Sarepta’s Exon 53 Skipping Therapy, Golodirsen, Improves Dystrophin Expression in Phase 1/2 Trial

Sarepta’s Exon 53 Skipping Therapy, Golodirsen, Improves Dystrophin Expression in Phase 1/2 Trial

Sarepta Therapeutics says its lead candidate therapy for exon 53 skipping, golodirsen, showed potential to treat Duchenne muscular dystrophy (DMD) in a first clinical trial of DMD patients.

According to results of the Phase 1/2 clinical study, 4053-101 (NCT02310906), golodirsen significantly boosted dystrophin protein production in 25 boys with confirmed deletions of the DMD gene amenable to exon 53 skipping. This mutation affects about 8 percent of all DMD patients, Sarepta reports on its website.

DMD is caused by mutations on the gene that encodes the dystrophin protein. Although expressed in very small amounts — representing only 0.002 percent of total muscle proteins — dystrophin is essential for muscle cells to work as they should.

Golodirsen, also known as SRP-4053, is based on Sarepta’s exon-skipping technology and works by binding to exon 53 of the dystrophin sequence so as to exclude, or skip, this part of the sequence. This helps produce a smaller but functional form of dystrophin protein.

The trial evaluated the safety, tolerability, phamacokinetics and efficacy of golodirsen. French, Italian and British boys received weekly 30 mg/kg intravenous infusions of the investigative therapy for at least 48 weeks.

After roughly 11 months of treatment, muscle biopsies confirmed that all patients had responded, showing increased levels of exon 53 skipping compared to baseline measures. Importantly, a 10.7-fold increase in levels of the dystrophin protein from the study’s start was also seen in measures taken using Western blot, rising from an initial mean of 0.095 percent of normal protein levels to a mean of 1.019 percent.

These results, the company said in a press release, both confirm the validity of the therapeutic approach and golodirsen’s potential as a new therapy.

“This is now the second exon-skipping agent [the first was Exondys 51] to have shown a statistically significant increase in dystrophin production, validating the exon-skipping approach to treating DMD boys with amenable mutations,” said principal investigator Francesco Muntoni, who is also a pediatric neurologist at London’s Great Ormond Street Hospital for Children NHS Foundation Trust and the UCL Great Ormond Street Institute of Child Health.

In the Phase 2 initial study (NCT01396239) and follow-up trial (NCT01540409)  that led to the U.S. Food and Drug Administration granting Exondys 51  accelerated approval in September 2016, the dystrophin protein level in patients rose to 0.44 percent of normal levels after 48 weeks of treatment.

“These data demonstrate statistically significant exon skipping, dystrophin production and localization, which further validate the broad application of our exon-skipping platform and aligns with our strategic imperative to expand and improve the treatment choices for the majority of patients with DMD,” said Douglas Ingram, Sarepta’s president and CEO.

The 4053-101 clinical trial is part of the SKIP-NMD project, involving 10 academic partners across the United States and Europe. Its 25 patients will continue to be evaluated for a total of 144 weeks. The study will likely finish in May 2019, and Sarepta plans to release study data at a future scientific meeting.

The safety and efficacy of golodirsen is also being evaluated in the Phase 3 ESSENCE study (NCT02500381) in patients with DMD gene deletions amenable to exon 45 or 53 skipping. This trial is now recruiting about 100 DMD patients at sites across the United States, Canada and Europe.

11 comments

  1. Vinu Joseph says:

    Dear Sir/Madam,
    I am delighted to see the advancement in medicine for DMD. I am wondering how this can be a benefit to my suffering children.

    I have two children both having Duchene Muscular Dystrophy (DMD)with deletion of exons 12-25. Our elder son is 11 years old and on a wheelchair and you younger son is 6.5 years and still walking.

    God bless and best regards
    Joseph

    • Alice Melão says:

      Dear Sir, I am afraid this exon 53 skipping strategy would not be suitable to restore DMD gene activity in the case of your children. Given they have exons 12-25 deletion they would require exon 11 skipping. I hope the best for you all.

      • Vinu Joseph says:

        Dear Alice, Thanks for the prompt reply. Please could you advise if there is any possibility to for starting trial medicines for exon 11 skipping.. If there is no possibility then please suggest me a way for initiating one..

        God bless and best regards
        Joseph

        • Alice Melão says:

          I believe the best way for you to achieve that goal is to keep in touch with muscular dystrophy patient support organizations, and your children’s physician. Commonly they are aware of the more recent treatment and clinical trial advances, as well as they may be in touch with clinical experts on the field that could be of help. The associations are also very much focused on fundraising events to support developments for these devastating diseases, which couls also help you to find new ways to help your children.

  2. Earl Clark says:

    We are so hopeful and excited about the new advances in treatment for dmd. My son is 10 and he has deletions 46 through 52. Will the exon 53 apply to him? Thank you

    • Alice Melão says:

      Dear Earl, from the information I could find your son’s DMD deletions are a bit complicated to solve. He would require exon 53 skipping but also an additional skipping (exon 45 or 54). Genetics can be very complicated and messy. But please don’t lose your hope.

  3. Shilpa says:

    Dear Sir
    My son is 7 years old and we recently found that he is with Dmd there is a deletion of exon 8 and exon 9 . How can this medicine help full to him because he is walking and doing his things right now.I am scared of his future please help me.

    • Alice Melão says:

      I’m afraid this exon 53 strategy would not be of help for your son. Since he has exon 8-9 deletion he would require an exon 6 and 7 deletion method to overcome the DMD gene deficiency.

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