June 19, 2018 / Clinical Trials,Research

Positive Preliminary Results from the First Three Children Dosed in Phase 1/2a Gene Therapy Micro-dystrophin Trial

Photo used with permission from the patient's family.

Sarepta Therapeutics announced that at the Company’s R&D Day, Jerry Mendell, M.D. of Nationwide Children’s Hospital presented positive preliminary results from its Phase 1/2a gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with Duchenne.

Ryan Fischer and I attended today’s R&D Day and to say that the energy in the room was electric, is an understatement. It is a moment so many of us have fought for, prayed for, and hoped for. It is an amazing day for this community!

For years, PPMD has been interested in the potential of gene therapy as a treatment for Duchenne. We are proud to have supported Dr. Jerry Mendell and Dr. Louise Rodino-Klapac at a critical moment in development in early 2017. We did not do this alone.  It takes a village and we are deeply grateful to our partners: Kindness Over Muscular Dystrophy, Team Joseph, Team Saij, The Fund for Pete’s Sake, Rashad’s family, and the Nicholoff family.

As announced last week, Sarepta will initiate an aggressive clinical program, including a partnership with Brammer Bio to support both gene therapy development and commercial supply.

To have reached this moment today is incredible and we are grateful to Sarepta for their investment and partnership in moving this therapeutic approach forward. We have three companies aggressively pursuing delivery of micro-dystrophin, a small, but efficient version of dystrophin.

And we would not be here without the incredible young people participating in this and all clinical trials in Duchenne. Because of their sacrifice and the sacrifice of their families, the fight to end Duchenne continues with more momentum than ever before.

While these are early days and work remains to fully understand the full potential of gene therapies, these first signals are encouraging. We remain hopeful that this will lead to a viable treatment for Duchenne.

To an outsider, this progress may seem like it has happened over night. But it is years, decades in the making, and PPMD has been along for the whole ride.

A Look at the Data

Dr. Mendell presented the following preliminary data on the first three 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, as measured by percentage of micro-dystrophin positive fibers was 76.2% and the mean intensity of the fibers was 74.5% compared to normal control.
  • All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 38.2% compared to normal utilizing Sarepta’s method, or 53.7% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
  • A mean of 1.6 vector copies per cell nucleus was measured in patients, consistent with the high micro-dystrophin expression levels observed.
  • All patients showed significant decreases of serum creatine kinase (CK) levels, with a mean reduction of CK of over 87% at Day 60. CK is an enzyme associated with muscle damage and patients with DMD uniformly exhibit high levels of CK. Indeed, significantly elevated CK is often used as a preliminary diagnosis tool for DMD, which is then followed by confirmatory genetic testing.
  • No serious adverse events (SAEs) were observed in the study. Two patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week and returned to baseline levels. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.

How We Got to Today

For the last 30 years, our community has been thinking about gene therapy – was it a therapeutic possibility for Duchenne?  We learned about virus, large and small capacity virus as vehicles for delivery, finally landing on the Adeno Associated Virus (AAV) and, particular serotypes that target the heart and skeletal muscle – AAV8 and AAV9. Based on the small carrying capacity of the AAV, we heard words describing a very small, but efficient version of the dystrophin protein, referred to as a micro dystrophin or in current vernacular micro-dys.

Long ago, we had hoped gene therapy would be ‘soon,’ but realized that ‘soon’ takes time. We waited and watched as knowledge increased, exploration of delivery vehicles was refined and a number of micro-dys proteins were explored in cells and animal models.

Patience has never been our virtue because time has never been on our side. In 2014, PPMD’s Scientific Advisor, Lee Sweeney, PhD and our Scientific Advisory Committee agreed, a significant investment in an investigator initiated study might accelerate the field. PPMD approached Jerry Mendell, MD (Nationwide Childrens), requesting a grant submission for an investigator initiated Gene Therapy study. The cost: $2.2 million.

PPMD reached out to our community and you responded like you always do – quickly and generously! Several Duchenne foundations also stepped up – Kindness Over Muscular Dystrophy, Team Joseph, Team Saij, The Fund for Pete’s Sake, Rashad’s family, and the Nicholoff family – and together, funding was in place.

With this grant, Nationwide was in the queue for clinical grade virus and the initiation of the study: Clinical Intramuscular Gene Transfer Trial of rAAVrh74.MCK.Micro-Dystrophin to Patients with Duchenne.

This grant marked PPMD’s largest single research investment to date.

A year later, in January 2018, we received the following text from Dr. Mendell with this update:

DMD gene therapy went well. Here is the conclusion of gene delivery.
Started at 1:15pm and ended at 2:27pm

Thanks for your support

Since that time, four children have been treated in the Nationwide Study. Several more will be treated in the next months.

That first investment, an investment you helped to fund, indeed accelerated the field. Sarepta agreed to match PPMD’s grant and optioned to license the product from Nationwide.  Other companies, including Pfizer/Bamboo and Solid Biosciences have opened their gene therapy studies.

To better understand all three gene therapy trials, click here for an overview of each of the ongoing trials provided by The Duchenne Registry team. You can also visit ClinicalTrials.gov to review all of the inclusion and exclusion criteria.

Gene therapy is here. Restoring dystrophin in skeletal and cardiac muscle is a possibility. And while only a few individuals have been treated thus far, there is so much promise, so much hope. It is a new day for Duchenne.

Every individual with Duchenne needs and deserves opportunities to participate in trials and access to treatment, including promising therapies like micro-dystrophin. This is part of our comprehensive mission at PPMD –to bring safe and effective therapies to people with Duchenne.

And we continue to hope in the potential of gene therapy to end Duchenne.

What’s Next

Learn more about today’s exciting announcement when Dr. Jerry Mendell speaks at PPMD’s Annual Conference later this month. To stream this and other important sessions from the Conference, visit PPMD’s live streaming page.

PPMD has also reached out to Sarepta and we hope to schedule a community webinar later this summer to learn more about today’s news and next steps in this study.

Support PPMD’s Gene Therapy Initiative

PPMD’s Gene Therapy Initiative is a long-term, multi-million dollar approach that seeks to accelerate the potential of gene therapy as a therapeutic for Duchenne. Donate to PPMD today and directly impact our mission to end Duchenne.


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