Sarepta Therapeutics this morning 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 being conducted in partnership with Roche. SRP-9001 demonstrated robust expression of micro-dystrophin protein at 12 weeks post-delivery. Two serious adverse events (SAEs) were reported and both SAEs have fully resolved.
The ENDEAVOR study is the first Sarepta trial using their commercial grade material, what would be manufactured and delivered if product is approved, this represents an important milestone for moving towards a pivotal Phase 3 study. Additionally, no new safety signals were seen in the study when compared with previous SRP-9001 studies not using the commercial grade product.
PPMD is proud to have been an early funder of the original study of SRP-9001 as part of our Gene Therapy Initiative and is thrilled for the progress to date. 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.
PPMD will host a community webinar with Sarepta on Wednesday, June 2 to discuss these latest results. Additional details & registration information will be available in the coming week.
Read Sarepta’s community letter:
May 18, 2021
Dear Duchenne community,
Today, Sarepta Therapeutics released data from Study 9001-103, ENDEAVOR, an open-label study conducted in partnership with Roche of SRP-9001, an investigational gene transfer therapy for Duchenne Muscular Dystrophy. The ongoing ENDEAVOR study is the first SRP-9001 study using commercially representative material. Use of this material is an important step in the clinical development program as it means that Sarepta will be able to manufacture the therapy at scale while also showing consistent and encouraging biological results. Today’s data reflect experiences of the first 11 participants to enter the study, ages 4-7.
Participants in ENDEAVOR underwent muscle biopsies before receiving SRP-9001 and again 12 weeks after administration of SRP-9001. Muscle biopsies are important tools in understanding how a gene therapy is working in a clinical trial. Here are three questions one may ask about gene therapy that are answered through the evaluation of muscle biopsies:
- How much of the transgene got into the muscle cells (transduction)? The participants in this study showed a mean of 3.87 vector genome copies per nucleus.
- How much micro-dystrophin is made, or expressed? Using a laboratory technique called a western blot, participants in the study achieved mean micro-dystrophin expression levels of 55.4% of normal at week 12.
- Did the micro-dystrophin get to the muscle cell membrane (dystrophin positive fibers and intensity)? Micro-dystrophin was localized to the muscle cell membrane (sarcolemma). The mean percentage of dystrophin positive fibers was 70.5% (baseline 12.8%) and mean % intensity was 116.9% (baseline 41%) after SRP-9001 infusion as measured by immunofluorescence.
Importantly, the ENDEAVOR study examines safety, and the safety profile of SRP-9001 has been consistent with prior studies with no new safety signals identified. Participants most commonly experienced vomiting in the early days following gene therapy administration. Increases in liver enzymes were also reported, and they were transient and responsive to steroids. Two patients experienced serious adverse events (transaminase elevation in one patient and nausea and vomiting in a second patient) that fully resolved.
Clinical efficacy, or how SRP-9001 impacts muscle function, is also being measured as an exploratory endpoint and will be shared in a future scientific meeting.
ENDEAVOR is the third ongoing human trial of SRP-9001 and Sarepta has been previously invited by Parent Project Muscular Dystrophy (PPMD) to discuss program updates. This Duchenne community webinar is being planned for June 2, 2021.
As members of the Duchenne community, you may wonder what the next steps for this program may be. Here’s a summary:
- Armed with these and other accumulated data, Sarepta and Roche will meet with regulators with the goal of rapidly starting the SRP-9001 registrational study.
- We will share more details about the pivotal Phase 3 study of SRP-9001 following these important discussions.
- We also intend to expand the ENDEAVOR study to include older individuals who are ambulatory and non-ambulatory. More information about these cohorts will be shared with the community and will appear on clinicaltrials.gov soon
We hear and acknowledge the urgency expressed by the Duchenne community. So many in the community are evaluating the emerging landscape of approved and investigational therapies and are gathering information that will inform understanding and decision making. Your questions are important to us and we hope that we will have more SRP-9001 program information to share in the near future. We are most certainly energized by the latest data and we are focused on working as quickly as possible to advance the next study.
Executive Director, Patient Affairs
Read the press release from Sarepta:
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
- Results from 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 mean percentage of dystrophin positive fibers of 70.5% and intensity of micro-dystrophin expression of 116.9% of normal control, as measured by immunofluorescence (IF)
- Safety profile consistent with prior studies and no new safety signals identified
CAMBRIDGE, Mass., May 18, 2021 (GLOBE NEWSWIRE) — Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today 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 being 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.
“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,” said Doug Ingram, president and chief executive officer, Sarepta. “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.”
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 mean micro-dystrophin expression of 55.4% of normal, as measured by western blot.
- Muscle dystrophin levels demonstrated a mean of 70.5% (baseline 12.8%) muscle fibers 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 fibers, 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 fiber intensity as measured by immunofluorescence (IF) and micro-dystrophin expression measured by IF percent dystrophin positive fibers 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.