#apaperaday: Phase I/II Trial of Brogidirsen: Dual-Targeting Antisense Oligonucleotides for Exon 44 Skipping in Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Phase I/II Trial of Brogidirsen: Dual-Targeting Antisense Oligonucleotides for Exon 44 Skipping in Duchenne Muscular Dystrophy

I was alerted to this @medrxivpreprint publication by Komaki et al at #AOMC2024 by Yoshitsugu Aoki during his keynote lecture, where he also mentioned results of the exon 44 skipping trial in Japan.

Exon skipping aims to allow Duchenne patients to produce Becker-type, partially functional dystrophins. This uses antisense oligonucleotides (ASO). 4 ASOs are approved by the FDA to skip exon 45, 51, and 53. Here, authors report an exon 44 ASO of the same chemistry (PMO).

Exon 44 skipping would apply to 6% of Duchenne patients. The exon 44 PMO ASO is called brogidirsen and was tested in 6 Japanese Duchenne patients in a dose escalation safety study: 3 patients started at 1.62 mg/kg, towards 40 mg/kg, and 3 at 10 mg/kg to 80 mg/kg per week.

Treatment was safe, with only a few treatment-related adverse events reported (as is the case for the approved PMOs). A biopsy was done, revealing exon 44 skipping before and after treatment (it is known that exon 44 is spontaneously skipped in patients and controls).

dystrophin was detected at baseline for all patients (again as expected), but levels increased with treatment by 10% for 40 mg/kg and 16% for 80 mg/kg (weekly for 24 weeks). Creatine kinase levels in the blood went down, as did other muscle damage markers.

Authors report they tested if brogidirsen increased exon 44 skipping and dystrophin production in cultured cells from patients (urine-derived or biopsy-derived). In the discussion, authors explain this is because for exon 53 skipping with viltolarsen, there was varied response.

For brogidirsen, this did not happen: all patients in the trial responded. Authors also discuss that with the dystrophin levels detected in the patients after treatment, they expect a clinical treatment effect. In the 24 weeks of the trial, patients had stable function.

Authors are cautiously optimistic about this, but for now, the numbers are small and the timeframe is short. They also outline that while all 6 patients responded, this does not mean that all will respond in the future. This will need to be monitored.

Not discussed but on most people’s minds: the avidity results with their exon 44 skipping compound with a transferrin receptor antibody (TRA), which also resulted in large increases in dystrophin expression. Based on brogidirsen, I think this level was not only due to the TRA.

Exon 44 skipping appears to be easier than skipping other exons, probably because it already is skipped spontaneously. This means that the high dystrophin restoration level Avidity reports is not only due to the TRA, but also because exon 44 skipping is ‘just’ more efficient.