A phase III study to evaluate investigational therapies in boys 6-13 years old with Duchenne muscular dystrophy

A 96-week, double-blind, placebo-controlled followed by a 48-week open label extension research study to evaluate the effectiveness and safety of investigational products, SRP-4045 and SRP-4053, in patients with Duchenne muscular dystrophy.

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Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (also referred to as Duchenne) is a rare, life-shortening genetic disorder that affects boys and causes their muscles to break down and lose strength over time. Duchenne is caused by specific genetic mutation (error) in the gene that codes for dystrophin. Dystrophin is a protein that plays a key role in the function of muscle cells and protects them from damage as muscles contract and relax. These mutations in the dystrophin gene lead to a lack of dystrophin protein in muscles. Without enough dystrophin, muscles gradually grow weaker until they can’t move at all, and eventually breathing and heart function are lost.

Dystrophin

Dystrophin is a protein our muscles need to work properly. Dystrophin plays a key role in the function of muscle cells and protects them from damage as muscles contract and relax. Without dystrophin, muscle cells are damaged, and, over time, are replaced with scar tissue and fat.

Understanding the Dystrophin Gene

The dystrophin gene is made up of 79 exons (portion of the gene) that are linked together to provide instructions for making dystrophin. Exons are like puzzle pieces as they are meant to fit together in specific ways. When exons fit together properly, the body can read through the gene’s instructions in order to make the dystrophin protein. Like a missing puzzle piece to a puzzle, if there are errors within the gene, like a deletion of one or more exons, the way the exons fit together could be disrupted. If so, the body may not be able to make adequate dystrophin protein. Without proper dystrophin development, muscle cells become damaged and weaken over time.

Exon Skipping

The drug is intended to skip over a specific exon to restore the connection of the dystrophin gene. This technique is called exon-skipping. This skipping allows the body to make a shortened form of the dystrophin protein.

KEY:

EXONS

PROTEIN

MISSING EXON

Investigational Study Drugs:

ESSENCE will study the effect of each investigational study drug, SRP-4045 (casimersen) and SRP-4053 (golodirsen), versus a placebo. Both study drugs use a technique referred to as exon skipping and are being evaluated in the ESSENCE study as an approach to help muscles make a shorter form of dystrophin protein and possibly slow the progression of Duchenne. Participants in the study will be assigned one investigational drug, or placebo.

What is placebo, and why is it being used in ESSENCE?

Placebo is made to look just like the active study drug, but it will not contain any active substance. Researchers use a placebo to compare how safe and how well the study drug works in individuals treated with the drug, versus those receiving placebo and standard of care. This study, like others in Duchenne, utilize a placebo group because it is considered a gold standard from regulatory agencies who may eventually decide whether the drugs are safe and effective.

The purpose of ESSENCE is to evaluate the safety and effectiveness of two investigational exon-skipping study drugs in boys with Duchenne who may have a deletion that is amenable to exon 45 or exon 53 skipping.

Goal of ESSENCE:

The goal of the ESSENCE study is to evaluate the effect on walking ability and muscle function for individuals assigned to the investigational study drugs SRP-4045 (casimersen) or SRP-4053 (golodirsen), compared to those individuals assigned to a placebo group (those who do not receive active drug). 

Why Consider Enrolling in This Trial?

While no benefit can be promised from participation in any clinical study, we believe some benefits may include: 
  • Access to highly experienced clinicians with strong expertise in treating Duchenne.
  • Opportunity to contribute to what is known about Duchenne progression.
  • Opportunity to help others by contributing to medical research that may accelerate the development of Duchenne therapies.
  • Patients who complete the placebo-controlled part of the study will be eligible to participate in the 1-year open-label period in which all patients will receive the active study drug.

More about the study:

ESSENCE is a randomized, placebo-controlled study. Each study participant will be randomly assigned to receive either active study drug (SRP-4045 or SRP-4053, depending on their exon skipping amenability) or placebo. 

The study will enroll approximately 222 participants into 3 Groups based on the investigational study drug assigned at the start of the study. 

GROUP 1: SRP-4045

Participants with deletions amenable to exon-45 skipping

GROUP 2: SRP-4053

Participants with deletions amenable to exon-53 skipping

GROUP 3: Placebo

Participants potentially amenable to either exon-45 or exon-53 skipping in this trial are randomly assigned to receive placebo during the study

What are my chances of receiving active study drug or placebo?

In ESSENCE, neither the participant nor the study doctor will know if the participant has been assigned the active study drug or placebo. During the first 2 years of the study the participant will have a 66% chance of receiving active study drug and 33% of receiving placebo. All participants will receive active study drug during the last year of the study (year 3). 

What will I have to do in this study?

Participants in the ESSENCE study will visit a study center for infusions, functional assessments, medical testing, and 2 biopsies over the course of the initial 2-year placebo-controlled portion of the study. This will be followed by the 1-year open-label period, during which all patients will be able to receive active study drug.

The ESSENCE study includes weekly visits where participants will receive an infusion of active study drug or placebo.

Participants will also periodically have blood drawn and physical exams done at their local site.

Approximately every 12 weeks there will be functional assessments which include tests of walking distance, other walking-related activities, muscle strength, breathing, heart function, and 2 biopsies. 

Who is Eligible?

  • Boys with Duchenne who are 6 - 13 years old and can walk between 300 and 450 meters on the 6-minute walk test.
  • Have a genetic test that shows a mutation in the dystrophin gene that is amenable to skipping of either exon 45 or 53*. Talk to your doctor if you are unsure.
  • Have been on a stable dose of corticosteroids for at least 6 months.
  • Have stable lung (breathing) and heart function.

There are additional requirements for participation that will be reviewed with patients and their families during the screening process.

*Deletions potentially amenable to exon 45 skipping include but are not limited to 12–44, 18–44, 44, 46–47, 46–48, 46–49, 46–53, or 46–55.
*Deletions amenable to exon 53 skipping include but are not limited to 42-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, and 54-58.

Who is not Eligible?

  • Have had major surgery within 3 months.
  • Have presence of any other significant genetic disease other than Duchenne.
There are additional requirements for participation that will be reviewed with patients and their families during the screening process.

Common Questions

In a randomized, placebo-controlled study, each participant is picked randomly, by chance (like tossing a coin) to receive either active study drug, or placebo. Placebo is made to look just like the active study drug, but it does not contain any active substance.

Participants in this study will have a 66% chance of receiving active study drug and a 33% chance of receiving placebo during the double-blind, placebo-controlled part of the study (up to 96 weeks).

Participants who complete the placebo-controlled part of the study will be eligible to participate in the 1-year open-label extension period. During the open-label extension all patients will receive active study drug. Open-label means that all participants receive active study drug (no one is on placebo).

Researchers use a placebo to compare how safe and how well the study drug works in individuals treated with the drug, versus those receiving placebo and standard of care. This study, like others in Duchenne, utilize a placebo group because it is considered a gold standard from regulatory agencies who may eventually decide whether the drugs are safe and effective.

It has been determined that at 96 weeks of treatment, it will be possible to determine whether or not there was a meaningful change in the 6MWT when comparing the active treatment group to those who received placebo.

Participants in this range of the six-minute walk distance are at the stage of their Duchenne when they are most likely to show an effect of treatment.

No, participants will not be paid for participating. Generally, reasonable costs associated with participation in the study, such as transportation, food, hotels, will be prepaid or reimbursed in accordance with the approved travel policy for study participation. Information will be provided by the study doctor.

Participation includes weekly travel to the study center. Additional travel may be required for certain study assessments if these cannot be done all at the same study center.

A biopsy will be taken at baseline (prior to any treatment) for all individuals. A second biopsy will be taken at either 48 weeks or 96 weeks, for a total of two biopsies per participant. This study will measure the change in the amount of dystrophin protein in muscle after 48 weeks of treatment in some muscle biopsy samples, and after 96 weeks of treatment in others. Because SRP-4045 and SRP-4053 are designed to increase levels of dystrophin in muscle, the only way to show that exon skipping by SRP-4045 or SRP-4053 is working as intended is to test muscle directly. This cannot be studied by testing blood or urine, for example.

Participation in this clinical trial could be up to 3 years long. There is a 96-week double-blind placebo-controlled period during which 66% of the participants receive active study drug and 33% of the patients receive placebo. The placebo-controlled period is followed by an up to 48-week open label period in which all patients receive active study drug.

As with all clinical studies, there can be risks associated with possible side effects of taking the study drug and with the standard medical tests carried out as part of the study at each visit. Information on the possible side effects participants may experience in the study is available in the consent form and this should be discussed with the study doctor.

How to Learn More:

To speak with someone to learn more about the ESSENCE study and to understand if your son might be eligible, please

Click here to schedule an appointment directly with a qualified Patient Navigator

If you have general questions about the trial or participation, you may also contact the Patient Navigator at SareptAlly@Sarepta.com

The ESSENCE study is actively recruiting in parts of Europe, Asia, and North America. 

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Additional information can be found at ClinicalTrial.gov or for EU, EudraCT, or you can email SareptaAlly@sarepta.com.

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