Eteplirsen

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.16.2021
Released 10.07.2016
Expires For CME 09.16.2024

Eteplirsen

Author: K K Jain MD†

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Eteplirsen

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Introduction

Historical note and terminology

Eteplirsen is an antisense-mediated exon skipping therapy for mutation suppression in Duchenne muscular dystrophy. Drisapersen, which has a similar mechanism of action, failed in phase 3 clinical trials followed by discontinuation of further development, but eteplirsen was granted accelerated approval by the U.S. Food and Drug Administration in 2016 for treatment of some forms of Duchenne muscular dystrophy. Approval under an accelerated pathway can be based on adequate and well-controlled clinical trials showing that the drug affects a surrogate endpoint that is reasonably likely to predict clinical benefit to patients. This pathway provides earlier patient access to promising new drugs while the manufacturer conducts clinical trials to verify the predicted clinical benefit. Early-stage development of this drug started 20 years earlier and was supported by the Muscular Dystrophy Association. There is some controversy about the FDAs approval of this drug as some critics have used terms like lowering the bar to approve an expensive placebo. Eteplirsen initially costs $300,000 to $400,000 per year per patient. Several insurance companies have already approved coverage of eteplirsen. Two years after approval by the U.S. Food and Drug Administration, the Committee for Human Medicinal Products of the European Medicines Agency gave a negative opinion for eteplirsen treatment, and it was not approved in Europe (02).

In December 2019 the U.S. Food and Drug Administration conditionally approved golodirsen (Vyondys 53), another exon-skipping therapy given by intravenous infusion designed to mask the mutated exon 53 in the mRNA produced from the DMD gene, to generate a shorter but working version of dystrophin. It will increase the number of patients to be treated with exon-skipping therapy, as approximately 8% of all Duchenne muscular dystrophy patients have mutations in this exon. The cost will be the same as that of eteplirsen. The ongoing clinical trial ESSENCE (NCT02500381) is now a postmarketing confirmatory trial, which is required under conditional approval.

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:

	• There is insignificant drug accumulation with this dosage schedule.
	• Eteplirsen is not metabolized by hepatic microsomes and is not a potent inducer or inhibitor of the major human CYP enzymes. Therefore, it is expected to have a low potential for drug-drug interactions.
	• The peak plasma concentrations (Cmax) of eteplirsen occur close to the end of intravenous infusion, and most of the drug is eliminated within 24 hours. Excretion is mainly by the kidneys.
	• Plasma protein binding of eteplirsen in humans is relatively low, ranging from 6.1% to 16.5%, and is independent of plasma concentration.

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

Trial description	Results/comments
A single-blind, placebo-controlled, dose-escalation study in patients with deletions in the open reading frame of Duchenne muscular dystrophy that are responsive to exon 51 skipping. Local intramuscular injection of eteplirsen in extensor digitorum brevis muscle on 1 side and saline injection on the opposite side.	Intramuscular eteplirsen was safe and induced the expression of dystrophin locally within treated muscles as shown by biopsy and immunostaining (08). The results led to the decision for further clinical trials of systemic eteplirsen therapy in Duchenne muscular dystrophy patients.
An open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) of eteplirsen in ambulant patients with Duchenne muscular dystrophy aged 5 to 15 years with amenable deletions in Duchenne muscular dystrophy.	Treatment was well tolerated. Muscle biopsy after 12 weekly intravenous infusions of eteplirsen compared to that before starting treatment showed dose-related increase of dystrophin expression (05).
A double-blind placebo-controlled trial of intravenous eteplirsen's ability to induce dystrophin production and improvement in the 6-minute walk test in boys aged 7 to 13 years with Duchenne muscular dystrophy and with confirmed deletions correctable by skipping exon 51.	Eteplirsen at doses of 30 and 50 mg/kg/week restored dystrophin with duration of treatment rather than dose, accounted for dystrophin production, and also resulted in stability on ambulation (15).
PROMOVI, a phase 3 open-label study to provide confirmatory evidence of efficacy of eteplirsen in Duchenne muscular dystrophy patients aged 7 to 16 years who are amenable to skipping exon 51 received eteplirsen 30 mg/kg/week intravenously for 96 weeks.	Results confirmed a positive treatment effect, favorable safety profile, and slowing of disease progression vs. natural history (12).

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).

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):

	• Current antisense-based therapeutic strategies should be continued, not only for exon 51 skipping but also for the skipping of other exons as well.
	• Enhancement of phosphorodiamidate morpholino oligomer uptake and efficacy by its conjugation with cell-penetrating peptides has been shown in animal models with a potential to enter clinical trials.
	• There is a need for sustaining collaborative efforts among the scientific, regulatory, and patient communities to maintain the progress in therapy of Duchenne muscular dystrophy.

References

01: Aartsma-Rus A, Krieg AM. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther 2017;27(1):1-3. PMID 27929755
02: Aartsma-Rus A, Goemans N. A sequel to the eteplirsen saga: eteplirsen is approved in the United States but was not approved in Europe. Nucleic Acid Ther 2019;29(1):13-5. PMID 30526286
03: Alfano LN, Charleston JS, Connolly AM, et al. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore) 2019;98(26):e15858. PMID 31261494
04: Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology 2018;90(24):e2146-54.** PMID 29752304
05: Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 2011;378(9791):595-605. PMID 21784508
06: Cirak S, Feng L, Anthony K, et al. Restoration of the dystrophin-associated glycoprotein complex after exon skipping therapy in Duchenne muscular dystrophy. Mol Ther 2012;20(2):462-7. PMID 22086232
07: Khan N, Eliopoulos H, Han L, et al. Eteplirsen treatment attenuates respiratory decline in ambulatory and non-ambulatory patients with Duchenne muscular dystrophy. J Neuromuscul Dis 2019;6(2):213-25. PMID 30856119
08: Kinali M, Arechavala-Gomeza V, Feng L, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol 2009;8(10):918-28. PMID 19713152
09: Kole R, Krieg AM. Exon skipping therapy for Duchenne muscular dystrophy. Adv Drug Deliv Rev 2015;87:104-7. PMID 25980936
10: Lim KR, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 2017;11:533-45.** PMID 28280301
11: LiverTox. Clinical and research information on drug-induced liver injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2020. PMID 32223120
12: McDonald CM, Shieh PB, Abdel-Hamid HZ, et al. Open-label evaluation of eteplirsen in patients with Duchenne muscular dystrophy amenable to exon 51 skipping: PROMOVI trial. J Neuromuscul Dis 2021;8(6):989-1001. PMID 34120909
13: Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 2016;79(2):257-71.** PMID 26573217
14: Mendell JR, Khan N, Sha N, et al. Comparison of long-term ambulatory function in patients with Duchenne muscular dystrophy treated with eteplirsen and matched natural history controls. J Neuromuscul Dis 2021;8(4):469-79.** PMID 33523015
15: Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 2013;74(5):637-47. PMID 23907995
16: Randeree L, Eslick GD. Eteplirsen for paediatric patients with Duchenne muscular dystrophy: a pooled-analysis. J Clin Neurosci 2018;49:1-6.** PMID 29254734
17: van Deutekom JC, de Kimpe SJ, Campion GV. Antisense oligonucleotides as personalized medicine for Duchenne muscular dystrophy. Drug Discovery Today: Therapeutic Strategies 2013;10:e149-56.
18: Zaharieva IT, Calissano M, Scoto M, et al. Dystromirs as serum biomarkers for monitoring the disease severity in Duchenne muscular dystrophy. PLoS One 2013;8(11):e80263. PMID 24282529

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Eteplirsen

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Drisapersen
golodirsen

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Duchenne muscular dystrophy
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Eteplirsen

Eteplirsen

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Eteplirsen

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Eteplirsen

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Eteplirsen

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Drug-induced myasthenic syndromes

Distal myopathies

Acupuncture

Amyotrophic lateral sclerosis

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

Paraspinal neuromuscular syndromes

Dementia associated with amyotrophic lateral sclerosis

This is an article preview.
Start a Free Account
to access the full version.