#apaperaday: Pharmacological Profile of Viltolarsen for the Treatment of Duchenne Muscular Dystrophy: A Japanese Experience

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Pharmacological Profile of Viltolarsen for the Treatment of Duchenne Muscular Dystrophy: A Japanese Experience.

Today’s pick is from clinical pharmacology: advances and applications on viltolarsen by Roshmi and Prof. Toshi Yokota DOI 10.2147/cpaa.5288842

Viltolarsen is an exon 53 skipping phosphorodiamidate morpholino oligomer (PMO) that can restore dystrophin production for ~8% of Duchenne patients. It is approved in Japan and the USA. In this paper authors reflect on the clinical development and the Japanese contribution to this.

Viltolarsen is a 21mer (golodirsen – also an FDA approved exon 53 skipping PMO – is a 25 mer). Viltolarsen dose is 80 mg/kg, while golodirsen dose is 30 mg/kg. However, because viltolarsen is shorter, the actual per molecule dose is 3.1 times more than for golodirsen.

Golodirsen & viltolarsen target the same sequence in exon 53. The safety profile of viltolarsen based on clinical trial findings is good. Adverse events were reported, but I thing many are disease (cardiac problems) or life (infections) related rather than treatment related.

It is recommended to monitor kidney function in treated patients, as renal toxicity was seen in animal models (also for golodirsen as it happens). So far no kidney toxicity has been seen in clinical trials or patients treated with viltolarsen. Like all PMOs, viltolarsen is cleared quickly via the urine (~80% within 24 hours). A clinical trial in Japan with low doses up to 20 mg/kg showed exon skipping in all treated patients, but dystrophin restoration only for 1 (treated with the highest absolute dose).

Two follow up trials were done in Japan and USA/Canada with higher doses 40 and 80 mg/kg. The trial in Japan showed 2.8% dystrophin, while the trial in USA/Canada ~5.8% dystrophin increased. The Japanese study showed a slower decline in motor function than natural history. USA/Canada study showed improvement in motor function compared to natural history. However, the trials were short and there was no placebo group so this data should be interpreted with caution.

The effects of longer term treatment are currently being evaluated in an open label extension study and a placebo controlled trial. However, viltolarsen is already approved in Japan (since March 2020) and USA (since August 2020).

I think levels of 5% of dystrophin should have some functional effects – really hope the placebo controlled trial will confirm this. Note that you cannot compare 5% dystrophin restoration after PMO treatment with Becker patients who express 5% dystrophin since birth.

Finally, the authors outline the ways Japanese researchers contributed to the exon skipping therapy development for Duchenne: they were one of the pioneers for early studies, they treated the first patient systemically with an ASO targeting exon 19 they showed systemic PMO treatment of a dog model restored dystrophin & finally they built a mutation registry Remudy (TREAT-NMD affiliated) that now has 2030 patients! This registry also arranges genetic testing which is not covered by public health insurance in Japan.

Authors also outline limitations (which I commend since @ToshifumiYokota was one of the Japanese researchers involved in exon skipping therapy development – always good to be critical also of your own work/approach)

Costs. Viltolarsen is expensive (~600,000$ per year for a patient of 25 kg). If health insurance does not cover it, this likely precludes treatment for most families. So far trials were short term with only young patients. More, longer term studies are needed (and ongoing)

PMOs do not reach the heart while cardiac complications are the major cause of death in patients. The approach is mutation specific. There are still many patients for which no dystrophin restoring therapy is available. So as always more work is needed. Kudos to the authors and I recommend this paper for everyone wanting a quick overview of viltolarsen therapy development for Duchenne.

I want to highlight the importance of patient registries for mutation specific approaches. The Remudy registry is a good example, but similar registries are needed around the world. Many are now available, federated to the TREAT-NMD global registry with oversight from TGDOC.

 

Pictures by Annemieke, used with permission.