Spinal muscular atrophy disease management
The spectrum of SMA phenotypes range from extremely compromised neonates and infants to adults with minimal symptoms. Disease management requires a multidisciplinary approach that addresses this broad range of clinical phenotypes. Best outcomes are linked to early diagnosis and intervention.
Genetic testing for SMN1 mutations/deletions is important for the diagnosis of spinal muscual atrophy (SMA). It is becoming increasingly important to also screen for SMN2 copy number. Reduced SMN2 copy number correlates with disease severity and hence is informative for prognosis and timely therapeutic intervention.
The consensus statement on the standard for care for SMA which was published in 2007119 was recently updated.111,120 It emphasises the importance of a multidisciplinary approach and an increased involvement of physicians to monitor disease progression for better management (Figure 6).
Neuromuscular evaluation and rehabilitation
The clinical assessment of the disease through physical examination of the musculoskeletal system and associated dysfunction is recommended every six months. Assessment and rehabilitation conditions differ according to the different SMA subtypes (Table 2).
SMA Type I and Type II are more severe and require extensive assessments and interventions that minimise impairment. For instance, preventing contractures and scoliosis is more relevant for SMA Type I and Type II patients. Whereas Type III (ambulant) require rehabilitations that help maintain and improve mobility, balance and endurance.
Table 2. Rehabilitation assessments and interventions in SMA.111
Patients with SMA Type I and Type II frequently develop scoliosis due to weakness in the muscles which support the spine. Scoliosis should be regularly monitored every six months. As most patients with Type I and Type II SMA are skeletally immature, interventions that improve deformity without affecting spine growth are recommended (Table 2 above).111
Respiratory distress is a significant source of morbidity and mortality in severe SMA patients (Type I and Type II). Management of pulmonary complications is a high priority. Frequent clinical visits once every three months, to monitor pulmonary complications, is recommended in severe SMA. Clinical assessment can be through physical examination for bulbar muscle weakness, scoliosis or chest wall deformities. For assessing respiratory failure, pulse oximetry or sleep studies should be used.120
The most recent recommendations advice introducing therapies improving airway clearance and ventilation. For instance, non-invasive positive pressure ventilation (NIV) is used in all symptomatic infants as well as non-sitters (Type I) prior to respiratory failure (Figure 7). A weak cough reflex also puts these patients at risk for mucosal plugging and pulmonary infections. Manual suctioning is hence recommended to assist the airway clearance.
SMA patients often suffer from nutrient deficiencies likely due to immobility, poor feeding and primary defects in gastrointestinal (GI) mobility. Documenting GI symptoms such as constipation, gastroesophageal reflux, vomiting and delayed gastric emptying is recommended in all SMA subtypes. In severe Type I and Type II SMA, assessing dysphagia and performing swallowing studies is recommended. To better assess the nutritional status of the patient, it is important to monitor their growth and analyse nutrient intake longitudinally. Given the complications regarding bone health in SMA, monitoring calcium and vitamin D levels and supplementing them as required is also recommended. Overall the involvement of dieticians and nutritionists may improve disease management.111
Other organ management
There is evidence for metabolic abnormalities such as pancreatic dysfunction and hyperlipidaemia in all SMA patients.20,22 Cardiac defects are also seen commonly in Type I SMA and should be monitored.6,8,11 Testing and treatment of other involved organs is based on the clinical symptoms as and when reported by the patients.
Spinal muscular atrophy treatment guidelines
Treatment guidelines developed by a working group of 15 SMA experts and moderated by a neutral third-party expert were published recently.121, 135
The SMA group concluded that early intervention is extremely important for maximal therapeutic benefit before irreversible motor neuron loss.
Early intervention is further supported by the evidence from preclinical and clinical studies.122,123 Diagnostic delay should be prevented and SMA newborn screening for SMN1 deletions and SMN2 copy number was recommended. The group recommended that all infants with 2, 3 or 4 copies of SMN2 genes should immediately receive SMN upregulating treatment.
For patients with five or more copies of the SMN2 gene, the group developed a strategy for monitoring the onset of symptoms accurately. These guidelines as defined by the authors are listed below:135
Guideline 1: For patients not treated immediately, ideal routine follow-up care should be provided by a neuromuscular specialist;
Guideline 2: Referral should be provided to sequencing laboratories which are capable of identifying and confirming exact SMN2 copy number;
Guideline 3: For patients not treated immediately, ideal routine follow-up care is every three to six months, up to two years, and every six to twelve months thereafter;
Guideline 4: For patients not initially treated, recommended follow-up assessments include: electromyography (EMG), compound muscle action potential (CMAP) monitoring, myometry, physical examinations, and motor function scales;
Guideline 5: Parents/caregivers should be instructed by physicians to contact them immediately when the following occur:
- changes in movement, feeding, or breathing patterns;
- change in voice/weak cry;
- increased fatigue without increasing activity;
- trouble feeding in young children or infants;
- decline or loss of function in previously attained motor ability or failure to show progress in expected motor ability;
- abdominal breathing
- failure to thrive
As SMA arises from defects in SMN protein levels, current strategies mainly aim to improve the disease by restoring SMN function. Of these, there are two treatment options, onasemnogene abeparvovec (Zolgensma®) and nusinersen (Spinraza®), currently approved in the clinic.124,125 These treatments address the underlying cause of the illness - deficiency of SMN protein.
Onasemnogene abeparvovec is the gene therapy developed by AveXis, now acquired by Novartis. It is a single IV infusion that delivers the corrected SMN1 gene packaged in an adeno-associated viral (AAV9) vector.
Onasemnogene abeparvovec showed beneficial outcomes in phase I (START) for SMA Type I. At the end of the study patients receiving the therapy survived and did not require permanent ventilation. Since onasemnogene abeparvovec corrects the underlying genetic defect and is distributed systemically, it has a high potential to stop SMA progression or protect from SMA if treatment intiates at the presymptomatic phase. A number of open label phase III trials are still ongoing to evaluate the efficacy in SMA Type I patients who have either one or two copies of the SMN2 gene. To find out more about these, click here.
Nusinersen is an anti-sense oligonucleotide treatment for SMA80,81 developed by researchers at Cold Spring Harbour Laboratories (NY, USA) and Ionis Pharamaceuticals and marketed by Biogen. It is a 29-O-(2-methoxyethyl) modified ASO which targets Intronic Splicing Silencer N1 (ISS-N1) and enhances full-length SMN mRNA transcript. Nusinersen is administered by an intrathecal injection of 12 mg in four loading doses which is then followed by a maintenance dose once every 4 months. It is predominantly distributed in the central nervous system and can thus effectively target motor neurons.
Nusinersen has been evaluated in clinical studies for a range of SMA subtypes: NURTURE trial, ENDEAR trial and CHERISH trial. The NURTURE trial was an open label phase II trial with pre-symptomatic infants genetically diagnosed with SMA.126 The ENDEAR trial was a randomised placebo-controlled phase III clinical trial with Type I SMA infants.122 CHERISH trial was a double blind, placebo controlled trial with late onset Type II SMA.123 In the ENDEAR trial motor milestones were achieved in 41% of the patients. Motor functions were also improved in patients in the CHERISH trial.123 However, the greatest overall improvement in motor milestones and mobility assessed by the Hammersmith Infant Neuromuscular Examination (HINE) score was higher when treatment was carried out in pre-symptomatic infants. Based on these clinical trials data, the timing of intervention is a crucial determinant for the treatment efficacy.
Clinical trials for spinal muscular atrophy
There are several ongoing clinical trials evaluating new treatments for spinal muscular atrophy (SMA) and different disease management strategies. New therapeutics being developed are based on restoring the SMN protein (SMN targeted), or increasing muscle protection (SMN independent) (Figure 9).
SMN targeted therapies in clinical development
In addition to the already approved (see 'Treatment guidelines' page in this section) onasemnogene abeparvovec and nusinersen, small molecules targeting SMN2 splicing are being developed to increase full length SMN protein. Of these risdiplam (Roche) and branaplam (Novartis) are at various stages of clinical development.
Risdiplam (RO7034067) is a small molecule pyridazine derivative for SMA treatment developed collaboratively by PTC therapeutics, Genentech, Roche, and the SMA Foundation.87,88 It acts by modifying splicing of SMN2 transcript to increase full-length SMN protein. Risdiplam has a high specificity for SMN2 to an exonic splicing enhancer site within the SMN2 pre-mRNA and also stabilizes the interaction between SMN2 pre m-RNA and the spliceosome.89
Risdiplam is administered orally, can cross the blood-brain barrier and shows a systemic distribution.90 In preclinical models of SMA risdiplam showed improved survival, body weight and normal, healthy neuromuscular pathology.87 It was also well-tolerated in phase I trials for safety in healthy volunteers (NCT02633709.) Currently, risdiplam is being evaluated in several phase II/III clinical trials enrolling patients of different SMA subtypes (Figure 10).
FIREFISH trial (NCT02913482)
The primary purpose of this open-label phase II/III trial was to assess safety, PK, PD and efficacy of risdiplam in Type I SMA. All participants were between 1–7 months of age and had two copies of the SMN2 gene.
The study was divided into two parts, the first to establish the optimal dosing (exploratory) and the second to evaluate the efficacy of treatment at the optimal dose as assessed by motor milestones (confirmatory). Overall, risdiplam is well tolerated.128
The primary outcome measure of the study was the proportion of infants sitting without support for at least five seconds at 12-months of treatment, assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III).134
Results from the second part of the study were presented at the 2020 AAN and EAN virtual congresses. The FIREFISH Part 2 study met its primary endpoint by demonstrating a significant increase in motor milestones in infants aged 1-7 months after 12 months of treatment and confirmed the clinically meaningful efficacy seen in the dose-finding Part 1 of the trial. At the time of analysis, the median duration of treatment was 15.2 months and the median age was 20.7 months. Ninety-three percent (38/41) of infants were alive and 85.4% (35/41) were event-free without the need for permanent ventilation. Without treatment, the median age of death or permanent ventilation was 13.5 months in a natural history cohort. In an exploratory endpoint, 95% of infants who were alive at 12 months (36/38) maintained the ability to swallow and 89% (34/38) were able to feed orally. In contrast, in a natural history cohort, all infants with Type 1 SMA older than 12 months required feeding support. 136,137
Sunfish trial (NCT02908685)
This is a randomised, placebo-controlled, two-part phase II trial to assess the safety, PK, PD and efficacy of risdiplam in Type II and Type III SMA and notably, is the first to deliver pivotal placebo-controlled data on a broad SMA patient population including children, teenagers and adults.
Part one of the study aimed to assess the safety profile and obtain the optimal dose (for use in part two), with participants given oral risdiplam daily for 12 weeks. Part two evaluates the dose selected from part one on improving and/or stabilising motor score. Pivotal 12-month data was presented at the SMA Europe 2nd International Scientific and Clinical Congress in February 2020 and demonstrated risdiplam efficacy in both primary and secondary endpoints.
Specifically, this data showed a significantly greater change from baseline in the primary endpoint of the Motor Function Measure scale (MFM-32) versus placebo (1.55 point mean difference, p=0.0156) and improvement in the Revised Upper Limb Module (RULM), a key secondary endpoint (1.59 pint difference, p=0.0028).
Exploratory sub-group analyses were also presented and showed that the strongest change in MFM-32 was observed in the youngest study cohort (2-5 years), with disease stabilisation observed in the adult (18-25 years) group.133
Jewelfish trial (NCT03032172)
This is an open-label trial designed to assess the safety and tolerability of risdiplam in infants, children and adults with SMA. The study participants have either received nusinersen, olesoxime or onasemnogene abeparvovec, or were previously enrolled in the MOONFISH trial (which is now terminated). All participants receive risdiplam orally every day for 24 months, with any adverse events and significant changes in blood biomarkers monitored.
Rainbowfish trial (NCT03779334)
This is an open-label phase II trial to determine the PK, PD and efficacy of risdiplam in pre-symptomatic infants with a genetically confirmed diagnosis of SMA. Risdiplam will be given orally daily for two years. The study is currently recruiting and is estimated to be completed by 2025.
Branaplam (LMI070, NVS-SM1; developed by Novartis) is a pyridazine derivative, which corrects splicing defects in the SMN2 gene by stabilising the interaction between SMN2 pre-mRNA and spliceosome. This leads to an increase in the levels of full-length functional SMN protein. Branaplam was shown to be protective in severe preclinical models of SMA by improving body weight and survival.85
Branaplam is administered orally and can cross the blood-brain barrier. It is being evaluated in an open-label phase I/II clinical trial (NCT02268552) for safety, tolerability, pharmacokinetics (PK), Pharmacodynamics (PD) and efficacy in infants with Type I SMA. Infants recruited into the study have two copies of the SMN2 gene. The drug is administered every week for 13 weeks. The primary purpose of this trial is to identify optimal dosing, which is well tolerated and efficacious in treating Type I SMA.127 Initial publication reported only ‘mild, reversible and manageable’ adverse events. Study participants also showed improvements in motor skills.127 The trial was paused in 2016 due to concerns arising from animal studies where the compound caused renal toxicity and damage to peripheral nerves. The trial resumed in 2017 but participants were subsequently monitored for neurotoxic adverse events by periodic nerve testing. Currently, enrolment into the study has closed, and results are expected by the end of July 2020. Find out more, here.
SMN independent therapies in clinical development
SMN independent strategies include drugs that aim to treat the neuromuscular dysfunction in SMA by enhancing muscle function.
Reldesemtiv (CK-2127107) is a fast muscle troponin activator that enhances muscle contractility. This compensates for the reduction in nerve signalling that occurs in SMA due to motor neuron death. It is being developed in collaboration with Astellas and Cytokinetics. It is well-tolerated, and no toxicity has been reported in phase I clinical trial. In a phase II double-blind, placebo-controlled trial (NCT02644668) to assess efficacy in SMA Type II, III and IV, reldesemtiv demonstrated benefits to endurance and stamina.129 There is increased interest in using it in combination with therapies that target SMN protein (see the 'Future landscape' page in this section).
SRK-015, developed by Scholar Rock, is a drug that enhances muscle mass by selectively inhibiting latent myostatin. In mouse models of SMA, it can increase muscle mass and function.130 It is also shown to be well tolerated in phase I trials. Recruitment into an open label phase II trial (NCT03921528) to evaluate its efficacy in Type II and Type III SMA is ongoing.
Myostatin, activins, and bone morphogenetic protein 9 (BMP9) are related growth factors with shared signaling pathways. Previous attempts to inhibit myostatin have resulted in safety concerns thought to be related to off-target effects on BMP9. BBI110 was originally developed by AliveGen and is currently in development by Biogen. BIIB110 is a hybrid inhibitor that acts on both myostatin and activins, but not on BMP9. The theory is that combined inhibition of myostatin and activins (but not BMP9) may boost the effect of the drug on muscle function, while improving the safety profile.131
In addition to the clinical trials involving new drugs, a number of trials that look into effective ways of disease management are also ongoing. For instance, a trial to assess non-invasive ventilation in providing respiratory assistance to patients with SMA (NCT03395795).
Future treatment landscape for spinal muscular atrophy
A few themes have emerged from recent research and clinical studies of spinal muscular atrophy (SMA) which emphasise a proactive and multidisciplinary approach to disease. One of these highlights the need for the early diagnosis and intervention before irreversible motor neuron damage. There is an increasing emphasis on newborn screening (see the 'Treatment guidelines' page in this section) for SMN1 mutations and SMN2 copy numbers.
Disease severity and progression is linked to the SMN2 copy number. Early intervention with treatments that restore SMN will be extremely beneficial for all infants with SMA but particularly those with low SMN2 copy numbers.
Restoring the SMN function has emerged as an essential strategy to modify disease. An improved understanding of SMN2 splicing has spurred the development of better-targeted strategies that modulate SMN2 splicing to enhance exon 7 inclusion.78,132 There are already some approved treatments like onasemnogene abeparvovec and nusinersen (see the 'Treatment guidelines' page in this section) that address this underlying genetic defect in SMA. Moreover, other small molecules such as risdiplam and branaplam (see the 'Treatment guidelines' page in this section) are at various stages of development. New drugs entering the market are likely to lower costs and improve the accessibility for patients.
SMA has been traditionally regarded as a motor neuron disease but there is increasing evidence for the whole-body complications of this disease. This evidence is being considered in the development of new disease monitoring and management strategies. The effects of SMN deficiency on cells other than motor neurons is increasingly being understood, but preclinical data suggest restoring SMN systemically may be more beneficial. As such, the small molecules which can be administered orally and have a systemic distribution may offer an advantage.
Beyond therapies that directly target SMN protein, some candidates aim to improve the cellular functions affected by SMN deficiency such as modulating actin dynamics, or endocytosis. Others work to enhance motor neuron survival and muscle function. There is an increased interest in combining these therapies with SMN targeted therapies. This approach may be beneficial in people with later onset and diagnosis of the disease.
Given the broad spectrum of SMA, there is a significant requirement to monitor disease progression and response to therapy accurately. Biomarkers are needed for neuromuscular dysfunction and complications associated with other organs. Translational research within ongoing clinical trials are likely to yield useful information that can inform the development of these biomarkers.
Learn about the core strategies for restoring SMN protein here.
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M-XY-00000009 Date of preparation: July 2020.