Fertility Outcomes in Risdiplam-Treated Male Patients with Spinal Muscular Atrophy: A Multicenter Case Series

Abstract

Introduction

Spinal muscular atrophy (SMA) is a genetic, progressive neuromuscular disease caused by pathogenic variants in the survival of motor neuron survival of motor neuron (SMN) 1 gene leading to a deficiency in SMN protein. Three disease-modifying therapies are available for the treatment of SMA, affording many with the opportunity for family planning. Fertility outcomes in patients with SMA treated with risdiplam have not been previously reported.

Methods

This study was a multicenter, non-interventional retrospective case review that included three adult male patients with SMA from three sites in Austria and the USA. The primary objective was to characterize the reproductive history and fertility journey of men with SMA who were exposed to risdiplam and whose partner had conceived.

Results

Three male patients aged 21–34 years with late-onset SMA were taking risdiplam during the window of conception. Of the three resultant pregnancies, two were full term and resulted in healthy babies and one was voluntarily terminated. The babies were healthy and developing normally.

Conclusions

This series presents three cases of successful conception while a male patient was receiving risdiplam, a US Food and Drug Administration–approved treatment for SMA. Although there were reproductive concerns due to impairment in spermatogenesis that arose during nonclinical studies, this case series demonstrates that there was sufficient sperm production while on risdiplam to result in pregnancy. More research is needed to provide a complete understanding of the effects of risdiplam on male fertility in humans.

Graphical abstract available for this article.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03171-1.

Key Summary Points

Why carry out this study?

Spinal muscular atrophy (SMA) is a progressive, neuromuscular disease caused by a deficiency of the survival of motor neuron (SMN) protein.

Risdiplam, an SMN2 pre–mRNA splicing modifier, is an approved oral treatment for pediatric and adult patients with SMA.

Reversible, off-target effects of SMN2 pre-mRNA splicing modifiers on male spermatogenesis were observed in animal studies; however, there are no available data on the potential impact of risdiplam on spermatogenesis or male fertility in humans.

What was learned from the study?

Three male patients with SMA successfully conceived with their partners during treatment with risdiplam, which demonstrates there was sufficient sperm production while on risdiplam to result in pregnancy.

This case series provides evidence that adult male patients with SMA who are on treatment with risdiplam have been able to conceive with their partners; however, more studies are needed to understand the effects of risdiplam on male fertility in a larger population of men with SMA.

Digital Features

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Introduction

Spinal muscular atrophy (SMA) is a genetic, progressive neuromuscular disease that is characterized by motor neuron loss and resultant skeletal muscle atrophy [1]. SMA is caused by a deficiency in survival of motor neuron (SMN) protein production due to homozygous deletions or more rarely other pathogenic variants in the SMN1 gene. Three disease-modifying therapies are now available for SMA; they exert their action by increasing the level of functional SMN protein [2]. In this era of disease-modifying therapies, quality of life has improved and the life expectancies for treated individuals have increased [2], affording many with the opportunity for family planning [3].

Risdiplam (EVRYSDI^®) is an approved, orally administered disease-modifying therapy for the treatment of pediatric and adult individuals with SMA [4]. As a pre-mRNA splicing modifier, risdiplam promotes the inclusion of exon 7 into SMN2 mRNA transcripts, thus producing stable SMN protein [5]. In animal studies, off-target effects of SMN2 pre-mRNA splicing modifiers on male spermatogenesis were observed [6]. Exposure to SMN2 pre-mRNA splicing modifiers interfered with spermatogenesis but did not result in a complete block of sperm production. Following drug cessation, these testicular changes were reversed after a complete spermatogenic cycle [6].

The effect of SMA disease on the male reproductive system and fertility is not fully understood, making it difficult to understand the impact that SMA disease-modifying therapies may have in this context [7]. A higher prevalence of testicular hypofunction and infertility, azoospermia, and cryptorchidism have been observed in male patients with SMA compared with the general population [7]. Fertility disorders have been correlated with disease motor severity (e.g., age at loss of ambulation and duration of wheelchair use; P < 0.001) and were more evident in men with Type 2 SMA compared with men with Type 3 [8]. Among men (n = 33) with available sperm analyses, 81% had abnormal sperm concentrations and about 30% presented azoospermia [8]. Additionally, a positive correlation was observed between Motor Function Measure score and sperm concentration (P < 0.01). Insufficient thermoregulation of the scrotum from prolonged sitting and the lack of SMN protein during germ cell development were factors hypothesized to contribute to the observed sperm abnormalities [8]. To date, there are no available data on the potential impact of risdiplam on spermatogenesis or male fertility in humans. This case series presents real-world fertility outcomes in male patients with SMA who have been treated with risdiplam and have conceived with their partner.

Methods

Study Design and Objectives

This study is a multicenter, non-interventional retrospective case review that included three adult male patients with SMA from three sites in Austria and the USA. The participating sites were Klinik Donaustadt (Austria), Memorial Healthcare (Michigan, USA), and University of Alabama at Birmingham (Alabama, USA).

These sites were selected on the basis of their ability to provide the data necessary to meet the study objectives. The primary objective was to characterize the fertility journey and pregnancy outcomes of male patients with SMA who were exposed to risdiplam and whose partner had conceived. The secondary objective was to understand the history of risdiplam treatment in patients, including the rationale for treatment initiation and any safety and effectiveness outcomes.

Data Collection and Analysis

Demographics, clinical characteristics, and information about the fertility journey were collected from electronic health records using a data cutoff date of September 30, 2024. Data about age and SMA characteristics, risdiplam and/or other SMA disease-modifying therapy treatment history, available motor, bulbar, and respiratory function before and after risdiplam, adverse events, hospitalizations, and disease burden were collected. Fertility journey included relevant fertility information on the partner, fertility testing, intent to conceive, estimated date of conception, contraception at time of conception, and outcome of conception. Individual cases were descriptive and not subjected to any statistical analysis.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted for the cases from the Memorial Healthcare and University of Alabama by the Western-Copernicus Group Institutional Review Board (2024-0786), an organization that is responsible for protecting the rights and well-being of patients who take part in research studies. The requirement for ethical approval was waived from the Clinic Donaustadt in Vienna, Austria. Patients signed an informed consent regarding publishing their data. Data were collected only after the appropriate approvals and waivers had been received.

Data Availability

Data generated and/or analyzed in this study are not available because of privacy and ethical restrictions and cannot be shared publicly or transmitted to a third party.

Case Presentations

Data from three adult male patients with late-onset SMA are presented in this case series. Two of the three individuals were diagnosed with Type 3 SMA and had four SMN2 copies. The third individual was diagnosed with Type 4 SMA and had four SMN2 copies.

All three individuals were counseled on the potential impact of risdiplam on male fertility, and there was no intention to conceive with their partners. The male patients were taking risdiplam (5 mg once daily) during the window of conception; there was no concern that the patients missed any doses. Of these three pregnancies, two were full term and resulted in healthy babies, and one was voluntarily terminated.

Patient 1

Patient 1 is a 34-year-old man who started having difficulty with walking at 8 years of age (Table 1). After increasing difficulty with school sports, the patient presented to a pediatrician and was diagnosed at 15 years of age with SMA via genetic testing, with a clinical course consistent with Type 3 SMA.

Table 1.

Demographics, clinical history, and fertility journey

	Patient 1	Patient 2	Patient 3
Demographics and clinical history
Age characteristics, years
SMA onset	8	2	14
SMA diagnosis	15	13	16
Risdiplam initiation	32	25	18
SMA characteristics
SMN2 copy number	4	4	4
SMA type	3	3	4
Risdiplam history
Start date–end date	Nov 2021–ongoing	Jan 2021–Feb 2023	Jan 2021–ongoing
Other SMA treatment history	No other SMA DMT	No other SMA DMT	Nusinersen (Jul 2019–Sept 2020)
Motor function before vs after risdiplama	Before vs after 30 months of treatment	Before vs after 25 months of treatment	Before vs after 28 months of treatment
6MWT (m)	390 vs 375	–	–
HFMSE	52 vs 53	–	42 vs 56
Modified HFMS	–	Not tested vs 27	–
RULM	74 vs 75b	Not tested vs 33	–
Bulbar function before vs after risdiplamc	Normal vs normal	Normal vs normal	Normal vs normal
Respiratory function before vs after risdiplam			Before vs 21 months of treatment
Pulmonary tests	Normal vs normal	–	–
MIP (cmH2O)	–	− 83 vs not tested	–
MEP (cmH2O)	–	88 vs not tested	–
FVC%	–	–	101% vs 98%
FEV1%	–	–	95% vs 98%
Peak cough flow (L/min)	–	–	730 vs 861
Adverse events	None related to risdiplam	GI side effects and anorexia presented 6 months after starting risdiplam, and symptoms continued until 2 weeks after stopping risdiplam	Chronic diarrhea since starting risdiplam
Hospitalizations	Left femur fracture in Jul 2022; the leg in a cast for 6 weeks, and the patient relied on a wheelchair for 3 months	One risdiplam-related hospitalization in Dec 2022 due to abdominal pain and anorexia with resultant weight loss	None
Disease burden	Experiences severe fatigue and limited mobility, making everyday life difficult	Non-ambulant, independent (drives with hand controls), and fatigues easily	Can eat, toilet, and dress independently. Needs assistance with walking longer distances and requires increased rest breaks. Avoids steep inclines when walking and hiking. Reported his greatest disease burden is his limited choice of work, as prior occupations involved physical labor
Conception and fertility history
Partner information	Has lipedema; otherwise healthy	Has PCOS; otherwise healthy	Prior to conception, partner did not use any form of hormonal contraceptives. Has normal menstruation, no prior pregnancies, and no anatomical concerns
Fertility testing	No formal testing reported	No formal testing reported	No formal testing reported
Date of conception	Jan 2023	Feb 2022	Sept 2023
Contraception method at time of conception	Oral contraceptive	None	Barrier method (condoms)
Risdiplam use during window of conception	Continued risdiplam treatment throughout the window of conception; no concern for missed doses	Continued risdiplam treatment throughout the window of conception and for 1 year after conception; no concern for missed doses	Continued risdiplam treatment throughout the window of conception; no concern for missed doses
Conception outcome	Full term, healthy male infant born in Oct 2023; child is developing normally	Full term, healthy female infant born in Nov 2022; APGAR score of 10; currently a healthy 18-month-old child	Elective abortiond

6MWT 6-min walk test, DMT disease-modifying therapy, FEV1 forced expiratory volume (FEV) in 1 s as a percentage of the predicted value, FVC forced vital capacity as a percentage of the predicted value, GI gastrointestinal, HFMSE Hammersmith Functional Motor Scale–Expanded, MEP maximal expiratory mouth pressure, MIP maximum inspiratory mouth pressure, PCOS polycystic ovary syndrome, RULM Revised Upper Limb Module, SMA spinal muscular atrophy, SMN survival of motor neuron

^aThe most recent clinical outcomes are reported

^bBilateral RULM was conducted

^cBulbar function for each patient was assessed clinically, and no swallow studies or other tests were conducted

^dAn elective abortion is defined as pregnancy interruption for reasons other than maternal health or fetal disease

This patient was initially prepared to receive nusinersen (SPINRAZA^®) treatment but began risdiplam treatment instead after approval in November 2021, when he was 32 years old. Over 30 months of risdiplam treatment, his motor function as measured by Hammersmith Functional Motor Scale–Expanded was stable; respiratory and bulbar functions were both normal (Supplementary Table S1). There was an improvement in fatigue as measured using the Fatigue Severity Scale before and after 30 months of treatment (score 3.7 versus 2.2, respectively). There were no adverse events or hospitalizations that were related to risdiplam treatment, and the patient remains on risdiplam to date. The patient and his partner had no formal fertility testing completed; the partner had lipedema but otherwise was healthy and taking oral contraceptives. While on treatment with risdiplam, he and his partner conceived in January 2023, which resulted in the birth of a healthy, male infant in October 2023. The baby was healthy and had a normal APGAR score of 10 at 1, 5, and 10 min. At birth, the baby was in the 7th percentile in weight and 16th percentile in length. At 3.5 months of age, the baby measured at the 11th percentile in weight and 70th percentile in length (Supplementary Table S2).

Patient 1 Perspective

The main concern for the patient was how SMA would impact everyday life, particularly as a result of fatigue. He was afraid of losing his ability to walk, of no longer being able to cope with everyday life and potentially having professional limitations. For a long time, the patient was aware that he might never be able to have children of his own. Treatment with risdiplam has brought about fundamental changes in his life: he has remained mobile, no longer suffers from fatigue, is better able to pursue his career, and, above all, suddenly has the opportunity to start a family with his partner.

Patient 2

Patient 2 is a 28-year-old man who presented with symptoms of SMA (abnormal gait, frequent falls) at 2 years of age (Table 1). At 13 years of age, he was diagnosed with SMA via genetic testing with a clinical course consistent with Type 3 SMA. In January 2021, he chose risdiplam treatment owing to a desire to slow disease progression and because of the route of administration (lumbar punctures) required for nusinersen treatment. Motor function before risdiplam treatment was not measured, but after patient 2 received risdiplam for 2 years, his modified Hammersmith Functional Motor Scale and Revised Upper Limb Module scores were 27 and 33, respectively. Bulbar function was normal before and after risdiplam. The patient was hospitalized with abdominal pain and anorexia that were related to risdiplam; the patient discontinued risdiplam in February 2023 because of gastrointestinal side effects. Two weeks after discontinuing risdiplam these side effects resolved.

The patient and his partner had no formal fertility testing completed, but the partner had polycystic ovary syndrome (PCOS). As a result of the misperception of infertility due to the PCOS diagnosis, patient 2 and his partner did not use contraception, and patient 2 remained on risdiplam during the window of conception. Patient 2 and his partner conceived in February 2022, which resulted in the birth of a full term, healthy female infant in November 2022. The baby is a healthy 18-month-old who at birth had an APGAR score of 10.

Patient 3

Patient 3 is a 21-year-old man who was diagnosed with SMA at 16 years of age via genetic testing, with a clinical course consistent with Type 4 SMA (Table 1). He was first treated with nusinersen from July 2019 to September 2020 but discontinued treatment because of nausea and back pain. He began risdiplam in January 2021 and remains on treatment to date.

When compared with baseline motor and respiratory function measures, there was an improvement after 21 months of risdiplam treatment in Hammersmith Functional Motor Scale–Expanded score (42/66 vs 56/66, respectively) and peak cough flow (730 vs 861 L/min, respectively). Bulbar function was normal before and after initiating risdiplam. The patient presented with chronic, but minimally bothersome diarrhea since starting risdiplam.

The patient and his partner had no formal fertility testing completed. The partner is healthy with no fertility concern. While on treatment with risdiplam, patient 3 and his partner were using condoms and had an accidental conception in September 2023. The pregnancy was voluntarily terminated through an elective abortion.

Patient 3 Perspective

Patient 3 graduated from high school and completed courses in local community college but struggles with workplace opportunities because of persistent weakness. The patient expressed stability since starting treatment with risdiplam. He is highly motivated to understand the impact that risdiplam had on fertility given his desire to have children in the future.

Discussion

This report presents the first known cases of conception while a male patient was receiving risdiplam or any approved disease-modifying therapy for SMA. With limited human reproduction data in men with SMA, there have been concerns that risdiplam treatment could impair male fertility based on data from animal studies [4]. Nonclinical studies of cynomolgus monkeys and rats showed sperm-cell degeneration in the testes after treatment with an SMN2-splicing modifier similar to risdiplam caused by off-target effects of secondary splice targets (e.g., forkhead box protein M1 [FOXM1]) [6]. Evidence showed exposure to SMN2-splicing modifiers affected the spermatocytes where high levels of FOXM1 is expressed [6]. This was observed in testes samples of male monkeys, which showed the presence of micronucleation and vacuoles that was specific to the meiosis 1 stage of spermatogenesis. However, the testes samples also showed evidence of mature sperm cells, which suggested sperm development was not fully interrupted by exposure to SMN2-splicing modifiers.

Unlike other cytotoxic drugs, which may damage primary DNA following treatment, exposure to risdiplam did not affect spermatogonia and any sperm cells that were genetically impacted were not likely to develop into viable sperm but cleared away by apoptosis [6, 7]. Therefore, testicular damage was reversible after stopping exposure for an appropriate period. Indeed, male rats treated with risdiplam were able to mate with untreated female rats following an 8-week treatment-free period with no reduction in fertility observed [6].

As a result of the conserved nature of the secondary splice targets between species, the effects of SMN2-splicing modifiers on spermatogenesis were suspected to translate to humans. Consistent with the animal data that showed evidence of mature sperm cells while treated with risdiplam, there was a sufficient level of sperm production by the male patients with SMA while on treatment with risdiplam to result in three successful conceptions. Additionally, the live births in this case series were healthy and developing normally. These findings are not surprising given that, in animal studies, risdiplam affected only the spermatocytes with little to no damage to sperm stem cells. The lack of primary DNA damage of sperm stem cells implies the impact of risdiplam is not genotoxic and unlikely to be heritable [6, 7].

A limitation of this study was that paternity testing was not performed to confirm that the patients with SMA were the biological fathers of the birthed children. Additionally, there is a limited amount of long-term health data on the children from this study. The study was also limited by the small sample size and, therefore, results may not be fully reflective of the SMA population. Lastly, this was a retrospective case study, and the possibility that risdiplam may reduce fertility was not assessed.

Conclusion

Adult male patients with SMA who are on treatment with risdiplam have been able to conceive with their partners. Continuing research is needed to provide a complete understanding of the effects of risdiplam on male fertility in humans given that availability of SMA treatment has allowed patients the opportunity for family planning.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Material preparation, data collection, and analysis were performed by Shelley Coskery, Marcus Erdler, Margaret R. Frey, and Michael A. Lopez. All authors reviewed and commented on previous versions of the manuscript and approved the final manuscript.

Funding

Sponsorship for this study, the Open Access fee, and the Rapid Service fee were funded by Genentech, Inc., South San Francisco, CA.

Data Availability

Data generated and/or analyzed in this study are not available because of privacy and ethical restrictions and cannot be shared publicly or transmitted to a third party.

Declarations

Conflict of Interest

Michael A. Lopez reports involvement in consulting and/or clinical trials for Sarepta, Octapharma, and Pfizer. Shelley Coskery, Marcus Erdler, and Margaret R. Frey have no conflicts of interest to declare.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval for the cases from the Memorial Healthcare and University of Alabama were granted by the Western-Copernicus Group Institutional Review Board (2024-0786), an organization that is responsible for protecting the rights and well-being of patients who take part in research studies. The requirement for ethical approval was waived from the Clinic Donaustadt in Vienna, Austria. Patients signed informed consent regarding publishing their data. Data were collected only after the appropriate approvals and waivers had been received.