Population-based New-Born Screening of Spinal Muscular Atrophy to Evaluate the Uptake and Feasibility in the UK Context

Spinal muscular atrophy (SMA) is a progressive, debilitating neuromuscular disorder that leads to the deterioration or loss of muscle strength, including that of the respiratory muscles, and continues to be the most common inheritable cause of infant mortality. SMA affects about 1/10,000 newborns. Although the age at symptom onset may vary, it most frequently occurs in infancy and early childhood, with more severe clinical phenotypes correlating with earlier symptom onset. In Type 1 SMA, which is both the most common and severe form of the disease, symptom onset typically occurs by the age 6 months. A majority of these patients, if untreated, will not survive beyond 2 years of age in the absence of permanent ventilation support; of those who do, many will not achieve independent sitting, and few, if any, will walk independently. In the relatively milder but less common Types 2 and 3 SMA, patients have a lower or largely normal lifespan but, if untreated, still frequently lose ambulation over time, even when it had previously been acquired. These clinical phenotypes, resulting from the loss of motor function, are driven by the irreversible degeneration and loss of motor neurons in the spinal cord. This begins during the first 3 months of life and, in patients with Type 1 SMA, 95% are lost before the age of 6 months. As a result , a significant portion of motor neurons may be irreversibly lost before symptoms appear, and before a clinical diagnosis can be made. Given this, a screening method that would facilitate earlier diagnosis and hence treatment, before pathophysiological deterioration, is necessary.

SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene, which can be detected through genetic testing before patients present clinical symptoms. This lends itself to newborn genetic screening, through which pre-symptomatic diagnosis of SMA patients can be made as early as possible, providing the opportunity for better therapeutic effects. As a genetic diagnosis, qPCR or MLPA present a 100% specificity, and a 100% sensitivity for the homozygous deletion. For patients with an heterozygous deletion and a point mutation, the diagnosis is done by qPCR and gene sequencing. In the current study, we will use qPCR as a first tier diagnosis.

There are currently three treatments available to SMA patients that can significantly improve their prognosis, particularly with early intervention. All of these treatment methods have shown to be able to target the underlying genetic cause of SMA, as opposed to providing palliative and symptomatic care. Nusinersen, approved by the European Medicines Agency (EMA) in June 2017 and reimbursed by The National Institute for Health and Care Excellence (NICE) since June 2019, is an antisense oligonucleotide treatment that is administered intrathecally to modify the gene splicing of the 'back-up' SMN2 gene, compensating for the reduced levels of SMN proteins in patients with SMA. Risdiplam, which shares a similar mechanism of action to Nusinersen, is an orally-available treatment, and is currently under review for approval by the EMA. Zolgensma, approved by the EMA in March 2020 and currently under review for reimbursement by NICE, is a one-time gene therapy, delivered in a single intravenous dose, that replaces the impaired SMN gene in patients with SMA.

While treatment efficacy has been established in the clinical trial studies for these therapeutic options, patient age and time from symptom onset to the start of treatment have been identified as predictive factors of treatment efficacy options. In two early Nusinersen trials with symptomatic patients (ENDEAR: NCT02193074 and CHERISH: NCT02292537), the treatment was found to be more effective when administered early. In ENDEAR, which focused on the treatment of early-onset patients, subgroup analyses showed that those who received Nusinersen treatment earlier in their disease course demonstrated an increased likelihood of both event-free survival and motor development improvement from baseline assessment. Similarly, CHERISH, which focused instead on the treatment of later-onset patients, observed greater improvements in motor function assessments from baseline among those with shorter disease duration at screening. The ongoing Risdiplam trials with symptomatic patients (FIREFISH: NCT02913482 and SUNFISH: NCT02908685) have corroborated this observation. In FIREFISH, early-onset patients (SMA1) treated with Risdiplam sooner in their disease course showed greater improvement in motor function, with the same also observed in SUNFISH with later-onset patients (SMA2 and 3). A Zolgensma trial for post-symptomatic SMA1 patients (START: NCT02122952) further showed that, regardless of a patient's initial disease severity (as measured by their baseline motor function), earlier treatment of the disease can lead to more significant motor function gains: Subgroup analysis revealed that patients who received Zolgensma treatment earlier into their disease progression showed a greater improvement in motor function when compared to those who received treatment later into their disease progression, despite the higher baseline motor function score of the latter group. Taken together, these studies point to the role of early intervention in yielding better clinical outcomes, irrespective of the treatment administered.

Building on this, more recent clinical trials with these treatment options have focused on identifying and treating patients pre-symptomatically. In the Nusinersen trial NURTURE (NCT02386553), which enrolled patients (≤42 days) who were pre-symptomatic with SMA, 88% acquired autonomous ambulation, and 100% survived without permanent ventilation; in an earlier trial ENDEAR (NCT02193074), which enrolled patients who were postsymptomatic with SMA, 0% acquired autonomous ambulation, and 61% survived without permanent ventilation. Data from a Zolgensma trial SPR1NT (NCT03505099), which similarly enrolled patients (≤42 days) who were pre-symptomatic with SMA, have also emphasised the value of early treatment. Since treatment initiation following early genetic diagnosis, SPR1NT patients have shown greater improvements in clinical motor assessments (CHOP-INTEND) in comparison with those enrolled and treated post-symptomatically in Zolgensma's earlier trial, START (NCT02122952). Furthermore, no SPR1NT patients have required ventilatory support, and all have shown age-appropriate motor development since pre-symptomatic treatment initiation. This never happens in post-symptomatic patients. A Risdiplam trial, RAINBOWFISH (NCT03779334), enrolling genetically diagnosed, pre-symptomatic patients (≤42 days), is also currently underway. Collectively, these studies emphasise the importance of early diagnosis of SMA, a key step to facilitating pre-symptomatic treatment.