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#apaperaday: Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy

#apaperaday from #Myologie2024 in Paris. Today’s pick is from @journal_nd

by Zaidman et al on the management of adverse events after treatment with delandistrogene moxeparvovec (aka elevidys) in anticipation of the gene therapy panel coming up later today. Doi 10.3233/JND-230185

Duchenne is caused by lack of dystrophin, which has a crucial function in stabilizing muscles during contraction. Adding a functional gene is a therapeutic option. However the only virus able to infect muscle efficiently is AAV and this has a small capacity for genetic content

Thus microdystrophins were engineered which contain the most crucial domains and are partially functional in animal models. Microdystrophin AAV74 is now approved in the USA for 4-5 year old patients with a mutation not involving exon 8-9.

This paper reports on how to manage the side effects seen after AAV gene therapy treatment with this construct (Elevidys). It is the result of an iterative approach with experts who came to a consensus after two rounds of questionnaires and an in person meeting

Note that this Delphi consensus process took place before elevidys was approved. So the management suggestions are based on adverse events seen in trials and not commercial treatment. The experts involved were from neurology, liver and GI fields

They had hands on experience with managing patients during and after elevidys treatment. The protocol of treatment assumed involved pretreatment with steroids up to 2 months after at 1 mg/kg on top of used doses (maximum of 60 mg)

Experts achieved consensus on 129/146 statements. This included doing a physical examination and blood work 1 month and 2 days before the treatment. Extra focus should be on liver function abdominal excluding ongoing infections just before treatment

Expected side effects including vomiting and potential iv treatment with steroids when that happens need to be well communicated with families. Patients should be monitored after treatment for 2-4 hours – so far no acute infusion reactions have been observed

As GI side effects are expected antinausea and vomiting medication can be given. There was no consensus on whether you give this prophylactically. Liver damage is often seen. When this is moderate or severe steroid dosing needs to be increased and blood lab work needs to be done

If steroids treatment does not reduce liver pathology the patient needs to be admitted to hospital and function carefully monitored. Myocarditis can occur, if this leads to symptoms one needs to check for complement activation and when in doubt patient should be hospitalized

When steroid treatment is not improving things IVig treatment should be considered. When the myocarditis is auto-immune mediated (against microdystrophin) patients should be monitored carefully and if needed immune suppression or IVig provided

Authors point out no results have been published on the antidystrophin immune response but that it has resulted in respiratory and bulbar weakness and can involve skeletal muscle and heart. Authors discuss that 96% of patients had adverse events of which 86% treatment related

Most are mild or moderate but more severe events have been reported. 1/3 have liver damage while only 1% had an autoimmune response to dystrophin (which is also related to the mutation). Most events occur within 1 month

Authors outline that monitoring liver damage should take into account CK levels: when CK is high AST and ALT will likely be from muscle. When CK goes down but AST and ALT do not most likely they derive from muscle.

Authors did not discuss the TMA response as this is seen for AAV9 and not for AAV74. Authors outline limitations such as that all experts were from the USA and that no immunologist was involved. With the approval of elevidys we need these management guidelines

Furthermore, we will need to reevaluate regularly when more patients are treated in a commercial setting rather than within the limited settings of a clinical trial.