
==== Front
Neurotherapeutics
Neurotherapeutics
Neurotherapeutics
1933-7213
1878-7479
Elsevier

S1878-7479(24)00123-5
10.1016/j.neurot.2024.e00437
e00437
Review
Clinical decision making around commercial use of gene and genetic therapies for spinal muscular atrophy
Waldrop Megan A. megan.waldrop@nationwidechildrens.org
ab
a Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus OH, 43205, USA
b Departments of Pediatrics and Neurology, Wexner Medical Center, Ohio State University, Columbus OH 43205, USA
05 9 2024
7 2024
05 9 2024
21 4 e004371 4 2024
28 7 2024
15 8 2024
© 2024 The Author
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Spinal muscular atrophy is no longer a leading cause of inherited infant death in the United States. Since 2016, three genetic therapies have been approved for the treatment of spinal muscular atrophy. Each therapy has been well studied with robust data for both safety and efficacy. However, there are no head-to-head comparator studies to inform clinical decision making. Thus, treatment selection, timing, and combination therapy is largely up to clinician preference and insurance policies. As the natural history of spinal muscular atrophy continues to change, more data is needed to assist in evidence-based and cost-effective clinical decision making.

Keywords

Gene therapy
Spinal muscular atrophy
Risdiplam
Nusinersen
Onasemnogene abeparvovec
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pmcIntroduction

Genetics of 5q SMA

Although the initial clinical descriptions of spinal muscular atrophy were in the late 1890s, the location of gene responsible for spinal muscular atrophy was not narrowed to the long arm of chromosome 5q until the 1990s [[1], [2], [3], [4]]. Quickly thereafter, in 1995, the survival motor gene was identified [5]. There is an inverted duplication with 2 nearly identical copies of the gene; one produces full length functional transcripts (SMN1) and the other produces significantly reduced numbers of functional transcripts (SMN2). The homozygous loss-of-function nature of the disease, along with the presence of a “backup” gene producing some full-length transcript was promising for therapeutic development. The first therapeutic trials attacking the genetic mechanism of SMA began in the fall of 2011 (NCT01494701) and many additional trials quickly followed.

Historical natural history of SMA

The incidence of SMA is ∼1:14,000 in the United States but varies around the world from 1:3900 to 1:16,000 [[6], [7], [8], [9], [10]]. Historically, individuals with SMA were classified based on clinical features and motor function skills achieved (Table 1). Although there is some variability seen between individuals with the same number of SMN2 copies, the generalization that increasing number of SMN2 copies results in a milder phenotype classification largely holds true [11,12]. There are two clear modifiers that result in milder disease phenotype, and the c.859C ​> ​G in SMN2 has been an exclusion criteria in some trials [13,14].Table 1 Historical Phenotypic classification of spinal muscular atrophy.

Table 1	Age of onset	Highest achieved motor milestone	Life expectancya	Proportion of SMA patients	SMN2 copies	
Type 0	Birth	Never sitting	<6 months	<1%	1	
Type I	<6 months	Never sitting	8–24 months	50–60%	2–3	
Type II	6–18 months	Sitting	20's-30's	30%	2–4	
Type III	18 months - 30 years	Walking	Normal	10%	3–5	
Type IV	>30 years	Walking	Normal	5%	3–5	
Reproduced without modification from Nicolau S, Waldrop MA, Connolly AM, Mendell JR. Spinal Muscular Atrophy. Semin Pediatr Neurol. 2021;37:100878. PMID: 33892848.

a Without disease modifying therapies or mechanical ventilation.

In anticipation of development of disease modifying therapies, several natural history studies were completed in all subtypes of SMA beginning in the early 1990s [[15], [16], [17], [18], [19]]. Two natural history studies of children with SMA type 1 were critical to initial drug approvals [20,21]. Without treatment, these children never achieve the ability to sit, develop feeding and respiratory failure in infancy and have a significantly shortened life expectancy [21]. A retrospective study confirmed historical studies where a median age of death or 16 ​h per day of ventilatory support by 13.5 months of age [20]. The second study was a prospective study that found the median age of death or permanent ventilation to be 8 months [21].

An additional natural history study of individuals with SMA type 2 or 3 was critical for subsequent drug approvals [22]. Individuals with type 2 SMA have symptom onset between 6 and 18 months of age. These children achieve the ability sit but never walk. They experience a slow progressive decline, with some periods of plateaus in function [19]. Lifespan for children with SMA type 2 is shortened due to weakness of the respiratory muscles and progressive scoliosis. Winjgaarde et al. endpoint free survival probabilities of 74.2% at 40 years and 61.5% at 60 years [11]. In SMA type 3, symptoms begin after 18 months of age with all achieving the ability to walk and quite a range in age when loss of ambulation occurs [[23], [24], [25]]. As is seen in SMA type 2, there can be periods of stability. Lifespan is typically normal due to limited respiratory muscle weakness. The mildest form of SMA is type 4 and these individuals do not experience any symptoms until adulthood with proximal muscle weakness and a normal lifespan [[26], [27], [28]].

The most severe type of SMA is also the least common. SMA type 0 has significant symptom onset in utero and these infants are severely symptomatic upon delivery. They require immediate respiratory support and death often occurs within the first few months of life without significant interventions [29].

Nusinersen

Nusinersen, an antisense oligonucleotide delivered intrathecally (Table 2), was the first genetic therapy in clinical trial in the fall of 2011. Nusinersen works by promoting inclusion of exon 7 in the SMN2 transcript to increase full length SMN2 mRNA and subsequent functional SMN protein [30]. The initial phase 1 trial to establish dose and safety was conducted in individuals ages 2–14 years of age with SMA types 2 and 3 [31]. Several studies have since been completed in both symptomatic and presymptomatic individuals with SMA types 1, 2 and 3 clearly showing efficacy and continued safety (Table 3) [[32], [33], [34], [35]]. Nusinersen was approved in December 2016 in the US for all individuals with SMA. Approvals in Europe and Canada followed shortly in 2017 and now it is approved in over 60 countries [36,37]. Nusinersen is the most thoroughly studied with approximately 12,000 dosed to date and side effects are largely related to complications from the lumbar punctures. After approval, there were reports of increased intracranial pressure and some individuals requiring shunts, but these complications are no longer being reported [38]. Additional rare complications include proteinuria, thrombocytopenia, and coagulation abnormalities. Studies in adults remain observational [[39], [40], [41], [42]]. Currently the dose is 12 ​mg in all individuals and dose escalation studies are underway [43].Table 2 FDA Approved therapies for spinal muscular atrophy.

Table 2	Nusinersen	Risdiplam	Onasemnogene abeparvovec-xioi	
Class	Antisense oligonucleotide	Small molecule	AAV-delivered gene therapy	
Mechanism of action	Enhances splicing of SMN2 to full-length SMN protein	Enhances splicing of SMN2 to full-length SMN protein	Delivers a functional human cDNA SMN1 transgene	
Route of administration	Intrathecal	Oral	Intravenous	
Dose	12 ​mg	<2 ​m 0.15 ​mg/kg
2 ​m to <2yr 0.2 ​mg/kg
≥2yr, <20 ​kg 0.25 ​mg/kg
≥2yr, ≥20 ​kg 5 ​mg	1.1 x 1014 vg/kg	
Frequency	4 loading doses in the first 2 months, then every 4 months	Daily	Single dose	
FDA-approved age ranges	All	All	<2 years	
Limitations to treatment	Inability to undergo lumbar puncture	Drug interactions	Presence of AAV9 antibodies at baseline	
Baseline evaluation	Platelet count
Coagulation studies
Urinalysis	None	Liver function tests
Platelet count
Troponin-I
AAV9 antibody titer
Prednisolone treatment for 30 or more days	
Adverse events	Thrombocytopenia
Proteinuria
Lumbar puncture complications	Fever
Diarrhea
Rash	Acute liver injury
Transaminitis
Thrombocytopenia
Troponemia	
Monitoring	Platelet count
Coagulation studies
Urinalysis
Opening pressure	None	Liver function tests
Platelet count
Troponin-I
Weight gain
Urine output	
Cost	375,000–750,000/yr	100,000–350,000/yr	2.15 million one time	
AAV ​= ​adeno-associated virus, FDA = United States Food and Drug Administration, SMN ​= ​survival motor neuron, m ​= ​month, y ​= ​year.

Reproduced with modification from Nicolau S, Waldrop MA, Connolly AM, Mendell JR. Spinal Muscular Atrophy. Semin Pediatr Neurol. 2021;37:100878. PMID: 33892848.

Table 3 Representative summary of clinical trials in SMA.

Table 3

Onasemnogene abeparvovec

The first clinical trial for onasemogene abeparvovec (OA) was initiated in 2014 with 15 infants enrolled [44]. OA uses an adeno-associated virus (AAV9) delivery system to introduce non-integrating SMN1 cDNA and is referred to as gene replacement therapy. The initial study was a dose finding and safety study, but clear functional benefit was seen in all 12 infants in the high dose cohort. One achieved stability in motor function and 11 others had significant improvements in function. Additional completed trials in early symptomatic and presymptomatic children confirmed significant and sustained improvements in function [[45], [46], [47], [48]]. OA was approved in May 2019 in the US for individuals with SMA under 2 years of age and without end-stage disease. Approval in Europe was obtained in June 2020 and a clinical diagnosis of SMA type 1 or up to 3 copies of SMN2 [49]. OA is now approved in 51 countries with approval definitions varying by country [50]. The most common complications seen with administration of OA are the temporary effects of daily prednisone use, elevations in AST, ALT and occasionally GGT as a result of the AAV9 effect on the liver, nausea, vomiting, thrombocytopenia, and asymptomatic troponin I elevations [51]. Rare complications include liver failure and death which seem to be related to abnormal liver function prior to treatment, development of severe illness around the time of treatment, atypical hemolytic uremia syndrome or thrombotic microangiopathy [52,53]. There have also been two reports of cancer in children many months post dosing [54]. Clinical trials assessing intrathecal administration to allow for dosing of larger and older individuals, were briefly halted after concerns arose due to dorsal root ganglia toxicity [55,56], but are again underway (NCT05089656, NCT05386680) [57].

Risdiplam

Clinical trials for risdiplam began in 2016. Risdiplam, with a mechanism of action similar to nusinersen, is a small molecule that can be taken orally. It is also a SMN2 splicing modifier that works by increasing inclusion of exon 7 in SMN2 [58]. Risdiplam has been studied in infants and adults with a good safety profile and significant improvements in function [[59], [60], [61], [62]]. Risdiplam was initially approved in the US for any individual with SMA over 2 months of age in 2020, but this was revised in 2022 to include individuals with SMA of all ages. Initial approval in Europe was in 2021 and approval was expanded to all ages in 2023 [63]. Risdiplam is now approved in over 100 countries [64]. Risdiplam dosing is age and weight based until 20 ​kg and then all receive the same dose. Risdiplam has not had any significant safety concerns in humans [65,66]. Drug-drug interactions with MATE transporters exist, so all new medication additions need to be reviewed for potential interactions.

Newborn screening

SMA was added to the Recommended Uniform Screening Panel in the US in July 2018. Missouri, Ohio, Utah and New York were among the first states to implement screening [67]. As of January 2024, all 50 states and Washington DC are screening for SMA. Each state chooses how to implement the program so some states are only screening for SMN1 homozygous deletions, while other states are also screening for SMN2 copy number at the time of birth. Newborn screening programs are also underway in several countries in Europe, Australia, Canada, Japan, Qatar, and Taiwan. With the approval of three disease transformative therapies between 2016 and 2020 and the implementation of newborn screening beginning in 2018, the natural history of spinal muscular atrophy has dramatically changed. Earlier treatment has led to improved functional outcomes for all and remarkable outcomes in most children with SMA. However, a subset of children with 2 copies of SMN2 still experience significant symptoms despite functional gains [[68], [69], [70]].

Clinical decision making in the SMA treatment era

A new era in spinal muscular atrophy has arrived and clinical decision can be quite complex. Unfortunately, there are no head-to-head trials comparing the three available treatments and each clinical trial population studied was slightly different from the others making even indirect comparisons difficult (Table 3) [71]. In an ideal scenario the clinician would be able to evaluate the evidence and determine which treatment option is likely to be most efficacious for each individual. However, in the setting of limited evidence, clinicians often rely on their prior clinical experiences and comfort level with these options. Further complicating the decision making is the significant role that insurance coverage can play in treatment availability for individuals.

Safety screening

Two of the three approved medications have significant safety concerns. To mitigate potential complications and determine eligibility, screening laboratories are required and are an important consideration in clinical decision making. For nusinersen, an antisense oligonucleotide, there is a risk of thrombocytopenia and kidney toxicity, so normal platelets and kidney function is required. Additionally, due to intrathecal administration, a normal coagulation profile may also be required [72]. Onasemnogene abeparvovec is an AAV9 mediated gene replacement therapy that delivers a large viral load which may trigger both complement mediated and T cell mediated immune responses [73]. If AAV9 antibodies are present, it is not safe to proceed with therapy. If the individual is a newborn, the AAV9 antibodies may be maternal and retesting in 4–6 weeks may result in a negative test result and eligibility for therapy [74]. Retesting may also be considered in older individuals. There are also significant risks of thrombocytopenia, kidney injury and livery injury post dosing, so normal platelets, and normal kidney and liver function are required prior to administration. If any of these abnormalities are present, risdiplam may be the only safe option for treatment.

Infants identified via newborn screening

When an infant arrives to the neuromuscular clinic, typically within the first week of life, the visit may vary depending on parent/caregiver comfort and desired information. In all scenarios, a thorough history and exam are completed and then a lengthy discussion of spinal muscular atrophy begins in reader friendly plain language. Most parents/caregivers wish to discuss all available treatment options, including known risks and benefits of each. However, some parents/caregivers have difficulty accepting the diagnosis and wish to await confirmatory testing before fully exploring treatment scenarios. In these cases, a follow up visit is scheduled on the day confirmatory results return. Typically, parents/caregivers are open to completing the needed screening laboratory testing at the initial visit to avoid additional blood draws and to minimize delays in treatment initiation if the SMA diagnosis is confirmed. In some scenarios when copy number is known, clinicians and parents/caregivers choose to initiate risdiplam utilizing a free drug program for all infants with 2 copies of SMN2. If copy number is not available at the initial visits, due to ease of administration and minimal side effects, the risdiplam free drug program is being increasingly utilized to ensure that best outcomes can be obtained. If the child's confirmatory testing returns negative, the drug will be discontinued. Regardless of the results of the SMN2 copy number when the diagnosis is confirmed, many parents will continue the risdiplam until the free supply is depleted. The ultimate goal is to begin treatment as soon as possible, on the day of the first visit, if possible.

Treatment selection is variable and is first driven by the available products considering the infants SMN2 copy number and country, followed by if any safety concerns arise during the screening process. Finally, treatment selection may be impacted by insurance coverage. With the goal of immediate treatment initiation, risdiplam is typically the first treatment and then the infant is switched over to onasemnogene abeparvovec once insurance approval is obtained. Infants are followed monthly to every three months in the first year of life and most do well. All infants with 3 or more copies of SMN2 and ∼50% of infants with 2 copies of SMN2 meet all motor milestones [68,70]. For those infants who have 2 copies and are suboptimal responders, the resumption or addition of risdiplam may provide benefit. Based on the knowledge that SMN protein levels are highest in utero and decrease significantly in the first few months of life [75], early dual or combination therapy may be most beneficial. This is currently under active investigation (NCT05861986, NCT05861999l). In the clinic setting, if gross motor development becomes delayed, risdiplam may be resumed.

Treatment initiation for infants identified with 4 copies of SMN2 remains controversial. A consensus statement that was developed before the approval of onasemnogene abeparvovec or risdiplam advocated for treatment of infants with 2 or 3 copies of SMN2, but consensus could not be achieved for infants with 4 copies of SMN2 [76]. However, this was updated in 2020 to recommend immediate treatment of infants with 4 copies [77]. This recommendation was based on data that clearly shows early treatment results in better outcomes and that significant motor neuron loss occurs prior to functional changes are seen. The recommendation remains to monitor those with 5 copies of SMN2. In the United States, infants with 4 copies of SMN2 are eligible for all approved therapies based on FDA approval definitions, although some insurance policies do exclude individuals with 4 copies. In Europe and other countries, drug approvals vary and 4 copies may be excluded, most often for onasemnogene abeparvovec. Given that infants with 4 copies are much less common, data gathered from registries may be the only way to support this recommendation with the current absence of strong biomarkers.

Treatment of an infant with 1 copy of SMN2 has been done with some improvement, but significant residual weakness and the need for continued nutritional and respiratory support [78]. Due to the severity of weakness after treatment with two therapies, review with an ethics panel is recommended before making any treatment decisions in these infants. Additionally, it is unlikely that treatment will be covered by insurance companies as most have stipulations for end-stage disease or severe weakness.

Symptomatic infants and children

Symptomatic infants and children include those born prior to newborn screening implementation but also the ∼5% of infants who will be missed by newborn screening and those born in areas where newborn screening has not yet been implemented. Treatment initiation as soon as possible is essential. At the initial visit, all available treatment options based on the age and/or weight of the child should be discussed, and screening laboratories sent for onasemnogene abeparvovec and nusinersen, if applicable. Because both risdiplam and nusinersen offer free or starter drug programs, these are typically the quickest to initiate. Nusinersen is becoming less popular in the pediatric population due to the need for repeated lumbar punctures and the potential need for sedation. If the child is eligible for onasemnogene abeparvovec and the provider anticipates insurance approval within a week, it may be appropriate to forego starting the child on risdiplam or nusinersen. However, if the provider anticipates any delays, risdiplam or nusinersen should be initiated to preserve as much motor neuron function as possible.

After initial treatment has begun, clinical practices further vary based on if and when to initiate an additional agent. This is an area with limited evidence, although there are clinical trials that are attempting to answer these questions (NCT05861986, NCT05861999, NCT05115110, NCT05156320, NCT04488133). Insurance coverage also has a large impact on the availability of dual or add-on therapy outside of clinical trials. If the child has a decline in function after a period of improvement or stability on a treatment regimen, the addition or change of treatment is reasonable.

Symptomatic adults

This group encompasses adults who were diagnosed as children or adults but did not have access to therapies until symptomatic in adulthood. For these individuals, risdiplam may be the only option due to prior spinal fusion surgery. Nusinersen has been given via reservoirs or cervical access, but this approach has not been widely used, perhaps due to the availability and ease of use of risdiplam [[79], [80], [81], [82]]. Additional consideration is given to those with long-standing disease duration prior to treatment initiation since earlier treatment is known to result in best outcomes. However, even in later stage disease, treatment with nusinersen or risdiplam may provide benefit and thus should be offered as preservation of residual function can impact quality of life [66,83,84]. For those diagnosed in adulthood with minimal disease progression prior to treatment initiation, risdiplam and nusinersen should be considered. The potential reproductive impact of risdiplam may lead to a preference for nusinersen in some individuals [85].

In each of the above categories, many questions remain unanswered (Table 4). In every group, highly reliable biomarkers would provide data to assist in decision making. At the moment, neurofilament and compound muscle action potentials are under investigation, but neither is used routinely in clinical practice and it is still not clear if these markers are sufficiently robust to inform clinical decisions [68,70,[86], [87], [88], [89]]. Patient reported outcomes may be another avenue to monitor for disease progression, treatment response, and treatment persistence.Table 4 Remaining clinical questions in the treatment of SMA.

Table 4Newborn screening	How can we best identify the optimal and suboptimal responders for 2 copy infants?
How early do the suboptimal responders need to be identified (in utero/day 1 of life)?
If identified early enough, will suboptimal responders only need mono therapy?
How long will treatment effect persist?
Are there any consequences to long term high SMN expression?
Which infants with 4 or more copies need early treatment initiation?
Is it important to include SMN2 copy number in the screen results?	
Symptomatic children	Which treatment is best?
Which children will need combination therapy?
What is the maximum anticipated benefit?	
Symptomatic adults	What is the maximum anticipated benefit?
How do we determine in whom we can expect benefit and in whom we can expect stabilization?
Which treatment is best?	
Presymptomatic children and adults	Can we identify a biomarker to determine when it is best to initiate treatment?	

Clinical decision making regarding treatment selection in spinal muscular atrophy is currently a tiered process based on limited comparative evidence. Physicians and parents/caregivers should have discussions regarding the risks and benefits of the available options. Screening laboratories may reduce available options and then finally, insurance approval or denial may dictate which treatment(s) the individual will receive. Further work to harmonize clinical trial outcome assessments, long term outcomes and biomarker development will be important to provide more evidence based and fiscally responsible care.

Author contributions

MAW is the sole author of this review. MAW confirms that this is original work that has not been submitted elsewhere.

Declaration of competing interest

MAW has received clinical trial support from and served as an advisory board member for Novartis Gene Therapies.

Acknowledgements

This publication was supported in part by the AHRQ-PCORI funded PEDSnet Scholars Training Program 5K12HS026393-03, which is a national faculty development program that trains individuals in the competencies of learning health systems science.
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