… i guess i still go by comments from some corners a long time ago that the mouse model hides a lot of issues with multi cell penetration, and the fact that effects can be seen in mouse model that may not translate so well to primate or human type models.
The effect of the cpp being absorbed by many more cells of various types in humans leads to more off target effects or requirement for much larger doses and consideration of the effect when absorbed or penetrating unintended target cells.
Andrew
I think it’s fairly well understood that great results seen in a mouse model may not translate to primate and human models. Hence the need for PYC to validate its technology by advancing through to human models.
Nevertheless, Sarepta has managed to successfully progress SRP-5051, which is a PPMO (CPP + PMO), from mouse to primate to human trials in DMD (exon skipping 23). If Sarepta can do it, why can’t PYC?
The SRP-5051 pre-clinical mouse model study was referenced in PYC’s 2018 AGM presentation. I’ve reproduced the relevant slide below. Sarepta tested four IV- administered doses in that study (10, 20, 40, 80 mg/kg). As shown in the slide, very little effect was seen in the heart muscle at sub-80mg/kg dose levels.
But SRP-5051 has since been taken to primate studies, had an IND approved and advanced to a Phase 1/2 study. The Phase 1 component completed recently and the Phase 2 dose escalation study at 4, 10, 16, 20 mg/kg, to determine MTD, has already commenced. Results are yet to be released.
Commenting on the preclinical results for SRP-5051, Sarepta’s President said they pointed to the potential of the company’s PPMO technology to substantially increase efficacy while reducing the frequency of dosing. He said that the company had an ambitious strategy to rapidly advance multiple PPMO-based therapies in DMD. He added that, if there were positive signals in the first PPMO trial, the company would in parallel explore applying its PPMO technology to a broad range of other neuromuscular diseases.
Notably, PYC used a similar mdx mouse disease model of DMD (exon skipping 23) to test its CPP +PMO. PYC reported that its conjugate PMO showed strong potency at concentrations as low as sub-micromolar. It was observed that this strong potency could potentially avoid high dosage concentrations, and consequently lower toxicity, membrane disruption and manufacturing costs.
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