The director of neurology and neuromuscular medicine at the Children’s Hospital of the King’s Daughters in Norfolk, Virginia, provided perspective on the phase 4 RESPOND study assessing nusinersen in individuals with SMA who already received gene therapy.
After years of no approved therapies, the spinal muscular atrophy (SMA) research community broke through in 2016, with the approval of nusinersen (Spinraza; Biogen), an antisense oligonucleotide designed as a SMN2 mRNA splicing modifier. Years later, in 2019, the FDA made a landmark decision, approving onasemnogene abeparvovec (Zolgensma; Novartis) as the first gene therapy indicated for SMA. Approved for infants less than 2 years old, Zolgensma’s mechanism of action replaces the function of the missing or nonworking SMN1 gene with a new, working SMN gene.
A year after Zolgensma’s approval, the community welcomed risdiplam (Evrysdi; Genentech), furthering the conversations around treatment optimization and improved quality of life. Announced in 2020, the ongoing phase 4 RESPOND study (NCT04488133) assesses the impact of nusinersen on individuals with SMA who’ve previously received gene therapy with Zolgensma. Newly released interim data from the study showed that this combination approach may be viable, with patients experiencing improvements in motor function.
As of the cutoff date (November 15, 2022), 29 children comprised the interim set and 38 made up the safety set. The majority of the cohort (26 of 29) had 2 SMN2 copies, and slightly more than half (n = 15) were at least 9 months of age at first nusinersen dose. Of note, the only 3 individuals with 3 SMN2 copies were at least 9 months of age at first dose. At day 183 of treatment, most participants with investigator-reported suboptimal motor function showed improvements. This included 12 of 13 individuals with 2 SMN2 copies who received their first nusinersen dose less than 9 months after birth. Additionally, all 3 individuals with 3 SMN2 copies showed improvements in motor function.
Following this data, lead investigator Crystal Proud, MD, director of neurology and neuromuscular medicine at the Children’s Hospital of the King’s Daughters in Norfolk, Virginia, sat down to discuss the results, including the notable take-home points the clinical community should be aware of. In addition, Proud talked about the unique nature of this study, how it works toward improving treatment optimization, and how it speaks to the progress made in the community.
The goal of the trial was to evaluate the potential for optimizing outcomes for patients who already have received gene transfer therapy with onasemnogene abeparvovec. This came out of the recognition that gene transfer therapy is not curative. While it improves outcomes, we were still seeing patients that had symptoms of their spinal muscular atrophy having already received this therapy. The question was: how do we hopefully optimize their long term outcomes with additional therapy through nusinersen? In order to enroll in the clinical trial, patients had to be symptomatic of their disease. This was evaluated both by the parent or caregiver of the patient, and also by the primary investigator. At the beginning of their enrollment, both the caregiver as well as the clinician identified areas of suboptimal outcomes and persistent symptoms of SMA that made the patient eligible to enroll. Throughout the clinical trial, we went back to those identified symptoms, commented on them, and observed how they improved or changed over the course of the trial.
I'm enthusiastic about the patients that were enrolled and the outcomes that we're seeing. We had some really interesting data reflective of the type of patients that were included in the clinical trial based on objective measures, such as electrophysiology. We all as clinicians may evaluate a patient differently based on our familiarity with disease, based on how specific we are with our examinations and what we consider to be significant may be different. But when we can find objective measures of disease burden, this is what helps us uniformly ensure that we are including similar patients in research, like this particular trial.
At baseline, we obtained what are called CMAP (compound muscular action potential), which is a measure of axonal function, as measured by a nerve conduction study. CMAPs in kids that are typically developing in this age are going to be greater than two millivolts. When we looked at the children enrolled in this clinical trial, these were electrophysiologically measurably symptomatic babies. Most of them had a CMAP measurement of less than or equal to 1 millivolt. They definitively were not cured of their disease, in fact, quite symptomatic, if we're looking at it from an electrophysiologic perspective. I think that helped to solidify that we’re truly looking to optimize outcomes for children that remain symptomatic of their disease. From an outcomes perspective, remember that this interim data cut include the effects of the loading dose phase because subsequently, we will get into the maintenance dosing. That's where I'm also excited to see what happens in the long term. But it's really encouraging to see significant improvements in measurements like the HINE-2 and CHOP-INTEND.
I personally have been thinking about this for many years because these medications work via different mechanisms of action. I do think that as we continue through this therapeutic landscape in neuromuscular diseases, we're really going to be looking at impacting the disease state at a variety of different locations. In this context, along the motor unit. That's going to extend from the motor neuron to the neuromuscular junction, and then to the muscle that it makes contact with. We know that Zolgensma is delivering a functional copy of the SMN1 gene. Nusinersen is not looking to replicate that, it's looking to build on that by leading to more SMN functional protein being produced by the SMN2 gene. I feel as though those approaches are going to potentially be complimentary and able to be combined to lead to more SMN protein, and perhaps a greater rescue for the phenotype.
The next steps are going to include trying to identify the optimal timing for this sort of a combination or synergistic approach. There was a good question that was raised at the Cure SMA National Conference, when we presented this data, whereby if we're waiting for patients to become symptomatic before we add their treatment, we know that they've already lost a certain percentage or proportion of their motor neurons that is leading to that symptomatic, observable effect. So should we be trying to intervene earlier? In particular, I think the most vulnerable population that has demonstrated persistent need are the kids with 2 copies of SMN2. When we go back and look at the gene therapy data in the pre symptomatic children that were treated, we can see that especially in those two-copy kids, they remain vulnerable. They’re falling off the typical Bailey curves of development. That lets us know that we do have room to optimize. Is there something we can do to help them remain on that typical trajectory or get a little closer to that typical trajectory?
In order to be included in this particular clinical trial, the patients had to be symptomatic. They had to demonstrate in the clinician’s eyes a suboptimal treatment response to initial Zolgensma treatment. I think we do have to be careful when we're generalizing using copy numbers. I just referred to the opportunity for us to optimize our kids with 2 copies; however, we can't forget that the SMN2 copy number does not solely dictate the long term outcome of our patients. Many of us can share stories of three-copy kids that were symptomatic at birth, or 2-copy kids that weren't symptomatic until they were in their later elementary school or teenage years. There are there are definitely children with 3 copies of SMN2 that are quite symptomatic of their disease. We should not consider the potential benefit that they may experience if they were to have an opportunity for combination or additional treatment.
It's pretty incredible to think of where we've come. To recall the conversations that I used to have with families when their child was diagnosed with infantile SMA, and then fast forward to a time where we had Spinraza as our first FDA approved therapy for the treatment of SMA. That offered us this opportunity to have hope. Now to see that the conversation has completely shifted to not just survival, but to optimizing function and optimizing outcomes. We're looking forward to the future where these children grow up to be teenagers and adults, and our job is to help make sure that what we're doing for them now is going to set them up for success later in their life. It's an incredible journey to see how far we've come. And I'm just glad to be a part of it.
Transcript edited for clarity. Click here for more iterations of NeuroVoices.