#apaperaday: Clinician Perspectives of Gene Therapy as a Treatment Option for Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Clinician Perspectives of Gene Therapy as a Treatment Option for Duchenne Muscular Dystrophy

Today’s pick is from @journal_nd by Cope et al on the clinician perspective of gene therapy for Duchenne patients. The study was done before elevidys was approved, but findings are still very relevant! DOI: 10.3233/JND-240033

Duchenne is caused by lack of dystrophin, so adding a gene copy from which dystrophin can be produced should have a treatment effect. However, only AAV (adeno associated virus) can deliver genes efficiently to skeletal muscle and heart, and the dystrophin gene is too big.

So, instead micro-dystrophins are delivered, which are about 1/3 of the full length size and also significantly shorter than the internally deleted dystrophins we know are functional that are found in Becker patients. So this will not be a cure.

Authors outline that clinicians have the primary responsibility to inform patients about gene therapy when it becomes available (now the case in the USA) and here wanted to study the understanding, expectations and experiences of clinicians with gene therapy discussions.

16 clinicians, 8 from the UK and 8 from the USA were participating, 8 males and 8 females. Clinicians saw 20-200 Duchenne patients annually. Only 1 had never participated in a  clinical trial and 5 had participating in clinical trials for gene therapy.

Most clinicians thought they had a good understanding of gene therapy, but from the quotes the authors list, it is clear that there are gaps, e.g. clinicians thought the micro-dystrophin will replace the mutated dystrophin gene in the DNA. This is not what happens:

the micro-dystrophin gene is added to the cells and exists as a separate DNA entity in the cell. The confusion is probably brought by people calling gene addition gene replacement therapy. Clinicians also had questions about gene therapy that are rather pertinent ????

When asked about expectations, some clinicians were very optimistic, some very skeptical, but most were cautiously optimistic (I am not a clinician, but I would be in the latter group :)). Most are aware of the limitations (micro-dystrophin, so only a partial treatment effect is expected).

Multiple clinicians expected a cure and/or lifelong treatment effect. The latter is unlikely, as micro-dystrophin will dilute with muscle turnover, which will happen in Duchenne patients since micro-dystrophin is not fully functional.

Some expected a switch to Becker—also not likely, as micro-dystrophin is significantly shorter. Some expected it to prevent cardiomyopathy. This is also not likely, as Becker patients also have heart problems, and micro-dystrophin is less functional than Becker dystrophin.

Clinicians expected a better treatment response when treatment was done earlier. They wanted better outcome measures, as micro-dystrophin was not relevant to them or to patients in daily life.

Most clinicians were aware of the risks, mentioning potential immune responses, liver damage, heart problems, and kidney toxicity. Some expected only mild side effects, while others mentioned the risk of death (which sadly has happened twice now).

Some clinicians said that death would be an acceptable risk (but if you overestimate the treatment effects, what becomes acceptable will shift as well…). Others said death was not acceptable, stating, “Duchenne is a fatal disease, but not an immediately fatal disease.”

Most clinicians had spoken with Duchenne families about gene therapy during clinic visits. However, 50% said that in reality, there was not enough time to discuss this properly. For implementation, U.S. clinicians expected earlier availability than those in the UK (which has been correct).

Clinicians worried about the costs—not just of the gene therapy product, but also the costs of infusions, hospitalization, and other monitoring. U.S. clinicians also worried about access and reimbursement. Logistics were a concern for many:

The scale of DMD gene therapy is larger than for SMA with Zolgensma, making things more challenging. But clinicians noted we could learn from the Zolgensma experience. Some expected the same treatment effect for Duchenne, but authors discuss this is not realistic. Zolgensma has the fully functional gene code, while micro-dystrophin is only partially functional. Furthermore, skeletal muscle is much more abundant than motor neurons. Clinicians also wanted to better understand the risks involved.

This includes the uncertainty of how much benefit gene therapy will bring. Sadly, by granting full approval to Elevidys based on a trial that did not show functional effects, the FDA created a situation where evidence for treatment effects in ambulant patients does not need to be provided.

I am not saying I don’t think micro-dystrophin works—the clinical trial was likely too short to pick up a treatment effect. However, it now falls to clinicians and the field to gather this evidence post-approval, rather than the sponsor pre-approval.

Authors also discuss the risk of death, citing studies where families suggested a minimal acceptable risk of death to be 3.5%. I must stress that the two unfortunate deaths were associated with AAV9, not with Elevidys (AAV74).

There are knowledge gaps about what gene therapy is and what can be expected from micro-dystrophin. Mor  education is needed. I agree and hope that TREAT-NMD masterclasses, as well as the Parent Project MD and World Duchenne care conferences, have helped in this regard.

Authors also mention that this set of 16 clinicians was a convenience sample and that these clinicians may have been better informed than the average clinician managing Duchenne patients. I agree this is likely true and hope education will help address this.

Families face a tough choice when deciding whether to go for gene therapy or not: there is no undo button, and it cannot be repeated. They need realistic information about the expected benefits and side effects in order to make an informed decision.

Kudos to the authors for doing this work and sharing it with the community. Full disclosure: I was the associate editor handling this publication, but was, of course, helped by expert reviewers when making editorial decisions.