About VYONDYS 53

WHAT IS VYONDYS 53 (golodirsen)?

VYONDYS 53 is used to treat patients with Duchenne muscular dystrophy (DMD) who have a confirmed mutation in the dystrophin gene that can be treated by skipping exon 53.

This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VYONDYS 53. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

ANSWERS TO YOUR MOST COMMONLY ASKED QUESTIONS

HOW IT WORKS

UNDERSTANDING EXON SKIPPING

VYONDYS 53 is an exon-skipping therapy. The goal of exon skipping is to allow the body to make a shorter form of the dystrophin protein. Let’s take a closer look at how:

The dystrophin gene is the largest gene in the body, made up of 79 exons (portions of a gene) that are linked together to form the instructions for making dystrophin — a protein muscles need to work properly.

Think of the exons like toy train cars, each with a special connection that allows one car to connect to another. In order for all the cars to move together as a train, the connections between cars must match so that they can connect to one another.

Duchenne is caused by a genetic mutation, or change, in the dystrophin gene. Most commonly, one or more exons are missing. This causes errors in the instructions for making dystrophin, and the body is not able to produce enough or any working dystrophin protein.

Imagining the toy train, one or more cars would be missing, leaving the remaining cars not connected. In this example, we can see that cars 50–52 are missing. This results in cars 49 and 53 not being able to connect.

Exon skipping technology allows the body to make dystrophin protein by skipping over a specific exon. VYONDYS 53 works using exon skipping and the result is a shorter form of the dystrophin protein.

So with our train, we would move a certain car aside to “skip over” it so we could find a car with the right connection to allow the remaining cars to connect. In our example, car 53 would be skipped over to allow car 49 to connect to car 54.

VYONDYS 53: DEVELOPED TO SKIP EXON 53

Clinical studies of VYONDYS 53 tested whether exon skipping happened on the dystrophin gene of boys treated with the drug. In those studies, exon skipping occurred in all 25 evaluated study participants.

STUDIES SHOWED VYONDYS 53 INCREASED DYSTROPHIN PRODUCTION OVER BASELINE

The average dystrophin protein level in muscle tissue in patients amenable to exon 53 skipping, as assessed by the Sarepta Western blot

After 48 weeks on treatment

• Efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Part 2.
• Mean dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.92% (SD 1.01) of normal levels (p<0.001); the median change from baseline was 0.88%.
• This increase in dystrophin protein expression positivity correlated with the level of exon skipping.
• Dystrophin levels assessed by Western blot can be meaningfully influenced by differences in sample processing, analytical technique, reference materials, and quantitation techniques. Comparing dystrophin results from other testing methods requires standardized reference material and additional bridging studies.
• Patients treated with VYONDYS 53 showed an average dystrophin increase of 15.96 fold.

INDIVIDUAL DYSTROPHIN EXPRESSION OVER BASELINE IN PATIENTS TREATED WITH VYONDYS 53

Study 1 (part 2): Sarepta Western blot test results from Baseline to Week 48 (N=25)

POSSIBLE SIDE EFFECTS OF VYONDYS 53

Allergic reactions, including rash, fever, itching, hives, and inflammation and/or peeling of the skin have occurred in patients who were treated with VYONDYS 53. Seek immediate medical care if signs and symptoms of allergic reactions occur.

Damage to the kidneys was seen in animals who received golodirsen. Although damage to the kidneys was not seen in clinical studies with VYONDYS 53, the clinical experience with VYONDYS 53 is limited. Fatal kidney damage has occurred with other drugs that work in a similar way. Your doctor may recommend urine collection and blood testing before starting treatment followed by urine testing every month and a blood test every 3 months to monitor your kidneys.

ADVERSE REACTIONS OBSERVED IN AT LEAST 20% OF TREATED PATIENTS AND GREATER THAN PLACEBO WERE (VYONDYS 53, PLACEBO)

Other adverse reactions that occurred in greater than 5% of patients treated with VYONDYS 53 and more often than in patients who received an inactive IV infusion were pain at the IV site, back pain, pain, diarrhea, dizziness, stretch or tear in a ligament, bruising, flu, pain in the mouth and throat, stuffy or runny nose, scrapes or scratches of the skin, ear infection, seasonal allergy, fast heartbeat, reactions related to the IV catheter site, constipation, and broken bones. Talk to your doctor if you experience any side effects.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Sarepta Therapeutics at 1-888-SAREPTA (1-888-727-3782).

Please see the full Prescribing Information for VYONDYS 53 (golodirsen).

A genetic test is required to confirm that a patient's mutation of the DMD gene is amenable to exon 53 skipping. For more information about genetic testing resources, visit Parent Project Muscular Dystrophy’s (PPMD) Decode Duchenne website.