Risdiplam therapy in adult patients with Spinal muscular Atrophy (SMA). A 24-month-real-world experience at a single muscle centre

Introduction. Treatment with Risdiplam has been recently extended to adult patients with Spinal Muscular Atrophy (SMA). We describe the experience of a single neuromuscular centre in Italy in treating adult SMA patients with risdiplam and analyze motor function during a follow-up period of 24 months.

Patients and methods. Twelve patients with type 2 or 3 SMA (three with SMA type 3, five with SMA type 3a and four with type 3b, age range: 24-61) were included. Of them, nine were “sitter” and three were “walker”patients. The Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE) were recorded at baseline and every six months. Treatment adverse events were collected at every follow-up visit.

Results. All the patients reached the 24-month follow-up. Based on the HFMSE score, 50% showed an improvement compared to the baseline total scores, 41,7% remained stable, and 8.3% experienced slight clinical worsening. Based on the RULM scores, the percentages were comparable: 50% demonstrated an improvement compared to the baseline total scores, 41,7% remained stable and 8,3% slight clinical worsening. The best results were observed in the patient “walker” group. The most common adverse events were transient gastro-intestinal problems and headache.

Conclusions. Our study confirms that risdiplam is well tolerated. Half of the patients improved after risdiplam initiation and about 42% remained stable. Most patients stated to be satisfied with the medication. Longitudinal studies are needed to better understand the long-term effects of risdiplam in adult SMA.

Introduction

Spinal Muscular Atrophy (SMA) is a rare, genetic neuromuscular condition causing progressive muscle wasting (atrophy) and weakness, often cited as the leading genetic cause of death in young children^1-5. The estimated prevalence of SMA in the U.S. and European Union is 30.000-35.000 cases, with an overall incidence of approximately 1 in 6000 to 1 in 10.000 births². In Italy, the prevalence of SMA has been recently estimated to be 2.12 in 100.000⁶.

A homozygous deletion and/or mutation in the survival motor neuron-1 (SMN1) gene, localized on chromosome 5q, is responsible for the autosomal recessive disorder in more than 95% of cases. In the remaining 5% of cases, the disease is due to a compound heterozygous mutation in the same gene⁵. There are two nearly identical SMN genes (SMN1 and SMN2)⁵. SMN1 expresses full-length survival motor neuron (SMN) protein, while the highly homologous SMN2 gene expresses only a small amount of full-length SMN, and primarily a shortened, unstable, and rapidly degraded isoform of the SMN protein. The SMN2 gene produces low levels of functional SMN protein that are not sufficient to fully compensate for the lack of the SMN1 gene but can modulate disease severity to produce a milder phenotype when the number of SMN2 gene copies is increased⁵.

SMA phenotypes vary widely in severity, but all are associated with some degree of muscle weakness. The mutations result in degeneration of motor neurons in the central nervous system (CNS) that may affect arm, hand, head and neck movement, crawling and walking abilities, breathing and swallowing^2,3.

Within the last years, three disease-modifying treatments were approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in SMA patients. They are:

1) Nusinersen (Spinraza®), a SMN2 splicing modifier was the first therapy approved by for the treatment of SMA of all types, in 2017⁶;

2) Onasemnogene abeparvovec (Zolgensma®)⁷, a gene therapy that was approved by both agencies in 2020, with different indications: EMA approved it for patients diagnosed with SMA type 1 or who have up to three copies of the SMN2 gene, while the FDA approved it for the treatment of pediatric patients under two years of age;

3) Risdiplam (Evrysdi®)⁸, which was the last therapy approved by the EMA, is indicated for the treatment of SMA patients aged two months and older, having one to four copies of SMN2 gene.

Since their approvals, several studies were conducted, primarily in SMA children, with nusinersen^9-17, onasemnogene abeparvovec^18-23 and risdiplam^24-26.

We aimed to describe the experience of a single neuromuscular centre in Italy in treating adult SMA patients with risdiplam and to analyze functional abilities and treatment satisfaction during a follow-up period up to 24 months.

Patients and methods

Patients

Patients with SMA types II and III were consecutively enrolled for treatment with risdiplam. Inclusion criteria were genetic diagnosis of SMA and known number of SMN2 copies. The following information were collected: current age, family and personal history, age at diagnosis, previous treatment with Nusinersen or other specific drugs, age at the initiation of treatment with risdiplam, duration of treatment. All patients signed informed consent.

Methods

To assess disease progression and treatment efficacy, the following outcome measures were used

• the Hammersmith Functional Motor Scale Expanded for SMA (HFMSE)²⁷,
• the Revised Upper Limb Module (RULM)^28-30, and
• the six minute walking test (6MWT)^31,32.

Results

Twelve patients with SMA, who met the inclusion criteria and had signed the informed consent for treatment were included in the risdiplam-treated group. Three of them shifted from the Nusinersen treatment.

At the enrolment, the mean age of patients, eight males and four females, was 45.5 (range 24-61 years). Three of them had SMA type II, five SMA type IIIa and four SMA type IIIb. According to the functional classification, 8/12 (66,7%) patients were able to maintain a sitting position unassisted (sitter group) and 4/12 (33,3%) were able to walk (walker group).

Based on the SMN2 gene copy number, the patients were sub-classified as follows:

• 2 copies: 4 patients (25%);
• 3 copies: 3 patients (43,75);
• 4 copies: 5 patients (31,25%).

The age at onset of symptoms varied from 8 months and 18 years (mean 98.0 ± 87.5). As expected, an early onset was typical of type II SMA. The mean age at treatment initiation was 42.8 years (range 18-58). The mean duration of treatment was 27,4 months, ranging from 24 to 36 months. The clinical and genetic characteristics of the patients enrolled in the study are reported in Table I.

All the patients reached the 24-month follow-up. The total scores of HMSFE and RULM, at baseline and after 24 months of treatment with Risdiplam are reported in Table II, according to the functional abilities.

Based on the HFMSE score, 50% showed an improvement compared to the baseline total scores, 41,7% remained stable, and 8.3% experienced slight clinical worsening. In particular, in the sitter group, 37,5% improved (a change of 1-3 points) and 62,5% showed stabilization (a change of ≥ 0). In the walker group, 75% of patient improved (a change of 2-4 points) and 25% showed a slight worsening (a change of 1 point).

Based on the RULM scores, the percentages were comparable: 50% demonstrated an improvement compared to the baseline total scores, 41,7% remained stable and 8,3% showed a slight clinical worsening. In particular, in the sitter group 50% improved (a change of 1-3 points), 37,5% showed stabilization (a change of ≥ 0) and 12,5% got worse (a change of 3 points). In the walker group, 50% showed an improvement (1-4 points) and 50% stabilization (a change of ≥ 0). The 6MWT in this group increased by an average of 49 meters, from 198,7 to 232,7 meters.

All patients retained bulbar function during the period of observation; none required permanent ventilation.

Safety results

No serious adverse events were observed except for sporadic gastrointestinal disorders, and headache.

Discussion

Risdiplam has been successfully used to treat children with SMA types 1 and 2 and several studies have appeared in the literature since its approval^24-26. The most commonly used scales to assess motor function in these patients were HFMSE and RULM.

The natural history of SMA types 2 and 3 is characterized by disease progression and continued loss of function abilities³³. A decline of – 0,4 points in the total RULM score over 12 months was reported by Pera²⁹ et al. in untreated patients with SMA types 2 and 3 (ambulant and non-ambulant) aged 2,7-49,7 years. Instead, a decline of - 0.79 points in patients aged 5-56 years was reported by Coratti³⁰ et al.

In a group of 165 adult patients with SMA, Maggi et al.³⁴ found that median HFRSE scores were significantly (p = 0,0040) lower in males than in females while median RULM scores did not significantly (p = 0,059) differ between males and females, although a trend towards worse performance in males was observed. Moreover, in SMA3 patients who carried three or four SMN2 copies, an effect of female sex in prolonging ambulation was found to be statistically significant (p = 0,034).

In the last 3-4 years, researchers’ attention has been focused on risdiplam treatment of SMA subjects in adult age, regardless of SMA type and functional abilities (sitters, nonsitters, nonambulant, and ambulant). Table III lists the articles published in the literature^36-45 regarding this topic. Table analysis shows that a total of 666 patients (42% men), aged 15 to 83 years, were treated with risdiplam worldwide for periods ranging from 9 to 36 months. Forty percent of these studies reported an improvement in HFMSE and RULM total scores, and 60% reported disease stabilization. In two studies^43,44, an initial improvement in functional abilities was observed at 6 and 12 months respectively, followed by prolonged stabilization.

Our results are in line with those of the above mentioned studies, as 50% of patients improved after 24 months of treatment with risdiplam, and about 41,7% remained stable. Decline in motor abilities was observed in one (8,3%) patient. Stabilization is to be considered a success given the relentless progression of the disease.

Conclusions

In all studies, adult SMA patients treated with risdiplam reported increased independence in daily activities, stabilization or even improvement in function abilities, reduction of respiratory and nutritional complications and improved social relationships resulting in improved quality of life. This occurred despite the initiation of treatment several decades after the onset of symptoms. A strength of risdiplam treatment is the non-invasive administration route, particularly appreciated by patients who had previously received intrathecal treatment with nusinersen.

Future longitudinal studies will better understand the long-term effects of risdiplam in adult SMA.

Acknowledgements

This work was supported by MER-SMA-18-003 STUDY. VN is member of the ERN EURO-NMD network.

Conflict of interest statement

The authors declare no conflict of interest to disclose.

Authors contributions

All authors contributed to the conception of the work, review of clinical data, case analysis, and drafting of the manuscript. All authors contributed to the final manuscript, critically reviewed its content, and approved the submitted version.

Ethical consideration

The study was approved by the L. Vanvitelli University Ethical Committee (approval n. 511 of 07/19/2021

History

Received: March 12, 2026

Accepted: March 13, 2026

Figures and tables

Table I. Clinical and genetic characteristics of the patients enrolled in the study.

	Currrent Age	Sex	SMA Type	SMN2 copies	Age in years at onset of symptoms	Function Ability	Age in years at the start of Risdiplam	Duration in months of treatment with Risdiplam
Patient 1	60	M	IIIb	4	13	Sitter	58	22
Patient 2	38	M	IIIb	3	14	Walker	36	21
Patient 3	53	M	IIIb	4	18	Walker	51	21
Patient 4	41	M	IIIb	4	12	Sitter	38	25
Patient 5	52	M	II	2	1.5	Sitter	49	31
Patient 6	29	M	II	3	0.8	Sitter	26	33
Patient 7	61	M	IIIa	4	15	Sitter	58	35
Patient 8	40	M	II	2	1.2	Sitter	37	33
Patient 9	24	F	IIIa	2	2	Sitter	21	36
Patient 10	51	F	IIIa	2	1,2	Sitter	48	36
Patient 11	61	F	IIIa	3	17	Sitter	58	14
Patient 12	36	F	IIIb	4	2,5	Walker	34	22
Mean ± SD	45.5 ± 12.6			3.1 ± 0.9	98.0 ± 85,7		42.8 ± 12.7	27.4 ± 7.4

Table II. Changes in total functional scale scores from baseline after 24 months of treatment with Risdiplam.

Functional Scale	Sitter Group of Patients (n = 9)		Walker Group of Patients (n = 3)
	Baseline	24 months	Baseline	24 months
HMSFE total score	16.38	17.12	36.25	38.25
RULM total score	20.5	21.5	30.75	32.0
6MWT (meters)			198.7	232.7

Table III. Papers published in the literature on the treatment with Risdiplam of adult patients with SMA

Authors, year of publication, [reference]	Number of pts (total = 666)	Mean Age in years (range)	Gender M/F	Duration of treatment in mos	HFMSE		RULM
					% ↑	% Stable	% ↑	% Stable
McCluskey G., 2023 [36]	6	33.7	1/5	9	100	0	100	0
Ñungo Garzón NC, 2023 [37]	6	17-46	3/3	12	83.3	16.7	33.3	66.7
Oskoui M., 2023 [38]	120	2-25	n.a.	24	32.0	58.0	50	50
Bjelica B., 2424 [39]	14	18-51	8/6	20	0	92.3	0	53.8
Gavriilaki M., 2025 [40]	14	18-57	8/6	28.5 (6-30)	0	85.7	0	50
Zhao X., 2026 [41]	n.a	n.a	n.a	n.a	n.a	n.a	n.a	n.a
Keritam O., 2025 [42]	57	> 16	25/32	18	30.8	n.a	52.9	n.a
Saito K., 2025 [43]	370	> 15-83	191/179	12	n.a	n.a	n.a	n.a
García Estévez DA., 2026 [44]	8	55 (41-66)	3/5	12		100*		100*
Parmova O., 2026 [45]	59	28.5 (17-59.2)	34/25	36		100**		100**
Cesarone E., 2026 (this study)	12	24-61	8/4	27.4 (24-36)	50	41.7	50	41.7
* Stabilization was observed after an initial improvement at 6* or 12** months of treatment.