Sarepta Therapeutics’ investigational treatment SRP-5051 enhanced cell penetration, exon skipping, and dystrophin levels at a lower dose than its Exondys 51 (eteplirsen) therapy in a Phase 2 clinical trial in patients with Duchenne muscular dystrophy (DMD).
The results are proof-of-concept for the company’s PPMO approach, a newer version of the PMO technique behind Exondys 51, the first DMD treatment approved by the U.S. Food and Drug Administration.
“Our next-generation PPMO technology is designed to increase cell penetration with the goal of offering significantly improved efficacy with more convenient dosing in Duchenne patients amenable to exon skipping,” Doug Ingram, president and CEO of Sarepta, said in a press release.
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% of all DMD cases. Exons are the parts of genes that code for proteins.
SRP-5051 uses a proprietary chemistry platform developed by Sarepta to help the protein-making machinery to skip over the mutated exon, and enable the production of a smaller but functional dystrophin protein.
The artificial molecule used in SRP-5051 works very similarly to Exondys 51, but unlike the approved treatment, it is coupled to a small peptide that increases the amount of drug that enters muscle cells. This is expected to improve the treatment’s effectiveness, and potentially reduce dosing frequency.
The ongoing MOMENTUM Phase 2 study (NCT04004065) was designed to investigate the safety and tolerability of SRP-5051 in DMD patients who are amenable to exon 51 skipping. It is recruiting up to 24 patients, ages 7–21, at clinical sites in the U.S., Canada, Australia, and Europe.
The trial will be conducted in two parts. Participants in Part A will receive monthly ascending doses of SRP-5051, starting at 4 mg/kg and increasing to 40 mg/kg, administered via into-the-vein infusions for 12 weeks. After an optimal dose is established, an additional group of patients will receive that dose for 24 weeks (about six months).
The main goal is to determine the treatment’s safety, and secondary measures include the amount of SRP-5051 reaching the muscles, exon-skipping, and the levels of dystrophin.
Results from Part A demonstrated that SRP-5051 was generally well-tolerated at all studied doses, with no serious adverse effects reported. The treatment also consistently increased dystrophin protein, exon-skipping levels, and muscle cell exposure, in a dose-dependent manner.
Notably, monthly treatment with SRP-5051 for three months resulted in greater muscle concentration, increased exon skipping, and higher dystrophin levels than six months of weekly treatment with Exondys 51, at greater doses.
In fact, when compared to patients in the previous PROMOVI Phase 3 study (NCT02255552), who received weekly 30 mg/kg doses of Exondys 51 for 24 weeks, the small group of patients receiving a 20 mg/kg monthly dose of SRP-5051 for 12 weeks yielded a 1.6 times greater increase in exon skipping and a fivefold increase in functional dystrophin.
These results indicate that SRP-5051 is potentially more effective than Exondys 51 at lower, less frequent doses, and support the investigation of greater doses of SRP-5051 in the trial and its continued development.
“While patient numbers in each dose arm are small, the higher tissue concentration, exon skipping and dystrophin production in the 20 mg/kg dosing group were observed at an early 12-week timepoint and with far less cumulative drug exposure when compared to our current PMO technology,” said Ingram.
“We know from our experience with PMOs that exon-skipping and dystrophin increase over time, and these results … give us confidence as we dose escalate and continue to advance our PPMO exon-skipping therapies for Duchenne,” he added.
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