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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

I appreciate authors sharing this case and while it is sad the treatment had to be stopped and the patient now cannot be retreated/given the rest of the dose, I am glad the patient is otherwise fine.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

They also considered the ondansetron, but that has rarely led to shock and also was given after initial symptoms started happening. To reduce the risk for anaphylaxis authors now pretreat patients undergoing Elevidys treatment with oral anti-allergens.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

The patient now has antibodies to AAV so retreatment is not feasible. Authors speculate the reaction was to poloxamer 188, an excipient of the gene therapy product.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

Studies were done, but no IgE was detected. Authors speculate the anaphylaxis might have been triggered by a toll like receptor activation or complement cascade activation. If possible, the guidelines (see yesterday’s #apaperaday) suggest restarting treatment, but this was not possible/safe here

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

Then he developed the anaphylaxis, with hives, angioedema, respiratory distress etc. He was treated with epinephrine and other anti anaphylaxis treatments and symptoms improved. He could be discharged after 4 hours.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

His AAV antibody titer was <1:400 and he had no history of allergies. During the infusion (1/7th into it) his heart rate and blood pressure suddenly went up, and he started vomiting. Infusion was stopped and for the nausea he was treated with ondansetron.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

A follow up on yesterday’s guidelines but now with a more detailed focus on a single case who developed anaphylaxis. The patient has a nonsense mutation in exon 70, and had been on steroids since 3 years 9 months. He was treated when he was 5.5 years.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 1d

#apaperaday @worldmusclesociety.org #WMS2025 themed still and now coming to you from Vienna. Today’s pick is a case report by Laine et al published in Muscle & Nerve about a patient who developed an anaphylactic shock during Elevidys treatment. DOI: 10.1002/mus.70029

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Only then can we fill the gaps of the current unknowns. More work is needed to assess who is at risk for which side effect & why. This would facilitate risk evaluation and also allow more optimal monitoring. Lots still to do! But I appreciate authors produce guidelines based on current information.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

So far auto-immune responses have not been reported for these. Authors stress the importance of reporting side effects in the FDA database and call for a joint effort to collect long term safety and efficacy data.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Not all patients with such deletion will develop an auto-immune response, but given the risks and consequences, all patients with relevant deletions are now excluded from treatment. Authors outline that patients with deletions covering other parts of the micro-dystrophin may also be at risk.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

For patients with a deletion involving exons 8 and 9 are at risk of developing an auto-immune response to the micro-dystrophin. This leads to myocarditis and rhabdomyolysis and can be very severe and life threatening. Patients lose muscle tissue and function due to this.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Thrombotic microangiopathy and related kidney problems have been reported but so far only for AAV9. Here treatment involves complement blockers and immune suppression. For AAV74 and AAV9 there is also a risk for myocarditis and liver failure. Proactive monitoring is important.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Authors stress that longterm safety and efficacy data are lacking and that data collection for longterm monitoring are crucial. They also stress the risk for severe side effects, which can even include death. A plan for autopsy needs to be discussed with the family before treatment.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

They also need to know when to contact the hospital or ER. Treatment takes usually a whole day (therapy preparation and infusion). After treatment immediate and later stage immune responses will occur to the virus capsids. Steroids can be weaned after ~8 weeks if all goes well.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Authors stress that there is no evidence on polytherapy otherwise and that this information needs to be collected over time. The authors list the many predosing tests that need to take place (Table 3) and also stress that patients and families need to be aware of the risks.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Eg. in clinical trials no patients with an ejection fraction <40% have been included. The steroid dose is increased prior to treatment, which in itself can also induce site effects. Patients who are using givinostat should temporarily stop treatment (due to the platelet drop side effect).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Before treatment patients must be in good health, have no antibodies to AAV (based on a recent test), vaccinations must be up to date. Especially when patients are non ambulant, cardiorespiratory function needs to be taken into account.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Authors point out that the monitoring requirements can be a burden for the clinical team (especially when patients 'stack' in a center after being treated consecutively). They also mention the challenge of costs: since this is hefty, institutes cannot buffer the costs pending insurance sign off.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Secondly treatment and monitoring requires a multidisciplinary team and a monitoring plan should be in place. Follow up with be long and burdensome and families must be aware of this and able to commit. They must also be aware what actions will be taken if there are severe side effects.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Authors here provide guidelines and considerations. For details I defer you to the document but I'll stress some pertinent points of the document. First, treatment should only be done by teams and in centers with experience in Duchenne management.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

So while over 1000 patients now have been treated with a form of AAV micro-dystrophin gene therapy there is a lot we do not know yet about the long and short term safety, but also about the efficacy (the treatment was approved for ambulant patients despite the trial missing its primary endpoint).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

Especially for non ambulant patients there is less evidence, and sadly recently 2 non ambulant patients died from liver failure after elevidys treatment, and earlier 3 patients (2 non ambulant) died after treatment with fordadistrogene movaparvovec (Pfizer's gene therapy).

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

The manuscript is written by a plethora of clinical Duchenne experts in the USA and patient representatives from Muscular Dystrophy Association and Parent Project Muscular Dystrophy. The document stresses that gene therapy for muscle diseases is in its early days.

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Annemieke Aartsma-Rus @oligogirl.bsky.social · 2d

#apaperaday is again #WMS2025 @worldmusclesociety.org conference themed with a pick from the society journal Neuromuscular Disorders, by Wolff et al on consensus recommendations and considerations for gene therapy treatment in Duchenne patients. Doi 10.1016/j.nmd.2025.106208.

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