Risdiplam’s Real-World Safety Profile Mirrors That of Clinical Trials

The new data suggest risdiplam can be a viable option for people with spinal muscular atrophy who cannot take or tolerate the 2 other approved disease-modifying therapies.

A new analysis of real-world cases suggests that the safety profile of risdiplam (Evrysdi) is similar in real-world usage to the safety profile reported in clinical trials of people with types 1 and 2 spinal muscular atrophy (SMA).

The data may offer hope for patients who cannot take nusinersen (Spinraza) and are ineligible for gene therapy. The report was published in the Orphanet Journal of Rare Diseases.

People with SMA experience progressive muscle weakness stemming from the functional loss of the survival motor neuron 1 (SMN1) gene. In the most severe cases, SMA appears in utero and patients generally do not live past 6 months of age. However, patients with the least severe form of SMA—type 4—do not experience symptom onset until adulthood and can reach a normal life expectancy.

The new study focuses on people with types 1 and 2 SMA. People with type 1 SMA typically see symptoms prior to 6 months of age and experience respiratory problems leading to respiratory failure and death, typically by age 2. People with type 2 SMA develop symptoms between 6 and 18 months of age. Those children are generally able to sit on their own, but are never able to walk without assistance.

Since 2016, a succession of disease-modifying therapies have been approved in the United States and Europe to treat SMA. Those include nusinersen, the first drug approved for SMA, along with risdiplam and the gene therapy onasemnogene abeparvovec (Zolgensma).

Risdiplam was approved by the US Food and Drug Administration in August 2020, and by the European Medicines Agency in March 2021. Corresponding author Tim Hagenacker, MD, of University Hospital Essen, in Germany, and colleagues, said prior to those approvals, some patients with SMA were left without treatment options. That’s because some patients cannot tolerate or stop responding to nusinersen and onasemnogene abeparvovec. While such patients could temporarily get access to risdiplam via clinical trials, the window for such access closed for German patients in January 2020.

“To bridge this treatment gap, this compassionate use program provided risdiplam to these patients with SMA 1/2,” Hagenacker and colleagues said, noting that risdiplam’s developer, Roche Pharma AG, created similar compassionate use programs in some 50 countries.

Hagenacker and colleagues wanted to better understand the safety profile of risdiplam, and so they decided to analyze the real-world experiences of people in Germany’s compassionate use program. Their goal was to see how real-world data compared to the safety signals identified in the clinical trials for the therapy.

Patients qualified for the study if they had SMA types 1 or 2, were at least 2 months old at enrollment, and were not able to use or respond to nusinersen or onasemogene abeparvovec. A total of 31 people with SMA type 2 and 80 people with SMA type 2 were included in the analysis; they were given doses of risdiplam that ranged from 0.2 mg/kg to 5 mg/kg, depending on their age and weight. Attending physicians were asked to report all adverse events. The trial period covered March 2020-March 2021.

Patients with type 1 SMA had a median age of 10.5 years; those with type 2 SMA had a median age of 26.5 years. About one quarter of people with type 1 SMA (22.2%) were treatment naive; about half (48.0%) of people with SMA type 2 were treatment naive. The most common reasons patients in the study were not eligible for nusinersen were scoliosis or safety risks, sedation-related risks, or a loss of efficacy.

The investigators found that risdiplam’s safety profile generally matched what was seen in clinical trials. Gastrointestinal disorders were the most common adverse events. In the SMA type 1 cohort, 2 serious adverse events were reported in the same patient. In the SMA type 2 cohort, 8 serious adverse events were reported in 2 patients. Only one patient discontinued risdiplam as a result of those adverse events. That patient suffered from exacerbations of pre-existing diverticulitis.

The investigators concluded that these data should offer reassurance to patients with SMA who cannot take nusinersen or onasemnogene abeparvovec, which they said amounts to a considerable number of patients.

“We expect that recently approved oral risdiplam, which can be self-administered at home, has significantly reduced this treatment gap,” they wrote.


Hahn A, Günther R, Ludolph A, et al. Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany [published correction appears in Orphanet J Rare Dis. 2022 Oct 25;17(1):387]. Orphanet J Rare Dis. 2022;17(1):276. Published 2022 Jul 19. doi:10.1186/s13023-022-02420-8

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