Muscular dystrophy description with needles and pills

What is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy (DMD), the most common form of childhood muscular dystrophy, results from the absence or reduction in levels of the dystrophin protein in muscle tissues. DMD manifests as muscle degeneration and weakness, and it is histologically characterized by features such as reduction in muscle fiber size and degeneration as well as presence of connective tissue and fat instead of muscle. DMD progresses quickly and can lead to loss of ambulation in the early teenage years, and subsequent early mortality.

What is eteplirsen and how does it work?

Eteplirsen, an antisense oligonucleotide, is the lead compound under development for a subpopulation of DMD patients by Sarepta Therapeutics. Antisense oligonucleotides are single-stranded synthetic nucleotides that bind to pre-mRNA and alter translational processing. Antisense oligonucleotides are being developed to induce skipping of exons in DMD patients with frameshift mutations in the dystrophin gene, allowing for expression of a shorter, yet partially functional dystrophin. Eteplirsen induces skipping of exon 51, making it a potential therapy for 13% of the DMD patient population who have that mutation.

How did eteplrisen perform in clinical trials?

Eteplirsen was tested in a very small, non-placebo controlled clinical trial of 12 patients with DMD. An extension of this study is ongoing and there is now four years of follow up data available for all patients treated with eteplirsen. Of the 12 patients, 10 maintain the ability to walk-a significant achievement as these patients are currently within the age range when loss of ambulation is very common. A comparison of these data to a historical control group of DMD patients found that eteplirsen-treated patients performed statistically better on the six minute walk test, a key measure of ambulation and muscle function often used in DMD clinical trials. Additionally, patients who received eteplirsen treatment displayed increases in the protein dystrophin, consistent with the drug’s mechanism of action. Eteplirsen is also buoyed by a stellar safety profile without drug associated severe adverse events throughout clinical testing.

What will happen at the Advisory Committee meeting?

At an advisory committee meeting (AdCom), a panel consisting of experts in the DMD field, experts in related fields, and patient and industry advocates will gather to evaluate eteplirsen through an examination of available data and testimony from the FDA, Sarepta, and patients and their families. Patient advocacy groups are particularly influential within the DMD community and are providing funding to allow patients and their families to travel to and testify at the AdCom meeting. Many if not all of these patients and family members are likely to voice their support for eteplirsen’s approval and could potentially influence the panel.  At the end of the meeting the panel will be asked to vote on a set of questions regarding eteplirsen, in general these questions revolve around the panel’s interpretation of the available data and may include a question on whether the panel feels eteplirsen should be approved. A recommendation from the committee is not binding and the FDA may decide to reject a drug recommended for approval and vice versa.

What happens next?

Eteplirsen has a Prescription Drug User Fee Act (PDUFA) date of May 26th, by which the FDA will announce whether they will approve the drug. Should eteplirsen be approved, it is likely to be under an accelerated approval and require the execution of larger trials than have currently been run in order to confirm eteplirsen’s clinical profile.

Can recent regulatory decisions inform eteplirsen’s fate?

In January 2016, the FDA rejected the application of drisapersen (BioMarin Pharmaceutical’s Kyndrisa), a similar exon 51 skipping compound for the treatment of DMD. Drisapersen had been studied in several late-stage clinical trials, but did not demonstrate convincing efficacy data on aiding patients on the six minute walk test. Drisapersen was also found to be associated with significant adverse events, including life threatening thrombocytopenia. Drisapersen remains under review by the EMA with a decision on approval expected this year.

In February the FDA sent PTC Therapeutics (PTC) a “refuse to file” letter for their prospective DMD treatment ataluren (Translarna), stating that the data provided did not meet agency standards for proving efficacy. Ataluren had failed to demonstrate significant improvement over placebo on the six minute walk test in both a Phase II and Phase III trials. This remains in contrast to ataluren’s fate in Europe where it was conditionally approved in 2014 and remains so, pending EMA’s review of the Phase III data. Despite the recent Phase III failure on the primary endpoint, ataluren was recently recommended for reimbursement by the United Kingdom’s National Institute for Health and Care Excellence (NICE), representing a reversal of a 2015 decision and likely reflecting significant discounts provided by PTC.

Recent decisions in DMD, as well as other rare diseases, convey that despite a lack of disease modifying therapies and significant unmet need, the FDA maintains strict parameters regarding drug efficacy and safety when evaluating orphan drug candidates. While eteplirsen has displayed a sterling safety profile thus far, a demonstration of efficacy by Sarepta will be a key factor for both a positive AdCom decision and an approval by the FDA, whose briefing documents indicate some skepticism regarding eteplirsen’s efficacy.

For a more in depth analysis of Eteplirsen, please see our recent report on Duchenne Muscular Dystrophy.

How Glympse Bio oversubscribed their Series B funding amidst the pandemic

View Now