Safety of Risdiplam in Japanese Patients with Spinal Muscular Atrophy: A 12‑Month Interim Analysis of a Postmarketing Surveillance Study

Abstract

Introduction

Risdiplam, an oral splicing modifier for the survival motor neuron-2 gene (SMN2), is approved for treating spinal muscular atrophy (SMA). While its safety and efficacy have been demonstrated in global trials, there are limited real-world data on its safety in Japanese patients with SMA. This all-case postmarketing surveillance (PMS) study aimed to assess the safety and usage patterns of risdiplam in Japan.

Methods

This 12-month interim analysis is part of an ongoing PMS study that includes Japanese patients with SMA who have received risdiplam. The full observation period for this PMS is 24 months from the initiation of risdiplam treatment. Safety data, including adverse drug reactions (ADRs), were collected from case report forms (CRFs) submitted by participating healthcare facilities. ADRs were coded using the MedDRA/J classification.

Results

This study included 538 patients with SMA from 259 institutions in Japan between August 2021 and August 2022. The median age (minimum–maximum) at enrolment was 22.5 (0–83) years, and 51.5% of patients were male. SMA type II (47.2%) and III (27.9%) were the most common phenotypes. The median treatment duration was 366.0 days, and 86.1% of patients continued risdiplam treatment. ADRs were reported in 112 patients (20.8%), while serious ADRs were reported in eight patients (1.5%). The most common ADRs (classified by MedDRA System Organ Class) were gastrointestinal disorders in 86 (16.0%) patients (diarrhoea in 43 [8.0%], faeces soft in 23 [4.3%] and stomatitis in 10 [1.9%] patients). Exploratory analysis suggested that advanced age, comorbidities and concomitant medication use might be associated with an increased incidence of gastrointestinal ADRs.

Conclusions

This 12-month interim analysis of PMS data indicated that risdiplam was well tolerated among Japanese patients with SMA, consistent with previous clinical trial findings. A comprehensive evaluation of the safety and efficacy of risdiplam will be provided in the final 24-month analysis.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00795-x.

Plain Language Summary

Spinal muscular atrophy is a rare disease that weakens muscles due to genetic pathogenic variants. Risdiplam was approved in Japan in 2021 to treat spinal muscular atrophy. While global studies have shown its safety and effectiveness, there are limited real-world data from Japan. This study examined the safety and usage pattern of risdiplam over 12 months in real-world settings, involving 538 patients from 259 medical centres in Japan. Most patients had spinal muscular atrophy type II or III, with an average age of 22.5 years. The study found that 86.1% of patients used risdiplam for about 1 year. About 20.8% of patients experienced side effects, and 1.5% had serious side effects. Common side effects included digestive issues and skin problems. Older patients, those with existing health conditions and those taking other medicines were more likely to have digestive issues, highlighting the need for personalised care. Overall, risdiplam was well tolerated, and no new safety issues were found. The final results after 24 months of risdiplam use will provide more information about its long-term safety in Japanese patients with spinal muscular atrophy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00795-x.

Key Summary Points

Why carry out this study?

While pivotal trials have established the safety of risdiplam in patients with spinal muscular atrophy (SMA), evidence from real-world clinical settings, particularly in Japan, remains limited

This all-case postmarketing surveillance study aimed to evaluate the safety and usage patterns of risdiplam in Japanese patients with SMA over a 12-month period in real-world settings

What was learned from the study?

Risdiplam was generally well tolerated, with 2.2% of patients discontinuing treatment because of adverse events

The incidence of adverse drug reactions (ADRs) was 20.8%. The most common ADRs were gastrointestinal disorders (16.0%), predominantly diarrhoea (8.0%) and faeces soft (4.3%)

Advanced age, the presence of comorbidities and the use of concomitant medications may contribute to a higher incidence of gastrointestinal disorders. A multivariate analysis will be performed in the final assessment to provide a clearer understanding of the associated risk factors

Introduction

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterised by a homozygous deletion or pathogenic variants of the survival motor neuron 1 gene (SMN1), leading to decreased production of SMN protein. This reduced level of SMN protein results in skeletal muscle weakness and atrophy [1]. SMN2, a gene homologous to SMN1, also produces functional SMN but at low levels because of the exclusion of exon 7 during premessenger RNA splicing [1]. Globally, SMA affects 1–2 per 100,000 individuals [2], while 1 in every 10,000 to 20,000 live births is diagnosed with the disease [3]. According to a nationwide epidemiological survey conducted in Japan, as of December 2017, the number of patients with SMA was estimated to be 1478 (95% confidence interval [CI] 1122–1834) [4]. The estimated prevalence was 1.17 per 100,000 individuals (95% CI 0.89–1.45), and the incidence was 0.51 per 10,000 live births (95% CI 0.32–0.71). The age at onset was < 2 years in 82.7% of patients with available records, and 20.0% had disease onset at ≤ 2 months of age [4]. Based on the age at disease onset and clinical course, SMA is categorised into the following phenotypes: type 0 (prenatal), type I (onset at < 6 months), type II (onset at 6–18 months), type III (onset at > 18 months) and type IV (adulthood-onset) [1]. Survival is poor, especially in patients with SMA type I or II (infantile-onset), due to respiratory muscle weakness leading to pulmonary function decline and respiratory failure in the absence of disease-modifying therapy [1]. Patients with SMA type I often require permanent ventilation [5]. Even in adults and patients with SMA type III, all-cause mortality is higher than that observed in healthy control individuals [6].

SMA has been considered untreatable until the last few decades; however, a better understanding of the pathogenetic mechanisms of SMA has led to the development of new therapies [7]. In Japan, nusinersen, an antisense oligonucleotide that modifies premessenger RNA splicing of the SMN2 gene [8, 9], was first approved in 2017 and is indicated for the treatment of SMA, including infantile and presymptomatic diseases [10]. Gene therapy with onasemnogene abeparvovec [11, 12] was approved in Japan in 2020 for the treatment of SMA in patients aged < 2 years who test negative for anti–adeno associated virus 9 (AAV9) antibodies [13]. However, these treatment options require intrathecal or intravenous infusion, which occasionally poses an additional burden to patients [14, 15].

Risdiplam is a small-molecule agent designed as an SMN2 premessenger RNA splicing modifier [16]. Oral administration of risdiplam to patients with SMA increases SMN protein production and improves motor function [17]. Risdiplam has demonstrated efficacy in the phase 2/3 FIREFISH trial (ClinicalTrials.gov ID: NCT02913482) for infants with SMA type I [18] and the phase 2/3 SUNFISH trial (NCT02908685) for patients with SMA type II or III [19, 20], and was approved in Japan in 2021 for the treatment of SMA in adults and children aged ≥ 2 months [10].

The recommended dosage of risdiplam varies depending on the patient’s age and weight. For patients aged 2 months to ≤ 2 years, the standard dosage is 0.2 mg/kg, taken orally once daily after a meal [21]. For patients aged > 2 years, the dosage is based on body weight: for those weighing < 20 kg, the usual dose is 0.25 mg/kg, whereas for those weighing ≥ 20 kg, the recommended dose is 5 mg, both taken orally once daily after a meal [21].

In addition to its efficacy, the safety of risdiplam has been studied in pivotal trials such as FIREFISH and SUNFISH [22, 23]. However, evidence regarding its safety and usage patterns in daily clinical practice for Japanese patients is limited in current clinical trials. This all-case postmarketing surveillance (PMS) study reported here was conducted as part of Japan’s legal and regulatory requirements and aimed to assess the safety and effectiveness of risdiplam in Japanese patients with SMA in daily clinical practice. Here, we present the results of a 12-month interim safety analysis. The effectiveness of risdiplam is beyond the scope of the current study and will be presented as part of the final analysis.

Methods

Study Design

This all-case PMS study (registration no: UMIN000044914) is an ongoing, prospective, observational, multicentre study conducted across 259 institutions in Japan to obtain real-world data on the safety and efficacy of risdiplam in patients with SMA. The surveillance period planned for this study extends from 12 August 2021 (start date of risdiplam marketing in Japan) to 30 June 2030. The cut-off date for this 12-month interim analysis was 19 June 2024. All patients who were prescribed risdiplam during the enrolment period were registered using the central registration system. Enrolment started on 12 August 2021 and was completed on 31 August 2022, except for patients with SMA type IV, for whom enrolment will continue until December 2027. No exclusion criteria were established. All patients were followed up for 24 months (or until withdrawal from the study) from the start of risdiplam treatment.

Outcomes and Assessments

Patient baseline characteristics, risdiplam dosage and duration and adverse drug reactions (ADRs) were documented using case report forms (CRFs). ADRs were defined as adverse events (AEs) in which a causal relationship with risdiplam could not be ruled out by the investigator. The incidence rates of ADRs were the primary safety objective. The proportion of patients with ADRs was calculated based on system organ class (SOC), preferred term (PT), severity and seriousness. According to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-E2D guidelines on post-approval safety data management, ‘serious ADR’ encompasses any unexpected medical occurrence at any dose that results in death, poses a life-threatening risk to the patient, necessitates inpatient hospitalisation or prolongs existing hospitalisation, leads to persistent or significant disability or incapacity, manifests as a congenital anomaly or birth defect or constitutes a medically important event or reaction [24].

Ethical Approval

The study was conducted in accordance with relevant regulations in Japan (Ministerial Ordinance on Good Post-Marketing Study Practice [GPSP]; Ministry of Health, Labour and Welfare Ordinance Number 38; 23 March 2005). The study protocol was reviewed and approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) prior to study initiation.

The study did not undergo review by the ethics committee of the participating medical institutions or follow procedures for informed consent as this was not required for PMS studies according to Japanese regulations of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices [25]. This exemption ensured the registration of all patients with SMA as part of the approval conditions in Japan. The patient data were collected after de-identification.

Statistical Analysis

The target sample size was determined based on the incidence of epithelial tissue disorders as an ADR in previous clinical trials (Chugai Pharmaceutical [Tokyo, Japan] data on file). Considering patient dropouts, the target sample size was set at 330 patients. ADRs were coded using the Japanese translation of MedDRA (MedDRA/J) version 27.0. To explore factors that may influence the incidence of ADRs and onset of gastrointestinal disorders, an exploratory univariate analysis was conducted without accounting for confounding factors. All analyses were performed using SAS Release software version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patient Disposition

A total of 568 patients were registered at 259 participating facilities across Japan and provided consent for data publication. CRFs could not be retrieved for 16 patients, and another 14 patients were excluded from the analysis because of duplicate entries. The remaining 538 patients were included in the safety analysis at the 12-month interim mark (Fig. 1).

Fig. 1.

Patient disposition. CRF case report form

Baseline Characteristics

At enrolment, the median patient age (minimum–maximum) was 22.5 (0–83) years, and 277 (51.5%) of those included in the safety analysis were male (Table 1). Most patients had SMA type II (47.2%), followed by type III (27.9%), type I (23.2%) and type IV (1.7%; Table 1). Of the 527 patients who underwent genetic testing, 444 (82.5%) were found to have homozygous deletion or pathogenic variants in the SMN1 gene. Additionally, 115 patients (21.4%) had two copies of the SMN2 gene, while 291 patients (54.1%) had three copies (Table 1). However, it is important to note that we are currently verifying the status of genetic testing across various survey facilities, including those where the survey forms do not contain genetic test results—potentially due to the facility not conducting genetic testing. Comorbidities were noted in 379 patients (70.4%), with scoliosis being the most common (313 patients, 58.2%; Table 1). Other frequently reported comorbidities included chronic respiratory failure (42 patients, 7.8%), constipation (25 patients, 4.6%) and hypertension (22 patients, 4.1%; Table 1). Overall, 284 patients (52.8%) had received prior treatment for SMA. The most frequently prescribed prior treatment was nusinersen, which was administered to 278 patients (51.7%; Table 1). Detailed baseline characteristics are provided in Electronic Supplementary Material (ESM) Table S1.

Table 1.

Baseline demographics and patient and treatment characteristics

	Safety analysis set (N = 538)
Age (years), median (min–max)	22.5 (0–83)
Age group (years), n (%)
< 15	168 (31.2)
≥ 15 to < 65	345 (64.1)
≥ 65	25 (4.6)
Sex, male, n (%)	277 (51.5)
Weight (kg), mean ± SD	34.9 ± 17.7
Type of SMA, n (%)
Type I	125 (23.2)
Type II	254 (47.2)
Type III	150 (27.9)
Type IV	9 (1.7)
Comorbidities, n (%)a	379 (70.4)
Scoliosis	313 (58.2)
Chronic respiratory failure	42 (7.8)
Constipation	25 (4.6)
Hypertension	22 (4.1)
Genetic testing performed, n(%) b	527 (97.9)
SMN1 pathogenic variant/deletion:present	444 (82.5)
SMN2 copy number: 1	3 (0.6)
SMN2 copy number: 2	115 (21.4)
SMN2 copy number: 3	291 (54.1)
SMN2 copy number: 4	70 (13.0)
SMN2 copy number: ≥ 5	4 (0.7)
SMN2 copy number: unknown	44 (8.2)
Previous treatment for SMA, n (%)	284 (52.8)
Risdiplam	5 (0.9)
Onasemnogene abeparvovec	5 (0.9)
Nusinersen sodium	278 (51.7)
Prior surgery, n (%)c	193 (35.9)

max maximum, min minimum, SD standard deviation, SMA spinal muscular atrophy

^aRefers to ongoing conditions or symptoms not cured at baseline. This section includes information on the presence or absence of complications, scoliosis-related conditions and additional free-text descriptions

^bInformation on genetic testing was collected from prescribing facilities. In some cases, the facility prescribing risdiplam differed from the facility conducting genetic testing, and complete documentation of genetic results may not have been available on the survey forms. We are currently verifying the status of genetic testing across various survey facilities, including those where the survey forms do not contain genetic test results—potentially due to the facility not conducting genetic testing

^cInformation related to history of scoliosis-related surgeries and other surgical procedures as free-text descriptions were captured

Treatment Status

The median (minimum–maximum) treatment duration was 366.0 (1–921) days (Table 2), while the median (minimum–maximum) daily dose of risdiplam was 5 (1.1–5.8) mg. At the end of the observation period, 463 patients (86.1%) continued risdiplam treatment, whereas 69 (12.8%) discontinued treatment. The most common reason for discontinuation was hospital transfer (29 patients, 5.4%), followed by insufficient effectiveness (15 patients, 2.8%) and AEs (12 patients, 2.2%; Table 2).

Table 2.

Risdiplam treatment details

	Safety analysis set (N = 538)
Daily dose of risdiplam (mg)
Mean ± SD	4.8 ± 0.6
Median (min–max)	5 (1.1–5.8)
Total risdiplam dose (mg)
Mean ± SD	2267.6 ± 1108.0
Median (min–max)	1830 (5–4605)
Total treatment duration (days)
Mean ± SD	472.0 ± 217.3
Median (min–max)	366 (1–921)
Administration status, n (%)
Ongoing	463 (86.1)
Discontinued	69 (12.8)
Terminated	6 (1.1)
Reason for discontinuation, n (%)
Adverse events	12 (2.2)
Insufficient efficacy	15 (2.8)
No visit	0
Patient convenience	7 (1.3)
Hospital transfer	29 (5.4)
Death	3 (0.6)
Other	3 (0.6)
Unknown	0

Total treatment duration=period during which the drug is administered (date of the last dose − date of the first dose)

max maximum, min minimum, SD standard deviation

Incidence of ADRs

In total, 112 patients (20.8%) reported 173 ADRs. The most commonly reported ADRs at the SOC level were gastrointestinal disorders (86 patients, 16.0%), followed by skin and subcutaneous tissue disorders (17 patients, 3.2%). At the PT level, the most commonly reported ADRs were diarrhoea (43 patients, 8.0%) and faeces soft (23 patients, 4.3%). Serious ADRs were observed in eight patients (1.5%), involving 17 events (Table 3). These events included vomiting (2 patients) and macrocytic anaemia, hypochromic anaemia, copper deficiency, urinary retention, palpitations, oropharyngeal pain, nausea, salivary hypersecretion, gastrointestinal movement disorder, azoospermia, feeling abnormal, pyrexia, reduced neutrophil count and weight decrease (1 patient each; ESM Table S2). The ADR rate for the 12-month treatment was 24.9 per 100 person-years, while the rate of serious ADRs was 2.4 per 100 person-years (Table 3).

Table 3.

Incidence of ADRs

	Safety analysis set (N = 538)a	Number of events (per 100 person-years)
Any ADRs occurring in ≥ 1% of patients	112 (20.8)	24.9
Serious ADRs occurring in ≥ 1% of patients	8 (1.5)	2.4
Gastrointestinal disorders	86 (16.0)	16.6
Diarrhoea	43 (8.0)	6.9
Faeces soft	23 (4.3)	3.5
Stomatitis	10 (1.9)	1.4
Abdominal pain	7 (1.3)	1.0
Skin and subcutaneous tissue disorders	17 (3.2)	5.2
Rash	9 (1.7)	1.3

^aData are presented as n (%)

ADR adverse drug reaction

Factors That May Influence the Onset of Gastrointestinal Disorders (Exploratory Analysis)

Given the high incidence of gastrointestinal disorders (16.0%) in patients receiving risdiplam, an exploratory analysis was conducted to identify potential influencing factors. The percentage of patients reporting gastrointestinal disorders as an ADR was 10.1% in patients aged < 15 years, 18.6% in those aged ≥ 15 and < 65 years and 20.0% in those aged ≥ 65 years (ESM Table S3). Similarly, patients with comorbidities had a higher incidence of gastrointestinal disorders (19.8%) than those without comorbidities (6.9%). A similar trend was observed in patients using concomitant medications (19.4%) compared with those who were not (11.9%), as well as in patients who started using concomitant medications after initiating risdiplam treatment (30.3%) compared with those who did not (11.6%; ESM Table S3).

Discussion

This 12-month interim analysis of an all-case PMS study represents a cohort of Japanese patients with SMA receiving risdiplam in real-world clinical practice. This study enrolled 538 patients with SMA, representing approximately 50% of the estimated 1042 patients with 5q-SMA in Japan, according to a nationwide epidemiological survey [4]. In this study, 75.1% of patients had SMA type II or III, whereas the previous nationwide epidemiological survey reported only 64.2% of patients as being classified under these types [4]. This difference may be attributed to the fact that risdiplam was initially approved for adults and children aged ≥ 2 months with SMA and only recently got approval for SMA infants aged < 2 months in Japan [10]. Almost half of the patients in this study had received prior treatment for SMA, with nusinersen being the most commonly prescribed treatment. Adults with SMA are vulnerable to comorbidities [26], which was also observed in this study, further emphasising the need for effective and well-tolerated treatments.

A 12.8% discontinuation rate was observed in this study. Although the incidence of ADRs was notable, risdiplam was generally well tolerated, as evidenced by the low rate of treatment discontinuation due to ADRs. This observation aligns with previous studies reporting low treatment discontinuation rates in patients treated with risdiplam [20, 27, 28]. Moreover, the overall incidence of ADRs (20.8%) did not notably increase when the patient population was limited to those receiving prior nusinersen treatment (17.3%; ESM Table S4). Some of the commonly reported AEs among patients receiving risdiplam in previous clinical trials were upper respiratory tract infection (URTI), diarrhoea, pyrexia, nausea, rash, nasopharyngitis, headache, vomiting and cough [20, 22, 23, 27, 28]. In this study, gastrointestinal disorders and skin and subcutaneous tissue disorders were the most common ADRs at the SOC level, whereas diarrhoea, faeces soft, stomatitis, rash and abdominal pain were the predominant ADRs at the PT level. Additionally, in this study, one patient (age: 42 years, male) experienced a serious ADR related to respiratory, thoracic and mediastinal disorders (oropharyngeal pain), in contrast to findings from the phase 2–3 open-label study in infants (age: 1–7 months, with SMA type I), which primarily reported serious AEs related to the respiratory system [29]. Furthermore, while prescribing information indicates a potential risk for male fertility [21], azoospermia was observed in one patient (age: 33 years) in our study. However, the patient reportedly recovered without the need for any specific treatment. Direct comparisons across studies might not be feasible due to differences in how events are reported; previous trials reported AEs rather than ADRs, thereby affecting the interpretation of the results. Furthermore, previous studies differed in terms of study design, patient characteristics and treatment duration, which may also account for the variability in the incidence of ADRs. Serious ADRs were rare in the present study, occurring in only 1.5% of patients, and no unexpected safety concerns were identified. This low rate of serious ADRs aligns with findings from the FIREFISH and SUNFISH trials [22, 23].

Several studies have highlighted gastrointestinal AEs associated with risdiplam in patients with SMA [20, 23, 27, 28]. In this study, a univariate analysis of the factors associated with gastrointestinal disorders was performed as an exploratory investigation to support the final analysis. There is a possibility that advanced age, comorbidities and concomitant medication use are associated with a higher incidence of gastrointestinal ADRs. Thus, patient-specific factors possibly influenced the higher incidence of gastrointestinal disorders. However, this study does not include specific analyses of individual concomitant medications or comorbidities, and the precise mechanisms remain uncertain. Furthermore, the category of concomitant medications includes drugs used for the treatment of gastrointestinal symptoms, which may limit the scope of interpretation. Thus, it is important to further investigate the causes and risk factors of gastrointestinal disorders during risdiplam treatment, including factors identified in the present study.

Yu et al. [30] observed an increased incidence of diarrhoea in patients aged ≥ 45 years receiving risdiplam in a real-world pharmacovigilance study assessing cases from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Additionally, the secondary effects of comorbidities such as scoliosis on the gastrointestinal system in patients with SMA have been discussed in the literature [31]. Overall, gastrointestinal ADRs associated with risdiplam were generally manageable and consistent with the favourable safety profile of this medication. The final outcomes of this PMS study are anticipated to provide a more thorough evaluation of the real-world safety and effectiveness of 24-month risdiplam treatment in Japanese patients with SMA.

This study had several notable strengths. First, it is the largest PMS study conducted to date on risdiplam in Japanese patients, encompassing a diverse cohort of 538 patients with SMA from 259 facilities nationwide. Second, this study provides valuable real-world data, capturing the safety profile of risdiplam under routine clinical conditions, which may differ from the controlled environments of clinical trials. Third, the inclusion of detailed baseline characteristics and exploratory analyses of potential risk factors for ADRs add depth to the findings and provide actionable insights for clinicians managing patients with SMA. Finally, the high retention rate of patients in this study strengthened the reliability of the reported safety data.

It is important to acknowledge the limitations of this interim analysis. First, the PMS study did not include a control group, limiting the ability to directly compare the incidence of ADRs between untreated patients and those receiving alternative treatments. Second, as data were derived from real-world settings, variations in data collection and reporting practices across facilities may have introduced bias. Patient characteristics may differ substantially between real-world scenarios and clinical trial settings [5], which makes direct comparison across PMS and clinical trials difficult. Finally, this is an interim analysis of 12-month data, and the results may change after the 24-month observation period.

Conclusion

This 12-month interim analysis demonstrated that risdiplam was generally well tolerated in Japanese patients with SMA in real-world clinical practice. No new safety concerns were identified. Our findings provide valuable insights into the safety of risdiplam in daily clinical practice and support its continued use as a therapeutic option for SMA in Japan. Further analyses, including the final PMS results, will offer additional clarity regarding long-term safety. The findings of this study are more relevant to patients with SMA aged ≥ 2 months, which aligns with the initial indication approved in Japan. However, in 2024, an additional indication was approved, allowing the administration of risdiplam treatment to patients with presymptomatic SMA and those aged < 2 months [10]. Newborn screening for SMA is an integral part of early disease detection and is widely implemented in Japan [32–34] as well as in many countries outside Japan [35]. Ensuring the safety of risdiplam in newborns will be a key consideration in the future. We hope that our results will provide insights into the treatment strategies for SMA and facilitate the appropriate use of risdiplam in real-world clinical practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Kayoko Saito, Toshio Saito, Reiko Arakawa, Yasuhiro Takeshima, Hisahide Nishio, Yuka Ishikawa, Masahisa Katsuno, Takahiko Tsumuraya, Hiromitsu Kawata, Yuki Miyano and Hirofumi Komaki contributed to the conceptualisation of the study, as well as to the writing—original draft preparation and writing—review and editing. Takahiko Tsumuraya, Hiromitsu Kawata and Yuki Miyano also performed the methodology, formal analysis and investigation. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have approved the final version of this manuscript for publication.

Funding

This study was funded by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan. Chugai Pharmaceuticals also funded the Rapid Service Fee of the journal.

Data Availability

The datasets generated and/or analysed during the current study are not publicly available, as informed patient consent was not obtained for this PMS study according to the Japanese regulations.

Declarations

Conflict of Interest

Kayoko Saito was also the Principal Investigator for clinical trials of Chugai (Roche) (SUNFISH), Biogen (CHERISH, ENDEAR, DEVOTE) and Novartis Gene Therapies, Inc./Novartis (SPR1NT, LT-002, STRENGTH), during the time this study was conducted. All these trials also involved patients with SMA. Payments were made to the university hospital for these trials. Reiko Arakawa was also the Principal Investigator for clinical trials of Chugai (Roche) (MANATEE, SUNFISH), and the Sub Investigator for clinical trials of Biogen (CHERISH, ENDEAR) during the time this study was conducted. All these trials also involved patients with SMA. Payments were made to the hospital for these trials.

Financial Disclosures for the Previous 36 Months

The following represents disclosure information provided by authors of this manuscript: All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I—immediate family member, Inst—my institution. Relationships may not relate to the subject matter of this manuscript.

Kayoko Saito: Grants or contracts from any entity (Biogen Japan [Inst]; National grant of Japan for AMED [Grant number: 20ek0109472h0001, 21ek0109472h0002, 22ek0109472h0003] and the MHLW Research in Rare and Intractable Diseases Program [Grant Number: JPMH23FC1008]); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd); participation on a Data Safety Monitoring Board or Advisory Board (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd); leadership or fiduciary role in other boards, societies, committees or advocacy groups, paid or unpaid (medical adviser of the Japan SMA Families Network). Toshio Saito: Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; payment for expert testimony (Biogen Japan; Chugai Pharmaceutical Co., Ltd.); participation on a Data Safety Monitoring Board or Advisory Board (Biogen Japan; Chugai Pharmaceutical Co., Ltd.). Reiko Arakawa: Consulting fees (Chugai Pharmaceutical Co., Ltd.); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd.; Roche Korea Co., Ltd.); participation on a Data Safety Monitoring Board or Advisory Board (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd.). Yasuhiro Takeshima: Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Japan; Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd.). Hisahide Nishio: Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Chugai Pharmaceutical Co., Ltd.). Yuka Ishikawa: Consulting fees (Kaneka Corporation); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Co.; Breas Co.; Cough Ventec Co.; Chugai Co.; Chest Co.; Nihon Shinyaku Co; Philips Japan); support for attending meetings and/or travel (Chugai Co.; Cough Ventec Co.). Masahisa Katsuno: Consulting fees (Chugai Pharmaceutical Co., Ltd.); research grants (Biogen Japan; Chugai Pharmaceutical Co., Ltd.); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Biogen Japan; Chugai Pharmaceutical Co., Ltd.). Takahiko Tsumuraya, Hiromitsu Kawata and Yuki Miyano are employed by Chugai Pharmaceutical Co., Ltd. Hirofumi Komaki: Consulting fees (Roche); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events (Chugai Pharmaceutical Co., Ltd.; Novartis Pharmaceutical Co., Ltd.); support for attending meetings and/or travel (Roche).

Ethical Approval

The study did not undergo review by the ethics committee of the participating medical institutions nor follow procedures for informed consent, as these were not required for PMS studies according to Japanese regulations under the Act on Securing Quality, Efficacy, and Safety of Products Including Pharmaceuticals and Medical Devices [25]. This was necessary to ensure the registration of all patients with SMA and all patients were included as part of the approval conditions in Japan. Patient data were collected after identification. The study was conducted in accordance with relevant regulations in Japan (Ministerial Ordinance on Good Post-Marketing Study Practice [GPSP]; Ministry of Health, Labour and Welfare Ordinance Number 38; 23 March 2005). The study protocol was reviewed and approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) prior to study initiation.