PPMD is excited to learn that Dr. Jerry Mendell of Nationwide Children’s Hospital today shared positive results for the fourth patient in Sarepta’s micro-dystrophin trial, indicating positive functional signals for all of the patients. Reporting from the World Muscle Society meeting in Mendoza, Argentina, Dr. Mendell’s update follows his presentation in June on the first three patients in the trial.

We remain hopeful that micro-dystrophin will prove to be a viable treatment for Duchenne. We again thank everyone in the community who continues to support PPMD’s Gene Therapy Initiative and we express our gratitude to all of the families participating in this important trial.

 

Read the press release from Sarepta:

Sarepta Therapeutics Announces that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., Presented Positive Updated Results from the Four Children Dosed in the Gene Therapy Micro-dystrophin Trial to Treat Patients with Duchenne Muscular Dystrophy

— Biopsy of fourth patient showed robust micro-dystrophin expression as measured by Western blot and immunohistochemistry

— Positive functional improvements shown across all measures —

— No serious adverse events (SAEs) observed —

CAMBRIDGE, Mass., October 3, 2018 (GLOBE NEWSWIRE) — Sarepta Therapeutics, Inc. (NASDAQ:SRPT), a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases, announced that at the 23rd International Congress of the World Muscle Society in Mendoza, Argentina, Jerry Mendell, M.D., of Nationwide Children’s Hospi-tal presented positive updated results from its gene therapy clinical trial assessing AAVrh74.MHCK7.mi-cro-Dystrophin in individuals with Duchenne muscular dystrophy (DMD). Dr. Mendell presented the fol-lowing updated data on the four patients enrolled in the study:

• All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry. Mean gene expression for the study, as measured by percentage of micro-dystrophin positive fibers was 81.2% and the mean intensity of the fibers was 96.0% compared to normal control. All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 74.3% compared to normal utilizing Sarepta’s method, or 95.8% compared to normal pursuant to Na-tionwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
• Gene expression for the fourth patient was robust, as follows:
  • As measured by immunohistochemistry, micro-dystrophin positive fibers was 96.2% and the mean intensity of the fibers was 160.0% compared to normal control.
  • As measured by Western blot, patient 4 showed robust levels of micro-dystrophin, with a mean of 182.7% compared to normal utilizing Sarepta’s method, or 222% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
• In all patients, expression of micro-dystrophin was associated with significant expression and up-regulation of the dystrophin-associated protein complex, an additional indication of functionality of dystrophin.
• All patients showed significant decreases of serum creatine kinase (CK) levels at last measure, with a mean reduction of CK of over 78% from baseline.
• Dr. Mendell also provided an update on functional endpoints for all four patients, including North Star Ambulatory Assessment (NSAA), Time to Rise, 4 Stairs Up, and 100M. Patients showed im-provements across all measured functions, with boys showing an average NSAA raw score im-provement of 6.5 points from baseline to last measure, or on a linearized NSAA basis, 12 points of improvement in the first 90 days. While results suggest functional improvements across all measures significantly greater than natural history predictions, it should be cautioned that this is a small, uncontrolled data set and these positive results must be reconfirmed in the larger, con-trolled registration trial.
• No serious adverse events (SAEs) were observed in the study. Three patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.

Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empiri-cally optimized the AAVrh74.MHCK7 specifically for DMD:

• The AAVrh74 vector is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat peripheral neuromuscular diseases.
• As a rhesus monkey-derived AAV vector, AAVrh74 has lower immunogenicity rates than reported with other common human AAV vectors.
• The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with DMD, who typically die from pulmonary or cardiac complica-tions. In pre-clinical models, micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels observed in skeletal muscles.
• The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be critical to maintaining the protective functional characteristics of dystrophin.

Dr. Mendell stated, “The goal of this study was to validate what we observed in pre-clinical models. We observed efficient transduction of our vector, AAVrh74, to all muscle types; robust expression in skeletal muscles via the MHCK7 promoter; a reduction in creatine kinase levels; and a favorable safety profile. Similar to pre-clinical models, we also observed in this early study that robust expression has the potential to positively impact the natural course of disease progression.”

Doug Ingram, Sarepta’s president and chief executive officer, added, “The encouraging results that we previously saw and reinforced in the fourth patient strengthen our resolve to rapidly move to a confirming trial and, assuming successful, to bring this therapy to the Duchenne community around the world with a sense of urgency.”

Mr. Ingram continued, “These results create for us an obligation to patients around the globe living with and being damaged by this cruel disease. We are investing our energy, resources and creativity to moving the development forward, planning meetings with the FDA and other agencies around the world to take their input, building a compelling access and reimbursement package, and establishing sufficient manu-facturing capacity to fully serve the community if our program is successful.”

Click here to read full press release.

Read Sarepta’s Community Letter:

Dear Duchenne Community,

At the World Muscle Society in Argentina today, Dr. Jerry Mendell of Nationwide Children’s Hospital shared additional data relating to our micro-dystrophin gene therapy program. In particular, as a follow up to his presentation of the first three patients at our R&D Day in June of this year, Dr. Mendell today shared micro-dystrophin results for the fourth patient and provided positive functional signals for all patients.

It is important to remember that while we are very encouraged by all of the results we have to date, these are early days relating to our first four patients. It is important that we quickly commence a controlled trial to confirm these results. Fueled by our preliminary data, we are moving with a sense of urgency to move to a study that, if successful, could bring this therapy to those patients who can benefit from it.

As mentioned in June, the next micro-dystrophin trial will take place in the United States, will be carried out by Nationwide Children’s Hospital, and will be limited in size. Sarepta is mapping ways to expand the gene therapy clinical program to a broader population with considerations of study inclusion and geography. We will update the community about the plans as we finalize them.

Given the volume of inquiries received about this investigational effort, we know that there is a high level of anticipation within the worldwide Duchenne community surrounding gene therapy. Physicians and advocacy groups alike have expressed hope that families will stay focused on current treatment plans and investigational options selected in consultation with their healthcare team.

Let us once again be reminded that as encouraged as we are, these are preliminary results and we must continue to follow our initial patients and commence a controlled trial. But also know this, we are investing our energy, resources and creativity to moving the development forward as fast as is possible, planning meetings with the FDA and other agencies around the world to take their input, building a compelling access and reimbursement package, and establishing sufficient manufacturing capacity to fully serve the community if our program is successful.

I will provide additional updates as the program moves forward.

Sincerely,

Douglas S. Ingram

President and Chief Executive Officer

Sarepta Therapeutics, Inc