Optimizing care of adults with SMA in the new era of disease-modifying therapies

Spinal muscular atrophy (SMA) is a genetic disorder characterized by progressive muscle weakness and atrophy, leading to impaired motor function. Until recently, management of SMA was primarily supportive, but new treatments have improved disease prognosis. At an industry-sponsored symposium organized by the Hong Kong Neurological Society, Professor Maggie Walter of the Ludwig Maximilians University of Munich, Munich, Germany, discussed the importance of early detection of SMA and timely administration of disease-modifying therapies, such as the oral drug risdiplam (Evyrsdi^®), to prevent rapid and irreversible loss of motor function in adult patients. Dr Shirley Pang of the Division of Neurology, Queen Mary Hospital, Hong Kong, shared local experience with the use of risdiplam in adults with SMA.

SMA: An inherited neuromuscular disorder
SMA is caused by autosomal recessive mutations in the survival motor neuron 1 (SMN1) gene and consequent decrease in the SMN protein, which leads to motor neuron degeneration and progressive muscle weakness. Affected individuals experience symmetrical muscular weakness evolving from proximal to distal muscles in the course of the disease. [J Neuromuscul Dis 2020;7:1-13; J Child Neurol 2007;22:1027-1049]

All SMA patients carry the SMN2 gene, a homologous copy of SMN1, capable of encoding the SMN protein. A higher SMN2 copy number is correlated with a milder presentation of SMA. [Am J Hum Genet 2002;70:358-368]

SMA has been classified into three main clinical subtypes (types I, II and III) according to age at onset (0–6 months, 7–18 months, and >18 months, respectively) and the maximum motor milestones achieved (non-sitters, sitters, and walkers, respectively). [J Child Neurol 2007;22:1027-1049]

“This is a lifelong progressive disease. Regardless of subtype, all SMA patients experience decline in motor function year by year,” noted Walter. “Therefore, patients consider disease stabilization as a positive [treatment] outcome. Maintaining residual motor function may promote social integration and prevent further loss of quality of life.” [Eur J Neurol 2018;25:512-518; Neuromuscul Disord 2017;27:428-438; BMC Neurol 2015;15:217]

How to diagnose SMA?
“Typical clinical features of SMA include proximal muscle weakness, neurogenic changes on electromyography [EMG], and absence of reflexes,” described Walter. “Muscle weakness and symptom severity are important considerations to prescribe SMA tests.”

When SMA is suspected, a genetic test for homozygous SMN1 deletion should be performed to confirm the diagnosis. SMN2 copy number analysis should also be performed. [Orphanet J Rare Dis 2011;6:71; Neuromuscul Disord 2017;27:596-605]

“In addition to family history and genetic tests, EMG can be useful to distinguish this neurogenic disorder from proximal myopathy, while nerve conduction tests can rule out Charcot-Marie-Tooth disease,” added Walter. “Muscle biopsy is no longer necessary for SMA diagnosis.”

Early treatment: Key to better clinical outcomes
Currently, two disease-modifying therapies (ie, nusinersen and risdiplam) are available through the safety net programme to eligible SMA patients in Hong Kong. (Table) Both agents increase SMN protein levels by targeting the SMN2 gene. [Neurology 2016;86:890-897; J Med Chem 2018;61:6501-6517; www.ha.org.hk/hadf/en-us/Updated-HA-Drug-Formulary/Drug-Formulary.html]

Nusinersen, an antisense oligonucleotide, is delivered intrathecally. As it does not cross the blood-brain barrier (BBB), its actions are limited to the central nervous system. [Neurology 2016;86:890-897] Risdiplam is an orally administered small-molecule drug that crosses the BBB, and has bioavailability in both central and peripheral tissues. [J Med Chem 2018;61:6501-6517]

A real-world cohort study (n=139) of nusinersen in adult SMA patients showed that lower disease severity at baseline correlated with greater improvement in motor function, highlighting the importance of timely diagnosis and treatment in preserving key motor function. [Lancet Neurol 2020;19:317-325]

“Treatment response is not associated with patient age at start of treatment,” remarked Walter. “What matters is the preserved motor function prior to onset of treatment. When you treat early and presymptomatically, you can expect to achieve [and/or maintain] next to normal motor function.”

SUNFISH (Part 2) trial
SUNFISH Part 2 was a randomized, placebo-controlled, double-blind study that assessed the efficacy and safety of risdiplam in 2- to 25-year-old, non-ambulant, type II–III SMA patients (n=180). Recently released 4-year results showed that the increase in motor function from baseline observed during the first year was maintained through the fourth year of treatment with risdiplam, as measured by changes in Motor Function Measure 32 (MFM-32) and Revised Upper Limb Module (RULM) scores. [Oskoui M, et al, MDA 2023]

“In patients who initially experienced better improvement in motor function [≥3 points], MFM32 scores were stable over 4 years. In those with 0–3 points of initial improvement, MFM32 scores were stable for up to 36 months, but still showed improvement compared with baseline after 4 years of risdiplam treatment,” noted Walter. “Subjective scores [SMAIS-ULM; SMA Independence Scale-Upper Limb Module] of the patients and caregivers also mirrored the motor function scores, demonstrating continuous improvement or stabilization in the level of help needed for activities of daily living.”

SMA treatment in Hong Kong
Under the current reimbursement policy in Hong Kong, nusinersen and risdiplam are available for SMA patients aged <18 years and <25 years, respectively. [Pang YY, 2023]

In December 2020, risdiplam was introduced under the Compassionate Use Programme (CUP) for type I and type II SMA patients. By 2022, 20 adult patients (median age, 30 years; age range, 19–50 years) had been enrolled and treated for a mean duration of 13 months.

Most patients either improved or remained stable in terms of MFM32 (mean change, 2 [-2 to 10]) and HFMSE (mean change, 0.28 [-2 to 2]) scores. “Remarkably, five patients [25 percent] attained a clinically meaningful improvement of ≥3 points on the MFM32 scale,” noted Pang. “None reported deterioration of their condition. Fourteen patients perceived improvements in fatigue, breathing, hand function, movement, swallowing, and speech.”

“These responses echo the views of other SMA patients around the world, indicating that existing clinical scales for motor function assessment do not seem to capture some aspects of improvement, such as level of endurance, fatigue, pain, voice, sleep and speech,” highlighted Pang. “There is a need to implement better scales that can measure more relevant patient outcomes.” [BMC Neurol 2021;21:143]

Summary
All adult SMA patients should receive treatment in a timely manner to achieve best clinical outcomes. Due to the progressive nature of SMA, stabilization is a realistic treatment goal for patients with more severe disease. Clinical data show that the treatment benefits of risdiplam are durable and cumulative. Any improvement in motor function, no matter how small, can be life-changing for patients.