Prof. Annemieke Aartsma-Rus’ personal highlights of the XIX International Conference on Duchenne and Becker Muscular Dystrophy organized by Duchenne Parent Project Italy.
I am still amazed about the progress made for AAV microdystrophin gene therapy and that phase 3 placebo-controlled trials are ongoing. However, this is not without risk, severe side effects have been reported for some patients and one patient passed away in a Pfizer trial.
This was a non-ambulant patient. It is now known that he had heart failure and dehydration – this trial is on hold. The phase 3 trial in ambulant patients is not. The names of the AAV gene therapy products are very complex: fordadistrogene movaparvovec & delandistrognee moxeparvovec
Other learnings: companies are now excluding patients with mutations in the N-terminal domain due to possible immunity against the micro-dystrophin for these patients. Solid is working on a new AAV microdystrophin in parallel with their current trial programme.
Kevin Flanigan reported on using AAV to deliver an antisense gene for exon 2 skipping. The findings in a 7 mo. old patient (no adverse events & a major drop in CK are promising) – cautiously optimistic. Audentes/Astellas is developing this approach for exon 45/51/53 skipping
For the exon skipping session many confirmatory trials are ongoing to prove that FDA approved compounds (eteplirsen, golodirsen, casimersen, viltolarsen) indeed slow down disease progression. Sarepta is also running a high dose eteplirsen trial now (144 weeks in 152 patients)
SRP50-51 (peptide-conjugated eteplirsen) phase 2 trial from Sarepta is ongoing. Hypomagnesemia is observed in treated patients, but can be treated with supplementation. PepGen is preparing exon 53 trials with peptide conjugated morpholino – they also observed hypoMG in animals.
Dyne and Avidity are both preparing for trials for later this year with antibody mediated delivery of exon skipping ASOs. Dyne uses a short antibody fragment, and focuses on exon 51. Avidity uses a whole antibody and targets exon 44. Antibodies target transferrin receptor.
Highlights for the improving muscle quality sessions for Duchenne and Becker. The Italfarmaco trial for Becker did not show reduction in fibrosis for treated patients, but did show a reduced fat fraction and improved contractile area. Results of Duchenne trial expected this June.
Vamorolone trials are ongoing in Duchenne with more results expected in the coming year. A trial for Becker with vamorolone in Italy and the USA is planned too. Edgewise prepares for a phase 2 trial in Becker to improve muscle fibre stability.
Antisense prepares an ASO treatment targeting T-cells (ATL1102) as an approach to improve muscle quality. This involves weekly subcutaneous injections. Personally I would prefer vamorolone (oral treatment) provided that efficacies are confirmed for both & similar (unsure yet).
Finally, Capricor aims to improve muscle quality using stem cells that produce growth factors that are protective for muscle and heart. They are preparing for a phase 3 clinical trial in the USA and are now collaborating with NS Pharma.