limb-Girdle Dystrophy


Clinical Stage and Regulatory Timeline
SRP-9003 is an investigational gene transfer therapy intended to deliver gene SGCB to muscle tissue for the targeted production of the beta-Sarcoglycan in the muscle. Sarepta is conducting phase 1/2 clinical study to determine safety, efficacy, and effective dose of SRP-9003 in patients with Limb-Girdle Muscular Dystrophy Type 2E with SGCB loss of function mutation. All patients have been enrolled in the study and administered with SRP-9003. The sponsors are awaiting two years of safety and efficacy endpoints data to initiate the pivotal trial.

Viral Vector and Gene Construct: 

AAVrh74.MHCK7.hSGCB- MHCK7 is a tissue-specific promoter that drives the expression in the muscle tissue. AAVrh74 is an adeno associated virus isolated from rhesus monkey and have high tropism for skeletal and cardiac muscle. 

Clinical Phase:

Sarepta is conducting a nonrandomized, sequential, the first-in-human, single-center, open-label, gene delivery study of SRP-9003 in LGMD2E patients. 
Total number of participant =6

Outcome Measures

Primary Outcome Measure

  • Safety based on the number of subjects with adverse events (AEs). [ Time Frame: Baseline upto 3 years ]. AEs will be monitored and scored for severity and relatedness to the study article.

Secondary Outcome Measures :
  • Change From Baseline in Quantity of Beta- Sarcoglycan (SG) Protein Expression at Week 8 Measured by Immunofluorescence [ Time Frame: Baseline Up to Week 8 ]. Beta-SG gene expression levels will be quantified by immunofluorescence and compared between pre and post muscle biopsies.
  • Change From Baseline in Quantity of Beta-Sarcoglycan (SG) Protein Expression at Week 8 Measured by Western Blot [ Time Frame: Baseline Up to Week 8 ]
  • Beta-SG gene expression levels will be quantified by Western Blot and compared between pre and post muscle biopsies.


Inclusion Criteria

  • A confirmed SGCB mutation in both alleles
  •  – Negative for AAVrh74 antibodies
  •  – >40% of normal 100-meter walk test

Key Results from Phase 1/2 with for Cohort with 2 e14 vg/kg

A single dose of 2.0 e14 vg/kg rAAVrh74.MCK-SCGB was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion).

Efficacy 
At 8 weeks, a mean 73% increase in expression of beta-sarcoglycan in muscle biopsies from baseline observed in immunohistochemistry.
At 8 weeks, mean 62.1% increase in beta-sarcoglycan in muscle biopsies from baseline as evident by western blot. 

89.1%  reductions in CK levels  from baseline 90 to Day  after treatment 

Durability:

Need a long-term follow up to determine the durability of expression

Safety: The majority of AEs were mild to moderate  (eg, vomiting, pain in the extremity) 

Severe Adverse Event
1 treatment-related SAE observed with Dehydration resulting from vomiting 3 days after infusion, which resolved within 2 days with ondansetron, promethazine, and IV fluids
1 patient had mildly elevated GGT – Returned to within normal limits while on a tapering dose of steroids
No clinical sequelae associated with complement activation

Immunogenicity

Antibody Response: Not Reported

T cell Response (ELISpot): Not Reported

Reference

Sarepta Therapeutics Press Release

Clinical Trial NCT03652259