Evaluation of Skin Biopsy as a Method to Assess Pharmacokinetic and Pharmacodynamic Properties of SRP-5051 in Preclinical Species


Clinical Trials

Poster Number: Virtual


Marie Claire Mukashyaka, MS, Sarepta Therapeutics, Inc., Mohammad Shadid, Sarepta Therapeutics, Inc., Leslie CL Wu, Sarepta Therapeutics, Inc., Mark Wysk, Sarepta Therapeutics, Inc., Jenna Wood, Sarepta Therapeutics, Inc., Jianbo Zhang, Sarepta Therapeutics, Inc., Miralem Prijic, Sarepta Therapeutics, Inc., Kamela Bellovoda, Sarepta Therapeutics, Inc., Bryan Mastis, Sarepta Therapeutics, Inc., Sam Foley, Sarepta Therapeutics, Inc., Annika Malmberg, Sarepta Therapeutics, Inc., Shawn Harriman, Sarepta Therapeutics, Inc., John R Hadcock, Sarepta Therapeutics, Inc.

Background: Pharmacokinetic/pharmacodynamic (PK/PD) properties of exon-skipping therapies for DMD are traditionally evaluated by invasive muscle biopsies limiting longitudinal study of individual patients. Skin biopsies may be a less-invasive alternative.
Objective: Skin was compared with other tissues in preclinical models to evaluate PK/PD properties of SRP-5051, an investigational peptide-conjugated phosphorodiamidate morpholino oligomer designed to target exon 51 skipping.
Methods: Skin, skeletal muscle, and other tissues were collected from healthy male nonhuman primates (NHP) and male hDMD del52/mdx mice after various doses of SRP-5051 and analyzed for drug concentration, exon skipping, and dystrophin expression.
Results: Single SRP-5051 30-mg/kg infusion in NHP resulted in greater mean drug concentration in skin (1620 ± 579 ng/g) versus biceps (267 ± 34 ng/g), but exon skipping was lower (skin, 3.1 ± 5.4%; biceps, 18.0 ± 4.6%; P = 0.0328) at Day 10. Total DMD transcript copies were lower in skin versus biceps (363 vs 39878 per 30 ng RNA). At Day 15 after single 60-mg/kg infusion, tissue concentration (479 ± 296 ng/g and 712 ± 680 ng/g) and exon skipping (20.0 ± 8.3% and 33.0 ± 8.3%) were similar in skin and biceps, respectively. SRP-5051 60-mg/kg every-4-weeks (Q4W) showed higher drug concentration in skin (6210 ± 1691 ng/g) versus biceps (1456 ± 1075 ng/g; P < 0.0001) and comparable exon skipping at Week 12 in both tissues (skin, 22.7 ± 6.3%; biceps, 32.4 ± 9.2%). Results were similar in del52/mdx mice: comparable drug concentrations but lower exon skipping in skin versus biceps 12 weeks after SRP-5051 100 mg/kg Q4W (P < 0.0001), and lower exon skipping after 200 mg/kg Q4W (P = 0.0002). Dystrophin expression corresponded to exon skipping levels.
Conclusions: Skin biopsy may allow less-invasive longitudinal PK/PD biomarker assessments after SRP-5051 treatment, with potential application to other exon-skipping or gene therapies in future clinical studies.