Risdiplam for Spinal Muscular Atrophy

(RISE Trial)

Overseen By Karlla W Brigatti, MS

Age: < 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Clinic for Special Children

Must be taking: Nusinersen

Disqualifiers: SMN gene therapy, Neuromuscular disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 9 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called risdiplam for people with spinal muscular atrophy (SMA). The goal is to compare risdiplam, taken alone for 36 months, to a previous treatment called nusinersen. Researchers assess factors like grip strength and arm function over time. It suits those who have received nusinersen treatment for at least 22 months and have a specific genetic profile related to SMA. As a Phase 4 trial, risdiplam is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you have been treated with nusinersen for at least 22 months before starting risdiplam.

What is the safety track record for risdiplam?

Research has shown that risdiplam is generally well-tolerated by people with spinal muscular atrophy (SMA). One study found that patients can safely switch to risdiplam from another treatment called nusinersen, even with a short break between treatments.

Risdiplam, also known as Evrysdi, has been tested in both symptomatic and asymptomatic SMA patients. The safety profile for infants without symptoms is similar to those with symptoms, indicating consistent safety across different stages of the condition.

Overall, these studies consider risdiplam safe. Common side effects are usually mild, but discussing any potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Risdiplam is unique because it is an oral treatment for spinal muscular atrophy (SMA), making it more convenient and less invasive than options like nusinersen, which requires spinal injections. Researchers are excited because risdiplam works by increasing the production of the SMN protein throughout the body, which is critical for muscle function and survival in SMA patients. This systemic effect could potentially lead to improved outcomes compared to treatments that work locally.

What is the effectiveness track record for risdiplam in treating spinal muscular atrophy?

Research has shown that risdiplam effectively treats spinal muscular atrophy (SMA). Studies have found that both adults and children with SMA who took risdiplam improved their movement and arm function. Specifically, after five years of treatment, 91% of children with Type 1 SMA were alive, a significant improvement since, without treatment, these children might not survive past infancy. Risdiplam helps the body produce more of the protein needed for muscle strength and function. This treatment is already approved for SMA, demonstrating its effectiveness. Participants in this trial will receive risdiplam in an open-label crossover design, following a comparable period of nusinersen treatment. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for people with Spinal Muscular Atrophy who have two missing SMN1 genes and either three or four copies of the SMN2 gene. They must have been treated with nusinersen for at least 22 months. Those who've had other experimental treatments, gene replacement therapy, or another neuromuscular disorder besides SMA cannot join.

Inclusion Criteria

I have a genetic condition with two missing SMN1 genes.

My genetic test shows I have 3 or 4 copies of the SMN2 gene.

I have been treated with nusinersen for at least 22 months.

Exclusion Criteria

You have a neuromuscular disorder other than SMA that could affect the study results.

Prior exposure to another investigational agent

I have previously received SMN gene therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants crossover to 36 months of open-label risdiplam monotherapy following a comparable period of nusinersen treatment

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Risdiplam

Trial Overview The study tests risdiplam in patients previously treated with nusinersen. Participants will switch to risdiplam for a continuous period of 36 months, and their motor functions will be assessed using established tests from previous studies along with an additional test called the Box and Block Test.

How Is the Trial Designed?

Group I: Open-label crossover Experimental Treatment 1 Intervention

Participants crossover to 36 months of open-label risdiplam mono therapy following a comparable period of nusinersen treatment.

Risdiplam is already approved in United States, European Union, Brazil, China for the following indications:

Approved in United States as Evrysdi for:

• Spinal muscular atrophy (SMA) in patients 2 months of age and older

Approved in European Union as Evrysdi for:

• 5q-autosomal recessive SMA with a clinical diagnosis of SMA types 1, 2, or 3 or with one to four survival motor neuron 2 (SMN2) copies

Approved in Brazil as Evrysdi for:

• Spinal muscular atrophy (SMA)

Approved in China as Evrysdi for:

• Spinal muscular atrophy (SMA)

Who Is Running the Clinical Trial?

Clinic for Special Children

Lead Sponsor

Trials

2

Recruited

50+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Risdiplam (Evrysdi®) is the first oral medication approved for treating spinal muscular atrophy (SMA) in patients aged 2 months and older, specifically targeting the production of the SMN protein essential for motor function.

In phase 2/3 clinical trials, risdiplam significantly improved motor function in infants with SMA type 1 and patients aged 2-25 years with SMA types 2 or 3, with benefits maintained for up to 2 years, and it was generally well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risdiplam: A Review in Spinal Muscular Atrophy. Paik, J.[2022]

In a Phase 3 study involving patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA), risdiplam significantly improved motor function after 12 months, with 32% of patients showing improvement and 58% stabilizing their condition by month 24.

The safety profile of risdiplam remained consistent over 24 months, confirming its long-term efficacy and safety as a treatment for SMA, with continued benefits observed in motor function compared to an external comparator.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). Oskoui, M., Day, JW., Deconinck, N., et al.[2023]

In a real-world study of 31 adult patients with spinal muscular atrophy types 2 and 3, risdiplam was well tolerated, with most patients reporting no side effects and some experiencing clinically meaningful improvements in motor function and quality of life.

The treatment not only stabilized motor functions but also led to unexpected benefits such as weight gain and improved appetite in a third of the patients, highlighting the need for monitoring effects beyond just neuromuscular outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risdiplam Real World Data - Looking Beyond Motor Neurons and Motor Function Measures. Sitas, B., Hancevic, M., Bilic, K., et al.[2023]

Risdiplam is the first oral medication approved for spinal muscular atrophy (SMA) and has shown disease-modifying potential, acting as a splicing modifier for the SMN2 gene, which is crucial for motor neuron survival.

Clinical trials have demonstrated risdiplam's efficacy across SMA Types 1, 2, and 3, with a satisfactory safety profile, although its comparative effectiveness against other approved SMA treatments remains to be established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA). Markati, T., Fisher, G., Ramdas, S., et al.[2022]

In a phase 3 study involving 180 patients aged 2-25 with type 2 or non-ambulant type 3 spinal muscular atrophy, risdiplam significantly improved motor function compared to placebo, with a treatment difference of 1.55 points on the Motor Function Measure at 12 months (p=0.016).

While risdiplam was generally well-tolerated, it was associated with a higher incidence of certain adverse events, such as pyrexia and diarrhea, compared to placebo, but serious adverse events were similar between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Mercuri, E., Deconinck, N., Mazzone, ES., et al.[2022]

Risdiplam treatment for spinal muscular atrophy (SMA) showed significant efficacy, with 57% of participants with SMA type 1 achieving a CHOP-INTEND score of 40 or higher after 12 months, indicating improved motor function.

In SMA types 2 and 3, motor function measures (MFM32, RULM, HFMSE) increased significantly, although respiratory function improvements were inconsistent, and 16% of participants experienced adverse events, suggesting risdiplam is generally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis. Pascual-Morena, C., Martínez-Vizcaíno, V., Cavero-Redondo, I., et al.[2023]

Risdiplam (Evrysdi™) is an oral medication that modifies RNA splicing to enhance the production of functional SMN protein, addressing the deficiency caused by spinal muscular atrophy (SMA).

In August 2020, risdiplam received FDA approval for treating SMA in patients as young as 2 months old, and it is currently in the pre-registration phase in several countries, indicating its potential global impact on SMA treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risdiplam: First Approval. Dhillon, S.[2021]

In the FIREFISH study involving 41 infants with type 1 spinal muscular atrophy, 44% of participants were able to sit without support for at least 30 seconds after 24 months of treatment with risdiplam, showing significant improvement compared to untreated infants.

While no infants were able to stand or walk alone after 24 months, the treatment was generally well-tolerated, with upper respiratory infections being the most common adverse event, indicating a need for ongoing monitoring of long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Masson, R., Mazurkiewicz-Bełdzińska, M., Rose, K., et al.[2022]

Citations

1. evrysdi.com evrysdi.com/results-with-evrysdi/results-in-adults-and-children.html

Powerful results in adults and children with Type 2 and 3 ... Adults and children improved their motor skills and upper limb function when taking Evrysdi, an at-home treatment. SUNFISH is a 2-part, placebo-controlled ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8567805/

Risdiplam for the Use of Spinal Muscular Atrophy - PMC Risdiplam is the first and only oral medication to be approved to treat SMA. As an SMN2 splicing modifier, it has provided stronger systemic therapies.

3. roche.com roche.com/media/releases/med-cor-2024-06-07

Five-year data for Roche's Evrysdi show the majority of ... After five years of treatment, 91% of children were alive — without treatment, children with Type 1 SMA would not be expected to live past ...

4. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00469-9/fulltext

Efficacy and safety of risdiplam in adults with 5q-associated ... Importantly, HFMSE outcome was not significantly influenced by treatment centre. n, Mean change from baseline (95% CI), p-value. Spinal muscular ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02908685

NCT02908685 | A Study to Investigate the Safety, ... A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39136364/

Safety of risdiplam in spinal muscular atrophy patients after ... Our study showed good safety data on patients who received risdiplam following nusinersen within the washout period of 90 days.

7. evrysdi-hcp.com evrysdi-hcp.com/safety/safety-profile.html

Evrysdi® (risdiplam) Safety Profile |Official Healthcare ... Review the safety information, adverse reactions data and side effects of Evrysdi® (risdiplam) in clinical trials treating Spinal Muscular Atrophy (SMA).

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40802943/

Risdiplam in Presymptomatic Spinal Muscular Atrophy The safety and efficacy of risdiplam in presymptomatic disease are unclear. Methods: We conducted an open-label study of daily oral risdiplam ( ...

9. neurology.org neurology.org/doi/10.1212/WNL.0000000000205694

RAINBOWFISH: Primary Efficacy and Safety Data in ... Objective:To assess the efficacy and safety of risdiplam (EVRYSDI®) in infants with presymptomatic spinal muscular atrophy (SMA).

10. evrysdi.com evrysdi.com/

Evrysdi® (risdiplam) | Spinal Muscular Atrophy (SMA ... The safety profile of presymptomatic infants is consistent with the safety profile for symptomatic SMA patients treated with Evrysdi in clinical studies.