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ENDEAVOR, gene therapy for DMD

Sarepta Therapeutics’ investigational gene therapy for the treatment of Duchenne muscular dystrophy, SRP-9001, demonstrates robust expression and consistent safety profile using Sarepta’s commercial process material.

 

  • The first 11 participants enrolled in Study 9001-103 ENDEAVOR showed robust transduction, delivering mean vector genome copies of 3.87 per nucleus.
  • Treated patients achieved mean micro-dystrophin expression levels of 55.4% of normal as measured by western blot.
  • Micro-dystrophin was properly localized to the muscle sarcolemma, with patients achieving a mean percentage of dystrophin positive fibres of 70.5% and intensity of micro-dystrophin expression of 116.9% of normal control measured by immunofluorescence (IF).
  • Safety profile consistent with prior studies and no new safety signals identified.

 

Original press release > CAMBRIDGE, Mass., May 18, 2021 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc. announced positive 12-week expression and safety results from the first 11 participants enrolled in Study SRP-9001-103, an open-label study known as ENDEAVOR conducted in partnership with Roche. In results from the first clinical study using commercially representative material, SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin) demonstrated robust expression of micro-dystrophin and no new safety signals from prior studies, supporting its potentially differentiated profile for the treatment of Duchenne muscular dystrophy. SRP-9001 is an investigational gene transfer therapy intended to deliver its micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein.

 

Doug Ingram, president and chief executive officer, Sarepta – “We are delighted by these seminal results from the ENDEAVOR Study, our first trial results with SRP-9001 made by our commercial-scale manufacturing process. These data show strong transduction of the micro-dystrophin gene, resulting in robust expression of the properly localized micro-dystrophin protein, and did so with no new or unexpected safety signals. In addition to characterizing and differentiating SRP-9001, these results confirm the extraordinary work done over the last two and a half years to build an at-scale gene therapy manufacturing process and corresponding analytics sufficient to meet the needs of the Duchenne population with what we believe will be a potentially life-changing therapy. Armed with these data, we will seek a meeting with the FDA with the goal of rapidly starting our registrational study.”

 

Observed results

In the open-label study, 20 participants between the ages of four and seven were treated with a single infusion of SRP-9001 at a dose of 1.33×1014 VG/kg. In muscle biopsies from the first 11 patients taken 12 weeks after treatment, the following results were observed:

  • All patients demonstrated robust transduction, with a mean micro-dystrophin expression of 55.4% normal, as measured by western blot.
  • Muscle dystrophin levels demonstrated a mean of 70.5% (baseline 12.8%) muscle fibres expressing micro-dystrophin at 12 weeks with a mean intensity at the sarcolemma of 116.9% (baseline 41.0%) compared to normal biopsies, as measured by immunofluorescence. Comparisons between baseline and post-treatment measures were statistically significant (p=0.001 for positive fibres and p=0.002 for intensity).
  • Mean vector genome copies per nucleus reached 3.87.

The safety profile of SRP-9001 observed in the first 11 participants in ENDEAVOR is consistent with the safety seen in earlier studies using clinical manufacturing process material. In line with previously reported clinical data, no clinically relevant complement activation was observed in these 11 patients. Two patients experienced serious adverse events (transaminase elevation in one patient and nausea and vomiting in a second patient) that fully resolved.

About SRP-9001-103 (ENDEAVOR)

Study SRP-9001-103 (Study 103) is an open-label clinical trial of SRP-9001 that has enrolled 20 participants with Duchenne muscular dystrophy between the ages of 4-7. Study 103 uses commercially representative SRP-9001, and the primary endpoint is the change from baseline in the quantity of micro-dystrophin protein expression measured by western blot at 12 weeks. Secondary outcome measures include change from baseline in micro-dystrophin expression fibre intensity measured by immunofluorescence (IF) and micro-dystrophin expression measured by IF percent dystrophin positive fibres at 12 weeks. Exploratory endpoints include the change in vector genome copies per nucleus, North Star Ambulatory Assessment (NSAA) and certain timed functional tests. Including the initial 12-week period, patients will be followed for a total of five years.

About SRP-9001 (rAAVrh74.MHCK7.micro-dystrophin)

SRP-9001 is an investigational gene transfer therapy intended to deliver the micro-dystrophin-encoding gene to muscle tissue for the targeted production of the micro-dystrophin protein. Sarepta is responsible for global development and manufacturing for SRP-9001 and plans to commercialize SRP-9001 in the United States upon receiving FDA approval. In December 2019, Roche partnered with Sarepta to combine Roche’s global reach, commercial presence and regulatory expertise with Sarepta’s gene therapy candidate for Duchenne to accelerate access to SRP-9001 for patients outside the United States. Sarepta has exclusive rights to the micro-dystrophin gene therapy program initially developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital.

About Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, fatal neuromuscular genetic disease 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 walking, climbing stairs or standing from a sitting position. As the disease progresses, muscle weakness in the lower limbs spreads to the arms 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.

About Sarepta Therapeutics

Sarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. They hold leadership positions in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), and they currently have more than 40 programs in various stages of development. Their multi-platform Precision Genetic Medicine Engine drives our vast pipeline in gene therapy, RNA and gene editing. For more information, please visit www.sarepta.com or follow them on TwitterLinkedInInstagram and Facebook.

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Positive clinical results from phase 2 MOMENTUM study

Sarepta Therapeutics reports positive clinical results from phase 2 MOMENTUM study of SRP-5051 in patients with Duchenne muscular dystrophy amenable to skipping exon 51

  • Results suggest a highly potent next-generation treatment that could offer greater efficacy with less frequent dosing.
  • SRP-5051 dosed monthly at 30 mg/kg delivered mean exon skipping of 10.79% and mean dystrophin expression of 6.55%, consistently higher than the other SRP-5051 dosing cohorts at 12 weeks and weekly eteplirsen at 24 weeks
  • Sarepta’s predictive model indicates that SRP-5051 at 30 mg/kg will achieve greater than 10% dystrophin with monthly chronic dosing.

Original press release > CAMBRIDGE, Mass., May 03, 2021 (GLOBE NEWSWIRE)

Sarepta Therapeutics, Inc. announced positive results from Part A of the MOMENTUM study (Study 5051-201), a global, Phase 2, multi-ascending dose clinical trial of SRP-5051, its next-generation peptide phosphorodiamidate morpholino oligomer (PPMO) treatment for patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping. In biopsies taken at a median of 12 weeks and after only three doses, results from Part A of the MOMENTUM study found that the 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 analysis of all available data indicates that the hypomagnesemia is monitorable and manageable. 

 

Doug Ingram, president and chief executive officer, Sarepta – “We are pleased to report strong, dose-dependent exon-skipping and dystrophin expression results with monthly dosing of SRP-5051 – in ambulant and non-ambulant patients. 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. While we saw exceptional expression after only a few initial doses, our models predict that we will exceed dystrophin expression levels of 10% of normal or greater over time with SRP-5051.We are excited to have chosen our target dose for further development. 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 accelerated approval of SRP-5051 in the United States.”

 

Adverse events

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 hypomagnesemia. Predictive modelling for dystrophin accumulation that includes assumptions of known turnover of dystrophin in the muscle and analysis of data generated with the PPMO platform indicates that SRP-5051 at 30 mg/kg is likely to deliver greater than 10% dystrophin over time with monthly dosing. Full results will be presented at a future medical meeting.

About MOMENTUM (Study SRP-5051-201)

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 U.S., Canada, Australia and the European Union. The primary endpoint is safety, and secondary and exploratory endpoints include exon-skipping, dystrophin expression and tissue concentration. More information can be found on www.clinicaltrials.gov. Read “Positive clinical results from MOMENTUM” here.

About SRP-5051

SRP-5051 uses Sarepta’s 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 the 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 the production of an internally truncated dystrophin protein. PPMO is Sarepta’s next-generation chemistry platform designed around a proprietary cell-penetrating peptide conjugated to the PMO backbone, intending to increase tissue penetration, increasing exon skipping and significantly increasing dystrophin production. Around 13% of DMD patients have mutations that make them amenable to skipping exon 51. If successful, the PPMO offers the potential for improved efficacy and less frequent dosing for patients.

About Duchenne Muscular Dystrophy

DMD is an X-linked rare degenerative neuromuscular disorder causing severe progressive muscle loss and premature death. One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500 – 5,000 male births worldwide. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fibre function. Progressive muscle weakness in the lower limbs spreads to the arms, neck, and other body areas. The condition is universally fatal, and death usually occurs before 30 due to respiratory or cardiac failure.

About EXONDYS 51

EXONDYS 51 (eteplirsen) uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 51 of dystrophin pre-mRNA, resulting in “skipping” 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 the production of an internally truncated dystrophin protein.EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in some patients treated with EXONDYS 51. Continued approval may be contingent upon verification of a clinical benefit in confirmatory trials. EXONDYS 51 has met the full statutory standards for safety and effectiveness and is not considered investigational or experimental.

What is exon skipping?

Mutations in the dystrophin gene are one cause of DMD. Most commonly, one or more exons (a portion of a gene) are missing, and the remaining exons don’t fit together correctly. (Think of a zipper that doesn’t work properly because teeth are missing.) Because of this error, cells cannot make the dystrophin protein that muscles need to work properly. Without it, muscle cells become damaged and, over time, are replaced with scar tissue and fat. Scientists are developing drugs that skip over parts containing missing or defective exons to fix the broken genetic machinery. In this way, the machinery can produce a less imperfect dystrophin protein, improving muscle function in children with exon mutations. > Pipeline exon-skipping

About Sarepta