In the space of a week we have another development that I view as having real importance for PYC.
As mentioned in my previous post, Dyne Therapeutics, like PYC, is developing PMO antisense drugs.
In Dyne’s case, the PMO is conjugated with proprietary antigen-binding fragments with the aim of enhancing delivery and hence efficacy/using much lower and safer doses than with standard naked antisense drugs/ dosing less frequently. Very early clinical data released earlier this month suggest that Dyne is on the right track. And that immediately attracted interest from both investors and pharma in Dyne.
PYC shares Dyne's aims, which it hopes to achieve by conjugating PMOs with cell-penetrating peptides (CPPs).
One problem for PYC, in terms of investor and pharma interest, has been that there are currently no FDA-approved CPP-conjugated PMO drugs, nor real clinical validation of the approach. The approach has been viewed as highly promising, but unproven.
The leading CPP-PMO drug in clinical development is Sarepta’s SRP-5051 (vesleteplirsen), which has recently completed a 28 week, 40 patient Phase 2 trial in DMD amenable to Exon 51 skipping, the same indication as its lead approved drug, Exondys51 (eteplirsen) and one of the indications that Dyne has just reported on.
These are the results for the SRP-5051 Phase 2 trial, which Sarepta released overnight:
High dose results at 28 weeks (~30 mg/kg, dosed every four weeks, n=20):
5.17% mean dystrophin expression as measured by western blot
4.53% mean change from baseline, P < 0.0001
Mean exon skipping of 11.11%, as measured by digital drop polymerase chain reaction (ddPCR), and a mean change from baseline in exon skipping of 10.07%
The changes from baseline represent a 12.2-fold increase in dystrophin expression and a 24.6-fold increase in exon skipping compared to a weekly 30 mg/kg dose of eteplirsen at 24 weeks (mean dystrophin expression of 0.82%, mean exon skipping of 0.59%, n=16).
Low dose results at 28 weeks (~20 mg/kg, dosed every four weeks, n=20):
2.81% mean dystrophin expression as measured by western blot
1.60% mean change from baseline, P= 0.0012
Mean exon skipping of 2.47%, as measured by ddPCR, and a mean change from baseline in exon skipping of 2.00%
The changes from baseline represent a 4.3-fold increase in dystrophin expression and a 4.9-fold increase in exon skipping compared to a weekly 30 mg/kg dose of eteplirsen at 24 weeks.
With these results, one might say that the CPP-PMO approach now has clinical validation.
The one catch for Sarepta is the safety profile of SRP-5051, especially at the higher dose. Treatment was associated with low potassium and magnesium levels. In seven instances, those side effects were judged to be serious but did not lead to any discontinuations during the course of the trial.
In 2018, in its AGM presentation, PYC outlined the thinking behind its pivot to utilizing its CPP platform to develop and take antisense therapies into the clinic
Cell Penetrating Peptides (CPPs) sit on the cusp of clinical validation….
Sarepta have taken promising pre-clinical results driven by Cell-Penetrating Peptides (CPPS) into the Clinic…
Phylogica has a major competitive advantage in CPPs….
Our CPPs deliver more cargo inside cells than competitor CPPs.
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