Exon Skipping for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, life-shortening genetic disorder that affects boys and causes their muscles to break down and lose strength over time.

DMD is caused by specific errors (mutations) 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.

Sarepta’s investigational therapies, SRP-4045 and SRP-4053, 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 DMD.

The Problem

Duchenne is caused by mutations to the dystrophin gene. Most commonly, one or more exons (a portion of the gene) are missing, and the remaining exons don’t fit together properly. Because of this error, cells cannot make dystrophin, a protein muscles need to work properly. Without dystrophin, muscle cells are damaged, and, over time, are replaced with scar tissue and fat.

Missing Exon

Exon Skipping

Our investigational therapies in the ESSENCE study use a technique referred to as exon skipping. Skipping a specific exon next to the mutation is intended to allow the body to make a shortened form of the dystrophin protein.

Purpose of the ESSENCE Study

The purpose of this Phase III research study is to evaluate the safety and effectiveness of
SRP-4045 and SRP-4053 in boys with DMD, who have a deletion that is potentially responsive to, or amenable to exon 45 or exon 53 skipping.

 

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 his deletion type) or placebo. Placebo is made to look just like the active study drug, but it will not contain any active substance. Researchers use a placebo to see if the active study drug works and to see how safe and effective it is compared to not taking anything. This trial design is the best way to get a clear answer about the safety and effectiveness of a new drug, and is usually required by regulatory authorities in the approval process for a drug.

SRP–4045

DMD patients with deletions potentially responsive to, or amenable to exon-45 skipping

SRP–4053

DMD patients with deletions potentially responsive to, or amenable to exon-53 skipping

Placebo

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

Two out of every three patients will receive the active study drug.

Why Consider Enrolling in This Trial?

Patients who complete the placebo-controlled part of the study will be eligible to participate in the 2-year open-label extension period. Open-label means all patients will receive the active study drug and you and the study team will know that your son is receiving it.

When 75% of patients have been in the trial for 48 weeks a group of independent experts will review key study results to decide if the information already gathered is enough to prove that SRP-4045 and SRP-4053 are safe and effective. If so, patients will have the opportunity to roll into the open-label period of the study early and receive active study drug. If the experts decide that more information is still needed, then the placebo-controlled period will continue out to Week 96 as originally planned.

This means that the faster patients enroll in the trial, the sooner experts will have enough results to review. This also means that patients on placebo may be able to transfer from placebo to active study drug.

 

Who is Eligible?

  • Boys with DMD who are 7 – 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 may be treated by skipping exon 45 or 53*. Talk to your doctor if you are unsure.
  • Have been on a stable dose of corticosteroids (such as prednisone or deflazacort) for at least 6 months.
  • Have stable lung (breathing) and heart function.

There are additional requirements for participation and those 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.

Frequently Asked Questions

Q:

What is a randomized placebo-controlled trial?

A:

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.

Q:

What is the chance that my son will receive placebo vs. active study drug?

A:

If your son takes part in this study, he will have a 2 in 3 chance of receiving active study drug and a 1 in 3 chance of receiving placebo during the double-blind, placebo-controlled part of the study (up to 96 weeks).

Q:

If my son gets the placebo drug, will he receive active drug at any point in the study?

A:

Patients who complete the placebo-controlled part of the study will be eligible to participate in the 2-year open-label extension period. Open-label means all patients will receive active study drug and you and the study team will know that your son is receiving it.

Q:

Why is Sarepta sponsoring a randomized placebo-controlled trial?

A:

Researchers use a placebo to see if the active study drug works and to see how safe. A placebo-controlled trial design is the best way to get a clear answer about the safety and effectiveness of a new drug and is usually required by regulatory authorities in the approval process for a drug.

Q:

How many boys will be enrolled in this study and where is it being run?

A:

Approximately 99 boys are planned to be enrolled in this study. We plan to have clinical trial sites in United States.

Q:

Why is the placebo-controlled period of this study 96 weeks?

A:

Based on Sarepta’s clinical trials and analyses, this may be the earliest time to potentially see a treatment effect on the six-minute walk test (6MWT).

Q:

Why is the baseline six minute walk test (6MWT) between 300 - 450 meters?

A:

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

Q:

Why is the age range 7 - 13 years old?

A:

To learn if SRP-4045 and SRP-4053 are effective in slowing the progression of DMD, this study will compare 6MWT results between patients who receive active study drug and patients who receive placebo. To allow the clearest comparison, all boys in the study need to be at a similar stage of their DMD.

Age 7-13 is the age range when boys with DMD start to have a decrease in how far and how fast they can walk. In addition, all patients need to be on steroids to enter the study. Steroids are usually not begun until 4-8 years of age. For these reasons, it is easiest to see an effect of treatment on walking ability in boys who are 7 to 13 years of age.

Q:

Will I be paid for participating?

A:

Generally, reasonable costs associated with participation in the study will be prepaid or reimbursed by Sarepta in accordance with the approved travel policy for the study procedures performed as part of the study. Information will be provided by the study site.

Q:

Why do you need to collect biopsies?

A:

This study will measure the change in the amount of dystrophin protein in muscle after 48 weeks of treatment. 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.

Q:

How long is this clinical trial?

A:

Your son’s participation in this clinical trial could be up to 4 years long. There is a 96-week double-blind placebo-controlled period during which 2/3 of the participants receive active study drug and 1/3 of the patients receive placebo.  The placebo-controlled period is followed by an up to 96-week open label period in which all patients receive active study drug.

Q:

What are some of the activities my son will be required to do to take part in this study?

A:
  • This clinical trial includes weekly visits to your nearest clinical trial site, where your son will receive an infusion of active study drug or placebo (depending on which treatment group your son is assigned to, and what part of the study he’s in). Your son will also periodically have blood drawn and physical exams done at your local site.
  • Approximately every 12 weeks there will be functional assessments which include tests of walking distance, other walking-related activities, muscle strength, breathing and heart function. You may need to travel to another site other than your nearest clinical trial site to do these functional assessments.
  • There are also 2 muscle biopsies, 1 at the beginning of the study and 1, after approximately one year. Depending on where you live it may be necessary to travel for the biopsy surgery.
  • You can learn more about all of the requirements and activities in this clinical trial from the study doctor.
Q:

What risks are associated with this study?

A:

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 you may experience in the study is available in the consent form and should be discussed with your study doctor.

Q:

What are some benefits to being a part of this clinical trial?

A:

The potential benefits of SRP-4045 and SRP-4053 in patients with DMD are unknown. Even if you do not benefit from being in this study, we might learn something that could advance research and help others.

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