Matt’s Promise is dedicated to making a difference
in the lives of young people affected by terminal illnesses.
Our cornerstone project is to find a cure for Duchenne Muscular Dystrophy (DMD).

Matt’s Promise is dedicated to making a difference in the lives of young people affected by terminal illnesses.
Our cornerstone project is to find a cure for Duchenne Muscular Dystrophy (DMD).

Exon Skipping

In DMD, exon skipping is a potential treatment approach to correct for specific genetic mutations and restore production of dystrophin protein.

The underlying cause of DMD is a mutation or error in the gene for dystrophin, an essential protein involved in muscle fiber function. The dystrophin gene is made up of 79 pieces called exons, which are joined together like the pieces of a puzzle.  A deletion of one or more exons often results in these pieces no longer fitting together, in which case protein is not made.  In Duchenne Muscular Dystrophy an exon, or exons are deleted which interfere with the rest of the gene being pieced together.

The principle of exon skipping is to encourage the cellular machinery to ‘skip over’ an exon of the dystrophin gene to correct for specific genetic mutations and restore the gene’s ability to make a functional, though shorter, form of the dystrophin protein.

Sarepta Therapeutics

Our Sister Organization, Charley’s Fund,  has partnered with Sarepta Therapeutics to optimize the company’s backbone chemistry for a suite of exon skipping drugs. Sarepta Therapeutics’ lead compound, eteplirsen, is currently in Phase 3 clinical trials at hospitals around the country. The company expects to submit a New Drug Application for eteplirsen to the FDA in 2015. Sarepta is also developing follow-on compounds, one of which could help Charley (SRP-4050). We are working with the company and the regulatory authorities to ensure that this promising suite of compounds is developed and approved as quickly as possible using a flexible process that reflects the urgency and rarity of Duchenne muscular dystrophy. For more information please visit


Eteplirsen is an antisense drug targeting exon 51 of dystrophin, developed by Sarepta Therapeutics. Skipping exon 51 enables the repair of the reading frame in 13% of the DMD population. The chemically-synthesized oligonucleotides in Eteplirsen are known as phosphorodiamidate morpholino oligomers (NYSE:PMO), which are molecules that stably block the interaction between RNAs and proteins.

Read More

Sarepta Therapeutics has submitted the New Drug Application (NDA) of Eteplirsen through the accelerated approval program. The program offers early approval for drugs treating serious diseases for which there is no effective treatment available. Different from the traditional NDA, which requires the proof of clinical benefits, the decision of the accelerated approval is based on surrogate endpoints, such as biochemical markers. After the approval, the company is required to conduct additional clinical trials to prove the clinical benefits, in order to keep the drug on the market.

Overview of clinical trials

Sarepta Therapeutics has been conducting a series of clinical studies on Eteplirsen. (1) Study 33 was a placebo-controlled phase 1/2 study that investigated the biochemical efficacy and safety of injecting Eteplirsen on single foot muscle. (2) Study 28 was an open-label phase 2 study with dose escalation of intravenous-infused Eteplirsen. (3) Study 201 was a double-blinded placebo-controlled phase 2b study for 24 weeks. (4) Study 202 was a three-year open-label extension trial of Study 201. (5) There are three ongoing clinical trials, including a phase 2 study evaluating the clinical efficacy of Eteplirsen, a phase 2 study on early-stage DMD, and a confirmatory phase 3 study.

Studies 201 and 202 serve as the key clinical trials for the NDA assessment.

Study 201/202

Study 201 enrolled 12 DMD patients aged 7-13 years with exon 51 amendable mutations. To be qualified for the enrollment, the patients were required to maintain stable steroid treatment and be able to walk 200-400 meters on the 6-minute walk test (6MWT). The patients were randomly assigned to three groups, receiving weekly 30 mg/kg Eteplirsen, 50 mg/kg Eteplirsen or placebo. After 24 weeks, the patients in the placebo group were randomized to receive 30 mg/kg or 50 mg/kg Eteplirsen treatment, and the placebo-controlled study was turned into an open-label study (Study 202). The efficacy and safety of Eteplirsen were monitored throughout the studies.


(1) Biochemical efficacy: dystrophin production

The production of exon-skipped dystrophin is the most relevant primary efficacy endpoint for the NDA accelerated approval. The loss-of-function dystrophin in DMD patients is generally unstable and undetectable. Therefore, increases of dystrophin in muscles under treatment should be contributed by production of the functional exon-skipped dystrophin. To evaluate the biochemical efficacy of Eteplirsen, incremental dystrophin under treatment was quantified.

The baseline dystrophin level of each patient was measured from a muscle biopsy prior to the onset of the studies. Four additional biopsies were performed during the studies: 1st in Week 12 on the 50 mg/kg treatment group plus two placebo patients, 2nd in Week 24 on the 30 mg/kg treatment group plus the other two placebo patients, 3rd in Week 48 and 4th in Week 180 on all the patients. Dystrophin was detected by immunostaining, and the percentage of dystrophin-positive fibers was quantified. The increase of dystrophin-positive fibers from the baseline level was compared between the treatment and placebo groups. Eteplirsen was shown to induce a significant increase of dystrophin in muscles with 24 weeks of treatment (p < 0.01, n = 4), which persists throughout the duration of the studies (p < 0.001, n = 11). The dystrophin-positive fibers were blindly quantified by at least four independent pathologists, with consistent results. Similar results were generated by quantifying the total fluorescence intensity of the immunostaining. At the fourth biopsy, the enhanced presence of dystrophin was also verified by Western blot. Dystrophin was detected on a higher percentage of patients in the treatment group (82%, n = 11) compared to untreated DMD patients (11%, n = 9). In addition, the correct exon-skipped mRNA was detected by RT-PCR in all the patients, which further confirmed the biochemical efficacy of Eteplirsen.

(2) Clinical efficacy: 6-minute walk test (6MWT)

The ability to preserve ambulation in DMD patients is an important primary efficacy endpoint in evaluating the clinical benefit of Eteplirsen. The distance each patient was able to walk in six minutes (6MWT) was used to quantify the ability to walk, and the change from the baseline performance was compared between the treatment and placebo groups. In Week 48, the 50 mg/kg treatment group showed significantly slower decline of the performance than the placebo group (87.4m difference, p < 0.001). Although the patients in the placebo group started to receive Eteplirsen after Week 24, the difference shown in Week 48 supported both the effective clinical benefit of Eteplirsen and the delayed appearance of the effect.

The DMD patients typically experience rapid disease progression in teenage years. Patients at a more advanced stage of the disease may not benefit from this treatment. The conclusion is supported by two patients in the 30 mg/kg group who quickly lost ambulation after enrollment, suggesting variability in patient response.

The subsequent period of the study did not involve a placebo control. The company identified additional DMD patients matching the enrollment requirements as an external control group. Compared to the documented 6MWT performance of the external control at the same age, the Eteplirsen-treated patients walked 151 meters more distance (p < 0.01, n = 12) on 6MWT by the end of Year 3. The result suggested that Eteplirsen was able to delay the loss of ambulation in DMD patients. However, the open-label design of the study is not able to exclude a placebo effect.

(3) Pulmonary functions

Report of pulmonary function is requested by FDA as an additional primary efficacy endpoint. The enrolled patients in Study 201/202 exhibited stable pulmonary functions during the three years, measured by maximum expiratory pressure, maximum inspiratory pressure, and forced vital capacity. Compared to the age-matched DMD patients, who showed declining performance in all three measures of pulmonary functions, the Eteplirsen-treated patients maintained better pulmonary functions.


The NDA submission combined the safety data from all the previous and ongoing clinical trials, which includes 72 total patients with 46 patient years' experience of receiving ≥ 30 mg/kg weekly Eteplirsen. The company claims that most adverse events were mild and unrelated to the Eteplirsen treatment. The drug-related adverse events include flushing, erythema, and mild temperature elevation.



In 2005, our sister organization, Charley's fund, made their first major investment in a biotechnology company. It turned out to be a solid bet. Prosensa is now in the process of applying for FDA approval for drisapersen, its lead compound. The drug, which could benefit approximately 15% of the Duchenne population, has been shown to increase the distance patients can walk on the “six minute walk test,” especially in younger patients. Prosensa is also developing follow-on drugs that will expand the pool of children who can benefit from exon skipping. Visit Website