Exondys 51 (eteplirsen), developed by Sarepta Therapeutics, is the first treatment approved by the U.S. Food and Drug Administration (FDA) for a specific group of patients with Duchenne muscular dystrophy (DMD). These patients — 13% of the total Duchenne population — have gene deletions that are amenable to exon 51 skipping.

Exondys 51 is designed to address the underlying cause of DMD. 

How Exondys 51 works

Genes consist of exons and introns. Exons are stretches of DNA carrying instructions, or coding regions, necessary to make a protein. Introns are regions that do not code for protein. For a protein to be correctly made, the gene is first transcribed into a so-called messenger RNA (mRNA) molecule. This happens in two steps. The entire gene with the exons and introns is first transcribed into pre-mRNA, which then undergoes the process of splicing. During splicing, the introns are removed and the exons are joined together, forming the mature mRNA molecule. The sequence of the code (reading frame) in the mature mRNA is critical for the correct synthesis of the protein.

DMD is caused by mutations in the DMD gene, which carries the instructions to make dystrophin. That protein stabilizes the muscle tissue, and is required for proper muscle development and function. The DMD gene has 79 exons.

Some genetic mutations in the DMD gene cause the deletion of certain regions of the dystrophin gene, disturbing the reading frame of the mature mRNA. This eventually results in the production of a dysfunctional, or non-working, dystrophin protein. In some cases, the removal of one the exons of the DMD gene, exon 51, along with the introns during the splicing process, can correct the reading frame of the mature mRNA that encodes for dystrophin. That facilitates production of a shorter, but still functional protein. This approach is called exon skipping.

Exondys 51 is a chain of nucleotides — the building blocks of DNA — that binds to exon-51 and triggers its excision during the splicing process. The therapy ultimately helps produce a working dystrophin protein.

The exon-skipping therapy is given intravenously (through the veins) as a once-weekly injection.

Exondys 51 in clinical trials

A Phase 2 clinical trial (NCT00844597) tested the safety and efficacy of Exondys 51 in 19 Duchenne patients, ages 5 to 15, with DMD mutations amenable to exon 51 skipping. The dose-escalation study started at 0.5 mg of Exondys 51 per kg of the patient’s body weight, and was increased to 1, 2, 4, 10, and 20 mg per kg. The treatment was given in weekly IV injections for a total of 12 weeks. Muscle biopsies were performed at the start of the study and after completion of treatment. Seven patients responded to treatment, with their dystrophin levels increasing from 8.9% at baseline to 16.4% after treatment. In general, the treatment was well-tolerated. Muscle biopsies also showed reduced inflammation in muscle tissue after the therapy.

The safety and efficacy of Exondys 51 were evaluated in people with advanced stage DMD in a Phase 2 clinical study (NCT02286947). A total 24 patients, with a mean age of 12.9 years, were recruited at multiple sites across the U.S. The participants received 30 mg per kg body weight of Exondys 51 once a week for 96 weeks. The main goal of this study was to identify any adverse events associated with the therapy. The most severe adverse reactions reported were cardiovascular issues, hand and feet deformities, scoliosis, and kidney disorders. Detailed results from this trial are awaited.

Another Phase 2 study (NCT02420379) is testing Exondys 51 in boys with early-stage Duchenne. A total 33 participants, ages 4 to 6, were enrolled for the study at multiple locations in Europe. The patients were divided into two groups based on the types of DMD mutation they had: the control group, comprised of patients not amenable to exon 51 skipping, and those amenable to exon 51 skipping. The treated group received 30 mg per kg of Exondys 51 once per week for 96 weeks. The dystrophin level, and any side effects of treatment, were assessed as the primary outcome. The trial was completed in December 2018, and the results are awaited.

Researchers conducted a Phase 2 trial (NCT01396239) and follow-up study (NCT01540409) to assess the safety and efficacy of Exondys 51 in alleviating lung symptoms in people with Duchenne. A total 12 patients were included in the studies, and were treated with either 30 or 50 mg of Exondys 51 per kg of their body weight for over five years. The results showed that, compared with the natural course of DMD, patients treated with Exondys 51 experienced a significantly slower decline in respiratory function. The treatment was found to be generally safe and well-tolerated by the participants.

An ongoing Phase 2 study (NCT03218995) is evaluating the safety, efficacy, and tolerability of Exondys 51 in male infants with DMD, ages 6 to 48 months. The study also will assess the way the body processes Exondys 51 (pharmacokinetics). The treatment will be administered for about 96 weeks. This dose-escalation study will assess increasing doses of Exondys 51, starting from 2 mg per kg, and increasing to 4, 10, 20 and 30 mg per kg over time. The trial aims to recruit 12 patients, with enrollment ongoing in Belgium, France, Germany, Italy, and the U.K.

A Phase 3 trial (NCT02255552) is studying the efficacy of Exondys 51 treatment in Duchenne patients with a mutation amenable to exon 51 skipping. Participants receive an intravenous infusion of  30 mg per kg of Exondys 51 once a week for 96 weeks. They are then moved onto a long-term efficacy study for the next 48 weeks. The most common adverse reactions reported in this study so far were balance disorders and vomiting.

Other information

The European Medicines Agency (EMA) refused marketing authorization for Exondys 51 in Europe, citing study limitations, including a small study population size, failure to compare with placebo, and use of historical data.

The FDA granted accelerated approval to Exondys 51 in 2016 for DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

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