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.

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  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

    • 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

        • 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.

  4. Earl Clark says:

    Thank you Alice for replying. No we will never lose hope, and by skimming through Serepta website I see the are working on 45 skipping. Am I right?

    • Alice Melão says:

      Yes they are working in several potential therapies for DMD, including the exon 45 skipping. We will keep our readers up to date on Saptera’s scientific and clinical advances.

        • Alice Melão says:

          Potentially yes, but compatibility of such treatments should be addressed before use in the clinics. You should talk with your son’s physician to request further information, and therapies viability.

          • Earl Clark says:

            Thanks again Alice. I see that exon 45 and 53 both in phase 3. Any idea to when they both we become available/ commercial? Last question then I’ll stop for now.

          • Alice Melão says:

            Dear Earl, It is very difficult to known all the timelines of the trials, and also FDA evaluations for potential regulatory approvals also take time. Hopefully they will be fast.

      • Agnieszka Urbanska says:

        Is there is anything i we can do to be part of clinical trials? Could you point me the right direction please.

        • Alice Melão says:

          In the website you can look for clinical trials registries. There you can find all information required to know more about the inclusion and exclusion criteria, locations where the trial is being conducted, and contact information. I hope this can help you.

  5. Agnieszka Urbanska says:

    Thank You Alice. We know that website but as far I know there isn’t clinical trial for age 2,5 years boy with deletion of exon 53. Thank you any way.

  6. Eman says:

    My son is 7 years old and we recently found that he has DMD there is a deletion of exon 48,exon 49,exon 50,exon 51,exon 52, exon 53,exon 54,that 5th end of the gene.The deletion in exon 48 -exon 54 is out of frame deletion according to mRNA DMD analysis; so How can this medicine helpfully to my son and he is walking and doing his things right now.

    • Alice Melão says:

      Dear Eman, from the information I could gather this is drug can not provide the correct strategy to “correct” the deletion that your son carries. He would requier an exon 55 skipping.

      • Eman says:

        Thank you Sir for your reply but I want to know you mean my son needs exon 55 skipping beside exondys 51 and exon 53 or only exon 55 for the deletion he is carring; is exon 55 skipping available now?

        • Alice Melão says:

          If I understood correctly your son has deletion of all 6 exons between 48 and 55. In this situation exon skipping for 51 and 53 would not work, only skipping the exon 55 could potentially work. From what I am aware, such targeted therapy is not yet available. Other gene therapies aer being explored as we speak that may be of help for your son.

          • Eman says:

            Thank you Sir for your reply.
            As I understood only exon 55 can work with my son’s deletion and it’s not available yet, so there is any medicine could help my son until exon 55 be available..
            Please give me advice.

    • Alice Melão says:

      Dear Kinga, Skipping exon 53 and this Sarepta new drug could potentially be a therapeutic strategy for your son. The company is currently recruiting volunteers with DMD aged 7 to 13 years for a Phase 3 trial in the U.S., Europe, and Israel. If you are interested on participating you can find additional information on inclusion criteria, trial locations and contacts at the trial registry page (

  7. Bill says:

    My son is 2 years old and we recently found that he has DMD. There is a delation of exons 49 – 52. Have we any hope for treatment? Thank you!

    • Alice Melão says:

      Dear Bill, such deletion could be potentially treated with skipping of exon 53. To date Sareptas investigative treatment has demonstrated good efficacy and safety in clinical trials. However it is still under evaluation and has not yet been approved to use in the clinics. Please check back here or sign up for our newsletter to receive further info on how the work advances.

  8. Sandra says:

    Hola. Nuestro hijo tiene 20 años y su de lecion es en el exon 45, usted me podría informar cual seria el indicado para el y en que fase se encuentra . Mil gracias

    • Alice Melão says:

      Hello Sandra, for patients with deletion of exon 45 only a skipping therapy that could target the exon 44 would potentially work. Has far I am aware such therapy is still under discovery phase by Sarepta. Another therapy (BMN 044) being developed by Biomarin has completed Phase 1/2 dose-escalation clinical trial (NCT01037309) that was conducted in Europe.

  9. Vanessa says:

    Alice you have been wonderful and informative in replying to everyone’s messages. This trial brings so much hope for my boys with deletions 48-52. Is there any word of trials being extended to Australia?

  10. Jaydeep Bhatt says:

    Alice, I can see you are replying each comment in blog – let me thank you for your sincere support. my son is 5 years old and gene 49-52 are delete, with this new golodirsen (SRP-4053) I have high hopes. can you please share 2018 clinical trial success figures. Thanks in advance keep up the good work! God is with us!

    • Alice Melão says:

      Dear Jaydeep, Thank you for following Muscular Dystrophy News. During 2018 we are going to continue pursue our aim, which is to share the most recent developments on discoveries and therapeutics for muscular dystrophies. Golodirsen will be subject of future publications on our website as soon new information is released.

  11. BASKAR says:

    can anyone help me out my son with 10 years DMD Exon deletion 46-48 any treatment starts with new medication please help us he is now walking with difficulty

    • Alice Melão says:

      Dear Baskar, Sarepta’s investigational drug SRP-4045 could be a potential treatment for your son, has the deletion he has on DMD could potentially be amenable by skipping of exon 45. Let’s hope this drug fulfills all the safety and efficacy requirements for its approval.

  12. BASKAR says:

    Thank you so much for your reply. can you tell us when SRP-4045 is available for treatment as he is losing his abilities day by day so kindly give us some clue of the treatment approval expected.

  13. Champa says:

    My youngest son is affected with exon 45 deletion.Is this SPR 4045 going to be a reality? What is the reserch status of that?
    Im very anxious to here about that

    Kind regards

  14. A. ehmedee says:

    My son is 9 years , have exon deletion 49-52 . is it under the category of exon 53 research ? whats the latest status /updates about progress with this research and when its expected to have this medicine approved ?
    Many Thanks

  15. Someshwari says:

    My son has deletion (Exons 52-54). I am new to this disease. None of my family has this. Please advise which therapy works for him?

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