Sarepta Therapeutics announces positive clinical results from MOMENTUM, a phase 2 clinical trial of SRP-5051 in patients with Duchenne muscular dystrophy amenable to skipping exon 51.
Original press release > CAMBRIDGE, Mass., Dec. 07, 2020 (GLOBE NEWSWIRE)
Overview
- Results from the multiple-ascending dose trial demonstrate proof-of-concept for SRP-5051 and support continued dose escalation.
- At a total dose exposure approximately 10x lower than eteplirsen, SRP-5051 at 20 mg/kg showed enhanced tissue exposure, greater exon skipping, and greater dystrophin production with no negative renal or other laboratory findings.
- These are the first clinical results from the Company’s peptide phosphorodiamidate morpholino oligomer (PPMO) technology, its next-generation chemistry platform.
Sarepta Therapeutics, Inc. announced results from the ongoing MOMENTUM study (Study 5051-201), a global Phase 2 clinical trial of SRP-5051, its next-generation treatment patients with Duchenne muscular dystrophy who are amenable to exon 51 skipping. This is the first clinical data from SRP-5051, an investigational treatment that uses Sarepta’s peptide phosphorodiamidate morpholino oligomer (PPMO) technology. PPMO technology includes a proprietary cell-penetrating peptide conjugated to Sarepta’s PMO backbone to increase cellular uptake of drug in the muscle tissue.
Results from Part A of the multi-ascending dose MOMENTUM study found consistently higher tissue exposure, exon-skipping and dystrophin production in patients taking a monthly dose of SRP-5051 compared to baseline. SRP-5051 was generally well-tolerated across all doses studied, with no clinical or laboratory findings reported. The results support continued dose escalation of SRP-5051 and further clinical development.
Doug Ingram, president and chief executive officer, Sarepta – “Sarepta’s PMO RNA technology is a vital platform on which we design therapies to treat those with Duchenne muscular dystrophy. 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. 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 time point and with far less cumulative drug exposure when compared to our current PMO technology. We know from our experience with PMOs that exon-skipping and dystrophin increase over time, and these results along with our preclinical experience, give us confidence as we dose escalate and continue to advance our PPMO exon-skipping therapies for Duchenne, including another five potential therapies that have already been designed, and explore the utility of the PPMO RNA platform for new disease indications.”
Compared to a control group of Duchenne patients from the PROMOVI study who received biopsies at 24 weeks after taking a weekly 30 mg/kg dose of eteplirsen, once-monthly dosing of SRP-5051 resulted in higher muscle concentration, increased exon-skipping and dystrophin at 12 weeks. A dose-dependent increase in exon-skipping and dystrophin was observed, with patients in the 20 mg/kg dose group of SRP-5051 seeing a 1.6-fold increase in exon skipping (n=4) and a 5-fold increase in the % of normal dystrophin (n=2) when compared to the group taking eteplirsen at 24 weeks.
The incidence of adverse events in the MOMENTUM study was similar across all dosed cohorts and does not suggest dose dependency. One treatment-emergent event, unrelated to the study drug, occurred in the 4 mg/kg dose group. No clinical or laboratory findings were observed. Full results will be presented at a future medical meeting.
About MOMENTUM (SRP-5051-201)
MOMENTUM is a multi-arm, ascending dose study designed to identify the maximum tolerated dose of SRP-5051. Informed by Study 5051-101, a single ascending dose study of SRP-5051, patients in the MOMENTUM study will receive monthly intravenous (IV) infusions of SRP-5051, starting at 4 mg/kg and ascending to 40 mg/kg. 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. All patients will undergo a muscle biopsy at baseline and 12 weeks in Part A and baseline and 24 weeks in Part B. More information can be found on www.clinicaltrials.gov.
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.
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.
To fix the broken genetic machinery, scientists are developing drugs that skip over parts containing missing or defective exons. In this way, the machinery can produce a less imperfect dystrophin protein, improving muscle function in children with exon mutations. > Pipeline exon-skipping
About eteplirsen (EXONDYS 51®)
This treatment uses a specific exon-skipping technique to jump over a portion of genetic machinery that does not produce dystrophin in children with DMD. More specifically, this injectable drug triggers the skipping of exon 51, which occurs in 13% of children with DMD. It aims to restore the machinery’s ability to read genetic code to produce a shortened form of dystrophin that works in some children with DMD. The production of this shortened form of dystrophin may delay muscle degeneration and the progression of this devastating, rare disease in some children.
In September 2016, the U.S. FDA granted unprecedented, accelerated marketing approval to eteplirsen to treat children with DMD who are amenable to exon 51 skipping. However, since clinical benefit has not been established, continued approval depends on whether the outcome of ongoing clinical trials can confirm its benefits in patients with DMD.
What about Canada?
At this moment, eteplirsen is not available in Canada. We hope that shortly, Sarepta Therapeutics will file a request for marketing approval with Health Canada.
About DMD
Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is sporadic that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.
About Sarepta Therapeutics
The Company has built an impressive position in Duchenne muscular dystrophy (DMD) and gene therapies for limb-girdle muscular dystrophies (LGMDs), mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The Company’s programs and research focus span several therapeutic modalities, including RNA, gene therapy and gene editing. For more information, please visit www.sarepta.com or follow them on Twitter, LinkedIn, Instagram and Facebook.
