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Monthly administration of SRP-5051 — Sarepta Therapeutics’ investigational, potentially improved version of its Exondys 51 (eteplirsen) therapy — increased exon 51 skipping, dystrophin levels, and grip strength in a dose-dependent way in preclinical models of Duchenne muscular dystrophy (DMD), a study shows.
These findings, supporting SRP-5051’s monthly regimen now being tested in clinical trials, were presented in the poster “Biological Efficacy of the Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer SRP-5051 in Preclinical Models of Duchenne Muscular Dystrophy,” at the 2021 MDA Virtual Clinical and Scientific Conference running March 15–18.
The most common DMD-causing mutations involve the deletion of one or more exons — sections of genetic information needed to make proteins — in the DMD gene, which provides the instructions to produce a key protein for muscle health called dystrophin.
This deletion breaks the ability of the remaining exons to link together properly in an intermediate process of protein production, affecting the generation of working dystrophin protein.
Similar to the approved exon-skipping therapy Exondys 51, SRP-5051 is designed to overcome this inappropriate fit by forcing the cell’s machinery to skip over exon 51 in eligible DMD patients, allowing the remaining exons to fit together. A smaller, but functional dystrophin protein, can then be produced.
Patients whose mutations are amenable to exon 51 skipping account for about 13% of all DMD cases.
A next-generation therapy, SRP-5051 was created using Sarepta’s proprietary next-generation chemistry platform, called PPMO. The platform has the potential to produce molecules with a greater ability to enter tissues, such as muscle, compared with Exondys 51.
This is expected to improve treatment effectiveness, and reduce dosing frequency. Notably, Exondys 51 is administered every week.
Researchers at Sarepta and Charles River Laboratories evaluated the effects of SRP-5051 in DMD patient-derived muscle cells, in a mouse model of DMD amenable to exon 51 skipping, and in healthy non-human primates.
Results showed that increasing doses of SRP-5051 resulted in dose-dependent increases in exon 51 skipping, and in dystrophin levels in both patient-derived cells and the mouse model.
These effects were sustained in the heart and bicep muscles of these mice for one month after a single dose; more subtle raises were still detectable at three months.
In healthy monkeys, a single SRP-5051 administration also resulted in a dose-dependent increase in therapy levels and the skipping of exon 51 in muscle tissue for up to 28 days (nearly a month).
Doses given once-a-month for five months (five doses) boosted exon 51 skipping and dystrophin accumulation in cardiac (heart) and diaphragm muscles, and restored grip strength in the mouse model.
Data from healthy primates given SRP-5051 monthly for three months showed that exon 51 skipping and treatment exposure increased with each dosing, and in a dose-dependent manner. The therapy appeared to be well-tolerated, with no new safety concerns identified.
“These data justify the monthly SRP-5051 dosing regimen (every 4 weeks) used in ongoing clinical studies, and support further clinical investigation,” the researchers wrote.
SRP-5051 is being tested in DMD patients who are amenable to exon 51 skipping in a proof-of-concept Phase 2 clinical trial, called MOMENTUM (NCT04004065). It is currently recruiting eligible patients, children through adults age 21, at clinical sites in the U.S., Canada, and select European countries. Sites in Australia may also be involved, Sarepta reported in a December 2020 release.
Interim results showed that the investigational therapy, given at a lower dose and in a less frequent regimen than that approved for Exondys 51, resulted in greater cell penetration, exon 51 skipping, and dystrophin levels, supporting its enhanced benefits.
MOMENTUM is expected to finish in May 2022.
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