Positive Results Reported From Phase 2 Study of SRP-5051 in DMD

Sarepta Therapeutics has announced positive results from a global study evaluating its investigational treatment SRP-5051 in people with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.

Results from part A of the study found the 30 mg/kg monthly dose resulted in eight times the dystrophin production at three months compared to Exondys 51 (eteplirsen), dosed weekly for six months.

Treatment with this dose also led to 18 times the exon skipping at this timepoint.

These results suggest that SRP-5051 is potentially more effective than Exondys 51 at lower, less frequent doses. They also support the administration of greater SRP-5051 doses in the trial and its ongoing development. Both therapies were developed by Sarepta using its new PPMO platform.

“We are pleased to report strong, dose-dependent exon-skipping and dystrophin expression results with monthly dosing of SRP-5051 — in ambulant [walking] and non-ambulant patients,” Doug Ingram, president and CEO at Sarepta, said in a press release.

“Even at an early time point of 12 weeks and after as few as only three doses, these data confirm the potential of Sarepta’s next-generation PPMO platform to be a step order improvement over our current PMO platform and to profoundly impact the course of Duchenne,” he added.

The Phase 2 MOMENTUM study (NCT04004065) is a global, multi-ascending dose clinical trial. It is designed to identify the maximum tolerated dose of SRP-5051 in up to 24 patients, ages 7–21, who are amenable to exon 51 skipping, which accounts for about 13% of all DMD cases. Clinical sites are recruiting participants in the U.S., Canada, Australia, the U.K. and the European Union.

Like Exondys 51, SRP-5051 helps the protein-making machinery skip over exon 51 — part of the DMD gene that codes for the dystrophin protein — enabling the production of a smaller but functional protein. But unlike Exondys 51, SRP-5051 is coupled to a small peptide that increases the amount of medicine that enters muscle cells, which is expected to improve efficacy and reduce dosing frequency.

Monthly administration of SRP-5051 is supported by recent preclinical studies in a mouse model of DMD amenable to exon 51 skipping and healthy non-human primates. 

In the mouse model, SRP-5051 resulted in dose-dependent increases in exon 51 skipping and in dystrophin levels, which were sustained in the heart and bicep muscles for one month after a single dose. Doses given once a month for five months increased exon skipping and dystrophin production in heart and diaphragm muscles, and restored grip strength. 

Similar results were seen in healthy monkeys, with a dose-dependent increase in SRP-5051 concentration and the skipping of exon 51 in muscle tissue for up to 28 days. 

MOMENTUM’s main goal is to determine the therapy’s safety, along with secondary measures, including the amount of exon-skipping and the levels of dystrophin.

The group of patients who received the 30 mg/kg dose, measured by biopsy at 12 weeks, showed a mean exon skipping of 10.79%, which was fourfold higher than the 2.57% in those receiving 20 mg/kg of SRP-5051. Also, the higher dose resulted in mean dystrophin production of 6.55% of normal, compared to 3.06% in the lower dose group. 

In comparison, patients in the previous PROMOVI Phase 3 study (NCT02255552), who received weekly 30 mg/kg doses of Exondys 51 for 24 weeks (six months), had a mean exon skipping of 0.59% and mean dystrophin of 0.82% of normal. 

To date, three serious treatment-related adverse events were reported in two participants in the 30 mg/kg group, including two cases of low magnesium in the blood (hypomagnesemia). These events did not result in symptoms and were resolved with magnesium supplementation. Markers of kidney function, which can be affected by hypomagnesemia, were generally normal.

Sarepta’s predictive modeling for dystrophin production suggested 30 mg/kg of SRP-5051 is likely to deliver more than 10% dystrophin with monthly dosing.

“We are excited to have chosen our target dose for further development,” said Ingram. “Part A of MOMENTUM is now complete, and Sarepta will work with great urgency to discuss the results with regulatory agencies and gain their insights, including the development path to support an accelerated approval of SRP-5051 in the United States.”

Part B of MOMENTUM, expanded to patients ages 4 to 21, will evaluate SRP-5051 administered at the maximum tolerated dose determined in Part A, or if applicable, at a second dose introduced in Part B.

The company expects to present the full results of Part A at a future medical meeting.