Pharmacology

Eteplirsen is a small molecule morpholino phosphorodiamidate antisense oligomer with the chemical formula C364H569N177O122P30. The uncharged nature of this compound makes it resistant to biological degradation. Eteplirsen is metabolically stable in vitro.

Pharmacodynamics. Eteplirsen may be considered a gene medicine because of its mode of action by antisense-mediated exon skipping. Eteplirsen targets the basic pathology, ie, the mutation in the Duchenne muscular dystrophy gene that alters the reading frame of the RNA downstream of the mutation so it no longer codes for functional dystrophin protein. This abnormality in the reading frame can be corrected by removing the exon with the appropriate number of bases, and production of partially functional dystrophin can be restored. Eteplirsen triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin and restores the reading frame of the dystrophin mRNA, resulting in production of functional dystrophin (09). Although dystrophin induced by skipping exon 51 in patients with amenable deletions is a truncated version, it can still restore the dystrophin-associated complex, suggesting preserved functionality of the newly translated dystrophin (06). The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase are also restored at the sarcolemma. Eteplirsen-induced dystrophin is effective for slowing or preventing the progression of Duchenne muscular dystrophy, but the clinical benefit of eteplirsen, including improved motor function, has not been established.

Pharmacokinetics. Conclusions of a phase 1 dose-ranging study following weekly doses of 0.5 to 20 mg/kg and efficacy trials with 30 and 50 mg/kg doses of eteplirsen include the following:

Routes of administration. Eteplirsen is given by intravenous infusion for systemic treatment of Duchenne muscular dystrophy.

Pharmacogenetics. Eteplirsen is a personalized mutation-specific therapy as it addresses mutations of the dystrophin gene that are amenable to therapies that skip exon 51, which are found in 13% of patients with Duchenne muscular dystrophy (17).

Therapeutic drug monitoring. Dystromirs, miR-1 and miR-133, are considered as exploratory biomarkers of response to therapy in Duchenne muscular dystrophy, and raised levels of these microRNAs tend to normalize with restoration of dystrophin level (18).

Clinical trials

Some of the clinical trials of eteplirsen are shown in Table 1.

Table 1. Clinical Trials of Eteplirsen

A pooled analysis of 4 clinical studies showed that the average increase in percentage of dystrophin-positive fibers after treatment with eteplirsen was 24.23% and the average rate of decline in distance walked was 65 meters, but the clinical significance of these findings is not clear; therefore, further clinical trials are required (16).

Indications

Eteplirsen is indicated for Duchenne muscular dystrophy patients who have a confirmed mutation of the dystrophin gene and are amenable to exon 51 skipping.

Contraindications

None so far.

Goals and duration of treatment

The aim of eteplirsen therapy is to restore dystrophin levels in Duchenne muscular dystrophy patients carrying Duchenne muscular dystrophy mutations with deletions ending at exon 50 and starting at exon 52, which comprise approximately 14% of the entire patient population. The aim is to reverse or retard the progression of the disease. It is not a cure, and the therapy needs to be maintained long term. Over 3 years of follow-up after a randomized study of 24 weeks, with a switch to open-label, eteplirsen-treated patients showed a slower rate of decline in ambulation as assessed by a 6-minute walk test compared to untreated matched historical controls (13). It was well tolerated. Although eteplirsen has a modest effect on restoring dystrophin expression, even small amounts of dystrophin provide clinical benefits to patients (01). Assessment of dystrophin content in muscle biopsy specimens with Duchenne muscular dystrophy in a randomized study using Western blot, Bioquant software measurement of dystrophin-associated immunofluorescence intensity, and percent of dystrophin-positive fibers have confirmed the efficacy of eteplirsen by muscle cell penetration, exon skipping, and induction of novel dystrophin expression (04). Reverse transcription PCR followed by sequencing in this study confirmed the mechanism of action of eteplirsen by skipping exon 51.

In an open-label extension of a randomized controlled trial, 2 nonambulatory twin patients with Duchenne muscular dystrophy, who had greater disease severity at baseline compared to other patients, maintained cardiac and upper limb function through combined week 240 despite their nonambulatory status, with outcomes similar to those of the patients who remained ambulatory (03). Dystrophin production was confirmed following eteplirsen treatment, and other biomarkers of disease progression remained relatively stable in the eteplirsen-treated twin patients and were similar to those of the ambulatory patients.

Clinically significant attenuation of forced vital capacity annual percentage decline has been observed during 2 to 4 years in eteplirsen-treated patients versus glucocorticoid-treated Cooperative International Neuromuscular Research Group Duchenne Natural History Study matched controls in clinical studies (07).

In a retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with Duchenne muscular dystrophy (14).

Future developments. Eteplirsen leaves most of Duchenne muscular dystrophy patients without a treatment option that addresses the molecular cause of the disorder. Although further development of eteplirsen is under way, the following approaches are considered promising (10):

Dosing

Once a week intravenous infusion of 30 mg/kg of eteplirsen.

Special considerations

Clinical trials of eteplirsen have been conducted in children. There are no other special groups.

Anesthesia. Patients with Duchenne muscular dystrophy undergoing surgery under halothane anesthesia can experience an episode of malignant hyperthermia. No information is available on anesthetic procedures in Duchenne muscular dystrophy patients during eteplirsen therapy.

Interactions

No interactions with other drugs have been reported thus far.

Adverse effects

The most common side effects reported by participants in clinical trials of eteplirsen were balance disorder and vomiting.

Eteplirsen has not been linked to serum enzyme elevations or to instances of acute liver injury with symptoms and jaundice (11).