Eteplirsen – Approved for Duchenne Muscular Dystrophy

Today US-FDA gave a fast track approval for Duchenne Muscular Dystrophy (DMD) | Eteplirsen (Exondys 51) | Manufacturer: Sarepta Therapeutics.

Duchenne Muscular Dystrophy:

It is an X-linked neuromuscular diseases typically caused by disrupting the reading frame in the dystrophin (DMD) gene located on Xp21.

The Dystrophin Gene and Its Mutations:

The dystrophin gene is one of the largest known human genes, with a total of 79 exons. Its messenger RNA (mRNA) measures 14 kilobases and takes 16 hours to transcribe. Its large gene size of 2.5 megabases provides a potential explanation for the large number (~4,700) of mutations documented so far.

There are three types of mutations that can disrupt the expression of dystrophin in DMD:

Exon deletions, point mutations, and Duplications.

Exon Deletions: The majority of DMD patients (60%- 70%) carry exon deletions, which cause frameshift mutations and generate non-functional proteins.

Point Mutation: An estimated 25% to 35% of DMD patients have point mutations, which can be further classified as nonsense mutations, small insertions/deletions, and splice site mutations. Nonsense mutations are point mutations that result in a premature termination codon, and accounts for about 12% of disease-causing mutations in DMD patients.

Duplications: Present in approximately 5% of DMD patients, could also lead to frameshift transcripts.

Eteplirsen, an Antisense Oligonucleotide (AON) 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; 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  dystrophin.It is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

Eteplirsen is given by intravenous infusion for the treatment of DMD. It costs around $300,000 per year, a net price based on patient’s weight.

Exon skipping is induced by Eteplirsen, a charge-neutral, phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon of dystrophin pre-mRNA, restoring the open reading frame and enabling production of functional, but truncated, dystrophin.The uncharged nature of the PMO helps make it resistant to biological degradation. This truncated dystrophin protein produced by eteplirsen causes a less severe form of dystrophinopathy, much like Becker muscular dystrophy. PMO technology to treat other genotypes amenable to exon skipping to potentially treat an estimated 70 to 80% of all DMD patients with dystrophin gene deletion. Eteplirsen’s proposed mechanism of action is increasing the production of muscle protein. By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD.

Eteplirsen: Mechanism of Action_Exon Skipping

Controversy surrounding its approval:

The FDA granted Etiplirsen fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

FDA approved Etiplirsen based on a study on 8 subjects (boys) with DMD. Two groups, n=4, compared Etiplirsen 30 & 50 mg/kg/wk vs placebo. Read about this study here. This has raised many questions on the approval process.

Read more about the delays in the approval of Etiplirsen here.

Read about the Eteplirsen Briefing document here and about the PI here.

One more drug in the race is: Biomarin’s Drisapersen

Also, if an exon deletion or point mutation still allows for in-frame reading, a truncated but partially functional dystrophin may be expressed, and the patient could present with Becker muscular dystrophy (BMD), a less severe form of muscle dystrophy that is found in three times fewer patients than DMD. A semi-functional dystrophin may be sufficient as Becker patients exhibit milder symptoms and can survive into their 60s.

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impas Natesh Prabhu Administrator & Chief Editor | Clinical Pharmacologist | Diabetic-Sexual Medicine-Regenerative Therapy Consultant | President, Indian Medical Pharmacologists Association