Eteplirsen

Clinical data
Legal status	Investigational
Routes of administration	Intravenous infusion
Identifiers
ATC code	None
UNII	AIW6036FAS Y
Chemical data

Eteplirsen, also called AVI-4658, is an experimental drug, currently in clinical trials. It is designed for treatment of some mutations that cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease. Eteplirsen is a product of Sarepta Therapeutics Inc.

Mechanism of action

Duchenne muscular dystrophy is caused when a mutation in the DMD gene changes the DMD RNA so that it no longer codes for functional dystrophin protein, usually due to a mutation that alters the reading frame of the RNA downstream of the mutation. If an exon with an appropriate number of bases lies near the mutation, by removing that exon the downstream reading frame can be corrected and production of partially functional dystrophin can be restored. This is the general strategy used for designing exon-skipping oligos for DMD; as there are 79 exons in the longest splice form of the dystrophin transcript, many different oligos are needed to address the range of mutations present in the population of people with DMD.

Eteplirsen is a Morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin;^[1] giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular frameshifting mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (though internally truncated) dystrophin.^[2] Eteplirsen is given by intravenous infusion for systemic treatment of DMD.

Clinical studies

Several clinical trials have been conducted to test eteplirsen, one in the UK involving local injection to the foot,^[3][4] one in the UK involving systemic injection at low doses^[5][6] and one in the USA at higher systemic doses^[7] that progressed to a rollover extension study.^[8][9] In the phase II study of 12 boys, dystrophin production was increased in 72% of the participants. it is questioned whether increasing the dose would benefit the non responders and whether this could result in any increased side effects. A phase III study has begun in the USA.^[10]

A similar drug is also in clinical trials, drisapersen, which is a 2'-O-methyl phosphorothioate antisense oligo that, like eteplirsen, triggers skipping of dystrophin exon 51.

References