Risdiplam for Spinal Muscular Atrophy

(PUPFISH Trial)

Recruiting at 19 trial locations

Overseen By Reference Study ID Number: BN44619 https://forpatients.roche.com/

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Hoffmann-La Roche

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers, MATE substrates

Disqualifiers: SMA Type 0, Blood pressure abnormalities, 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: 4 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called risdiplam (Evrysdi) to determine its movement through the body and safety for treating spinal muscular atrophy (SMA) in newborns. SMA is a genetic condition that weakens muscles, and this trial targets babies under 20 days old diagnosed with SMA. Newborns identified through genetic screening and deemed healthy enough to participate are suitable candidates for this trial. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to important early findings.

Will I have to stop taking my current medications?

The trial requires that the infant (or the person breastfeeding the infant) must stop taking certain medications, specifically any inhibitors or inducers of CYP3A4 and MATE substrates, at least 2 to 4 weeks before starting the trial.

Is there any evidence suggesting that risdiplam is likely to be safe for humans?

Research shows that risdiplam is generally safe for treating spinal muscular atrophy (SMA). Studies have found that patients did not experience side effects severe enough to discontinue treatment. In one study, risdiplam was well-tolerated even when patients switched from another SMA drug, nusinersen, without serious side effects. Additionally, the safety of risdiplam in infants who have not yet shown symptoms of SMA is similar to its safety in older patients with symptoms, suggesting it is well-tolerated across different age groups. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Risdiplam is unique because it offers an oral treatment option for spinal muscular atrophy (SMA), unlike many existing treatments that require injections or infusions. This is a game-changer for patients who prefer a more convenient and less invasive administration method. Additionally, risdiplam works by increasing the production of the SMN protein, which is essential for muscle function, thereby targeting the underlying cause of the disease. Researchers are excited about risdiplam because it has the potential to improve motor function and quality of life for people with SMA, especially those with limited access to frequent medical visits.

What evidence suggests that risdiplam might be an effective treatment for spinal muscular atrophy?

Research has shown that risdiplam, which participants in this trial will receive, effectively treats spinal muscular atrophy (SMA). As the first oral medication approved for SMA, it helps the body produce more of a protein essential for muscle function. In earlier studies, both adults and children with SMA improved their ability to move and use their arms. Additionally, evidence confirms that children who start taking risdiplam before showing symptoms experience significant benefits, with most reaching important developmental milestones. These findings suggest that risdiplam can be effective for young infants with SMA. ^{6 7 8 9 10}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for newborn infants under 20 days old diagnosed with spinal muscular atrophy (SMA) or identified as SMA-positive through screening. They must be born after a full-term pregnancy, well-nourished, hydrated, and recovered from any acute illness. Parents should be open to tube feeding if recommended.

Inclusion Criteria

My newborn is less than 20 days old.

My newborn has been diagnosed with 5q-autosomal recessive SMA.

Gestational age equal to or greater than 37 weeks

Exclusion Criteria

I show symptoms of SMA Type 0.

My veins are not suitable for the required blood tests.

Systolic blood pressure or diastolic blood pressure or heart rate abnormalities

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive risdiplam once daily for 28 days

4 weeks

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's pharmacokinetics—how the drug moves into, through, and out of the body—and safety in infants with SMA. It aims to understand how young patients process this medication.

How Is the Trial Designed?

Group I: Risdiplam Experimental Treatment 1 Intervention

Participants will receive risdiplam once daily for 28 days.

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?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

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]

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 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 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]

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]

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]

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. 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 ...

4. roche.com roche.com/media/releases/med-cor-2024-10-14

Majority of children with spinal muscular atrophy (SMA) ... Positive data confirm Evrysdi efficacy and safety in children first treated pre-symptomatically before six weeks of age, with most achieving ...

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. 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).

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0960896623002924

Risdiplam clinical trial program for spinal muscular atrophy ... Risdiplam has a favorable safety profile, with no treatment-related adverse events (AEs) leading to treatment withdrawal.

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.