How SRP-5051 works
DMD is a type of muscular dystrophy, a group of genetic disorders characterized by muscle weakness and wasting. DMD is caused by mutations in the DMD gene that provides information for cells to make a protein called dystrophin. In order to make a protein, a temporary sort of gene copy is made, with information in its DNA transferred to a temporary molecule called messenger RNA (mRNA). The mRNA is used by the protein-making machinery of the cell.
Dystrophin is an essential protein for muscle health. Mutations in the gene encoding for dystrophin cause no or little working protein to be made, so that muscle cells weaken and die over time.
The most common Duchenne mutations are deletions in large sections of the DMD gene that cause protein synthesis to stop prematurely. Deletions in the specific region called exon 51 accounts for about 13 percent of all DMD cases.
SRP-5051 uses a proprietary chemistry platform developed by Sarepta, a specific type of oligonucleotide called a peptide phosphorodiamidate morpholino oligomer (PPMO). This artificial molecule contains a portion that resembles DNA, and a small proprietary peptide. The peptide portion can penetrate cells to carry the PMO backbone into cells. Once there, the oligomer portion binds specifically to the mRNA for dystrophin and helps the protein-making machinery to skip over exon 51. This is expected to result in the production of a slightly smaller but still functional dystrophin protein.
SRP-5051 in clinical trials
A Phase 1 clinical trial (NCT03375255) is now recruiting 30 DMD patients, ages 12 and older and with mutations amenable to exon 51 skipping, to test the safety and tolerability of one of five escalating doses of SRP-5051 given via intravenous (IV) infusion. Patients’ blood will be sampled at 15 minutes, 30 minutes, and 1, 2, 4, 8, and 12 hours following infusion to evaluate levels of the treatment present in the blood. Adverse events will be recorded for up to 14 weeks post-treatment. Patient enrollment is ongoing at seven sites in the U.S. and one in Canada; information is available here.
Patients who participate in this trial will be eligible to take part in a Phase 1/2 open-label extension study (NCT03675126), which will continue to measure the safety and tolerability of repeated treatment. The dose level and number of doses given will be determined based on results of the Phase 1 trial.
A two-part Phase 2 clinical trial (NCT04004065) is currently enrolling 24 DMD patients, ages 7 to 21 (at one site in Florida and in Georgia), to assess the safety and tolerability of SRP-5051 at multiple ascending doses. In the first part, patients will receive one of four escalating doses of SRP-5051 monthly for three months. After the maximum safe dose has been established, all will transition to the study’s second part, which will be dose expansion. Patients will be infused with SRP-5051 monthly for six months. Adverse events will be recorded at each stage.
SRP-5051 is based on the same technology that Sarepta has used to develop Exondys 51, which is conditionally approved to treat this same group of DMD patients. However, Exondys 51 is a phosphorodiamidate morpholino oligomer (PMO) rather than a peptide phosphorodiamidate morpholino oligomer (PPMO). In other words, Exondys 51 does not contain the small peptide modifier present in SRP-5051.
Although the difference between these two exon 51-skipping therapies is not fully explained, the addition of the peptide modifier to SRP-5051 may make the treatment more effective, possibly by improving its ability to enter muscle cells.
Last updated: 07/17/2019
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