John Brandsema, MD: When we’re thinking about treatment options for SMA [spinal muscle atrophy], it depends on the age of the patient and their severity in terms of what you might be considering based on the FDA label. We have nusinersen available for all people with SMA regardless of their age, risdiplam is available for anybody over 2 months of age, and gene transfer is available for anybody under 2 years of age based on the FDA labeling for those 3 medications. If you have somebody under age 2 but above 2 months of age, then you have 3 options to use. But if your patient is above 2 years of age, and you’re considering treatment for their SMA, then you’re deciding between nusinersen, risdiplam, or nothing.
The challenges in terms of implementing these therapies are protean for our teams and the families involved. These are not straightforward in terms of treatments. Nusinersen requires serial lumbar punctures for delivery, which is a big ask for somebody who is living with weakness because they’re often not comfortable being positioned for the procedure itself. If they have any degree of scoliosis or especially if they have spinal hardware, it is difficult to get access to the intrathecal space with the medication nusinersen sometimes. We’ve sorted this out for our patients in 2016 with the availability: anybody who wanted access to nusinersen at our center [Children’s Hospital of Philadelphia] was able to start treatment successfully with some creative approaches to intrathecal injection.
In terms of gene transfer, 1 of the practical barriers is simply age based on the label. If you’re above 2 years of age, then it’s not currently available to you. There is ongoing research that is looking at dosing older patients. The challenge there is that the intravenous delivery of gene therapy that is approved becomes unsafe at a certain point because of the sheer burden of viral vector that you’re giving as the patient gets bigger, and it starts to become toxic to other tissues.
The thought is that there’s a point at which you need to start thinking about giving the therapy directly intrathecally the way that we do for nusinersen through lumbar puncture. In that situation, the medication gets just to the motor neuron itself, which is the target where most of the pathology of this disease is going on.
However, the question remains: how much does the SMN deficiency affect the rest of the body in terms of what’s going on in other tissues that are deficient in SMN. Both nusinersen and gene-transfer therapy may get somewhat to the systemic circulation, but the option that does that most effectively is risdiplam, which is the small molecule that can be given orally for this disease or through a G-tube [gastrostomy tube] if the patient cannot swallow. That small-molecule therapy, however, is unique because it needs to be given every day. It’s a daily medication with a short half-life.
You can imagine the compliance issues that we’re considering now that this has been was approved in mid-2020 in the United States. If a patient goes on a trip and forgets their medication at home, if they are vomiting and can’t tolerate po [by mouth], or if the patient is a teenager and thinks that they’re too cool for medication and doesn’t tell their parents that they’ve stopped taking it, what is the amount of time that the motor neurons still have resilience in someone who’s been taking treatment before the motor neurons start to irreversibly die?
It’s the same issue in epilepsy. If somebody comes into the emergency department having a seizure, then you know they’ve not been taking their medication. If their level is low, then you can say, “You really need to take your medication” and get them started again. Hopefully there’s not a bad outcome for that person, but if there’s no forgiveness, if you’re not taking your medication, then your motor neurons are going to die, and we can’t get them back.
This is a huge concern regarding compliance with daily treatment. At least with nusinersen, we know when people are coming for their doses and when they’re overdue, and we can start interacting with families or patients about that. With risdiplam, there’s a lot of trust involved, and it’s a little nerve-racking for the provider. We want to keep a close relationship with people and ensure that they’re getting the treatment they need.
Consultant: Alexion, Audentes, AveXis, Biogen, Cytokinetics, Genentech, Momenta, NS Pharma, PTC Therapeutics, Sarepta, Scholar Rock, WaVE
Research support: Alexion, Astellas, AveXis, Biogen, CSL Behring, Cytokinetics, Fibrogen, Genentech, Pfizer, PTC Therapeutics, Sarepta, Summit, WaVE
Speaker: AveXis and Biogen