Role of Nusinersen in SMA: Efficacy and Treatment Response

John Brandsema, MD: In terms of the efficacy piece, that part has always been interesting to think about from the perspective of pathophysiology of SMA [spinal muscular atrophy]. Obviously, we are not losing motor neurons and then reinnervating every time there is a maintenance dose of this given that is causing people to feel differently. Also, the initial response to nusinersen is variable with patients in terms of how they first start to notice the improvement or stabilization of their disease. You start to think about other ways that the SMN protein is important for the lower motor neurons’ function, whether it would be nerve signaling, transport of proteins along the nerve, or neuromuscular junction integrity. There is even a role for the SMN protein in muscle function itself, whether it is the denervation of the muscle or the way SMN functions in the muscles. That is still being teased out on a basic scientific level. In terms of the efficacy, in general, I think what we have seen across all the development programs is that this disease has different phases to it where, if you have the early onset, severe form, it is easy to see an even less steep decline, or what we hope for, which is stabilization or normal development to allow for improvement on a stabilized background of motor neurons. 

There is a phase for every patient when they have gone through that initial period, and then they are going at a slower pace in terms of how this disease changes. I think that is where some of the challenge of evaluating the higher functioning patients has come through. If you are treating a walker with SMA or a sitter with SMA, those patients will tell you—even in the natural history—that, “I did not notice much over the past year compared to what I was doing a year ago that is different.” You really have to go back 5 or 10 years before you can start to see differences that are meaningful in terms of day-to-day activity for those patients. There is the same issue with our functional scales; if you are trying to measure them, they do not change much in this phase of this disease. It is harder to tease out whether someone is responding to an intervention because you need time to do that. How do you approach that in your clinic [Children’s Hospital Colorado] in terms of deciding whether someone is responding to being treated with nusinersen?

Julie Parsons, MD: My goal is always to have them maintain function. There initially were challenges with insurance companies because some of the trials that were published said, “We gained 2 points on the Hammersmith [Functional Motor] Scale.” So they were saying, “We are not going to approve this drug unless you gain 2 points on the Hammersmith,” which is completely unrealistic. If the goal is to maintain function, we maintain function, and I am thrilled about that. Our metrics and our measures are not great, you are right, about how this has improved patient function. Asking the patient things is important: “Are you able to take your dishes?”—even seated patients—“Are you able to pick up your dishes, or your dinner plate, and take it to the sink? Are you able to open doors? Are you less fatigued?” Patients will tell me that, when riding in a car, their head does not joggle as much as it used to, that they have better head and neck control. Some of the younger kids will say, “Oh my gosh, it is incredible; if I drop a toy, I can pick it up.” They can actually flex at the trunk and extend themselves. 

These are things that we do not measure. Or patients may say, “My fatigue is less than it was; my stamina and endurance are better; I get through the workday better; I am able to walk a little bit longer.” These are things we are not great about measuring on our scales, but as quality-of-life issues for these patients, they are improved. I do try to ask about bulbar oral motor function, fatigue, and activities of daily living, basically to ask, “What is it that you can do now that you could not do before? Do you notice anything different?” That to me has been really helpful. I am looking forward to patients who are seated and in power chairs to have increased independence, so that they are able to go to school or go to work and able to have a better quality of life. I do think that is something, if picked up, that patients and families can give us information about, but it does take time.

John Brandsema, MD: I think one thing we saw in the way that nusinersen development programs were structured is they very clearly looked at survival or a Kaplan-Meier analysis of needing respiratory support. Looking at that pulmonary intervention, it is very clear if somebody needs noninvasive ventilation or even invasive ventilation and how much time that is in a day. It is a very objective thing that you can track. But otherwise it is very hard to come up with nuanced ways of looking at the respiratory function until somebody can actually do the pulmonary function testing at around 6 years of age. Even then, for people who have facial weakness and other things, it is sometimes hard to get reliable PFT [pulmonary function test] measurements to look at respiratory function. In terms of bulbar function, it is even more diffuse in how you actually objectively follow how well somebody is swallowing and what they are able to do in vocal production. 

Something I hear from my patients a lot is, “I just feel like people can understand me a lot better.” I can notice that too, as the examiner. I can have a conversation with somebody without having to rely on any assisted devices and other things as much. We do not have great scales for precisely measuring that and seeing that improvement in people. I think that is something we are working on as a community, how to better look at some of those aspects of what SMA does in terms of the phenotype. We just do not know how to measure it very well.

Julie Parsons, MD: I think that too. I have to say that I am a very basic person, and with all of the medications and all of the trials, we talk about the Hammersmith scale and MFM [Motor Function Measure] and the CHOP-INTEND [The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders] score and the numbers. For the general child neurologist, those are useless numbers, really. We talk about them; we say, “Oh my God, there was a 3-point increase.” What the heck does that mean? Can the kid sit up? Can they walk? Can they stand? Can they eat? Can they breathe? If we are looking at that and looking truly at what the abilities are of each patient, it is really helpful. The bottom line is that every single one of these therapies makes an improvement the earlier you treat with each of those metrics.

John Brandsema, MD: Thank you to the audience for watching this NeurologyLive® Peers & Perspectives®. If you enjoyed this content, please subscribe to our e-newsletters to receive upcoming programs and other great content right in your inbox. Thanks for watching and have a great day.

Transcript Edited for Clarity