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#apaperaday: Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study

Today’s pick is by Clemens et al from Journal of Neuromuscular Disease on the 4 year open label extension data for open label phase of viltolarsen. DOI: 10.3233/JND-221656. Exon skipping aims to allow Duchenne patients to produce Beckertype, partially functional dystrophin proteins. The approach is mutation specific and multiple exon skipping drugs are approved in the USA for exon 45 51 & 53.

Viltolarsen induces exon 53 skipping, which applies to 10% of patients. This includes the 2% of patients with a deletion of exon 52 where exon 51 skipping also would restore the genetic code. Viltolarsen is approved in the US and Japan based on a 24 week open label phase 2 trial.

Here, eligible Duchenne patients were treated weekly with 40 of 80 mg/kg. This resulted in ~5-6% dystrophin in a biopsy. Functional effects still have to be confirmed in a placebo controlled trial that is ongoing.

All 16 patients from the the 24 week study were enrolled in an open label study receiving weekly doses of 40 or 80 mg/kg. Between week 178 and 197 patients who received 40 mg/kg were swapped to the higher 80 mg/kg dose.

Note that viltolarsen is smaller than golodirsen so 80 mg/kg is close to 4 times more ASO molecules than 30 mg/kg golodirsen. Functional analyses were done every 12 weeks & compared to natural history data from age, bmi, steroid & baseline function matched patients from CINRG.

For the time to stand and time to walk/run 10 meter the viltolarsen treated patients improved for 2 years and then started to decline, but slower than the natural history group. For the time to climb 4 stairs no difference was seen between viltolarsen and natural history.

For NSAA & 6 minute walk test limited data for the natural history group was available so no comparison could be made. However NSAA & 6 MWT distance was stable for the viltolarsen group for 4 years. Side effects were mild, treatment related side effects: injection site reactions.

Severe side effects were not treatment related (eg fractures due to falls). Authors discuss the limitations of this study: the number is small and there is no placebo group. However results so far are encouraging with regards to safety and function.

The fact that differences are seen for timed function tests but not for stair climbing is not surprising for the mouse doctor. In mice we see that a small amount of dystrophin improves function but that higher levels are needed to increase strength.

The stair climb test has a stronger strength component than the timed function test so maybe the same goes for humans. Encouraging results for now, but sadly encouraging in early phase does not always deliver in the Duchenne field. Learned to be cautious.So we have to wait for the results of the ongoing placebo controlled trial (Racer-53) to be able to draw conclusions about functional efficacy.