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Sarepta Reports High-Dose SRP-5051 Increases Dystrophin in Certain DMD Patients

May 4, 2021

Sarepta Therapeutics reported positive results from part A of its MOMENTUM study of SRP-5051, its next-generation treatment for patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping.

Photo: Doug Ingram, president and CEO, Sarepta

In biopsies taken at a median of 12 weeks and after only three doses, the study results found that the high dose of 30 mg/kg of SRP-5051 dosed monthly resulted in 18 times the exon skipping and eight times the dystrophin production as eteplirsen, dosed weekly for 24 weeks. Exon-skipping and dystrophin production in the 30 mg/kg cohort were also consistently higher than the 20 mg/kg cohort of MOMENTUM. Hypomagnesemia was identified in patients taking SRP-5051. Cases have resolved with magnesium supplementation and an analysis of all available data indicate that the hypomagnesemia is monitorable and manageable.

“Even at an early timepoint 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. While we saw exceptional expression after only a few initial doses, our models predict that we will exceed dystrophin expression levels of 10 percent of normal or greater over time with SRP-5051,” said Doug Ingram, president and CEO, Sarepta.

Duchenne muscular dystrophy (DMD) is a rare, fatal neuromuscular genetic disease that occurs in approximately one in every 3,500-5,000 males worldwide. DMD is caused by a change or mutation in the gene that encodes instructions for dystrophin. Symptoms of DMD usually appear in infants and toddlers. Affected children may experience developmental delays such as difficulty in walking, climbing stairs or standing from a sitting position. Disease progression leads to muscle weakness in the lower limbs that spreads to the arms, neck, and other areas. Most patients require full-time use of a wheelchair in their early teens, and then progressively lose the ability to independently perform activities of daily living such as using the restroom, bathing, and feeding. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. The condition is universally fatal, and patients usually succumb to the disease in their twenties.

SRP-5051 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PPMO) chemistry and exon-skipping technology to skip exon 51 of the dystrophin gene. SRP-5051 is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein. Around 13 percent of DMD patients have mutations which make them amenable to skipping exon 51. If successful, the PPMO offers the potential for improved efficacy and less frequent dosing for patients.

MOMENTUM is a multi-arm, ascending dose study designed to identify the maximum tolerated dose of SRP-5051, infused monthly. The study will enroll up to 24 patients, both ambulant and non-ambulant, between the ages of 7 to 21 at sites in the United States, Canada, Australia, and European Union. The primary endpoint is safety, and secondary and exploratory endpoints include exon-skipping, dystrophin expression and tissue concentration.

In biopsies taken at a median of week 12, 30 mg/kg of SRP-5051 dosed monthly resulted in mean exon skipping of 10.79 percent. Exon skipping was measured by digital drop polymerase chain reaction.

This correlates to greater than 4x increase in exon skipping compared to the 20 mg/kg cohort of SRP-5051 at 12 weeks and an 18x increase in exon skipping compared to a weekly 30 mg/kg dose of eteplirsen at 24 weeks.

At a median of week 12, 30 mg/kg of SRP-5051 resulted in mean dystrophin production of 6.55 percent of normal. Dystrophin expression was measured by western blot.

This is twice the dystrophin expression compared to the 20 mg/kg cohort at week 12 (mean expression of 3.06 percent) and eight times that of the eteplirsen comparison group (mean expression of 0.82 percent). 

There were three serious, treatment-emergent adverse events in two patients in the 30 mg/kg cohort, including two cases of hypomagnesemia. The events were asymptomatic and have resolved with magnesium supplementation. Markers of kidney function have generally been normal and not shown any consistent relationship to the hypomagnesemia.

Predictive modeling for dystrophin accumulation that includes assumptions of known turnover of dystrophin in the muscle and an analysis of data generated with the PPMO platform indicates that SRP-5051 at 30 mg/kg is likely to deliver greater than 10 percent dystrophin over time with monthly dosing.

Sarepta will present full results at a future medical meeting.

The U.S. Food and Drug Administration has granted accelerated approval to eteplirsen under the trade name Exondys 51, for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Continued approval may be contingent upon verification of a clinical benefit in confirmatory trials.

Author: Rare Daily Staff

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