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

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Risdiplam Exchange (RISE) is a study of spinal muscular atrophy (SMA) patients who crossover to 36 months of open-label risdiplam monotherapy following a comparable period of nusinersen treatment. The schedule of assessments (SOAs) carry over seamlessly for the cohort from studies done while treated with nusinersen and continue to track the most informative outcomes from that trial (e.g. nine hole peg test and grip strength), while adding the Box and Block Test (BBT) as an additional measure of upper limb endurance and function.

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 evidence supports the effectiveness of the drug Risdiplam for treating spinal muscular atrophy?

Risdiplam has been shown to improve motor function in patients with spinal muscular atrophy types 2 and 3, with significant improvements observed in clinical trials. After 24 months of treatment, many patients experienced either improvement or stabilization in their motor function, indicating the drug's long-term benefits. ^{1 2 3 4 5}

Is Risdiplam safe for humans?

Risdiplam, also known as Evrysdi, has been generally well tolerated in clinical trials for spinal muscular atrophy, with a favorable balance between benefits and risks. About 16% of participants experienced adverse events, but serious adverse events were not common. ^{1 2 3 6 7}

What makes the drug risdiplam unique for treating spinal muscular atrophy?

Risdiplam is unique because it is the first oral drug for spinal muscular atrophy, making it more convenient than other treatments that require injections. It works by modifying the SMN2 gene to increase the production of a protein essential for muscle function, which is lacking in people with this condition. ^{1 2 3 4 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 (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]

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 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]

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]

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 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 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]

References

1. England 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. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

Risdiplam: First Approval. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Risdiplam Real World Data - Looking Beyond Motor Neurons and Motor Function Measures. [2023]

5. Germany 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). [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy of risdiplam in spinal muscular atrophy: A systematic review and meta-analysis. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA). [2022]

8. England 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. [2022]