Patients with spinal muscular atrophy (SMA), a rare disease that results in progressive muscular weakness and atrophy, experience a worsening loss of muscle function. When the respiratory muscles are affected, patients require ventilatory support to continue to live.
SMA type 1 is the most severe form of this disease, typically diagnosed within the first few months of life. Patients with this subtype experience rapid motor deterioration, with a life expectancy of 1 year.
“Most patients with (SMA type 1) experience the complications of respiratory deterioration in the first year of life and require various therapies to support airway clearance and ventilation,” Lavie and colleagues wrote in Pediatric Pulmonology.
New therapies, including nusinersen (Spinraza®), are making a difference in the therapeutic landscape of SMA. Nusinersen was approved by the US Food and Drug Administration in 2016 for patients with SMA and was the first drug approved to treat all forms of SMA in both pediatric and adult patients. It is an antisense oligonucleotide that works by increasing the expression of the SMN2 protein.
Real-World Respiratory Experience
So how does nusinersen fare in improving the clinical outcomes of patients with SMA? Given that it has been in use in the United States and in other countries for at least a few years, we have some data that elucidate its real-world efficacy.
A team of Israeli scientists sought to study the impact of nusinersen on respiratory variables. Arguably, the ability of the drug to ameliorate respiratory dysfunction is 1 of its most important properties, given that respiratory failure is a leading cause of death among patients with SMA.
In Israel, nusinersen was introduced as a compassionate treatment in 2017, and its success paved the way for a national funding scheme to be approved for all patients with SMA nationwide.
Read more about SMA etiology
Lavie and colleagues prospectively collected data from patients with SMA type 1 who received 2 years of nusinersen treatment. This study was conducted at a multidisciplinary center that treats most of the patients diagnosed with SMA nationwide.
“Our aim was to describe the clinical characteristics, mainly respiratory, of these patients over a 2-year treatment period. There was no control group,” they wrote.
After the initial 4 loading doses, participants received maintenance therapy (administered intrathecally in 12 mg (5 mL) doses) every 4 months.
The findings of the study were illuminating. At baseline, 12 of the 20 participants studied were already on permanent assisted ventilation, and 4 were on partially assisted ventilation (noninvasive). A total of 17 of the 20 participants completed 2 years of nusinersen treatment.
Patients who had been on permanent assisted ventilation continued to be ventilated but achieved stable ventilatory pressures (apart from transient respiratory exacerbations). Patients who were on noninvasive assisted ventilation at baseline continued to be on noninvasive assisted ventilation at the end of the study. Patients who were not on assisted ventilation at baseline subsequently required assisted ventilation during the 2 years of follow-up.
“No respiratory complications or side effects were reported during or after nusinersen treatments,” the researchers wrote.
The key point from this study is that most of the patients on nusinersen remained stable in terms of their respiratory function. Although nusinersen has not been shown to be able to improve respiratory parameters, the research team concluded that greater stability of respiratory function may be achieved among patients who were started on nusinersen at an earlier age.
A Broader Picture
We now turn our attention to a study conducted by Acsadi and colleagues on the safety and efficacy of nusinersen among pediatric patients with either infantile- or late-onset SMA. This study, published in Muscle & Nerve, differed from the one conducted by the Israeli research team in that it recruited patients with different subtypes of SMA and included a control group receiving sham treatment.
In part 1 of the study, participants in the nusinersen group received 12 mg of the drug via intrathecal lumbar puncture in 4 loading doses and then in maintenance doses every 4 months. Due to the demonstrable efficacy of nusinersen, participants in both the nusinersen and control group were administered the drug in part 2 of the study.
A total of 21 participants were recruited for the study—7 were in the control group, while 14 received nusinersen. In the study’s phase 2 open-label extension portion, all remaining participants received nusinersen.
The study demonstrated that nusinersen was generally well-tolerated, with no adverse effects considered significant enough for the drug to be discontinued in any participant. The most common adverse effect was vomiting within the first 72 hours of intrathecal injection.
“There were no clinically significant nusinersen-related changes or patterns in electrocardiograms, vital signs, clinical laboratory testing results, neurological examination, or physical examination,” Acsadi and colleagues wrote.
Read more about SMA treatment
In terms of the efficacy of nusinersen, researchers noted that, in a study, the overall mean percentage time on ventilator support was significantly lower among patients in the nusinersen group compared to the control.
“Nusinersen demonstrated a favorable benefit-risk profile in the unique population of symptomatic infants and children,” the research team concluded.
The studies reviewed above complement each other in confirming that nusinersen helps patients with SMA achieve disease stabilization. This is incredibly important in terms of improving patients’ quality of life and extending survival. In addition, the groundbreaking properties of nusinersen in preventing further decline in respiratory function buy researchers more time to conduct studies that may yet yield life-saving therapies for patients with SMA.
Lavie M, Diamant N, Cahal M, et al. Nusinersen for spinal muscular atrophy type 1: real-world respiratory experience. Pediatr Pulmonol. Published online October 28, 2020. doi:10.1002/ppul.25140
Acsadi G, Crawford TO, Müller-Felber W, et al. Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study. Muscle Nerve. Published online January 26, 2021. doi:10.1002/mus.27187