Risdiplam for Spinal Muscular Atrophy

(HINALEA 2 Trial)

Recruiting at 27 trial locations

Overseen By Reference Study ID Number: BN44621 https://forpatients.roche.com/

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Hoffmann-La Roche

Must not be taking: Antisense oligonucleotides, Splicing modifiers

Disqualifiers: Invasive ventilation, Feeding tube, 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: 72 weeks

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a drug called risdiplam for children with spinal muscular atrophy (SMA), a condition that weakens muscles. It focuses on young children under 2 years old who have already received onasemnogene abeparvovec but are not improving or are worsening. Children with genetically confirmed SMA who received the previous treatment at least 13 weeks ago might be suitable for this study. Participants will take risdiplam daily for about 2.5 years. As a Phase 4 trial, this study involves an FDA-approved treatment and aims to understand how risdiplam can benefit 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. However, you cannot participate if you have been treated with certain investigational therapies or specific SMA treatments before the study.

What is the safety track record for risdiplam?

Research has shown that risdiplam is generally safe for children with spinal muscular atrophy (SMA). In earlier studies, some children experienced common side effects like colds and stomach problems, but these were usually mild.

One study found that the safety of risdiplam for babies who took it before showing SMA symptoms was similar to those who already had symptoms, indicating reliable safety.

The FDA has also approved risdiplam for treating SMA in various age groups, which adds confidence in its safety. Overall, while some side effects exist, research indicates that the treatment is safe for children with SMA. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Risdiplam is unique because it can be taken orally, which is a big advantage over the traditional treatments for Spinal Muscular Atrophy (SMA) that often require injections or infusions. Most treatments for SMA work by replacing or boosting the missing or defective SMN protein, but risdiplam is exciting because it helps increase the production of this protein by modifying how the SMN2 gene is spliced. This innovative mechanism not only simplifies the treatment process but also has the potential to increase accessibility and improve quality of life for patients.

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

Research has shown that risdiplam, the treatment under study in this trial, effectively treats spinal muscular atrophy (SMA). It improves movement skills in both children and adults with SMA, particularly in types 2 and 3. Studies have also found that children who begin taking risdiplam early, often before symptoms appear, experience better movement abilities. Taken orally, this medication helps the body produce more of a protein essential for muscle function. Risdiplam is already approved for treating SMA, confirming its effectiveness in managing the condition. ^{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 children under 2 years old with a genetic condition called SMA and have two SMN2 gene copies. They must have had gene therapy before but are not improving or getting worse. The child should be able to swallow and show changes in breathing, moving, or other abilities.

Inclusion Criteria

I have two copies of the SMN2 gene.

I am under 2 years old.

I have been diagnosed with 5q-autosomal recessive SMA.

Exclusion Criteria

Treatment with investigational therapy prior to initiation of study treatment

Any unresolved standard-of-care laboratory abnormalities per the onasemnogene abeparvovec prescribing information

I haven't been hospitalized for a major illness in the last month or had a fever in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive risdiplam orally once daily

72 weeks

Treatment Extension

Participants continue to receive risdiplam for an additional year

48 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 effectiveness and safety in young kids with SMA who stopped getting better after receiving gene therapy. It's an open-label trial, meaning everyone knows they're getting Risdiplam, without comparing it to another treatment.

How Is the Trial Designed?

Group I: Risdiplam Experimental Treatment 1 Intervention

Participants will receive risdiplam orally once daily for 72 weeks (Treatment Period). The Treatment Period will be followed by a 1-year Treatment Extension Period for a total study duration of 120 weeks (approximately 2.5 years) for each participant enrolled.

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 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]

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 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 (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]

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]

Citations

1. 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.

2. 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 ...

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38189761/

Risdiplam in Spinal Muscular Atrophy: Safety Profile and ... Sixty adverse events (AEs) were reported occurring in 34 patients. The commonest were respiratory tract infections and gastrointestinal disturbance. Four life- ...

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.