#apaperaday: Evolving Role of Viltolarsen for Treatment of Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Evolving Role of Viltolarsen for Treatment of Duchenne Muscular Dystrophy

Today’s pick is a perspective on the role of viltolarsen for treatment of Duchenne by Vincik et al in Advanced Therapies. I thought it would be an in depth review with critical feedback by the authors, but it is a summation of results. DOI: 10.1007/s12325-024-02801-4

Authors introduce Duchenne and how exon skipping works. I disagree with their explanation (skipping the exon that causes the frame shift –> the DELETION/mutation causes the frame shift, not the exons that are left. You skip an exon to restore the frame..

also, sometimes you skip the exon before the deletion, where you could argue the frame shift has not happened yet, but by doing so you prevent the frameshift for the exon after the deletion). Authors point out that Duchenne is a globally occurring disease.

The incidence seems to be 1 in 10000 newborns (1 in 5000 boys) around the world. There is no neonatal screening yet. Authors explain about the symptoms and that the care aims to manage the disease by addressing the symptoms with orthopedics, physiotherapy and steroids.

In the USA 5 drugs that aim to restore dystrophin are approved: elevidys and 4 PMOs. The paper focuses on one of these: viltolarsen, which targets exon 53. The approval of all FDA approved dystrophin restoring drugs was based on dystrophin restoration.

Additional studies to confirm efficacy are ongoing. Authors outline that the cost of viltolarsen is about 600k $ per year for a 25 kg patient. So far the treatment is tolerated well by patients with limited side effects, mainly injection reactions due to weekly IV dosing.

Notably upper respiratory infections are seen as a side effect in 63% of patients. I do not know whether this is drug related or whether this just happens naturally (I currently have a cold and probably have one every year so I do not think this is a drug related side effect).

Another PMO for exon 53 is approved as well in the USA: golodirsen. Authors explain that viltolarsen has better protein binding capacity and therefore is cleared less quickly from the serum than golodirsen. Both compounds are excreted primarily via urine

Authors mention that effects on pregnant women and lactating women have not been tested. Note that Duchenne is an X-linked disease and that female dystrophinopathy where exon skipping would be an option is extremely rare. So this information is of little relevance I think.

Authors outline the development of viltolarsen: in vitro optimization in control and patient cells, then a phase 1 study with 10 patients between 6 and 16 years with 1.25, 5 and 20 mg/kg. Safety was OK and 70-80% of viltolarsen was excreted via urine within 24 hours.

As the highest dose was not that efficient with regards to dystrophin restoration, in a follow up study, 40 and 80 mg/kg doses were tested in 16 patients aged 5-18. Here increased dystrophin levels were seen after 24 weeks of weekly IV treatment.

No functional effects could be observed, but this is also not expected in 6 months especially with such a large variation in age. In a phase 2 trial, 16 patients aged 4-9 years were treated with 40 and 80 mg/kg or placebo for 4 weeks, followed by 20 weeks open label extension

This resulted in 5-6% increase in dystrophin expression and better function than a natural history comparator. After 192 weeks of open label treatment it was shown that treatment was safe and function was still better than a natural history control.

Here I was hoping authors to be somewhat critical pointing out that the dystrophin levels reported here cannot be directly compared to those reported for the Sarepta PMOs and pointing out the caveats of natural history comparators. For further reading see:  Letter to the Editor: In response to P.R. Clemens et al., Efficacy and Safety of Viltolarsen in Boys with Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study, and Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Authors explain that results from the phase 3 confirmatory study (placebo-controlled comparison of functional effects) are expected next year, as the study is expected to be completed in December 2024. Until then we can only be cautiously optimistic about efficacy.

The last sentence is my own addition. As mentioned, authors are not very critical and outline that the results suggest that treatment will create a milder presentation of symptoms. Of course we all hope for this, but we have to be cautious to not overinterpret the data we have.

And we have to present the evidence as is: we know it increases dystrophin levels, we do not have hard data to show that it slows down disease progression. We can be hopeful but have to be aware of what we do not know yet.