Onasemnogene abeparvovec (OA) is the only gene replacement therapy currently approved for spinal muscular atrophy (SMA) treatment. We sought to assess real-world patient and caregiver outcomes after OA treatment for SMA.
Methods
Patients who received OA were identified from the 2021 Cure SMA Membership Survey. Those treated at 6–23 months of age were matched to non–patients treated with OA on the basis of age at the time of survey and survival motor neuron 2 gene copy number. Patient characteristics, motor milestones, and resource and supportive care use, as well as caregiver proxy-reported health-related quality of life (HRQOL), were described. Caregiver unmet needs and HRQOL were also assessed.
Results
Of the 614 patients in the survey, 64 received OA, and 17 were matched with 28 non–OA-treated patients. In general, a greater percentage of OA-treated patients achieved various motor milestones, including 100% sitting without support and 58.8% walking with assistance. OA-treated patients also had numerically lower rates of hospitalization and surgery. None required tracheostomy with a ventilator. The rate of using oxygen or a breathing machine for more than 16 h was also lower for OA-treated patients. OA-treated patients had less frequent trouble swallowing. HRQOL was reported to be similar to non–OA-treated patients. Caregivers of OA-treated patients reported better patient mobility scores and less work impairment.
Conclusions
The study suggests that treatment with OA is associated with greater rates of motor milestone achievements and less resource and supportive care use for patients with SMA treated at 6–23 months of age in the real world. For caregivers, it may also potentially reduce unmet needs, improve HRQOL, and reduce work impairment.
Spinal muscular atrophy exhibits substantial impact on patients and families, including requirements for mobility, nutritional, and respiratory support for patients and economic burdens and health-related quality of life impairments for families.
Understanding real-world outcomes for patients and their caregivers, particularly after disease-modifying treatments, is important.
We sought to assess real-world patient and caregiver outcomes after onasemnogene abeparvovec treatment for spinal muscular atrophy by identifying patients who received onasemnogene abeparvovec from the 2021 Cure SMA Membership Survey.
What was learned from this study?
We found that treatment with onasemnogene abeparvovec was associated with greater rates of motor milestone achievements and less resource and supportive care use for patients with spinal muscular atrophy who were treated at 6–23 months of age in the real world.
For caregivers of onasemnogene abeparvovec-treated patients, unmet needs may be reduced, health-related quality of life may be improved, and fewer work impairments may be reported.
Introduction
Spinal muscular atrophy (SMA) is a rare, genetic, neuromuscular disease characterized by progressive muscle weakness and atrophy. The most common form of SMA is caused by homozygous disruption of survival motor neuron1 gene (SMN1) on chromosome 5q [1, 2], with an estimated incidence of 1:6000 to 1:10,000 live births [2, 3]. With an early childhood onset, untreated SMA is the leading genetic cause of infant mortality [2]. Patient phenotype, including disease severity, is determined mainly by the number of survival motor neuron 2 (SMN2) gene copies, which are inversely associated with disease severity [4]. Clinically, SMA is typically classified into four types—SMA type 1 to type 4—based on the age of disease onset and the achieved motor milestones [2, 3, 5, 6]. SMA type 1 typically presents with severe weakness and hypotonia, with respiratory and bulbar function impairments developing within the first 6 months of life. Without intervention, these patients generally do not live beyond 2 years [2, 3]. Patients with SMA type 2 typically have symptom onset between 6 and 18 months of age. These patients are unable to walk independently and have trouble breathing, chewing, and swallowing, and have a reduced life expectancy, but generally survive into adulthood [2, 3]. Patients with SMA type 3 usually develop initial symptoms after 18 months of age. Although type 3 patients have a normal life expectancy, muscle weakness can occur over time [2]. SMA type 4 is the least common type for live births, with less severe symptoms that present during adulthood (usually in the second or third decade of life) [2, 3, 5, 6]. In addition to these four types, SMA type 0 is rare and the most severe, with onset in utero and patients often survive only a few weeks or less [5, 6]. For all types, SMA type 1 and type 2 are the most common, accounting for approximately 60% and 30% of live births with SMA, respectively [3, 5, 6]. As SMA type is classified on the basis of disease severity and highly correlated with the number of SMN2 copies, most patients with two copies have type 1, whereas those with four or more copies have type 3 [4].
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Because of its early onset and severity, SMA can lead to substantial burden on patients and their families. Based on a recent literature review, the mean annual direct cost ranges from $75,047 to $196,429 in 2020 USD for SMA type 1, and from $27,157 to $82,474 in 2020 USD for SMA types 2–4 [7]. In addition to direct costs, the indirect costs associated with SMA, particularly informal care, are also substantial, accounting for 44–80% of the total costs in various countries [8, 9]. Beyond the economic burden, SMA can substantially impair the health-related quality of life (HRQOL) of patients and caregivers [8, 10, 11].
Historically, patients with SMA were mostly treated with supportive care, such as mobility, nutritional, and respiratory support, as well as orthopedic/rehabilitative care [3]. The development of disease-modifying therapies (DMTs), including nusinersen, onasemnogene abeparvovec, and risdiplam, has drastically improved the treatment of SMA. Onasemnogene abeparvovec is the only gene replacement therapy with a one-time treatment delivering a construct capable of expressing full-length and fully functional SMN into target motor neurons through an adeno-associated virus vector. Onasemnogene abeparvovec was approved by the US Food and Drug Administration (FDA) in 2019 [12] for the treatment of patients with SMA up to 24 months of age and by the European Medicines Agency (EMA) in 2020 for the treatment of patients with three or fewer SMN2 copies and weighing 21 kg or less [13]. Several clinical studies have demonstrated long-term safety and efficacy associated with onasemnogene abeparvovec treatment, demonstrating improvements in overall survival and motor function, along with a reduction in the need for nutritional and respiratory support compared with untreated natural history cohorts or nusinersen for patients with SMA type 1 [14‐21]. In addition, onasemnogene abeparvovec is considered cost-effective compared with nusinersen on the basis of published economic evaluations [22, 23].
Real-world evidence on patients with SMA and their outcomes in the post-onasemnogene abeparvovec era is scarce. Moreover, most clinical trials on onasemnogene abeparvovec only included patients younger than 6 months of age at time of treatment. Little evidence exists on the outcomes associated with onasemnogene abeparvovec for patients older than 6 months of age, even though the treatment is approved up to 24 months of age in the USA. To our knowledge, only two real-world studies describe the outcomes of patients treated with onasemnogene abeparvovec at age 6 months or older [24‐26]. However, these studies did not evaluate patient HRQOL outcomes and caregiver burden. Therefore, we sought to describe the patient characteristics of the general SMA population and onasemnogene abeparvovec-treated patients after onasemnogene abeparvovec approval, as well as real-world patient outcomes and caregiver burden for patients who were treated with onasemnogene abeparvovec at 6–23 months of age. In addition, to the extent possible, the study also evaluated the outcomes for patient subgroups defined by the number of SMN2 gene copies and SMA type.
Methods
Data Source
Cure SMA, a patient advocacy organization that provides support and funding for care and treatment of SMA, manages one of the largest self-reported databases for individuals affected with SMA. The database was launched and has been enrolling self-identified patients with SMA since 1996 [27]. The database includes information on patient demographics, SMA type, and diagnosis date. As of 2021, the database contained self-reported information on more than 9500 patients with SMA [28]. Beginning in 2017, adults with SMA and caregivers for living or deceased patients from the Cure SMA database have been invited to complete an online membership survey annually [29, 30]. The survey collects data on demographics and disease characteristics, clinical health outcomes, health care resource utilization, and disease burden from patients and caregivers [30]. Data from the 2021 Cure SMA Membership Survey were used for this study. Institutional review board approval was obtained for the membership survey and all data were de-identified prior to analysis.
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Study Samples
The study included different samples to address various objectives. First, all self-identified patients with SMA who responded to the 2021 Cure SMA Membership Survey were included in the analysis to represent the patient characteristics of the overall SMA population in the post-onasemnogene abeparvovec approval era (overall SMA sample). A subgroup of onasemnogene abeparvovec-treated patients from the survey were included for the evaluation of patient characteristics associated with onasemnogene abeparvovec treatment (overall onasemnogene abeparvovec sample).
For the analysis of patient and caregiver outcomes associated with onasemnogene abeparvovec treatment, patients treated with onasemnogene abeparvovec at 6–23 months of age were selected. This age range was chosen to supplement the currently published evidence from clinical trials, which only included patients treated with onasemnogene abeparvovec at 6 months of age or younger. To better understand the outcomes for patients treated with onasemnogene abeparvovec, a reference group with matched non–onasemnogene abeparvovec-treated patients was created. Specifically, each onasemnogene abeparvovec-treated patient was matched with up to two non–onasemnogene abeparvovec-treated patients on the basis of age at the time of the 2021 survey and number of SMN2 copies. This matching ratio was selected to maximize sample size in order to reduce the impact of rare events on the outcomes in the reference group. Patients who were reported to be deceased prior to the survey were excluded from the analysis. Caregivers of successfully matched patients were also included in the analysis of caregiver burden. In addition, the matched samples of patients and caregivers were further classified into subgroups based on the number of SMN2 copies and SMA type in a subgroup analysis.
Study Measures
Patient Characteristics
Patient demographics and disease characteristics were described for the overall SMA sample, the overall onasemnogene abeparvovec sample, and the matched sample. Demographics included age at the time of survey, sex, race/ethnicity, weight at the time of survey, relationship to patient, and death status (for the overall SMA and onasemnogene abeparvovec samples only). Disease characteristics included age at diagnosis, age at symptom onset, diagnosis delay, diagnostic screening, SMN2 copy number, SMA type, and age at onasemnogene abeparvovec treatment.
Patient Outcomes
Patient outcomes included motor milestones, resource and supportive care use, and caregiver proxy-reported outcomes.
Achieved motor milestones, obtained from the US Centers for Disease Control and Prevention (CDC) developmental milestones checklists [31], are commonly used to assess the motor function of patients with SMA. The percentage of patients who achieved each motor milestone was derived according to the milestones achieved at the time of the 2021 survey. Because the milestones are achieved at various ages, each motor milestone was assessed only for patients who reached the expected age to achieve that milestone at the time of the survey. Specifically, the denominators were adjusted on the basis of the following age cutoffs obtained from the CDC checklist [31]: head control at 4 months, voluntary grasping at 4 months, kicking at 4 months, rolling over at 6 months, hands and knees crawling at 9 months, sitting without support at 9 months, standing with support at 9 months, and walking with support at 12 months. Patients who were younger than the age cutoff and did not achieve the milestone or those with missing data were removed from the denominator.
Resource and supportive care use included hospitalization within the past 12 months, history of SMA-related surgeries, mobility device use, feeding tube use, and respiratory interventions.
Caregiver proxy-reported health outcomes included trouble swallowing, weak voice, and HRQOL. The membership survey uses the Health Utilities Index-2 (HUI-2) to measure HRQOL [32]. The HUI is a validated generic questionnaire designed to assess various attributes of HRQOL, including sensation, mobility, emotion, cognition, self-care, pain, fertility, vision, hearing, speech, ambulation, and dexterity. The HUI consists of a generic comprehensive health status classification and a generic HRQOL scoring system. The HUI-2 scores range from 0 (death) to 1 (perfect health).
Caregiver Outcomes
Caregiver outcomes included caregiver unmet needs, employment status, number of hours spent caregiving, the Assessment of Caregiver Experience in Neuromuscular Disease (ACEND), and the Work Productivity and Activity Impairment (WPAI) questionnaire. Caregiver unmet needs included emotional care, fatigue, financial assistance, flexible work schedule, and other unmet needs.
ACEND is a self-administered instrument used to assess the caregiver impact experienced when caring for children with neuromuscular disease across two domains: general caregiver impact and physical impact [33]. The Cure SMA survey data included the physical subdomains of transfers and mobility, with higher scores indicating less caregiver impact.
The WPAI is a validated instrument designed to assess the impact of a disease on productivity and ability to conduct regular activities over the last 7 days [34]. Though not yet validated in the SMA patient population, the WPAI has been used in SMA clinical assessments [29]. The WPAI outcomes included absenteeism (defined as the percentage of work time missed owing to health problems), presenteeism (defined as the percentage reduced productivity while working), overall work productivity loss (defined as the total percentage of work impairment owing to health problems from both absenteeism and presenteeism), and activity impairment (defined as the percentage of impairment in regular daily activities other than work).
Analysis
Continuous measures were described using means, medians, and standard deviations (SDs), whereas categorical measures were summarized using numbers and percentages. Outcomes were summarized descriptively for onasemnogene abeparvovec-treated patients compared with non–onasemnogene abeparvovec-treated patients in the matched sample, and the subgroups were stratified by SMN2 copy number and SMA type. However, statistical comparisons were not performed because of the limited sample size.
Results
Characteristics of the Overall SMA Population and Onasemnogene Abeparvovec-Treated Patients
A total of 614 patients with SMA responded to the 2021 Cure SMA Membership Survey. The mean age of the overall SMA sample at time of survey was 22.0 years (SD 18.9 years); 58.5% were female, and 78.2% were White (Table 1). Most (87.1%) patients were from the USA. The mean (SD) age at diagnosis was 56.7 (119.5) months, and 70.8% of the patients were diagnosed clinically. The majority of patients had two or three copies of SMN2 (25.7% and 32.9%, respectively), but nearly 30% had an unknown number of SMN2 copies. In terms of SMA type, SMA type 2 was most common, contributing to 42.0% of the overall SMA sample, followed by type 3 (26.7%) and type 1 (26.5%) (Table 1).
Table 1
Characteristics of the overall SMA population and onasemnogene abeparvovec-treated patients in the 2021 Cure SMA Membership Survey
Patient characteristicsa
Overall SMA sample (N = 614)
Overall OA-treated sample (N = 64)
Demographics
Age at time of survey (months)
263.9 (227.3)
25.0 (18.3)
Weight at time of survey (kg)
59.2 (392.1)
11.1 (4.2)
Female
359 (58.5%)
37 (57.8%)
Race/ethnicityb
White
480 (78.2%)
54 (84.4%)
Black/African American
14 (2.3%)
1 (1.6%)
Native American/American Indian
6 (1.0%)
1 (1.6%)
Hispanic/Latino
69 (11.2%)
8 (12.5%)
Asian/Pacific Islander
34 (5.5%)
4 (6.3%)
Other
43 (7.0%)
4 (6.3%)
Unknown
37 (6.0%)
0 (0.0%)
Country
USA
535 (87.1%)
60 (93.8%)
Other
40 (6.5%)
0 (0.0%)
Unknown
39 (6.4%)
4 (6.3%)
Relationship to patient
Caregiver
346 (56.4%)
64 (100.0%)
Disease characteristics
Age at SMA diagnosis (months)
56.7 (119.5)
3.9 (7.3)
Age at symptom onset (months)
6.9 (14.2)
2.6 (4.5)
Diagnostic screening
435 (70.8%)
61 (95.3%)
Prenatal screening
35 (5.7%)
10 (15.6%)
Newborn screening
48 (7.8%)
23 (35.9%)
Genetic testing
435 (70.8%)
61 (95.3%)
SMN2 copy number
One
15 (2.4%)
3 (4.7%)
Two
158 (25.7%)
37 (57.8%)
Three
202 (32.9%)
21 (32.8%)
Four
51 (8.3%)
2 (3.1%)
Five or more
7 (1.1%)
0 (0.0%)
Unknown
181 (29.5%)
1 (1.6%)
SMA type
0
2 (0.3%)
1 (1.6%)
1
163 (26.5%)
44 (68.8%)
2
258 (42.0%)
16 (25.0%)
3
164 (26.7%)
2 (3.1%)
4
9 (1.5%)
0 (0.0%)
Other/unknown
18 (2.9%)
1 (1.6%)
Treatment with OA
64 (10.4%)
–
OA onasemnogene abeparvovec, SMA spinal muscular atrophy, SMN2 survival motor neuron 2 gene
aMeans and standard deviations are presented for continuous characteristics; counts and percentages are presented for categorical characteristics, unless otherwise noted
bThe 2021 Cure SMA Membership Survey asked about race and Hispanic/Latino ethnicity separately; therefore, patients could identify as more than one of the categories listed
Of patients in the overall SMA sample, 10.4% (64/614) had been treated with onasemnogene abeparvovec by the time of the survey. The onasemnogene abeparvovec sample had distinctive characteristics compared with the overall SMA sample (Table 1). Most prominently, onasemnogene abeparvovec patients appeared to have more severe disease. The percentages of these patients with one or two copies of SMN2 were 4.7% and 57.8%, respectively. Most (68.8%) patients had SMA type 1, followed by type 2 (25.0%) and type 3 (3.1%). Greater percentages of patients treated with onasemnogene abeparvovec were diagnosed via genetic testing (95.3%) and newborn screening (35.9%). The mean (SD) age at diagnosis was 3.9 (7.3) months, and the mean (SD) age at symptom onset was 2.6 (4.5) months. Regarding the timing of onasemnogene abeparvovec treatment, 60.9% received onasemnogene abeparvovec when younger than 6 months of age, whereas 9.4% received onasemnogene abeparvovec at age 24 months or older. A total of 19 patients received onasemnogene abeparvovec at 6–23 months of age.
Outcomes of Onasemnogene Abeparvovec-Treated Patients
Patient Characteristics
For the 19 patients treated with onasemnogene abeparvovec at 6–23 months of age, 17 were successfully matched to 28 comparable non–onasemnogene abeparvovec-treated patients (Table 2). The mean ages at the time of the survey were 33.9 and 34.6 months for onasemnogene abeparvovec- and non–onasemnogene abeparvovec-treated patients, respectively, with 88.2% and 78.6% being at least 24 months of age in each group. The mean age at diagnosis was older than the overall onasemnogene abeparvovec sample at 7.4 (5.5) months and 6.3 (8.0) months for onasemnogene abeparvovec- and non–onasemnogene abeparvovec-treated patients, respectively. All patients were diagnosed with SMA via genetic testing. No onasemnogene abeparvovec-treated patients were reported to have been diagnosed via prenatal or newborn screening methods. The percentage of patients with two SMN2 copies was 64.7% for onasemnogene abeparvovec-treated patients and 71.4% for non–onasemnogene abeparvovec-treated patients. The percentage of patients with SMA type 1 was 70.6% and 75.0%, respectively in the two groups. For onasemnogene abeparvovec-treated patients, the mean (SD) age at which patients received onasemnogene abeparvovec was 11.9 (5.1) months. On average, patients were surveyed 22.0 (16.1) months after receiving onasemnogene abeparvovec treatment (Table 2).
Table 2
Characteristics of patients who received onasemnogene abeparvovec at 6–23 months of age and comparable non–onasemnogene abeparvovec-treated patients, overall and stratified by SMN2 copy number
Patient characteristicsa
Full sampleb
Two SMN2 copies
Three or more SMN2 copies
OA-treated (n = 17)
Non–OA-treated (n = 28)
OA-treated (n = 11)
Non–OA-treated (n = 20)
OA-treated (n = 6)
Non–OA-treated (n = 8)
Demographics
Age at time of survey (months)
33.9 (14.4)
34.6 (15.4)
37.5 (16.7)
37.3 (17.0)
27.2 (4.7)
27.9 (7.7)
Weight at time of survey (kg)
12.4 (2.8)
12.7 (3.1)
12.9 (3.2)
13.2 (3.3)
11.4 (1.5)
11.2 (1.9)
Female
10 (58.8%)
16 (57.1%)
6 (54.5%)
11 (55.0%)
4 (66.7%)
5 (62.5%)
Race/ethnicityc
White
14 (82.4%)
20 (71.4%)
9 (81.8%)
15 (75.0%)
5 (83.3%)
5 (62.5%)
Black/African American
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Native American/American Indian
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Hispanic/Latino
1 (5.9%)
3 (10.7%)
1 (9.1%)
2 (10.0%)
0 (0.0%)
1 (12.5%)
Asian/Pacific Islander
1 (5.9%)
1 (3.6%)
0 (0.0%)
0 (0.0%)
1 (16.7%)
1 (12.5%)
Other
2 (11.8%)
3 (10.7%)
2 (18.2%)
2 (10.0%)
0 (0.0%)
1 (12.5%)
Unknown
0 (0.0%)
3 (10.7%)
0 (0.0%)
2 (10.0%)
0 (0.0%)
1 (12.5%)
Country
USA
16 (94.1%)
22 (78.6%)
10 (90.9%)
16 (80.0%)
6 (100.0%)
6 (75.0%)
Other
0 (0.0%)
3 (10.7%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
2 (25.0%)
Unknown
1 (5.9%)
3 (10.7%)
1 (9.1%)
3 (15.0%)
0 (0.0%)
0 (0.0%)
Relationship to patient
Caregiver
17 (100.0%)
28 (100.0%)
11 (100.0%)
20 (100.0%)
6 (100.0%)
8 (100.0%)
Disease characteristics
Age at SMA diagnosis (months)
7.4 (5.5)
6.3 (8.0)
4.6 (3.8)
3.3 (4.2)
12.3 (4.6)
13.8 (10.3)
Age at symptom onset (months)
5.0 (4.5)
3.1 (4.2)
2.7 (2.2)
2.0 (2.2)
9.6 (4.6)
6.4 (6.5)
Diagnostic screening
17 (100.0%)
28 (100.0%)
11 (100.0%)
20 (100.0%)
6 (100.0%)
8 (100.0%)
Prenatal screening
0 (0.0%)
3 (10.7%)
0 (0.0%)
2 (10.0%)
0 (0.0%)
1 (12.5%)
Newborn screening
0 (0.0%)
4 (14.3%)
0 (0.0%)
3 (15.0%)
0 (0.0%)
1 (12.5%)
Genetic testing
17 (100.0%)
28 (100.0%)
11 (100.0%)
20 (100.0%)
6 (100.0%)
8 (100.0%)
SMA type
1
12 (70.6%)
21 (75.0%)
11 (100.0%)
19 (95.0%)
1 (16.7%)
2 (25.0%)
2
4 (23.5%)
6 (21.4%)
0 (0.0%)
1 (5.0%)
4 (66.7%)
5 (62.5%)
3
1 (5.9%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (16.7%)
0 (0.0%)
Other/unknown
0 (0.0%)
1 (3.6%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (12.5%)
OA treatment-related characteristics
Age at time of treatment with OA (months)
11.9 (5.1)
–
11.1 (5.5)
–
13.3 (4.4)
–
Age category at time of treatment with OA
6–11 months
9 (52.9%)
–
6 (54.5%)
–
3 (50.0%)
–
12–23 months
8 (47.1%)
–
5 (45.5%)
–
3 (50.0%)
–
Time since OA treatment (months)
22.0 (16.1)
–
26.5 (17.9)
–
13.8 (8.0)
–
OA onasemnogene abeparvovec, SMA spinal muscular atrophy, SMN2 survival motor neuron 2 gene
aMeans and standard deviations are presented for continuous characteristics; counts and percentages are presented for categorical characteristics, unless otherwise noted
bOnasemnogene abeparvovec-treated and non–onasemnogene abeparvovec-treated patients were matched up to 1:2 on age at the time of the survey (± 6 months) and SMN2 copy number
cThe 2021 Cure SMA Membership Survey asked about race and Hispanic/Latino ethnicity separately; therefore, patients could identify as more than one of the categories listed
The patient subgroups with two SMN2 copies and three or more SMN2 copies demonstrated characteristics similar to the full matched onasemnogene abeparvovec sample but with certain distinctions (Table 2). Patients with two SMN2 copies were generally older at the time of survey (mean age 37.5 months), whereas those with three or more copies were younger (mean age 27.2 months). Compared with patients with three or more SMN2 copies, patients with two SMN2 copies were generally diagnosed earlier (mean age 4.6 months vs. 12.3 months), had earlier symptom onset (mean age 2.7 months vs. 9.6 months), and were treated with onasemnogene abeparvovec earlier (mean age 11.1 months vs. 13.3 months). A longer gap from the time of onasemnogene abeparvovec treatment to the survey occurred in the group with two SMN2 copies (26.5 months) compared with those with three or more copies (13.8 months) (Table 2).
Patient characteristics for the three subgroups of SMA types (1, 2, and 3) are presented in Table S1 in the supplementary material. They generally confirmed the trends observed in the subgroups defined by SMN2 copy number.
Motor Milestones
Seventeen onasemnogene abeparvovec-treated patients and 25 non–onasemnogene abeparvovec-treated patients were old enough at the time of the survey for motor milestone evaluation (Fig. 1A). Onasemnogene abeparvovec-treated patients had a numerically greater percentage of motor milestone achievement than the comparable non–onasemnogene abeparvovec-treated patients in six out of eight measures (Fig. 1A). Non–onasemnogene abeparvovec-treated patients had a comparable but slightly greater percentage of achieving hands and knees crawling compared with onasemnogene abeparvovec-treated patients (32.0% vs. 29.4%, Fig. 1A).
Fig. 1
Motor milestones for patients who received onasemnogene abeparvovec at 6–23 months of age and comparable non–onasemnogene abeparvovec-treated patients, overall (A), in subgroups with two SMN2 copies (B), and three or more SMN2 copies (C). Motor milestones were assessed only for patients old enough to achieve each developmental milestone. Cutoffs for each motor function were defined as follows: head control, 4 months; voluntary grasping, 4 months; kicking, 4 months; roll over, 6 months: sitting without support, 9 months; hands and knees crawling, 9 months; standing with assistance, 9 months; walking with assistance, 12 months. Patients who were missing data for this question and those who were younger than the age cutoffs and had not yet reached the milestone at the time of the survey were removed from the denominator. Three non–onasemnogene abeparvovec-treated patients were missing information on developmental milestones and were not included in this analysis. OA onasemnogene abeparvovec, SMN2 survival motor neuron 2 gene
×
Eleven onasemnogene abeparvovec-treated patients and 19 non–onasemnogene abeparvovec-treated patients were evaluated for motor milestones in the subgroup of patients with two SMN2 copies. Compared with non–onasemnogene abeparvovec-treated patients, onasemnogene abeparvovec-treated patients had a numerically greater percentage of motor milestone achievements in head control, kicking, rolling over, sitting without support, and walking with assistance, but a smaller percentage of achievements in hands and knees crawling (Fig. 1B). In the subgroup of patients with three or more SMN2 copies, 100% of onasemnogene abeparvovec-treated patients achieved all milestones except hands and knees crawling, which was achieved by 83.3% (n = 5/6) patients (Fig. 1C). Onasemnogene abeparvovec-treated patients had a numerically greater percentage of motor milestone achievement than their comparable non–onasemnogene abeparvovec-treated patients in kicking, rolling over, sitting without support, standing with assistance, and walking with assistance (Fig. 1C).
Resource and Supportive Care Use
Approximately 25% of onasemnogene abeparvovec-treated patients (23.5%) and non–onasemnogene abeparvovec-treated patients (28.6%), all of whom had two SMN2 copies and SMA type 1, were hospitalized in the 12 months prior to the survey (Tables 3 and S2). Eight (47.1%) onasemnogene abeparvovec-treated patients and 15 (53.6%) non–onasemnogene abeparvovec-treated patients reported an SMA-related surgery (Table 3). The most common surgery type for both groups was gastrointestinal surgery, accounting for 75.0% and 93.3% of the patients who ever had a surgery in the onasemnogene abeparvovec and non-onasemnogene abeparvovec groups, respectively. All patients undergoing surgery had two SMN2 copies and SMA type 1 (Tables 3 and S2).
Table 3
Outcomes of patients who received onasemnogene abeparvovec at 6–23 months of age and comparable non–onasemnogene abeparvovec-treated patients, overall and stratified by SMN2 copy number
Patient outcomesa
Full sampleb
Two SMN2 copies
Three or more SMN2 copies
OA-treated (n = 17)
Non–OA-treated (n = 28)
OA-treated (n = 11)
Non–OA-treated (n = 20)
OA-treated (n = 6)
Non–OA-treated (n = 8)
Clinical outcomes
Hospitalized in the past 12 months
4 (23.5%)
8 (28.6%)
4 (36.4%)
8 (40.0%)
0 (0.0%)
0 (0.0%)
Reason for hospitalization(s)
Pneumonia
2 (50.0%)
2 (25.0%)
2 (50.0%)
2 (25.0%)
0 (0.0%)
0 (0.0%)
Respiratory distress
3 (75.0%)
5 (62.5%)
3 (75.0%)
5 (62.5%)
–
–
Surgery
1 (25.0%)
5 (62.5%)
1 (25.0%)
5 (62.5%)
–
–
Other
3 (75.0%)
5 (62.5%)
3 (75.0%)
5 (62.5%)
–
–
Ever had surgery related to SMA
8 (47.1%)
15 (53.6%)
8 (72.7%)
15 (75.0%)
–
–
Surgery type
Gastrointestinal
6 (75.0%)
14 (93.3%)
6 (75.0%)
14 (93.3%)
–
–
Spinal rods and fusion
1 (12.5%)
2 (13.3%)
1 (12.5%)
2 (13.3%)
–
–
Tracheotomy
1 (12.5%)
5 (33.3%)
1 (12.5%)
5 (33.3%)
–
–
Mobility device usec
Bath/shower chair
5 (29.4%)
9 (32.1%)
5 (45.5%)
9 (45.0%)
0 (0.0%)
0 (0.0%)
Hospital bed
1 (5.9%)
5 (17.9%)
1 (9.1%)
5 (25.0%)
0 (0.0%)
0 (0.0%)
Hoyer
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Scooter
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Walker
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Manual wheelchair
11 (64.7%)
9 (32.1%)
9 (81.8%)
8 (40.0%)
2 (33.3%)
1 (12.5%)
Power wheelchair
3 (17.6%)
3 (10.7%)
3 (27.3%)
3 (15.0%)
0 (0.0%)
0 (0.0%)
Toilet chair
2 (11.8%)
1 (3.6%)
2 (18.2%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Stander
12 (70.6%)
12 (42.9%)
10 (90.9%)
10 (50.0%)
2 (33.3%)
2 (25.0%)
Activity therapy chair
7 (41.2%)
7 (25.0%)
6 (54.5%)
7 (35.0%)
1 (16.7%)
0 (0.0%)
Adaptive stroller
5 (29.4%)
9 (32.1%)
5 (45.5%)
9 (45.0%)
0 (0.0%)
0 (0.0%)
Car bed
1 (5.9%)
1 (3.6%)
1 (9.1%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Other
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Feeding tube use
Gastronomy tube
5 (29.4%)
10 (35.7%)
5 (45.5%)
10 (50.0%)
0 (0.0%)
0 (0.0%)
Uses feeding tube but takes half of nutrition by mouth
1 (5.9%)
3 (10.7%)
1 (9.1%)
3 (15.0%)
0 (0.0%)
0 (0.0%)
Uses feeding tube but takes less than half of nutrition by mouth
1 (5.9%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (16.7%)
0 (0.0%)
Jejunostomy
2 (11.8%)
2 (7.1%)
2 (18.2%)
2 (10.0%)
0 (0.0%)
0 (0.0%)
Nasogastric tube
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Any respiratory intervention
10 (58.8%)
17 (60.7%)
9 (81.8%)
17 (85.0%)
1 (16.7%)
0 (0.0%)
BiPAP
8 (47.1%)
11 (39.3%)
7 (63.6%)
11 (55.0%)
1 (16.7%)
0 (0.0%)
Cough machine
9 (52.9%)
16 (57.1%)
8 (72.7%)
16 (80.0%)
1 (16.7%)
0 (0.0%)
CPAP
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Oxygen
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Tracheostomy only for suctioning
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Tracheostomy with ventilator
0 (0.0%)
5 (17.9%)
0 (0.0%)
5 (25.0%)
0 (0.0%)
0 (0.0%)
Average daily duration of respiratory interventions (among users)
< 8 h
4 (40.0%)
3 (17.6%)
3 (33.3%)
3 (17.6%)
1 (100.0%)
–
8–16 h
6 (60.0%)
5 (29.4%)
6 (66.7%)
5 (29.4%)
0 (0.0%)
–
> 16 h
0 (0.0%)
7 (41.2%)
0 (0.0%)
7 (41.2%)
0 (0.0%)
–
Unknown
0 (0.0%)
2 (11.8%)
0 (0.0%)
2 (11.8%)
0 (0.0%)
–
Caregiver proxy-reported health outcomes
Trouble swallowing (currently)
Always (100%)
0 (0.0%)
8 (28.6%)
0 (0.0%)
7 (35.0%)
0 (0.0%)
1 (12.5%)
Usually (80–99%)
4 (23.5%)
2 (7.1%)
4 (36.4%)
2 (10.0%)
0 (0.0%)
0 (0.0%)
Often (60–79%)
2 (11.8%)
2 (7.1%)
1 (9.1%)
2 (10.0%)
1 (16.7%)
0 (0.0%)
About half of the time (40–59%)
1 (5.9%)
1 (3.6%)
1 (9.1%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Sometimes (20–39%)
2 (11.8%)
1 (3.6%)
2 (18.2%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Rarely (1–19%)
4 (23.5%)
3 (10.7%)
3 (27.3%)
3 (15.0%)
1 (16.7%)
0 (0.0%)
Never (0%)
4 (23.5%)
8 (28.6%)
0 (0.0%)
3 (15.0%)
4 (66.7%)
5 (62.5%)
Unknown
0 (0.0%)
3 (10.7%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
2 (25.0%)
Weak voice
Always (100%)
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
Usually (80–99%)
1 (5.9%)
2 (7.1%)
1 (9.1%)
2 (10.0%)
0 (0.0%)
0 (0.0%)
Often (60–79%)
0 (0.0%)
1 (3.6%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
0 (0.0%)
About half of the time (40–59%)
2 (11.8%)
0 (0.0%)
2 (18.2%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Sometimes (20–39%)
1 (5.9%)
2 (7.1%)
1 (9.1%)
1 (5.0%)
0 (0.0%)
1 (12.5%)
Rarely (1–19%)
7 (41.2%)
4 (14.3%)
4 (36.4%)
4 (20.0%)
3 (50.0%)
0 (0.0%)
Never (0%)
6 (35.3%)
15 (53.6%)
3 (27.3%)
10 (50.0%)
3 (50.0%)
5 (62.5%)
Unknown
0 (0.0%)
3 (10.7%)
0 (0.0%)
1 (5.0%)
0 (0.0%)
2 (25.0%)
HUI-2d
Any Health Utilities Index response
16 (94.1%)
18 (64.3%)
10 (90.9%)
14 (70.0%)
6 (100.0%)
4 (50.0%)
Overall score
0.5 (0.1)
0.5 (0.2)
0.5 (0.1)
0.4 (0.1)
0.5 (0.1)
0.7 (0.2)
BiPAP bi-level positive airway pressure, CPAP continuous positive airway pressure, HRQOL health-related quality of life, HUI-2, Health Utilities Index-2, OA onasemnogene abeparvovec, SMA spinal muscular atrophy, SMN2 survival motor neuron 2 gene
aMeans and standard deviations are presented for continuous characteristics; counts and percentages are presented for categorical characteristics, unless otherwise noted
bOnasemnogene abeparvovec-treated and non–onasemnogene abeparvovec-treated patients were matched up to 1:2 by age at the time of the survey (± 6 months) and SMN2 copy number
cResponders have been classified as using other mobility devices if they indicated they used mobility devices but did not select one of the mobility device types listed. This category may include a mobility device already captured in the survey (e.g., “Hoyer ceiling lift” or “Walker Sometimes”)
dHUI is a validated questionnaire designed to assess health status and HRQOL. HUI consists of a generic comprehensive health status classification and a generic HRQOL scoring system. Attributes of the HUI questionnaire include sensation, mobility, emotion, cognition, self-care, pain, fertility, vision, hearing, speech, ambulation, and dexterity
The most common mobility devices used by onasemnogene abeparvovec-treated patients were the stander (70.6%), manual wheelchair (64.7%), activity therapy chair (41.2%), bath/shower chair (29.4%), and adaptive stroller (29.4%) (Table 3). Percentages were similar for the non–onasemnogene abeparvovec-treated group.
The most common nutritional support device used for onasemnogene abeparvovec-treated patients was the gastronomy tube (29.4%), followed by the jejunostomy tube (11.8%). No patients used the nasogastric tube (Table 3). Rates of nutritional support usage were similar for non–onasemnogene abeparvovec-treated patients. However, the rate of gastronomy tube use was greater (35.7%) and the rate of jejunostomy tube use was less (7.1%) than for onasemnogene abeparvovec-treated patients.
Approximately 60% of the patients in each group received respiratory interventions, with a slightly greater percentage in the non-onasemnogene abeparvovec group compared with the onasemnogene abeparvovec group (60.7% vs. 58.8%; Table 3). No patients treated with onasemnogene abeparvovec reported usage of oxygen and continuous positive airway pressure or underwent a tracheostomy with or without a ventilator. Approximately 17.9% of non–onasemnogene abeparvovec-treated patients had a tracheostomy with a ventilator. Although the overall percentage of patients receiving respiratory interventions was similar, the duration of intervention was quite different between the two groups. Specifically, none of the patients in the onasemnogene abeparvovec group reported more than 16 h of respiratory intervention usage, whereas the corresponding rate was 41.2% in the non-onasemnogene abeparvovec group (Table 3).
In both onasemnogene abeparvovec and non-onasemnogene abeparvovec groups, resource and supportive care use was mostly incurred by patients with two SMN2 copies (Table 3). These results were similar to those in the full sample. The most common mobility devices used in the subgroup with two SMN2 copies were the same as those used in the full sample but with greater rates. Similarly, rates of respiratory interventions were also greater in this subgroup, with an overall rate of 81.8% (Table 3). The number of patients who reported resource and supportive care use in the subgroup of patients with three or more SMN2 copies was too small to interpret (Table 3).
The results for the subgroups of patients with SMA type 1 and type 2 were similar to those with two and three or more SMN2 copies, respectively. Patients with SMA type 1 incurred the most resource and supportive care use (Table S2).
Caregiver Proxy-Reported Patient Outcomes
On the basis of the caregiver-reported outcomes, 47.1% of onasemnogene abeparvovec-treated patients rarely or never had trouble swallowing, and 76.5% rarely or never experienced a weak voice. Both rates were greater than the corresponding outcomes in the non–onasemnogene abeparvovec-treated group (39.3% and 67.9%, respectively) (Table 3). In addition, 28.6% of non–onasemnogene abeparvovec-treated patients reported always having trouble swallowing, whereas no difficulty was reported in the onasemnogene abeparvovec group. In terms of HRQOL, 94.1% and 64.3% of caregivers in the onasemnogene abeparvovec and non-onasemnogene abeparvovec groups, respectively, responded to the HUI questionnaire. The mean HUI-2 score of 0.5 was the same for both groups (Table 3).
In the subgroup of patients with two SMN2 copies, the percentages of patients reported to rarely or never have trouble swallowing and experience weak voice were comparable between the onasemnogene abeparvovec- and non–onasemnogene abeparvovec-treated patients (Table 3). However, the rate of patients always having trouble swallowing was much greater for non–onasemnogene abeparvovec-treated patients (35.0% vs. 0% among onasemnogene abeparvovec-treated patients). Moreover, a greater percentage of patients were reported to have trouble swallowing at least 40% of the time in the non-onasemnogene abeparvovec group than the onasemnogene abeparvovec group (65.0% vs. 54.5%). In the subgroup of patients with two SMN2 copies, the percentages of patients reported to rarely or never have trouble swallowing or experiencing weak voice were 83.3% and 100.0% among onasemnogene abeparvovec-treated patients; both rates were numerically greater than those for non–onasemnogene abeparvovec-treated patients (Table 3). Regarding HRQOL, the mean HUI-2 score was 0.5 in the onasemnogene abeparvovec group versus 0.4 in the non-onasemnogene abeparvovec group for patients in the two SMN2 copies subgroup. The corresponding mean scores were 0.5 and 0.7, respectively, in the three or more SMN2 copies subgroup (Table 3).
The results stratified by SMA type were similar to those stratified by the SMN2 copy number (Table S2).
Caregiver Burden of Onasemnogene Abeparvovec-Treated Patients
A total of 17 caregivers of patients treated with onasemnogene abeparvovec and 29 caregivers of patients who did not receive onasemnogene abeparvovec responded to the caregiver burden questions (Table 4).
Table 4
Caregiver outcomes of patients who received onasemnogene abeparvovec at 6–23 months of age and comparable non–onasemnogene abeparvovec-treated patients, overall and stratified by SMN2 copy number
Caregiver outcomesa,b
Full samplec
Two SMN2 copies
Three or more SMN2 copies
OA-treated (n = 17)
Non–OA-treated (n = 29)
OA-treated (n = 11)
Non–OA-treated (n = 21)
OA-treated (n = 6)
Non–OA-treated (n = 8)
Caregiver unmet needs
Emotional care
6 (35.3%)
13 (44.8%)
3 (27.3%)
11 (52.4%)
3 (50.0%)
2 (25.0%)
Fatigue
6 (35.3%)
10 (34.5%)
4 (36.4%)
6 (28.6%)
2 (33.3%)
4 (50.0%)
Financial assistance
5 (29.4%)
13 (44.8%)
4 (36.4%)
11 (52.4%)
1 (16.7%)
2 (25.0%)
Flexible work schedule
10 (58.8%)
6 (20.7%)
7 (63.6%)
6 (28.6%)
3 (50.0%)
0 (0.0%)
Other
1 (5.9%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (16.7%)
0 (0.0%)
Have non-family caregiver
8 (47.1%)
10 (34.5%)
6 (54.5%)
8 (38.1%)
2 (33.3%)
2 (25.0%)
Non-family caregiver hours
None
9 (52.9%)
19 (65.5%)
5 (45.5%)
13 (61.9%)
4 (66.7%)
6 (75.0%)
< 20
2 (11.8%)
3 (10.3%)
2 (18.2%)
1 (4.8%)
0 (0.0%)
2 (25.0%)
21–40 h
4 (23.5%)
4 (13.8%)
2 (18.2%)
4 (19.0%)
2 (33.3%)
0 (0.0%)
> 40 h
2 (11.8%)
3 (10.3%)
2 (18.2%)
3 (14.3%)
0 (0.0%)
0 (0.0%)
ACEND scored
Transfer score [range 0–30; lower = worse outcomes]
Work productivity and activity impairment (WPAI)e (range 0–100%), mean (SD)
Absenteeism (%)
2.3 (4.0)
32.1 (47.2)
3.5 (4.9)
33.3 (57.7)
0.0 (–)
28.6 (–)
Presenteeism (%)
20.0 (26.5)
24.0 (28.8)
30.0 (28.3)
25.0 (33.2)
0.0 (–)
20.0 (–)
Total productivity impairment (%)
21.2 (28.4)
43.2 (41.9)
31.7 (30.8)
43.3 (51.3)
0.0 (–)
42.9 (–)
Total activity impairment (%)
54.4 (28.5)
48.1 (38.3)
65.0 (27.6)
56.9 (38.6)
36.7 (21.6)
20.0 (21.2)
ACEND Assessment of Caregiver Experience in Neuromuscular Disease, OA onasemnogene abeparvovec, SD standard deviation, SMA spinal muscular atrophy, SMN2 survival motor neuron 2 gene, WPAI Work Productivity and Activity Impairment
aCaregiver outcomes are assessed based on all available surveys for individual patients
bMeans and standard deviations are presented for continuous characteristics; counts and percentages are presented for categorical characteristics, unless otherwise noted
cOnasemnogene abeparvovec-treated and non–onasemnogene abeparvovec-treated patients were matched up to 1:2 on age at the time of the survey (± 6 months) and SMN2 copy number
dACEND is an instrument designed to assess the caregiver impact experienced when caring for children with neuromuscular disease
eAbsenteeism: mean % work time missed due to problem; Presenteeism: mean % impairment while working due to problem; Total productivity impairment: mean % overall work impairment due to problem; Total activity impairment: mean % activity impairment due to problem. WPAI questions capture caregiver’s SMA-related work/productivity experience during the past 7 days. All four outcomes are reported for caregivers who are employed
The most common unmet needs in the onasemnogene abeparvovec group were flexible work schedule (58.8%), emotional care (35.3%), and fatigue (35.3%), whereas emotional care (44.8%), financial assistance (44.8%), and fatigue (34.5%) were the top three needs reported in the non-onasemnogene abeparvovec group (Table 4). A greater percentage of patients in the onasemnogene abeparvovec group reported having a non-family caregiver than the non-onasemnogene abeparvovec group (47.1% vs. 34.5%). For those with a non-family caregiver, approximately 25% of caregivers in both groups reported more than 40 h per week of non-family caregiver time.
Caregivers in both groups reported similar ACEND transfer scores (mean score 10.6) but caregivers in the onasemnogene abeparvovec group reported a higher mobility score than those in the non-onasemnogene abeparvovec group (21.6 vs. 15.8, with a higher score indicating a better outcome) (Table 4).
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The caregiver employment rate was approximately 17%, similar between the two groups (Table 4). However, for employed caregivers, work impairment was reported less in the onasemnogene abeparvovec group compared with the non-onasemnogene abeparvovec group, particularly absenteeism (2.3% vs. 32.1%) and total productivity impairment (21.2% vs. 43.2%). Total activity impairment was comparable between the two groups, but slightly higher for the onasemnogene abeparvovec group (54.4% vs. 48.1%).
The results in the subgroups defined by SMN2 copy number and SMA type were generally consistent with those in the full sample (Tables 4 and S3). Overall, the results demonstrated more caregiver unmet needs, more frequent use of a non-family caregiver, higher physical impact, and more work productivity and activity impairment in more severe SMA subgroups (i.e., two SMN2 copies and SMA type 1) (Tables 4 and S3).
Discussion
Onasemnogene abeparvovec is the first gene replacement therapy approved by the FDA and EMA for the treatment of children with SMA [35]. Although its safety and efficacy are supported with solid clinical trial data for patients treated younger than 6 months of age [15‐21], the real-world use of onasemnogene abeparvovec and associated outcomes for a broader age group have not been thoroughly evaluated. The current study uses one of the most recent and largest self-reported SMA databases, the 2021 Cure SMA Membership Survey, to enhance our understanding of the SMA population and onasemnogene abeparvovec-treated patients and their outcomes in the post-onasemnogene abeparvovec approval era. To our knowledge, this is the first real-world study evaluating a comprehensive array of patient and caregiver outcomes for patients treated with onasemnogene abeparvovec at 6–23 months of age. The study demonstrated that onasemnogene abeparvovec-treated patients had distinctive characteristics compared with the overall SMA patient population included in this survey. Notably, these patients had more severe disease, with more than 60% having two SMN2 copies and close to 70% diagnosed with SMA type 1. Although more than 60% of onasemnogene abeparvovec-treated patients received treatment when younger than 6 months of age, close to 30% were treated at 6–23 months of age, which underscores the importance of studying outcomes for this age group that were not studied in onasemnogene abeparvovec clinical trials.
Overall, our findings support favorable patient and caregiver outcomes associated with onasemnogene abeparvovec treatment when results were compared with the outcomes in a matched non–onasemnogene abeparvovec-treated group. Specifically, compared with non–onasemnogene abeparvovec-treated patients, those who received onasemnogene abeparvovec generally had greater rates of motor milestone achievements, experienced slightly less hospitalization and surgery, and had fewer hours of overall respiratory interventions and less use of tracheostomy with ventilator. Caregivers reported their onasemnogene abeparvovec-treated patients also had less trouble swallowing compared with their non–onasemnogene abeparvovec-treated counterparts, with similar HRQOL as measured by HUI-2 score. Patients treated with onasemnogene abeparvovec reported more occurrences of the usage of certain mobility devices, such as stander, manual wheelchair, and activity therapy chair, possibly because greater percentages of onasemnogene abeparvovec-treated patients achieved certain motor milestones (e.g., walking with assistance and sitting). In addition to favorable patient outcomes, caregivers of onasemnogene abeparvovec-treated patients reported fewer unmet needs related to emotional care and financial assistance, less mobility impact related to SMA, and less work impairment, possibly benefiting from the treatment. Similar results were observed in the subgroups defined by SMN2 copy number and SMA type, though the results must be interpreted with caution because of the small sample sizes, particularly for the less severe subgroups (three or more SMN2 copies and SMA types 2 and 3).
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The findings from the current study are consistent with the results from clinical trials of onasemnogene abeparvovec. In an open-label, single-arm, phase 1 trial for patients with SMA type 1 and two SMN2 copies, 11 of 12 patients (91.7%) who received the proposed therapeutic dose achieved sitting without assistance at 2 years post-treatment [21]. The same percentage of patients maintained or improved swallowing function. The BiPAP use rate of 41.7% was similar to the current study. A follow-up comparative study based on the phase 1 trial demonstrated that motor function as measured by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders score substantially improved following onasemnogene abeparvovec treatment while it worsened over time for a comparable natural history cohort [20]. In addition, all onasemnogene abeparvovec-treated patients remained alive at the end of 2 years post-treatment [21] compared with 38% in the natural history cohort [20]. Several phase 3 trials had similar findings on motor function, with 44–100% of patients achieving functional independent sitting at any visit up to the 18 months of age study visit [15, 16] or 18 months of age [18, 19] in the onasemnogene abeparvovec arm, a substantially greater percentage than their respective natural history cohorts.
The evidence supporting onasemnogene abeparvovec effectiveness for patients in a broader age group largely relies on real-world studies. To date, published real-world studies focused on the clinical outcomes evaluated by clinicians [24‐26, 36‐38]. These studies varied in sample size (ranging from 9 to 76) and geographic location but unanimously demonstrated that patients experienced meaningful motor function improvement after receiving onasemnogene abeparvovec. Two studies reported the outcomes in patients who received onasemnogene abeparvovec at 6–24 months of age [24, 25], including one subgroup analysis of patients 8–24 months of age [25], and both studies demonstrated improved motor function for onasemnogene abeparvovec-treated patients in these age groups. Two studies reported that 44–76% of onasemnogene abeparvovec-treated patients achieved any motor milestone [25, 37], with the lower rate reported for patients treated at age 24 months or later [25, 26]. Comparatively, the current study exhibited a greater percentage of onasemnogene abeparvovec-treated patients achieving motor milestones.
In addition to motor function, some studies also demonstrated that patients treated with onasemnogene abeparvovec experienced stable or improved bulbar function (including swallowing) [24, 37‐39] and had reduced or limited use of ventilation support following treatment compared with baseline [37‐39]. Because of its cross-sectional nature, our study could not evaluate functional improvement or change in resource or supportive care use. However, lower rates of reported swallowing issues, tracheostomy with ventilator, and oxygen/breathing machine use in the onasemnogene abeparvovec group support the positive effect of onasemnogene abeparvovec on bulbar function and respiratory support, as demonstrated in previous studies. In addition, real-world studies consistently demonstrated that onasemnogene abeparvovec is effective for both nusinersen-naïve and nusinersen-treated patients [24, 25, 36, 37]. One study evaluating the outcomes of patients treated with onasemnogene abeparvovec and patients receiving nusinersen monotherapy indicated earlier motor milestone achievement for onasemnogene abeparvovec-treated patients [24]. A survey of caregivers of nusinersen-treated children (also recruited from the Cure SMA database) [40] demonstrated much lower rates of motor milestone achievements than those indicated in the current study, although the two studies are not directly comparable owing to their study designs. Because the data sharing agreement between Novartis and Cure SMA does not allow the disclosure of information on treatments other than onasemnogene abeparvovec, the current study was not able to evaluate the outcomes of onasemnogene abeparvovec-treated patients on the basis of their prior exposure to other DMTs or compare the outcomes between onasemnogene abeparvovec and other DMTs. Nonetheless, the current study complements the literature on the real-world outcomes of onasemnogene abeparvovec by including proxy-reported patient HRQOL and caregiver outcomes.
In summary, the current study expands the knowledge on the outcomes for onasemnogene abeparvovec-treated patients from clinical trials and real-world studies by providing firsthand evidence on the characteristics, HRQOL, and caregiver burden of onasemnogene abeparvovec-treated patients. The study suggests that onasemnogene abeparvovec may benefit patients who receive treatment at 6–23 months of age and those treated at an earlier age, as well as patients with various SMN2 copy numbers and different SMA types. These benefits may not be limited to improving clinical outcomes, such as motor function, swallowing, and respiratory support. Onasemnogene abeparvovec may reduce caregiver burden and improve caregiver HRQOL. These outcomes may have long-term implications. For example, the greater rates of motor milestone achievements may translate into long-term survival [23, 41]. Less use of respiratory support for patients and reduced work impairment for caregivers may lead to decreased direct and indirect costs. Further evidence is required to establish the long-term benefits of onasemnogene abeparvovec.
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This study should be interpreted in the context of its limitations. First, the study shares the common limitations that exist in all survey studies, including responder bias, potential misinterpretation of survey questions, and recall bias. In addition, proxy-reported data by caregivers may not accurately reflect the actual patient experience. However, given the ages of the patients, it is the only method that can be used to evaluate patient HRQOL. Because of this limitation, certain outcomes may not be accurately estimated using the survey data. Second, the outcome analysis had a small sample size due to the age restriction (6–23 months of age at the time of onasemnogene abeparvovec treatment), particularly when evaluating certain outcomes and subgroups. For example, given the relatively young age and small sample size, the study was not able to evaluate the motor milestones, such as standing or walking alone, that are expected to be achieved at a later stage of development. In addition, missing data for a small number of patients could have a large impact on the results. Thus, the results need to be interpreted with caution. The study is cross-sectional and descriptive in nature, and the non-onasemnogene abeparvovec group was constructed to facilitate the interpretation of the results for onasemnogene abeparvovec-treated patients. Owing to the limited sample size, the non-onasemnogene abeparvovec group was only matched to the onasemnogene abeparvovec group on age at the time of the survey and number of SMN2 gene copies. With a limited sample size and lack of availability for all relevant variables, the matching was unable to account for many factors that could potentially impact the outcomes. Therefore, the results may only suggest a trend and should not be used to draw conclusions on the comparative effectiveness between onasemnogene abeparvovec- and non–onasemnogene abeparvovec-treated patients. Lastly, the current study does not clearly inform how onasemnogene abeparvovec compares with other DMTs because the analytic data did not disclose treatment exposure other than onasemnogene abeparvovec. The non-onasemnogene abeparvovec group could comprise those patients who may or may not have received treatment with another available DMT or combination of DMTs. Such information would be important for evaluating comparative outcome differences between onasemnogene abeparvovec and alternative DMTs. Future studies with specific treatment exposure, larger sample sizes, and longitudinal follow-up could shed more light on the real-world outcomes associated with onasemnogene abeparvovec and other DMTs. Particularly, comparative studies between onasemnogene abeparvovec and other DMTs are desirable to further inform treatment decisions.
Conclusions
The study indicates that onasemnogene abeparvovec is associated with greater rates of motor milestone achievements, lower hospitalization and surgery rates, and less nutritional and respiratory support use for patients treated at 6–23 months of age when assessed with patients not treated with onasemnogene abeparvovec in the real world. It may potentially reduce unmet needs, improve HRQOL, and reduce work impairment for caregivers.
Acknowledgements
The authors would like to thank Cure SMA, Elk Grove Village, IL, USA, which provided the data from their 2020 and 2021 Community Surveys for this analysis. The authors would also like to thank Lisa Belter of Cure SMA for her contributions in analyzing and interpreting the data from the Cure SMA surveys.
Medical Writing/Editorial Assistance
Medical writing assistance was provided by Jipan Xie, an employee of XL Source, Inc., Pasadena, CA, USA, and funded by Novartis Gene Therapies, Inc. Editorial support was provided by Jennifer Weintraub, Kay Square Scientific, Newtown Square, PA, USA, and funded by Novartis Gene Therapies, Inc.
Declarations
Conflict of Interest
Walter Toro, Anish Patel, and Omar Dabbous are Novartis Gene Therapies, Inc., employees and own Novartis stock or other equities. Nicole LaMarca was an employee of Novartis Gene Therapies, Inc., at the time of the study and analysis. Min Yang, Annika Anderson, and Hanane Akbarnejad are employees of Analysis Group, Inc., which has received consulting fees from Novartis Gene Therapies, Inc., for this research. Mihaela Georgieva was an employee of Analysis Group, Inc., at the time of the study and analysis.
Ethical Approval
Data from the 2021 Cure SMA Membership Survey were used for this study. Institutional review board approval was obtained for the membership survey and all data were de-identified prior to analysis.
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