Prof. Annemieke Aartsma-Rus is taking on a challenge by reading and commenting on a paper a day. She shares her insights, findings and thoughts via her @oligogirl Twitter account. See below the overview of June 2022.
Prof. Aartsma-Rus reads and comments on the paper titled: Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy. #apaperaday Today’s (or rather yesterday’s) pick is from @journal_nd by Paula Clemens et al on the 109 week treatment effects of viltolarsen. Doi 10.3233/JND-220811
Viltolarsen is a PMO oligonucleotide targeting dystrophin exon 53. Skipping exon 53 applies to 10% of Duchenne patients. However both exon 53 skipping and exon 51 skipping (for which eteplirsen is approved) apply to exon 52 deletions. This deletion occurs in 2% of patients. This is why skipping exon 51 (14% of patients) & skipping exon 53 (10% of patients) together applies to 22% of patients. The 2% of exon 52 deletions is in both percentages. Back to the paper: viltolarsen was approved by FDA based on a study where 16 patients were treated 24 weeks.
This was safe for both doses (weekly 40 or 80 mg/kg) and resulted in ~5% of dystrophin. All 16 patients were on steroids and all were offered the possibility to continue treatment in a long term extension study. All accepted and have now been treated for 109 weeks or more.
Patients were 4,3 – 9,8 years at the start of the study and were followed every 12 weeks. As the treatment is open label the controls are from a natural history study where patients were matched for baseline characteristics. 9 had a 53 skippable mutation, 56 another mutation. patients with mutations known to lead to slower disease progression (44 skippable mutations & deletions of exon 3-7) were excluded from the comparator group. For timed function tests the treated patients were stable for time to rise and time to run 10m while controls declined.
No differences were seen for stair climbing tests. Due to limited availability of NSAA and 6MWT data for the controls this comparison could not be made. Viltolarsen was well tolerated with no severe side effects. Treatment related side effects were due to intravenous infusions. For the rest side effects were disease related (fracture, rhabdomyolysis) or life related (insect bite, common cold). Authors discuss this data suggests a slower disease progression as was also suggested for natural history comparisons for golodirsen (53 skip) and eteplirsen.
Authors mention limitations such as a small number of patients, the lack of placebo data and the inability to compare for NSAA. They outline that previous analyses of C-TAP has shown that natural history and placebo are similar for 6MWT and NSAA. However it is not yet knows if that also applies to the timed functions used here. A placebo controlled study with viltolarsen (RACER53) is currently ongoing to elucidate the effect of viltolarsen in ambulatory patients. Stay tuned
Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK).
Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy. In addition, in collaborative efforts she aims to bridge the gap between different stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.
In 2013 she was elected a member of the junior section of the Dutch Royal Academy of Sciences (KNAW), which consists of what are considered the top 50 scientists in the Netherlands under 45. From 2015 to 2022, she was selected as the most influential scientist in Duchenne muscular dystrophy by Expertscape.