PII-139 - PHARMACOMETRICS-BASED APPROACH TO FIRST-IN-HUMAN INTRAVENOUS DOSE DETERMINATION FOR SRP-6004 IN PATIENTS WITH LIMB GIRDLE MUSCULAR DYSTROPHY 2B

S. Dong¹, O. Rogers¹, B. Paleo¹, S. Maurya¹, A. Ostermann¹, A. Haidet-Phillips¹, R. Potter¹, L. Rodino-Klapac¹, L. East¹; ¹Sarepta Therapeutics, Inc..

Background: SRP-6004 is a dual vector AAV-based gene transfer therapy for dysferlinopathy, limb girdle muscular dystrophy Type 2B/R2 (LGMD2B/R2). Extensive dose-ranging pharmacokinetic/pharmacodynamic (PK/PD) evaluations were performed in a dysferlin-deficient mouse model (Bla/J mice), representative of LGMD2B/R2, to determine the first-in-human (FIH) intravenous (IV) SRP-6004 dose.

Methods: Bla/J mice were administered a single dose of SRP-6004 via IV bolus injection at dose levels from 2.43×10¹³ vg/kg to 1.46×10¹⁴ vg/kg. The PK/PD relationship was evaluated between tissue vector genome exposure (PK), PD response on dysferlin protein expression (percent dysferlin-positive fibers [PDPF] and western blot [WB]), and motor function improvement (relative specific force from diaphragm and tibialis anterior) using data on SRP-6004 in skeletal muscle, diaphragm, and heart tissue in Bla/J mice.

Results: Muscle tissue PK (dysferlin cDNA [reconstituted vector genome from the dual vectors] exposure, vector copies/nucleus) increased proportionally with dose within the 10-fold dose range. Correspondingly, a dose-dependent increase in dysferlin protein expression (PDPF by immunofluorescence [IF] and WB) was observed. For dysferlin protein, an apparent plateau was observed at higher doses, with the dose–response relationship best characterized and quantified using a nonlinear model (sigmoid E_max model). The same model structure also best described the PK/PD relationship between dysferlin cDNA tissue exposure and protein expression measured by IF and WB, with an apparent saturation of protein expression observed at a tissue PK level well achieved by the FIH dose. A dose level predicted for FIH clinical evaluation achieved the target biologic efficacious threshold of 25% dysferlin protein expression, which is within the range of endogenous protein expression level reported in asymptomatic carriers of dysferlin gene mutation.

Conclusion: The dual vector composition of SRP-6004 successfully achieved robust tissue transduction and protein expression. The FIH IV dose was determined based on biologic efficacy targets of dysferlin protein expression, incorporating both WB and PDPF endpoints. The totality of these findings supported the clinical translation of SRP-6004 into patients.