Introduction
Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation or a deletion in the gene SMN1, while the number of SMN2 copies partly explains the phenotype. Reference Coovert, Le and McAndrew1,Reference Calucho, Bernal and Alías2 Generally, the higher a patient’s SMN2 copy number, the more full-length SMN protein is present and the more attenuated the SMA phenotype. Reference Lefebvre, Bürglen, Frézal, Munnich and Melki3–Reference Lefebvre, Burlet and Liu5 The incidence in Canada is not well defined, but an international literature review estimated it between 5 and 24 cases per 100,000 persons. Reference Verhaart and Robertson6 The disorder can be subdivided according to severity and age of presentation into five clinical groups from the very severe neonatal phenotype (type 0) to mild adult phenotype (type 4). The most common form is type 1, with approximately 60% of cases. Reference Verhaart and Robertson6 SMA is mainly characterized by muscle weakness, atrophy and paralysis, ultimately leading to pulmonary impairment. Respiratory failure is the main cause of death in children with type 1 and 2. Reference Kolb and Kissel7
Previous natural history studies on patients with SMA type 2 and 3 documented the progression of the main impairments found in this population. According to the motor function, as measured with the Hammersmith Functional Motor Scale Expanded (HFMSE), the mean rates of decline would be −0.35 to −0.56 points over one year and -1.71 points over three years. Reference Wadman, Wijngaarde and Stam8–Reference Kaufmann, McDermott and Darras10 For the Revised Upper Limb Module (RULM), which assesses the upper limb motor performance, a decline of 0.4 points over 12 months was previously observed. Reference Pera, Coratti and Mazzone11 For the walking capacity, a mean decline of 1.46 m at the 6-Minute Walk test (6MWT) was documented after 12 months in ambulatory adult patients with SMA type 3. Reference Mazzone, Bianco and Main12 With regards to the pulmonary function, Kaufmann et al. Reference Kaufmann, McDermott and Darras10 previously documented a non-linear decline of ∼ 3% for the forced vital capacity (FVC) at two and three years of follow-up.
Nusinersen is the first disease-modifying therapy available for SMA. It was initially offered to infants with SMA type 1 and was found to be highly effective (e.g., ENDEAR study, Reference Finkel, Mercuri and Darras13 CHERISH study Reference Mercuri, Darras and Chiriboga14 and EMBRACE study). Reference Acsadi, Crawford and Müller-Felber15 The treatment was approved for children in 2016 by the U.S. Food and Drug Administration 16 and in 2017 by Health Canada, 17 and is now approved for adults with SMA type 2 and 3 since December 2018 in the province of Quebec. 18 It is the only province in Canada offering the full reimbursement of the treatment for this population, which was recommended by the Institut national d’excellence en santé et en services sociaux (INESSS), 19 the other provinces having followed the recommendations of the Canada’s Drug and Health Technology Agency (CADTH) 20 to not reimburse the treatment for adults. Nusinersen is an antisense oligonucleotide used to increase SMN2 function and restore functional levels of the SMN protein. Reference Pera, Coratti and Mazzone11 Its effects on functional capacity and mobility in adults with SMA are increasingly documented with real-world evidence (RWE) in cohorts from different countries with various sample sizes. In 2021, a review by Coratti et al. Reference Coratti, Cutrona and Pera21 , which included 13 studies involving adult patients and reporting RWE, suggests that nusinersen would have positive effects on motor function over 10-14 months of treatment, with positive changes reported on at least one functional measure in all studies. Reference De Wel, Goosens and Sobota22–Reference Yeo, Simeone, Townsend, Zhang and Swoboda36 Some benefits in pulmonary function have also been reported. Reference De Wel, Goosens and Sobota22,Reference Duong, Wolford and McDermott23,Reference Maggi, Bello and Bonanno29,Reference Walter, Wenninger and Thiele35 The results of a meta-analysis published in 2022, which pooled the results of 12 studies, indicated that the HFMSE and RULM scores would significantly improve at 10 and 14 months of follow-up, while the 6MWT and pulmonary function would remain stable. Reference Gavriilaki, Moschou and Papaliagkas37 Studies reporting on long-term follow-up of patients (26 to 50.5 months) showed some improvement or stabilization of their functional capacity and mobility, effects varying between studies and outcome measure used. Reference Veerapandiyan, Eichinger and Guntrum34,Reference Fainmesser, Drory and Ben-Shushan38–Reference Funato, Kino and Iwata43 Stability in the mean pulmonary function was also observed up to 30 months.
Although several studies have now documented the long-term monitoring of adult cohorts being treated with nusinersen, there are limited evidence on the use and long-term effectiveness of nusinersen in Canadian SMA patients. Thus, this study aimed to report real-world longitudinal data up to 36 months on motor function, pulmonary function and patient-reported outcome measures (PROM) of adult patients with SMA type 2 and 3 treated with nusinersen.
Methods
Study design and participants
All patients with a clinical and genetic diagnosis of SMA who were followed at the Institut de réadaptation en déficience physique de Québec (IRDPQ) in the neuromuscular adult clinic and receiving nusinersen were included (n = 17). A preliminary evaluation of the patient’s condition was made before receiving the treatment to be sure that they had no contraindications for nusinersen, which are related to hematologic effects (increased risk of bleeding complications may occur) and renal toxicity. From all SMA patients followed (n = 29) at the clinic, twelve patients did not receive the treatment due to contraindications related to a kidney transplant (n = 1), geographic accessibility (n = 3), technical problem related to significant scoliosis (n = 2), extreme pain during injection (n = 2) and personal decision (n = 4). Data were collected during routine clinical visits every 12 months for three years (T0 = baseline; T1 = 12 months; T2 = 24 months; T3 = 36 months). However, some assessments had to be canceled or postponed due to the restrictive measures applied during the COVID-19 pandemic. Data was collected and entered into the Canadian Neuromuscular Disease Registry, based at the University of Calgary by trained coordinators. Reference Hodgkinson, Lounsberry and M'Dahoma44 This study was approved by the University of Calgary Health Research Ethics Board (under the Canadian Neuromuscular Disease Registry). All patients provided written informed consent to be followed for clinical research and participate in the registry.
Nusinersen treatment
Nusinersen was intrathecally administered as recommended. Reference Wurster, Winter and Wollinsky45 The loading doses were given following the current guidelines, with 12 mg loading doses at 0, 2, 4 and 8 weeks, followed by maintenance doses every four months. The injections were performed by using the standard lumbar puncture procedure with anatomic landmarks only in six patients (35%), with fluoroscopy guidance in two patients (12%) and assisted by computed tomography guidance in nine patients (53%). Most walkers received treatment through standard lumbar puncture, but functional status was not the only criterion for choosing the injection technic (e.g., resource availability). No patients received combination disease-modifying therapy.
Clinical evaluations
Assessments were made by trained therapists (occupational therapists and physiotherapists) in four rehabilitation centers. Outcome measures were used at each time point and selected based on the recommendations for the standard of care for SMA Reference Finkel, Mercuri and Meyer46,Reference Mercuri, Finkel and Muntoni47 and the Canadian consensus Reference Slayter, Hodgkinson and Lounsberry48 according to their functional status (Table 1).
Table 1. Clinical evaluations according to the functional status of patients
6MWT = 6-Minute Walk Test; CHOP-ATEND = Children’s Hospital of Philadelphia Adult Test of Neuromuscular Disorders; FVC = forced vital capacity; HFMSE = Hammersmith Functional Motor Scale Expanded for SMA; Non-sit = non-sitter; PCF = peak cough flow; PROM = patient reported outcome measures; RULM = Revised Upper Limb Module; SMAFRS = Spinal Muscular Atrophy Functional Rating Scale.
Four outcome measures were used to assess motor function. The HFMSE, which includes 33 items each scored between 0 and 2, to a maximum of 66, with a higher score representing better motor function. Reference Glanzman, O'Hagen and McDermott49 The RULM, a 20-item scale designed to measure upper limb motor performance in patients with SMA, has a total score ranging from 0 to 37, where a higher score means better performance. Reference Mazzone, Mayhew and Montes50 The 6MWT, which is a test that assesses long-distance walking capacity in the ambulatory population, measuring the maximum distance in meters (m) walked in 6 minutes. Reference Dunaway Young, Montes and Kramer51 The Children’s Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND) to assess functional motor capacity in sitters and non-sitters. Reference Duong, Wolford and McDermott23 It includes 13 items with a maximum total score of 52, with a higher score indicating better performance.
Pulmonary function outcomes were also assessed in a respiratory laboratory. The FVC in % and peak cough flow (PCF) in L/min were reported at each time point.
One PROM, the SMA functional rating scale (SMAFRS), was used to assess functional disability in 10 activities of daily living. Each item is scored from 0 (entirely dependent) to five (completely independent) for a maximum score of 50.
In addition to these measures, participants were asked yes/no questions on whether they perceived any improvement since the beginning of treatment in various domains; strength, endurance/energy, tone, respiratory, swallowing, chewing, mouth opening and voice. All side effects were also registered. As data was collected through the context of routine clinical follow-ups, patients were also asked how they were generally doing and if they or their families and caregivers had any additional comments.
Statistical analyses and missing data
Descriptive statistics (mean and standard deviation for continuous variables, frequency and percentage for categorical variables) were used to present participant characteristics and performance in outcome measures at each time point. The differences between the three follow-up time points (12, 24 and 36 months) and baseline performances were compared with the minimal clinically important difference (MCID) reported in the literature for the primary outcomes using the following values: RULM: ≥ 2 points; HFMSE: ≥ 3 points; 6MWT: ≥ 30 m. Reference Pera, Coratti and Mazzone11,Reference Bohannon and Crouch52,Reference Pera, Coratti and Forcina53 Comparisons between baseline and time point data were made using the Wilcoxon Signed Rank Test. Due to ceiling effects in some evaluations for patients having the ability to walk, patients were grouped into (1) walker and (2) sitter/non-sitter, and analyses were performed separately for these two groups of patients. In some cases, baseline assessments were not performed due to COVID-19 restrictions or lack of available trained therapists. In these cases without baseline data, if 6-month data was available, this value was used as baseline visit (HFMSE: 1 patient; CHOP-ATEND: 4 patients). Other patients without baseline or 6-month data recorded for a particular measure were removed from the analysis. A pairwise deletion approach was used to handle missing data due to the small sample size. The statistical significance level was set at p < 0.05, while p < 0.1 was considered a trend toward statistical significance. Reference Thiese, Ronna and Ott54 Data were analyzed using IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY: IBM Corp.).
Results
As shown in Table 2, a total of 17 patients were included in the study, nine males and eight females, with a mean age of 26.6 years at the time of the first nusinersen treatment. Most patients had type 3 SMA (76.5%), and seven were still walking. For a detailed description of individual patient characteristics, see Supplementary Table S1.
Table 2. Patient characteristics
Max = maximum; min = minimum; SMA = spinal muscular atrophy; SD = standard deviation.
Treatment effects of nusinersen: quantitative analysis
Treatment effects between baseline and each follow-up (12, 24 and 36 months) are presented in Table 3. Significant changes were observed for the HFMSE (12 and 24 months) and the SMAFRS (36 months) for the sitter/non-sitter subgroup of patients. For this subgroup of patients, median changes at the RULM tended toward improvement, particularly at 12 and 24 months, however changes were not significant. For the 6MWT, there is a trend of increased total distance walked at 36 months (median change = 45 m, p = .063). No statistically significant changes of improvement or decline were observed for the CHOP-ATEND, FVC and PCF outcome measures.
Table 3. Treatment effect of nusinersen in adult SMA patients type 2 and 3 according to their functional status
6MWT = 6-Minute Walk Test; CHOP-ATEND = Children’s Hospital of Philadelphia Adult Test of Neuromuscular Disorders; FVC = forced vital capacity; HFMSE = Hammersmith Functional Motor Scale Expanded for SMA; Non-sit = non-sitter; N/A = not available; PCF = peak cough flow; RULM = Revised Upper Limb Module; SD = standard deviation; Sit = sitter; SMAFRS = Spinal Muscular Atrophy Functional Rating Scale.
* Comparisons between Baseline and Time point data were made using Wilcoxon Signed Rank Test.
The individual change scores between the three time points and baseline are presented in Figure 1 and Supplementary Tables S2 and S3. The individual absolute scores over the three years are presented in Figure 2 for all patients, including those without baseline. After 36 months of treatment exposure, for the three outcomes having a known MCID (HFMSE, RULM, 6MWT; Fig. 1), 9 patients (A, C, G, H, I, K, O, P, Q) showed an improvement above the MCID in at least one outcome, two patients (J, N) showed an improvement in at least one outcome but also a deterioration below MCID in another outcome, and five patients showed stabilization of their condition at 36 months (no change or changes not beyond MCID; D, E, F, L, M). From these five stable patients, two (D, E) had gains at 36 months on the CHOP-ATEND, although there is no published MCID for this outcome (Fig. 1; D: baseline score = 28 and 36-month score = 37; E: baseline score = 28 and 36-month score = 31). Finally, one patient (B) had a decrease greater than the MCID in the HFMSE score at both 24 and 36 months (4 points and 5 points less compared with baseline, respectively) and a loss of 28 m from baseline for the 6MWT at the 36 months' time point, which is close to the MCID. For the SMAFRS, five patients out of 10 demonstrated an improvement of two points or more after 3 years. Among them, two patients showed an important score increase of 8 points (A) and 11 points (K) (Fig. 2).
Figure 1. Individual variations from baseline at 12, 24 and 36 months compared with the minimal clinically important difference (MCID) when available for the ( a ) Hammersmith Functional Motor Scale Expanded for SMA (HFMSE), ( b ) Revised Upper Limb Module (RULM), ( c ) 6-Minute Walk Test (6MWT), ( d ) Children’s Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND), ( e ) Spinal Muscular Atrophy Functional Rating Scale (SMAFRS), ( f ) forced vital capacity (FVC) and (B) peak cough flow (PCF). L = liter; min = minute. * indicates that the patient had missing data at one, two or all follow-up time points. When the patient’s condition was stable, a small line is visible.
Figure 2. Individual score evolution over time from baseline for the ( a ) Hammersmith Functional Motor Scale Expanded for SMA (HFMSE), ( b ) Revised Upper Limb Module (RULM), ( c ) 6-Minute Walk Test (6MWT), ( d ) Children’s Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND), ( e ) Spinal Muscular Atrophy Functional Rating Scale (SMAFRS), ( f ) forced vital capacity (FVC) and ( g ) peak cough flow (PCF). L = liter; m = meter; min = minute.
For the pulmonary function (see Figure 1F, 1G, and Supplementary Table S3), changes in FVC at 36 months vary between −5 and + 12%. Six patients showed an improvement of ≥ 3% (range: +3 – + 12%) and two patients showed a deterioration of ≥ 3% (range: −3 to −5%). For PCF, changes vary between −26 and + 45 L/min; five patients showed an improvement between + 11 and + 45 L/min and three patients a deterioration between −12 and −26 L/min at 36 months. As a whole, pulmonary function remained stable over three years for all patients (see Fig. 2f,g).
Treatment effects of nusinersen: Self-reported changes
According to the self-perception of change, 15 patients out of 17 reported a subjective improvement since the start of the treatment in at least one of the eight areas questioned (Fig. 3). Strength and energy level are the two areas having the highest number of patients reporting an improvement (13 and 14 patients out of 17, respectively). None of the walker patients reported improvement in areas linked to bulbar function (chewing, mouth opening and voice), and only one walker patient reported a gain in swallowing. Also, all non-sitter patients (n = 5) reported a gain in voice.
Figure 3. Number of participants reporting a gain in strength, level of energy, trunk control, respiratory, swallowing, chewing, mouth opening and voice according to their functional status.
Many other subjective changes were also reported by patients. Among these changes, we noted themes of improved mobility, which was reported by patients as less falls, the ability to stand up from a chair without armrests and walking without assistive gait devices. Bulbar improvements such as longer phonation, louder voice and less pausing required while talking were reported from multiple patients, which allowed one patient to provide increased hours of teaching. Another patient also reported the ability to eat an apple peel, which had been impossible for the previous 10 years. Multiple patients reported increased strength, resulting in more time allocated for physical exercise, the ability to hold their baby, more independence for personal care (e.g., washing hair alone while help was previously required) and better tonus and trunk balance, facilitating transfers for their caregiver. A higher level of energy was also noted by multiple patients. For example, due to increased energy, one individual started a PhD which they did not think was possible before treatment.
Side effects
Eight patients reported end-of-dose effects between one to four weeks before the next planned injection. The most frequent side effect reported by patients were pain at the injection site (that lasted two days for the longest) (n = 6), headache (n = 2), low back pain (n = 2), fatigue (n = 1), sciatalgia (n = 2) and buttock pain (n = 1) post-injection. Two patients reported anxiety before the injection. Three patients did not report any side effects.
Discussion
Our study documented some positive effects of nusinersen in a Canadian cohort of adults with SMA type 2 and 3. While the objective of treatment with disease-modifying therapy in adults is primarily to stop the progression of the disease and thus stabilize patients’ condition, improvements in motor function beyond MCID (available for the HFMSE, RULM and 6MWT) were observed after 36 months of follow-up for nine individuals. However, mixed responses were also observed in two patients, five patients showed stabilization and one patient showed deterioration.
For the two patients with mixed response (J and N), the effectiveness of the treatment on their motor function is unclear as an improvement at the HFMSE is observed but also a decline at the RULM. For J, a health issue unrelated to SMA led to time off work and underutilization of upper limb. This may partly explain the decrease in the RULM score. During this time period, patient J did report subjective gains in swallowing and breathing. For N, at the end of the first year of treatment, a fall caused several maxillofacial contusions and upper body injuries. This event correlates with the decrease observed in PCF, HFMSE and RULM at 12 months, and could possibly explain the mixed response on motor scales for this patient at 36 months. It is important to note that this patient was not able to perform the 6MWT before starting the treatment but walked 30 m after two years, thus suggesting positive treatment benefits, despite the decrease in HFMSE and RULM. In addition, this patient subjectively reported maintenance of their capabilities, as also observed with the SMAFRS (+2 points at 36 months). For patient B, treatment was continued despite deterioration since the psychosocial context (e.g., many changes in personal life) might have influenced his/her physical capacities beyond the impact of SMA. Subjective effects of the treatment were always documented in the annual evaluations, and the treatment was pursued for this reason. In one case (F), nusinersen was discontinued after three years of treatment due to post-injection sciatalgia, which appeared during the second year of treatment and led to bed rest for many months. A deterioration of 5 points was observed at 36 months with the CHOP-ATEND for this patient. While RULM and HFMSE remained stable, the floor effect of these two tests could have prevented the ability to observe deterioration. The treatment was continued for three years despite the pain since the patient still felt bulbar benefits at 36 months. After stopping nusinersen and beginning another medication (risdiplam), the pain significantly decreased.
The treatment effects of nusinersen obtained in this real-world study are positive when compared to the natural history of SMA and consistent with results from previous real-world studies Reference Veerapandiyan, Eichinger and Guntrum34,Reference Fainmesser, Drory and Ben-Shushan38,39,Reference Łusakowska, Wójcik and Frączek41–Reference Funato, Kino and Iwata43,Reference Bjelica, Wohnrade, Osmanovic, Schreiber-Katz and Petri55 that report stabilization and/or improvement of the patients’ condition. In our cohort, we observed a stabilization (walkers) or some improvement (non-sitters/sitters) at the HFMSE with a median difference at 36 months of 0 and + 2.5, while a mean rate of decline of −0.35 to −0.56 points over one year and −1.71 points over three years at the HFMSE was previously documented. Reference Wadman, Wijngaarde and Stam8–Reference Kaufmann, McDermott and Darras10 These results are comparable to those obtained by Pechmann et al., who documented a stabilization in adult walkers treated with nusinersen (mean difference = −1.4 points after 38 months). Reference Pechmann, Behrens and Dörnbrack40 Significant improvement at the HFMSE score was documented in two other studies after 15 months (+4 points) 39 and 30 months (+5.1 points) Reference Łusakowska, Wójcik and Frączek41 . For the RULM, a decline of 0.4 points over 12 months was observed in a previous natural history study, Reference Pera, Coratti and Mazzone11 while we observed in our cohort a median difference of 0 (walkers) and + 1.0 points (non-sitters/sitters) over 36 months. By comparison, Pechmann et al. Reference Pechmann, Behrens and Dörnbrack40 observed a mean difference of −0.5 points over 38 months, and Łusakowska et al. Reference Łusakowska, Wójcik and Frączek41 observed a significant score increase of 1.96 points at 30 months. However, it is important to note that the cohort of Pechmann was solely composed of adult walkers and we noticed a ceiling effect in our cohort with this outcome in strong walker patients, which may prevent detection of potential improvement. In another study by Iwayama et al., a worsening at the RULM was reported in two patients, a decrease that authors explained by the prolongation of the treatment interval due to COVID-19 pandemic. Reference Iwayama, Kawahara and Takagi42 There is variability in published reports of 6MWT response post-nusineresen treatment. Arslan et al. reported a significant improvement of 20 m after 15 months, 39 while Łusakowska did not find a significant difference in the total distance walked at 30 months, but reported an increase above the MCID in 50% of patients, Reference Łusakowska, Wójcik and Frączek41 and Pechmann et al. reported a clinically meaningful improvement in 26.5% of adult walkers. Reference Pechmann, Behrens and Dörnbrack40 Our findings are in alignment with these studies, while not demonstrating statistical significance, nonetheless, showing 71% (5/7) of walkers have improved 6MWT distances. In comparison to the natural history of decline of 1.46 m per year, Reference Mazzone, Bianco and Main12 this gain may be significant in a patient’s life.
In comparison to the 3% decline in natural history of pulmonary function, Reference Kaufmann, McDermott and Darras10 stabilization of it following nusinersen use was reported in other studies Reference Fainmesser, Drory and Ben-Shushan38,Reference Pechmann, Behrens and Dörnbrack40,Reference Bjelica, Wohnrade, Osmanovic, Schreiber-Katz and Petri55 and is in alignment with our findings, wherein the majority of individuals showed minimal improvement or minimal decrease. As respiratory failure is an important cause of death in this population, this stabilization may result in improved life expectancy with the long-term use of nusinersen. While data was not routinely captured in clinic visits, and thus not presented herein, respiratory improvements were reported by multiple patients and caregivers as a decrease in hospitalizations from viral/bacterial infections and respiratory complications following nusinersen treatment. It will be important to capture these changes more rigorously to support effectiveness and value of these therapies in adult patients.
Importantly, findings from our study support the need for appropriate outcome measure selection. An important ceiling effect was observed for walker patients on the RULM (4 patients out of 4, score range 36 to 37, maximum possible score = 37) and HFMSE (5 patients out of 6, score range 53-57, maximum possible score = 66), which prevents the ability to detect improvement that could occur in their motor function. As also observed in Pechmann et al., Reference Pechmann, Behrens and Dörnbrack40 the only outcome for this subgroup of patients in our cohort that is responsive to change is the 6MWT. Thus, the treatment effects that seem to be higher in the sitter/non-sitter subgroup of patients are likely not properly detected by the outcome measures utilized in ambulatory SMA patients. Most walkers reported subjective benefits of the treatment. In addition, a floor effect was observed in non-sitters at the HFMSE, RULM and SMAFRS. Due to the floor effect observed at the HFMSE in non-sitter patients, the CHOP-ATEND was introduced later in our study, which explains the number of patients not performing the baseline assessment. Also, only three patients performed the CHOP-ATEND at 36 months due to a change in outcome measure (clinical practice adjusted to utilize the ATEND 3.0, not included in the present study).
In addition to the need for appropriate motor outcome selection that may be responsive to change, there remains a gap in validated outcome measures that can be effectively utilized to assess response to therapy on many items that were highlighted through subjective patient and caregiver reports in this cohort. Ongoing work in the SMA community should continue to focus on how to objectively measure fatigue, energy, swallowing and speech functions. These domains are essential to understand response to therapy and impacts on activities of daily living.
Limitations
The main limitation of the present study is the relatively small sample size, which may have prevented reaching statistical significance or results could have been influenced by patients with large changes. For these reasons, caution around the interpretation of statistical significance is warranted. In small real-world case studies, the individual circumstances are essential to interpret therapy effects. It will be important to combine this data with other Canadian cohorts, and global collaborators to increase the statistical power. The collection of real-world data is useful to better understand the impact of treatment on the patient’s life, however, in real-world clinical practice, as in this study, there are data collection obstacles that impact the ability to assess response to therapy. Nevertheless, this study is of great importance for the SMA scientific community due to the duration of the follow-up and number of assessments which was carried out despite the real-world context.
While data collection for adults with SMA accessing disease-modifying treatment is a requirement of the Institut national d'excellence en santé et en services sociaux (INESSS), the Quebec authority on medications, no funding was granted. Therefore, it was exceedingly difficult to secure time for physiotherapists or occupational therapists to complete clinical assessments. Due to this lack of resources, different evaluators carried out annual follow-ups. In certain cases, the absence of an available and qualified professional to perform assessments led to missing data. In addition, sanitary restrictions that occurred during the COVID-19 pandemic also prevented performance of some assessments, increasing the extent of missing data. Finally, some patients started the treatment before their initial evaluation due to the delay between the drug approval by Health Canada (2018) and the pretreatment assessment requirement by the INESSS (2020). This issue has led to some missing baseline data. Additionally, outcome measures are episodic in nature and performance may be hampered by how an individual is feeling on a given day, level of effort, time of day and potential anxiety of impacting continued access to therapy. Patient-reported outcomes or remote monitoring techniques may support a more holistic continued view of patient functioning in their daily lives.
Conclusion
This real-world study demonstrated some benefits of nusinersen treatment in adults with SMA types 2 and 3, particularly in terms of motor function. The small sample size and responsiveness to change of some outcome measures in certain sub-populations may have limited the ability to detect statistically significant changes for most measures. However, overall individual responses to treatment after 36 months showed improvement in several patients in motor function, a stabilization of respiratory function and significant gains in PROMs. Despite all the obstacles encountered and limitations inherent in real-world longitudinal evaluations, this study demonstrates effectiveness of the treatment in an adult population, in alignment with other international studies. Future research should focus on establishing optimal outcome measures for different patient profiles and include patients’ perception as a complementary evaluation. It will be essential to build a national consensus within the Canadian and global communities, based on experience treating individuals with nusinersen and a better understanding of the gaps in existing measures (significant floor and ceiling effects) to accurately assess the response to treatment. Outcome measures addressing bulbar function along with documentation of respiratory complications (e.g., hospitalizations due to respiratory infections) should be considered for future research to be able to better capture the response to treatment.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/cjn.2024.49.
Data availability
Deidentified data used and/or analyzed during the current study may be shared with any qualified investigator upon reasonable request from the corresponding author following the proper evaluation of the research protocol by an Ethics Review Board, and approval of data-sharing practices through the Canadian Neuromuscular Diseases Registry.
Acknowledgements
We thank Cynthia Gagnon for the sharing of professional resources that allowed the writing of this manuscript.
Author contributions
IC: analyzed and interpreted the data, writing–original draft, review and editing.
VH: analyzed and interpreted the data, writing–review and editing.
MN: writing–review and editing.
LBB: writing–original draft, review and editing.
XR: conceptualization, investigation, supervision, data curation, writing–review and editing.
Funding statement
Funding for data collection was received from the Canadian Neuromuscular Disease Registry, who is supported by Biogen, Roche and Novartis. No industry funder was involved in study design, data collection or data analyses.
Competing interests
VH reports honoraria and expert consultancy fees from Biogen and Roche. MN and XR report having travel expenses covered by Biogen for attending the CURESMA congress in 2022. XR reports honoraria and expert consultancy fees from Biogen, Novartis and ROCHE. All are unrelated with the patient’s follow-up and assessments, and data analyses for the present manuscript. IC and LBB have no competing interests to disclose.
