Reducing Disease Burden Through Early Diagnosis and Treatment of Spinal Muscular Atrophy (SMA) - Episode 7
Emma Ciafaloni, MD and a panel of experts in SMA review the efficacy of nusinersen by discussing difference between clinical trial results and real-world clinical application.
Dennis Scanlon, PhD: We’ve had lots of discussion about these 3 recently approved therapies. Let’s talk through them 1 by 1. I’ll call on 1 of you to lead the discussion on each, and others can jump in. Dr Ciafaloni, I’ll start with you with nusinersen. If you could, please review the indication, dosing, the route of administration, and talk about the mechanism of action. I understand that 3 trials have developed the evidence for this that ultimately led to approval. Could you tell us a little about nusinersen, please?
Emma Ciafaloni, MD: Nusinersen was the first. It is an antisense oligonucleotide. It’s an interesting mechanism because it doesn’t act on the SMN1 gene; it acts on the backup SMN2 gene. It’s an RNA-splicing modifier that allows the SMN2 gene to produce more full-length, functional SMN protein. It is an antisense that is delivered through a lumbar puncture. There is a loading dose in the first 2 months; 4 doses through a lumbar puncture. After that, it’s a lumbar puncture delivery every 4 months. At this point, the label is for all patients with genetically proved SMA [spinal muscular atrophy], regardless of age or SMN2 copy numbers. This was what opened the field. It’s a historical clinical trial program, and the first pivotal trial, ENDEAR, enrolled 122 type 1 patients. Because of the well-established natural history in type 1, the most severe form, this trial was designed for babies with type 1 treated with the first dose before 7 months of age. It was stopped early by the FDA because of the statistically significant efficacy on the primary outcome.
We have extensive, rich results from fully published trials focused on teenagers and presymptomatic babies. The NURTURE trial is now being published. It focused on treatment in babies identified very early, presymptomatic with 2 or 3 copies, and treated before they turned 6 weeks of age. The outcome there is mind-blowing because these are babies who are reaching and exceeding major milestones, like walking, talking, and eating on their own. This is for type 1. There’s no major contraindication medically with nusinersen, except that you have to figure out the access with the lumbar puncture, which can sometimes be challenging in our prevalent older patients who have been with us much longer. The other main unanswered question is that there are no clinical trials in patients 18 years of age or older, although the evidence is accumulating in other prospective cohorts and postcommercial real-life experience. The data are very rich for nusinersen.
Dennis Scanlon, PhD: I was going to ask you about the clinical end points built into the trials, but you already hit on some: walking, talking, and sitting. Are there any other important end points that were used to judge the efficacy and effectiveness of this therapy?
Emma Ciafaloni, MD: Yes. It’s very important to mention that although the earliest trial’s primary outcome might have been survival, tracheostomy, and maybe some points establishing the HINE [Hammersmith Infant Neurological Examination] outcomes, when you hear this primary outcome in clinical trials and then switch to using a medication in 1 of your patients, we cannot automatically translate 3 points in a HINE scale and care only about that. There is so much more that goes on, especially in the prevalent cases. We care about milestones. We care about patients who, even with very minimal residual hand function, might be lawyers and fully employed and very able. Preserving that minimal hand function is extremely meaningful. That’s not measurable in the clinical trial with the CHOP [Children’s Hospital of Philadelphia] [Infant Test of Neuromuscular Disorders] or HINE, yet it’s very important. There is nuance that we all need to use when we translate clinical trial parameters to real life, and we need to be wise about it.
Dennis Scanlon, PhD: I want to talk about the concept of real-world evidence relative to evidence from trials if we could, Dr Ciafaloni. The ENDEAR trial was 1 of the trials published in 2017. Could you say a few words about that?
Emma Ciafaloni, MD: ENDEAR was the pivotal trial for type 1, the most severe. It was a phase 3, 2:1 randomized trial. The data hit their primary outcome early so everybody was moved into an open-label extension. That’s what really made the FDA approval happen for type 1. Importantly, we also have the CHERISH trial, which treated older children, so we’re moving more into type 2. That’s very important data that also met their primary outcome early, and everybody had to be switched into open label. With the NURTURE trial, we already touched on the presymptomatic, but there are fully published data called the CS2/CS12 that has almost 4 years of longitudinal open-label data on those patients who were initially enrolled in the phase 1 and 2 dose-finding studies and were followed for years. That also shows potential for some patients to really improve their upper-extremity motor function, 6-minute walk, and other parameters.
The data that have accumulated from the clinical trials for nusinersen are very rich and continue to grow. There are also many cohorts. The most important to highlight is a prospective cohort out of Germany for adults, ages 18 and older, who were followed prospectively. Those are very important data because it’s unlikely there will ever be a randomized clinical trial in adults because of the landscape right now. That data also showed the potential in real-life patients. The inclusion and exclusion criteria are very bold in a way. These are adult patients with scoliosis and contracture. That cohort has demonstrated the potential for improvement in different scales and different motor functions, even in adults. The adult population has been a little harder because the early data were on the type 1 babies, which is how you have to do studies and trials, but the adult population is a very rich and prevalent cohort in our clinics. That’s where we had the hardest time accessing nusinersen early on, because we couldn’t show a phase 3 clinical trial. Things have improved very much, but that’s 1 aspect that could probably do better.
Dennis Scanlon, PhD: In addition to clinical endpoints often built into studies, there has been such an emphasis on patient-reported outcomes [PROs]. In the case of patients, I would also imagine caregiver-reported outcomes, perhaps. Could you talk a little about whether those types of data have been incorporated into any of our evidence, either through trials or real-world studies?
Emma Ciafaloni, MD: Absolutely. A very smart colleague of mine has this expression: Not everything that’s meaningful is measurable, and not everything that’s measurable is meaningful. It is very true for SMA, because what you study in trial is what you have to do to prove a drug works. But when you translate into a real life, there are many more nuances. What we are seeing in patient-reported outcomes in the clinic is that they might not hit the point of 3-point improvement in the HINE or CHOP scales that payers frequently focus on. Patients can tell us that they were able to walk in their high school graduation rather than being in their scooter because they can walk much longer, they have better endurance, their voice is stronger, their teacher can finally hear them, and they don’t have to always ask mom for help. These are very meaningful outcomes that we, as clinicians, document in our notes. It’s very important to work together with physical therapists to measure an outcome, but we need to have a certain nuance; especially in the older patients. Maybe they don’t gain 3 points, but they’re not losing 3 points. That’s very meaningful and maybe a good goal for treatments.
Dennis Scanlon, PhD: I want to go to our other panelists and hear the payer perspective in terms of evidence. Are there any comments from the other panelists as it relates to nusinersen, either trial evidence or real-world evidence, or the types of measures that we have for this treatment?
Maria Lopes, MD, MS: I agree with Dr Ciafaloni. It’s important to bring out that type of information. I remember seeing videos with nusinersen. Sometimes we struggle with the scales: what they mean and what a clinically meaningful difference is. As she pointed out, if it doesn’t make that cut, we may have a negative impression, but when you are looking at more and connect emotionally to what you’re seeing, it’s more nuanced. I remember looking at some of the open-label data with nusinersen. If you’re treating presymptomatic babies, what they look like at 6 months and watching them reach developmental milestones, you can’t help but connect with the quality-of-life side that this represents in terms of the magnitude of benefit. Some of the PROs very much relate to complications. The ability to connect if you’re functioning better, you’re ambulating, and regarding other resources you’re not consuming is important. There are already some preliminary data with nusinersen around the reduction in inpatient stays and hospitalization rates. The importance of having this data, but also understanding beyond on the scales what kind of impact this is having on preservation of function and survival as we have more information that can be published, justifies the importance of early treatment.
Transcript edited for clarity.