A study published in the Journal of Neuromuscular Diseases presents the first evidence of mild improvement or stabilization of motor and respiratory function in adults with spinal muscular atrophy type 3 (SMA3) treated with Nusinersen, which was the case even in patients who have had the disease for 20 years or more.
These findings prove the efficacy of Nusinersen beyond types and age groups, paving the way for adult treatment.
In June 2017, US and European drug regulatory agencies approved Nusinersen for the treatment of all SMA subtypes without age restrictions.
However, until now, there was no data to support its use for adults with SMA3.
Therefore and despite broad approval, Nusinersen has only been prescribed to patients under 18 years of age in some countries.
“With no data from clinical trials or real-life data in adult SMA patients, healthcare systems in several countries have been covering the cost of Nusinersen only for SMA patients up to 18 years of age or even younger.
This exclusion of adult patients with SMA has resulted in the continuation of a high unmet need,” explained Maggie C. Walter, MD, MA, Associate Professor for Neurology, Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.
“Our research indicates a mild treatment effect in adults with longstanding SMA3 after 10 months of treatment with Nusinersen resulting in a positive change in functional measures, which had never been seen in the natural history of the disease.”
In this prospective, open-label, observational study, 17 of 19 patients with SMA3 completed a 10-month observation period. Patients ranged in age from 18 to 59 years and disease duration ranged from six to 53 years.
The majority (63 percent) of patients could walk while 37 percent could not. Nusinersen was administered intrathecally (into the spinal fluid) at day 1, 14, 28 and 63, followed by maintenance doses every four months up to 300 days.
Functional testing was performed at baseline and then repeated after two (visit four), six (visit 5) and 10 (visit 6) months.
Results of the study indicated that even in patients with a longstanding disease course – up to 53 years prior to onset of treatment – improvement of motor function exceeded the investigators’ expectations of mere disease stabilization, justifying treatment beyond childhood and early adolescence.
Significant improvements were noted on the 6-Minute-Walk-Test (6MWT) when evaluated at six and 10 months. The improvement in distance ranged from 24 meters to 83 meters in seven patients.
The mean improvement in the 11 ambulatory patients was 8.25 meters (median 40.5 meters).
Compared to the natural history of the disease, where an annual decline of 9.7 meters has been described (Montes J et al., PLoSOne, 2018;13:e0199657), the difference adds up to nearly 18 meters.
Nusinersen treatment also showed significant changes in the revised upper limb test (RULM), improving upper limb motor function in six of 17 patients on visit six while nine patients remained stable. Peak Cough Flow, a measure of respiratory function, significantly improved on visit five.
In biomarker studies, a significant decline in neuron-specific enolase (NSE) and pTAU was observed. These biomarkers are thought to be indicative of neuroaxonal damage in neurodegenerative diseases.
“Within the last decades, we could see our patients progressively deteriorate over the years, and our only option was to recommend physiotherapy.
Now, for the first time, there is hope that the disease progression can be slowed or even stopped, and improvement is possible, even in patients with longstanding disease, if there is still residual preserved motor function,” commented Dr. Walter.
SMA is a progressive autosomal recessive motor neuron disease that affects one per 8,000 to 10,000 people worldwide. While individuals with SMA may initially stand and walk without help, eventually muscle weakness worsens until wheelchair assistance is needed.
SMA is caused by loss or damage to the survival motor neuron 1 (SMN1) gene that produces the SMN protein. The severity of the disease is related to the number of copies of the SMN2 gene.
This disease manifests as severe and progressive muscular wasting (atrophy) and weakness caused by the loss of motor neurons. Of the five subtypes of SMA, SMA3 is on the milder end of the spectrum and can begin between 18 months until 12 years of age or more.
Nusinersen is a medication designed to treat SMA caused by mutations in chromosome 5q. It is an antisense oligonucleotide (ASO) that helps overcome SMN protein deficiency by functionally converting the SMN2 gene into the SMN1 gene, allowing more SMN protein to be produced. It is typically administered intrathecally as a series of loading and maintenance doses.
SMA Clinical Spectrum
Spinal muscular atrophy (SMA) encompasses a group of autosomal recessively inherited progressive, degenerative neuromuscular disorders. They range in severity from prenatal/neonatal onset (SMA-0), to onset before 6 months of age with rapidly progressive weakness and early mortality (SMA-1), to onset in mid-infancy (SMA-2), and to adolescent or adult onset with indolent clinical course (SMA-3/-4). SMA patients share mutations in the survival motor neuron (SMN) gene, and variations in clinical phenotypes are attributed to copy numbers of the closely related SMN2 gene (more copies result in less severe disease).1 There is only a single nucleotide that is different in the coding of SMN1 and SMN2. Although the amount of protein produced by SMN2 is less than that produced by SMN1, that lower amount is enough that the severity of SMA is modulated by the number of copies of SMN2.2 The pathologic hallmark of SMA is degeneration of large motor neurons (“anterior horn cells”) in the spinal cord and brainstem, and the primary resulting deficits are progressive loss of motor function. SMA-1 typically results in respiratory failure in infancy, and it is the leading genetic cause of death in infants.1 SMA-1 was previously referred to as Werdnig-Hoffmann disease. There are up to 5% of SMA cases attributable to other rare genetic mutations and these will not be discussed in this review.3
There are multiple subtypes of SMA and within the subtypes there is variability in disease progression, severity, and patient prognosis.1,3 SMA-1 has the earliest onset, and most stereotyped clinical course. Patients with SMA-1 may appear normal at birth but become symptomatic within the first 6 months of life. They manifest severe hypotonia, lack age-appropriate head control, lose strength and movement in all but very distal parts of their limbs including fingers and toes, and develop marked diaphragmatic weakness. These infants are unable to sit or roll, they have progressive difficulty in oral feeding, and develop progressive respiratory failure. They generally die by age 2 years, unless they are supported with continuous mechanical ventilation. SMA-2 is less severe and initial symptoms begin between the ages of 6 and 18 months. Children with SMA-2 are able to sit, but typically never walk independently. SMA-2 manifestations include progressive weakness of the shoulder and hip girdle and inability to move arms and legs against resistance. In early childhood, although cognitive maturation is typically normal, self-care including dressing and bathing is limited by weakness.1,3 Most individuals with SMA-2 develop hypoventilation, which is most pronounced during sleep and requires assisted ventilation. Often, they are treated with non-invasive ventilation such as bilevel positive airway pressure. SMA-3 becomes symptomatic after 18 months of age. Typical initial features include delayed age for initiation of walking, sometimes followed by slow progress in learning to run, climbing stairs independently, or increasingly frequent falls. Most individuals with SMA-3 achieve the ability to walk during the course of their life, but may not retain that ability. The need for assisted ventilation is more variable in SMA-3. Individuals with SMA-4 become symptomatic in adulthood; manifestations include slowly progressive decline in strength and rarely, scoliosis. Individuals with SMA-3 and -4 may have normal lifespans and rarely require mechanical ventilation support during adolescence or early adulthood. Table 1 summarizes typical clinical features and SMN2 copy numbers of the major SMA types.4
Clinical SMA Types4
|SMA Type||Clinical Manifestations||SMN2 Copy Number|
|0||Reduced prenatal movement, symptoms at birth, death early||Typically 1|
|1||Symptoms by 6 months of age; lack of sitting; respiratory, feeding, orthopedic complications||Most commonly 2, sometimes 1 or 3|
|2||Symptoms between 6–18 months, able to sit but not walk, respiratory, feeding and orthopedic complications||Most commonly 3, sometimes 2 or 4|
|3||Symptoms after 18 months, able to sit, stand, and walk. May have respiratory, feeding, and orthopedic complications||Most commonly 3–4, but variable|
|4||Symptoms onset in adulthood, typically mild||Typically 4|
SMA, spinal muscular atrophy; SMN, survival motor neuron
Optimal treatment of individuals requires a multi-disciplinary clinical team. The most common areas to address include respiratory, gastrointestinal/nutritional, and orthopedic.1
Respiratory Management. SMA-1 causes respiratory insufficiency and failure. Initially, non-invasive ventilation may suffice, but typically with progressive respiratory failure, infants require tracheostomy and continuous mechanical ventilation. SMA-2 is associated with sleep-related hypoventilation, commonly during early childhood; initial treatment is with non-invasive ventilation during sleep. Severity of pulmonary manifestations varies but some affected children require intensive airway clearance and ventilation support. Children with SMA-1 and -2, in particular, are at heightened risk of respiratory infections and often have marked declines in function in association with relatively mild pulmonary infections. All routine immunizations are recommended for all individuals with SMA.
Nutrition. Children with SMA should be routinely evaluated for aspiration, constipation, feeding, and swallowing. These complications are universally experienced by those with SMA-1, increasingly seen with SMA-2 as they near late childhood or adolescence, and are uncommonly part of the course of SMA-3. Caloric intake, nutrition supplementation, and required food consistency should be regularly evaluated. If poor oral intake or aspiration is identified in a patient, management with a nasogastric tube or percutaneous gastric tube is recommended.
Orthopedic Management. Orthopedic surgeons participate in the care of individuals with SMA because contractures and scoliosis are significant comorbidities. Spinal fusion or the placement of spinal growing rods often is recommended for individuals affected by SMA-2 when severe scoliosis results in restrictive lung function. Typically, those with SMA-1 are at lower risk for severe scoliosis because they are unable to sit upright. Durable medical equipment to assist with patient mobility, including power wheelchairs and patient lifts, physical therapy, and spinal surgery to treat scoliosis all may be required. The presence of scoliosis may complicate the administration of nusinersen (Spinraza, Biogen, Cambridge, MA).
Other Modalities. Patient counselling and pharmacotherapy may be required to help the patients and/or families with the management of depression and anxiety associated with SMA, its comorbidities, and its treatments throughout the individual’s lifespan.5
SMA is caused by mutations in the SMN1 gene but humans have an extra SMN gene called SMN2. There is only a single nucleotide that is different in the coding of SMN1 and SMN2. Although the amount of protein produced by SMN2 is less than that produced by SMN1, that lower amount is enough that the severity of SMA is modulated by the number of copies of SMN2.2,6 Thus SMN2 was chosen as a target at which to aim therapeutic treatments, specifically antisense oligonucleotides (ASOs), to increase the amount of SMN protein produced.2,6
In seminal studies, in rodent SMA models, Passini et al6 demonstrated that increased SMN2 expression could augment production of functional SMN protein and thereby overcome the genetic defect in SMA. Additional work focused on using ASOs as the means to increase SMN2 production.2,6 These studies, complemented by robust research in other laboratories, laid the foundation for the development of nusinersen.7
Results of the clinical trials, summarized in the section Clinical Trials of Nusinersen, provided the evidence that led the US Food and Drug Administration (FDA) to approve nusinersen as the first agent to modify the disease course of SMA, which results from mutations of SMN1 in chromosome 5q.8,9 In December 2016, the FDA approved nusinersen for use in all types of SMA.8,10 Nusinersen is an SMN2-directed ASO.8,10 Antisense oligonucleotides for SMA work by blocking splicing once they are bound to pre-mRNA.11 This allows exon 7, the single exon by which SMN1 and SMN2 differ, to be preferentially included and therefore produce more full-length SMN protein.9–11
Pharmacokinetic and Pharmacodynamic of Nusinersen
Nusinersen is administered into the cerebrospinal fluid (CSF) because ASOs do not penetrate the blood brain barrier and all studies to date have relied on intrathecal drug delivery.11 The pharmacokinetics of nusinersen is best described as a 4-compartment model.12 The central nervous system (CNS) tissue is the primary site of action for nusinersen.10,12 The CNS tissues and CSF are distinct pharmacokinetic compartments when considering the pharmacokinetics of nusinersen. However, at steady-state, the CSF concentration should be proportional to the CNS tissue concentration of the medication.12 Once nusinersen is in the CNS, it is estimated that there is a redistribution into the CSF before the medication is cleared into the systemic circulation.12 Although the clinical trials used dosing based on age-to-CSF volume relationships, post hoc CSF half-life values from the pharmacokinetic analysis showed that the CSF half-life of nusinersen was not age or body-weight dependent.10,12 Therefore, although the trials used age-based dosing, a fixed dose for all ages and weights was recommended for commercial use because there was no dose-limiting toxicity documented for any trial participants.12 Dosing for nusinersen was based solely on the pharmacokinetics of the CSF owing to the need to distribute nusinersen throughout the CNS to all tissues containing the targeted SMN neurons.12
Trough plasma concentrations of nusinersen following intrathecal administration remain relatively low when compared with trough concentrations in the CSF.8 The pharmacokinetics of nusinersen in the plasma is biphasic.12 The plasma serves solely as the primary site for CSF clearance of nusinersen. There are no biologically active sites for nusinersen within the tissues or plasma. The kinetic model of nusinersen in the plasma mirrored any medication with a 2-compartment model following systemic administration.12
Metabolism and elimination of nusinersen is via exonuclease hydrolysis and urinary excretion.8,10 To date, nusinersen has no known interaction with the cytochrome P450 enzymes, indicating limited drug interactions.10 The manufacturer estimates that the terminal elimination half-life for nusinersen is 135 to 177 days in the CSF and approximately 63 to 87 days in the plasma.8 The prolonged half-life of nusinersen is estimated to be due to the distribution of the medication from the CSF to the CNS tissues and a slow elimination phase of clearance back to the CSF and then systemic circulation.12
The most common adverse events associated with nusinersen were lower respiratory tract infection, upper respiratory tract infection, and constipation.8,10 Patients treated with nusinersen were also found to have a higher incidence of paradoxical breathing, pneumonia, respiratory symptoms, and increased requirements for respiratory support than patients who underwent sham procedures in clinical studies.10 Table 4 summarizes adverse effects as cited in the phase 3, SMA-1 study.15 These adverse effects were not attributed to nusinersen. These are all common in infants and children diagnosed with SMA, and therefore it is challenging to determine and differentiate when adverse effects are related to the disease or to the intervention.
Nusinersen Adverse Reactions, SMA-1, Phase 3 Trial15
|Adverse Reaction*||Nusinersen (N = 80)||Sham/Control (N = 41)|
|Any adverse event||77 (96)||40 (98)|
|Pyrexia||45 (56)||24 (59)|
|Constipation||28 (35)||9 (22)|
|Upper respiratory tract infection||24 (30)||9 (22)|
|Pneumonia||23 (29)||7 (17)|
|Respiratory distress||21 (26)||12 (29)|
|Respiratory failure||20 (25)||16 (39)|
|Atelectasis||18 (22)||12 (29)|
|Vomiting||14 (18)||8 (20)|
|Acute respiratory failure||11 (14)||10 (24)|
|Gastro reflux disease||10 (12)||8 (20)|
|Decreased O2 saturation||10 (12)||10 (24)|
|Cough||9 (11)||8 (20)|
|Dysphagia||9 (11)||9 (22)|
SMA, spinal muscular atrophy
* All data presented as n (%)
In open-label studies of patients aged 2 to 15 years, the reported side effects could be considered common for patients undergoing a lumbar puncture.10 These side effects included headache, back pain, and post lumbar puncture syndrome.
Antisense oligonucleotides have been associated with coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia.8,11 Patients may be at an increased risk of bleeding complications associated with nusinersen therapy. The manufacturer recommends that all patients have platelet counts and routine coagulation assays checked before each dose of nusinersen and as needed based on clinical status.8 In clinical trials, no participant developed a platelet count of fewer than 50,000 cells/mL or developed a sustained low platelet count with continued medication exposure.10 However, among patients with normal platelet levels at baseline, 11% of nusinersen recipients developed a platelet level below the lower limit of normal during the course of treatment.8
Antisense oligonucleotides have also been associated with renal toxicities, including fatal glomerulonephritis.8 The manufacturer recommends quantitative urine protein checks at baseline and before each dose with recommendations to consider repeated testing and further evaluation for patients in whom the urinary protein concentration is greater than 0.2 g/L.8 In clinical trials, of 51 patients treated with nusinersen, 33% developed an elevated urine protein level.10 This is compared with 25 patients receiving placebo therapy, of whom 20% developed elevated urine protein. Renal toxicity from nusinersen was not associated with any increases in serum creatinine or cystatin C.
The immunologic response to nusinersen has been evaluated.10 In 126 patients, baseline and post exposure antidrug antibody assessments were made.
Five patients (4%) developed antidrug antibodies; in 3, antibodies were transient, and in 2 cases, these antibodies persisted. Currently, there is insufficient data to evaluate the impact of antidrug antibodies on the pharmacokinetics, efficacy, or tolerability of nusinersen.
One open-label study of infants with symptomatic SMA reported severe hyponatremia in a patient receiving nusinersen therapy.10 The patient required salt supplementation for 14 months to correct the electrolyte abnormality.
More information: Maggie C. Walter et al. Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study, Journal of Neuromuscular Diseases (2019). DOI: 10.3233/JND-190416