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#apaperaday: Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Perspectives on the advances in the pharmacotherapeutic management of Duchenne muscular dystrophy

Today’s pick is from ExpertOption in pharmacotherapy by Kracht et al on pharmacotherapy option in Duchenne DOI: 10.1080/14656566.2022.2130246

Duchenne is a severe progressive muscle wasting disease. The review paper focuses on approved treatments for Duchenne in the USA. Glucocorticosteroids have been used off-label to treat Duchenne patients. They slow down disease progression.

This results in a later loss of ambulation, later need for assisted ventilation, later development of cardiomyopathy and reduction of the percentage of patients requiring scoliosis surgery. Steroids act by binding to the glucocorticoid receptor (GR).

Authors outline that deflazacort is approved for use in Duchenne in the USA, while prednisone is used off label. They outline that perhaps deflazacort has more functional effects – we’ve gone over this multiple times already in #apaperaday, but here we go again:

When you compare deflazacort and prednisone, you should compare daily use of both or intermittent use of both. If you compare daily use of both the FOR-DMD study found no difference functionally. Deflazacort is rarely used in an intermittent regimen…

Prednisone is used both daily and intermittently, where daily leads to better functional effects. Thus when you compare deflazacort and prednisone, you compare mostly daily deflazacort with ~50:50 daily and intermittent prednisone –> not a fair comparison.

Authors outline that steroid use leads to side effects, as glucocorticosteroids (GC) also bind the mineralcorticoid receptor (MR) as an agonist. Vamorolone is an alternative to GC that inhibits inflammation and are an MR antagonist.

As such you expect less side effects. Preliminary results suggest that the functional effects are comparable for GC and vamorolone, while side effects may be less for vamorolone. HOWEVER, vamorolone has so far only been used in short term studies.

Authors also discuss the results of edasalonexent – this is a compound that inhibits inflammation and this compound did not slow down disease progression in Duchenne, thus highlighting again that GC do more than only inhibiting inflammation in Duchenne.

Another hint was that GC also improve function in c.elegans worms without a functional dystrophin protein. This worm does not have an immune system, so GC treatment cannot have exerted its beneficial effect only through anti-inflammatory effects in that model.

Authors then discuss the for exon skipping compounds that were approved by FDA: eteplirsen, golodirsen, casimersen and viltolarsen. They stress the eteplirsen approval was controversial and that the costs of the compounds are high ($300,000/year for eteplirsen…

$300,000/year for a 20 kg patient for golodirsen, $733,000/year for a 30 kg patient for viltolarsen & up to 1 million/year for casimersen. It is difficult to compare the costs like this (some with weight, some without, some up to some x), but it is clear the drugs are expensive

The authors stress that the question is how much dystrophin is needed and whether the low levels restored by the exon skipping compounds is enough to slow disease progression. I do not know the answer. It is clear there is room for improvement though.

Authors very briefly highlight some of the new exon skipping compounds in clinical development – they also omit a lot. Same for compounds aimed at improving muscle mass. They seem to be a random selection and they are discussed very succinctly

For those reading the paper, some additions on the selected compounds: the phase 3 trial results for givinostat are in and Italfarmaco will go for marketing authorization in the EU and the USA. Idebenone development was stopped after the interim analysis.

Ataluren was tested in a new phase 3 trial and PTC will go for marketing authorization in the EU and the USA (they have conditional authorization already in the EU). In the expert opinion section authors indicated that crispr/cas9 could work for any mutation…

I disagree – first the approach is mutation specific, so to make it work for the mutation it applies to you would need to develop different crisprs. Secondly, there are mutations for which it will not work as yet (e.g. those not eligible to exon skipping).

I do agree with the final statement of the authors though: in the future likely patients will all get a personalized combination therapy based on what is available for them with regards to dystrophin restoring and muscle sparing compounds.

Personally, I do not think this is the best review…the problem is that the authors probably had a maximum number of words and they now tried to squeeze in everything they could, meaning there was little space to actually provide context. Focus would have been better.