How SRP-4045 works
DMD is a rare, life-shortening genetic disease, mostly affecting boys, that causes their muscles to break down and lose strength over time.
It is caused by mutations in the DMD gene. Most commonly, one or more exons (a portion of the gene) are missing, and the remaining exons do not ﬁt together properly. Because of this error, cells cannot make the dystrophin protein that muscles need to work properly. Without dystrophin, muscle cells are damaged, and, over time, are replaced with scar and fat tissue.
SRP-4045 works by using Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology. PMO directs the cell to skip exon 45 when processing RNA (a molecule that ultimately leads to the production of a protein). Skipping a specific exon allows the body to make a shortened but still functional dystrophin protein.
By addressing the underlying cause of DMD and promoting the synthesis of a shorter dystrophin protein, SRP-4045 intends to slow the decline in the ability to walk and move seen in DMD patients.
SRP-4045 in clinical trials
The safety, tolerability, and pharmacokinetics of SRP-4045 are being evaluated in a randomized, placebo-controlled dose-adjustment Phase 1 study (NCT02530905). About 12 patients with advanced-stage DMD and deletions amenable to exon 45 skipping are enrolled.
A separate study is set to evaluate the efficacy and safety of SRP-4045 and another exon-skipping therapy, golodirsen or SRP-4053, in about 99 boys, ages 7 to 13, with DMD amenable to skipping exons 45 or 53. It is currently recruiting patients at test sites across the U.S. and Europe, and in Canada and Israel.
In this Phase 3, double-blind, placebo-controlled, trial (NCT02500381), called ESSENCE, patients will be randomized to receive either treatment or placebo as a once-weekly intravenous (IV) infusion for up to 96 weeks. This will be followed by an open-label extension period, in which all patients will receive open-label active treatment for up to 96 weeks.
The study’s primary outcome will be changes in muscle strength from study start (baseline) as measured by changes in the six-minute walk test. Secondary goals include changes in dystrophin protein production and respiratory strength (measured by forced vital capacity, or the amount of air that can be expelled in one forced breath).
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