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#apaperaday: The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation duchenne muscular dystrophy – a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden

Today’s pick is from @BioMedCentral Neurology by Golli et al on the clinician perspective on the role of ataluren treatment in slowing down disease progression in Duchenne patients with nonsense variants DOI: 10.1186/s12883-024-03570-x

Duchenne is caused by lack of dystrophin. For 10-15% this is due to a nonsense variant, i.e. a single typo in the coding part of the dystrophin gene changing an amino acid code into a stop (normally located at the end of the code to indicate protein translation is done).

Ataluren can suppress nonsense variants so instead of stopping midway in the gene code, translation continues to the end. Ataluren was conditionally approved in the EU and is available also in Kazakhstan, Israel, Korea, Belarus, Russia, Brazil, Chile, Saudi Arabia, and Ukraine.

Since its approval in the EU in 2014, real-world evidence has been collected, suggesting a delay in loss of ambulation and respiratory dysfunction. Not mentioned in the paper: last year EMA gave a negative opinion for renewing the conditional approval (done every year).

The company (PTC) appealed, but this January, EMA again said the conditional approval should not be renewed. Pending vetting by the European Commission, ataluren is still on the market in European countries where it was marketed, but it is expected to be taken off the market.

This publication gives a perspective of clinicians prescribing ataluren to Duchenne patients. A Delphi method was used, first with 12 expert clinicians looking after >30 Duchenne patients and prescribing ataluren to 1-10 patients each.

From these interviews, 42 consensus statements were distilled, and a second group of clinicians with Duchenne expertise (neurologists, pediatric neurologists, and pediatricians) were asked to vote on whether they agreed with these statements.

This was the case for 41/42 statements. Note that statements involved general statements on Duchenne (e.g., the speed of progression varies between patients) and ataluren-related statements (treating earlier with ataluren will have a larger impact on delay in muscle decline).

The panel agreed that ataluren is expected to delay the loss of ambulation and reduce scoliosis development. A very important (not ataluren related) statement is that there is life beyond loss of ambulation. I think this is a very important message.

Many trials focus on ambulatory patients, which may give the impression that beyond the loss of ambulation, there is nothing to rescue, while instead arm function, respiratory function, and cardiac function are still relatively good at the time of loss of ambulation.

The statement on which there was no consensus was whether ataluren has an effect on delaying muscle decline regardless of ambulatory status. This may be related to the indication (ambulatory patients). Clinicians agreed ataluren treatment should continue beyond loss of ambulation.

Clinicians agreed ataluren treatment likely maintained pulmonary function & most patients die due to loss of pulmonary & heart function. The tolerability of ataluren was seen as very good. Finally, experts agreed the real-world evidence was more convincing than the trial data.

Authors discuss that ataluren is a disease-modifying treatment and not a cure and that it delays muscle loss so treatment should continue as long as there is muscle left. They outline also limitations: there was a 4-point scale for agreeing and no neutral option.

This may have resulted in a bias towards agreement. Also, the clinician perspective did not always match the literature: clinicians expected ataluren to prevent scoliosis formation, while there is no evidence of this reported in literature.

Finally, due to GDPR, authors could not check whether the clinicians involved in the interviews were also involved in the votes on the statements. Retrospective checking revealed this to be the case for at least 4 of the clinicians.

The study was funded by PTC, but it was independently done without the involvement of PTC. We will have to wait and see what happens in the EU if ataluren is taken off the market. Hopefully, patient trajectories will be followed once patients are off treatment.