We don't know if it is eteplirsin but its a case of what else could it be!
Good question waynesworld, so I thought I’d try to find an answer to that as well as check the research to date on cell-penetrating peptide mediated delivery of antisense oligomers.
Eteplirsen has been designed to skip the 51 dystrophin exon ( there are 79 dystrophin exon and approximately 13% of patients with DMD are amenable to exon 51-skipping). Professors Fletcher and Wilton pioneered antisense oligomer induced exon skipping to overcome these dystrophin mutations and have already developed antisense oligomers to skip each of the 79 dystrophin exon, except the first and last.
I note that Sarepta has multiple other exon-skipping candidates for DMD in its pipeline. Candidates for exon 53-skipping (SRP-4053) and for exon 45-skipping (SRP-4045) are already in clinical development and other drug candidates designed to skip exons 44, 52, 50, 43, 55, 8, and 35 are at discovery and preclinical stage.
It was stated that the PYC collaboration with the team at Murdoch will focus on improving the effectiveness of oligonucleotide therapies for DMD, so I’m expecting multiple candidates to be involved.
I’ve also done some research on both eteplirsen and the state of current research on CPP-mediated delivery of antisense oligomers.
Eteplirsen is described as a phosphorodiamidate morpholino oligomer (PMO) and is not conjugated with any delivery vehicle (and hence is called a bare-morpholino). Eteplirsen’s key advantage is its strong safety profile. However its weakness is its low efficacy. Clinical trial data for eteplirsen submitted to the FDA show that dystrophin protein was increased by just 0.9% over 180 weeks in eteplirsen-treated patients compared to untreated DMD patients. In April, accelerated approval was denied to eteplirsen, with the FDA review panel citing insufficiently persuasive evidence from Sarepta that eteplirsen helps increase levels of dystrophin to a point likely to provide clinical benefit.
The reason for low efficacy appears to lie in the drug’s poor cellular uptake and relative rapid clearance, which necessitates relatively high doses and repeated administration (with major implications for treatment cost) in order to achieve even limited therapeutic efficacy. It also appears that high variability in exon-skipping efficiency among muscle types means some muscles respond better than others. Low efficacy is demonstrated in the cardiac muscle which is a disadvantage as cardiomyopathy is the second leading cause of death in patients with DMD.
It has already been established that improved efficacy can be achieved with cell-penetrating peptide (CPP) -conjugated PMO (PPMO). Over the past decade, studies in many laboratories have demonstrated that PPMO can be used at a much lower dose than PMO and can achieve more widespread restoration of dystrophin throughout the whole body's muscle including the heart. While this would suggest that delivering PMO with cell-penetrating peptides is the obvious solution to overcome the poor efficacy of PMO, the issue of toxicity remains a challenge.
Sarepta has already tested a PPMO in animal models. AVI-5038 is a (RXRRBR)2 peptide-conjugated PMO targeted to skip human exon 50. AVI-5038 demonstrated efficacy in monkeys with a once-weekly IV injection for 4 weeks at 9 mg/kg. (In clinical trials, eteplirsen was administered via a once- weekly injection at dosing levels of 30 and 50mg/kg). The PPMO induced an average of 40%, 25%, and 2% exon-skipped product in diaphragm, quadriceps, and heart of four monkeys. However, some toxicity was noted, with mild tubular degeneration found in the kidneys. As well as toxicity, another major concern said to arise with the use of peptides as delivery enhancers for PMO is the immune response they might elicit.
Hence the statement in PYC’s announcement
A further study aim is to determine whether Phylogica’s delivery technology can improve drug activity without compromising drug safety – a challenge the previous generation of cell penetrating peptides failed to overcome.
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