Interesting reading on FDA's trouble with using mdx mice for proof-of-concept.
4. Nonclinical Data
Proof-of-concept (POC) studies for SRP-9001 were conducted using rodent models of DMD. The Dmdmdx
mouse (C57BL/10ScSn-DMDmdx/J) exhibits a mild phenotype with minimal clinical signs, compared with
the severe muscle dysfunction in patients with DMD. Dmdmdx mice undergo an acute phase of skeletal
muscle necrosis that peaks around 3-4 weeks of age, followed by robust regeneration and stabilization
of the disease phenotype which is not observed in patients with DMD. With the exception of the
diaphragm, which displays more severe and progressive pathology, skeletal muscles of the Dmdmdx
mouse remain at a chronic low level of damage and muscle pathology as they cycle between muscle
degeneration and regeneration.
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Damaged skeletal muscle fibers in the Dmdmdx mouse show a decrease of approximately 20%-30% in
specific force; unlike in patients with DMD, myofibers in the Dmdmdx mouse hypertrophy without
atrophy in later stages. The Dmdmdx mouse has a mild cardiac phenotype, and more severe dystrophic
phenotypes such as fibrosis become more pronounced around 15 months of age. Finally, the Dmdmdx
mouse has a lifespan equivalent to 80% that of a healthy mouse, whereas the lifespan of patients with
DMD is only about one-third of the normal human lifespan.
Three primary nonclinical POC studies (Study Report Numbers: SR-20-001 [Process A material,
Nationwide Children Hospital], SR-19-061 [Process B material, Thermo Fisher], and SR-21-025 [Process B
material, Catalent]) were performed with single intravenous administration of SRP-9001 at dose levels
between 8 × 1013 vg/kg to 6 × 1014 vg/kg (Process A) and 4.43 × 1013 vg/kg to 4.01 × 1014 vg/kg (Process
B) in 4-8 week old Dmdmdx mice. Due to use of different methodologies to determine the physical titers,
the dose levels between Processes A and B cannot be directly compared. Functional assessment in these
studies was limited to isolated muscle force measurements of the diaphragm and tibialis anterior
muscles.
Unlike other shortened forms of dystrophin expressed from the endogenous DMD gene, Sarepta’s
micro-dystrophin is expressed from an AAV vector with a MHCK7 promoter and is thus regulated
differently. The biodistribution analysis indicated that the number of vector genomes per nucleus varied
widely across tissues, with the highest quantities of vector DNA present in the liver, followed by the
heart and skeletal muscles. Additionally, there were distinct differences in the micro-dystrophin
expression profile compared to endogenous dystrophin expression, with supraphysiological levels of
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(20min delay)