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#apaperaday: Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls

Paper a day is TREAT_NMD and JWMDRC themed, today’s pick is on real world evidence for eteplirsen, an exon skipping drug approved in the USA for eligible patients with Duchenne muscular dystrophy in 2016. Paper is by Iff et al and published in Muscle&Nerve DOI: 10.1002/mus.28075

Once a drug is approved, data is gathered for patients who are commercially treated. This is different from gathering data in a clinical trial setting – there usually there is a placebo group but also there are strict in- and exclusion criteria.

As eteplirsen was granted accelerated approval, confirmatory data still had (and has) to be collected to show an effect on muscle function. The drug was now only approved based in increased dystrophin production in skeletal muscle. Confirmatory trial is still ongoing.

However, as said, in the meantime, also data is captured from patients who are treated with the drug commercially. This is long term data as the drug was approved 7.5 years ago. You cannot compare the results to placebo, but you can compare to natural history.

While this is not optimal (because you do not have in- and exclusion criteria for natural history like you have in trials), it can still provide insight on the activity of the drug and the safety. Authors here compared it to natural history from patients born after 1980.

This is important as the natural history of the disease has changed due to improved care. So the groups studied for treatment (579 patients, born in 1985-2020, starting treatment age 1-35 years) and the natural history patients were similar.

The treated patients were treated for 0-8.5 years (some patients were treated in a trial before the drug was approved so they had treatment for longer than the drug was approved, i.e. 7.5 years). 1224 contemporary controls were compared to the 579 eteplirsen treated patients.

307 of the 1224 controls died during follow up at an average age of 27.4 years vs 29 of the 579 eteplirsen treated patients at an average age of 32.8 years. You do not need statistics to see that this is different.

Furthermore, authors observed that there was more benefit in survival for patients where treatment had started younger, and that there was no benefit for patients treated for less than 2 years, while there was for patients treated for 4 years or more.

Now the question is: can we really compare these 2 groups? Authors discuss several aspects. 1. the geographic area: the treated patients are all from the USA while those in the control groups are also from Europe. However, the survival curves are similar for US and Europe.

Furthermore, the results fit with earlier data suggesting a slower decline of ambulatory and pulmonary function for eteplirsen treated patients compared to controls – though this was also using natural history controls.

In an ideal comparison you match treated patients with controls based on baseline characteristics. However, authors did not have all the required baseline characteristics, so they could match on age (date of birth) but not on e.g. functional status.

Authors discuss that the genotypes did differ: all treated patients had by definition exon 51 skippable mutations, while those in the control group also had other mutations. However, it is known that exon 51 skippable mutations have a more severe trajectory.

It is possible that those treated receive better care as a result of their treatment (more monitoring) or that they are treated because they received better care (more active/aware family/clinician). Authors compared care criteria between eteplirsen treated and controls:

The same percentage was on steroids and used assisted ventilation suggesting there were no major differences in care (though of course this says nothing about physiotherapy and other parts of care).

The most convincing aspect is the ‘dose’ effect, where only patients treated for 4 years show an effect. This fits with the working mechanism of eteplirsen: it takes time to restore dystrophin and for it to accumulate to clinically relevant levels.

This does pose questions about trials though. It underlines that short trials are unlikely to show functional effects and that the 1.5-3 year trials now ongoing are likely really necessary. Another question is whether regulators will accept the real-world evidence.

For PTC’s ataluren trials did not show clinical benefit (1-1.5 year trials), while real-world evidence suggested a later loss of ambulation and slower decline of respiratory function. The question with these comparisons will always be how comparable the groups are.As such, that comparison is less reliable than comparing placebo & treated groups. Authors stress that more work is needed to fully elucidate the treatment effects of eteplirsen. The Mission (Mis51on) trial is ongoing to collect placebo-controlled evidence.