Last updated Feb. 9, 2022, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD
Exondys 51 (eteplirsen or AVI-4658), developed by Sarepta Therapeutics, is an exon skipping therapy that may be used to treat patients with Duchenne muscular dystrophy (DMD) who have genetic mutations that are amenable to exon 51 skipping — about 13% of the total DMD population.
It works to address the underlying cause of Duchenne by increasing the amount of dystrophin protein produced in muscle cells.
The U.S. Food and Drug Administration (FDA) approved Exondys 51 in September 2016 under the accelerated approval pathway. This pathway grants marketing authorization to therapies that are likely to be beneficial based on biomarker data, but where clinical evidence of a benefit to patients has not been thoroughly established. Specifically, Exondys 51 was approved based on evidence that it could increase levels of dystrophin protein. As part of the approval, Sarepta is required to conduct further studies to confirm the therapy’s effect on motor function.
The Committee for Medicinal Products for Human Use (CHMP) — part of the European Medicines Agency — recommended against approving Exondys 51 in June 2018, citing limitations of available clinical trial data, such as small study size and a failure to compare against a placebo. The CHMP confirmed the refusal later that year after a requested re-examination of the decision.
How Exondys 51 works
DMD is caused by mutations in the gene DMD, which provides instructions for making a protein called dystrophin that helps to cushion muscle cells from damage during movement. Like other protein-coding genes, the DMD gene is separated into sections called exons, which contain the code for the dystrophin protein, and introns, which are sections of interspacing DNA that don’t code for proteins.
When the DMD gene is “read,” the genetic code — including exons and introns — gets copied into a temporary molecule called messenger RNA. Then, the RNA is edited to remove all of the introns, and the remaining exons are spliced together to form the mature protein-coding sequence that is sent to the cell’s protein-making machinery.
The DMD gene has 79 exons. Certain mutations can result in a frameshift — when the DNA sequence gets out of alignment, causing all of the subsequent parts of the code to be read incorrectly. In these cases, removing exon 51 can “re-align” the code, allowing cells to produce a shorter, but still functional version of the dystrophin protein.
Exondys 51 is an antisense oligonucleotide — lab-made DNA molecules — that binds to exon 51 and causes it to be removed from the messenger RNA along with introns during splicing.
Exondys 51 in clinical trials
Sarepta launched a Phase 2 clinical trial (NCT00844597) in 2009 that tested the safety and efficacy of Exondys 51 in 19 Duchenne patients, all males 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 weekly for a total of 12 weeks, or about three months. Muscle biopsies were performed at the start of the study and after completion of treatment. Of the 19 participants, seven responded to treatment, with their dystrophin levels increasing from 8.9% of normal before treatment to 16.4% after treatment. Muscle biopsies also showed reduced inflammation in muscle tissue after the therapy. The therapy generally was well-tolerated.
Another Phase 2 trial (NCT01396239) enrolled 12 boys with DMD, ages 7 to 13, who were given Exondys 51 at one of two doses (30 or 50 mg/kg), or a placebo, once weekly for 24 weeks, or about six months. All of the participants then continued into an extension study (NCT01540409) where all were treated with Exondys 51. The results showed that, compared with the natural course of DMD, patients treated with Exondys 51 experienced a significantly slower decline in lung function.
After 180 weeks, or nearly three and a half years of treatment, the average dystrophin level was just under 1% of what is seen in people without DMD. Notably it was not clear whether this represented an increase due to insufficient data on levels prior to treatment. The treatment’s effect on physical function also was unclear: over the three-year study, two of the 12 participants lost the ability to walk, as did six of 13 historical controls in a similar period of time.
Sarepta then sponsored a Phase 3 study called PROMOVI (NCT02255552) that enrolled boys with DMD, ages 7 to 16, who were treated with Exondys 51 at 30 mg/kg per week for about two years. The study included 79 boys with mutations amenable to exon 51 skipping; 30 with ineligible mutations also were included, but these patients were deemed unusable as a control group because the natural course of DMD varies based on mutation. Results showed that the treatment increased dystrophin levels by about sevenfold. Comparisons with historical data and data from prior trials suggested that treatment with Exondys 51 led to clinically meaningful improvements in lung function and in the distance that participants could walk in six minutes, a measure commonly used to assess physical function in ambulatory patients.
An analysis of combined data from these trials and another Phase 2 study (NCT02286947) indicated that treatment with Exondys 51 could significantly slow the decline in lung function compared with treatment with glucocorticoids, a standard therapy for DMD. Benefits in lung function were seen regardless of whether participants were able to walk. Several other Phase 2 clinical trials sponsored by Sarepta (NCT02420379, NCT03218995) have further evaluated the safety profile of Exondys 51 in boys with DMD.
Sarepta is currently running a two-part Phase 3 study (NCT03992430) — slated to run through 2026 — to further investigate the safety, efficacy, and pharmacological properties of the treatment. The first part will be an open-label dose escalation trial investigating higher dosages than the previously used 30 mg/kg in about 10 patients amenable to exon 51 skipping therapy. The second portion of the study will be a double-blind, dose-finding and dose-comparing (to the 30 mg/kg dosage) trial in an estimated 144 patients. The study is ongoing at sites in North America, Korea, and Taiwan; participants are actively being recruited at some sites.
Exondys 51 is given via a weekly infusion into the bloodstream at a dosage of 30 mg/kg. Each infusion lasts about 35 to 60 minutes.
The most common side effects associated with Exondys 51 treatment include vomiting and balance problems.
Some people may experience an allergic reaction to Exondys 51, which can manifest with symptoms such as cough. lung spasms, or abnormal heart rate. If such a reaction occurs, appropriate medical management should be given to control symptoms, and the Exondys 51 infusion may be slowed or stopped.
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