AAVrh74.MHCK7.micro-dystrophin (Serapta Therapeutics)- SRP- 9001 for Duchenne Muscular: Update From Phase 2 Clinical Studies

AAVrh74.MHCK7.micro-dystrophin (Serapta Therapeutics- SRP- 9001)

Clinical Stage and Regulatory Timeline
SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. U.S. Food and Drug Administration (FDA) has granted Orphan and Fast Track designation to SRP-9001 (AAVrh74.MHCK7.micro-dystrophin). Sarepta’s expectation to have results from Study 102 in early 2021; and potentially submit biologic licencing application to FDA in 2021.

Viral Vector and Gene Construct: 

AAVrh74.MHCK7.micro-dystrophin, MHCK7 is a tissue specific promoter that drive the expression in the muscle tissue. AAVrh74 is an adenoassociated virus isolated from rhesus monkey and have high tropism for skeletal and cardiac muscle. 

Clinical Phase:

Sarepta is currently conducting a Phase 2 (NCT03769116) randomized, double-blind, placebo-controlled study to safety and efficacy of the exogenous gene transfer in DMD subjects. The Phase 1/2b (NCT03375164) study to determine the safety and tolerability of the AAVrh74.MHCK7.micro-dystrophin is completed and one year data is published in JAMA Neurology (2020). 

Outcome Measures

Primary Outcome Measure

  • Change From Baseline in Quantity of Micro-dystrophin Protein Expression as Measured by Western Blot. (Baseline up to Week 12)
  • Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score (Baseline up to Week 48)
Secondary Outcome Measure include timed walk test, quantity of microdystrophin in muscle fibers and Serious Adverse Events

Key Results from Phase 1/2a 
A single dose of 2.0 e14 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion).

At 12 weeks, immunohistochemistry of muscle biopsy specimens showed a mean of 81.2% micro-dystrophin-positive fibers in the gastrocnemius muscle. The presence was confirmed by western blot analysis
All 4 patients showed improvements in NSAA scores and reductions in CK levels from baseline throughout the study and up to 1 year after treatment 

Durability (Up to 2 years):

Improved NSAA Total Score By Age at Time of Assessment Over 2 Years showed that the durable expression of transgene after administration of SRP-9001.

Safety: There were total 18 treatment related adverse events. The most common treatment-related adverse event was vomiting (9 of 18 events [50%]) after rAAVrh74 administration.

Serious Adverse Events: No serious Adverse events were observed 


Antibody Response: Antibody response against rAAV74 capsid peaked around 30 days and remained stable for one year

T cell Response (ELISpot): No T-cell responses were observed toward micro-dystrophin. T-cell response toward AAV peptide pools demonstrated transient increases as early as 14 days after gene delivery. Most importantly, elevations were not associated with liver enzymes or transgene expression.


Sarepta Therapeutics 101 Study Updates

SPR-9001 JAMA Neurology