RO7204239 + Risdiplam for Spinal Muscular Atrophy

(MANATEE Trial)

Recruiting at 59 trial locations

Overseen By Reference Study ID Number: BN42644 https://forpatients.roche.com/

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Hoffmann-La Roche

Must be taking: Risdiplam

Must not be taking: Anti-myostatin, riluzole, valproic acid, others

Disqualifiers: Recent surgery, Major illness, Hereditary fructose intolerance, 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

Compensation: Varies

Number of Visits: Unknown

259 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining two treatments, RO7204239 and risdiplam, for patients with spinal muscular atrophy (SMA). Risdiplam helps the body produce a protein needed for muscle movement, while RO7204239 allows muscles to grow bigger and stronger. The study includes SMA patients to see if this combination improves their muscle function and overall health.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before participating. Specifically, medications like riluzole, valproic acid, and others must not have been used within 90 days prior to screening. Additionally, participants should be tapered off steroids before receiving risdiplam.

What data supports the effectiveness of the drug Risdiplam for treating Spinal Muscular Atrophy?

Risdiplam is an oral drug that has been shown to improve motor function in patients with spinal muscular atrophy (SMA) types 1, 2, and 3 by increasing the production of a protein called SMN, which is crucial for muscle function. Clinical trials have demonstrated significant motor improvements in patients treated with Risdiplam, and these benefits have been maintained for up to two years. ^{1 2 3 4 5}

Is the treatment with RO7204239 + Risdiplam generally 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. In studies, 16% of participants experienced adverse events, but serious adverse events were not common. ^{1 2 3 6 7}

How is the drug Risdiplam unique in 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 6 8}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

This trial is for individuals aged 2-25 with confirmed genetic diagnosis of 5q-autosomal recessive Spinal Muscular Atrophy (SMA). Participants must be able to walk or sit unassisted, as applicable, and have not had certain treatments or surgeries recently. They should not have severe heart issues, skin conditions at injection sites, major recent illnesses, or require daytime ventilation.

Inclusion Criteria

I can walk or run 10 meters in 30 seconds or less without help.

I am between 2 and 10 years old.

I have a genetic diagnosis of 5q-SMA.

Exclusion Criteria

I have not taken any drugs that are cleared by the kidneys in the last 2 weeks.

I have not taken specific medications in the last 90 days.

I have hereditary fructose intolerance.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in Period

Participants receive risdiplam monotherapy until randomization

8 weeks

Treatment Part 1

Participants receive placebo + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks

96 weeks

Treatment Part 2

Participants receive risdiplam for 8 weeks, followed by placebo + risdiplam or RO7204239 + risdiplam for 72 weeks

80 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment with RO7204239 + risdiplam for 2 additional years

2 years

Treatment Details

Interventions

• Placebo
• Risdiplam
• RO7204239

Trial Overview The study tests the safety and effectiveness of RO7204239 combined with Risdiplam in SMA patients. Part 1 determines the proper dose among ambulant/non-ambulant children; Part 2 assesses its impact on a broader age range. The goal is to improve muscle function by increasing SMN protein production and inhibiting myostatin.

Participant Groups

Group I: RO7204239 + Risdiplam Experimental Treatment 2 Interventions

Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization. Participants enrolled in Part 1 will receive RO7204239 (low or high dose) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks. Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with RO7204239 + risdiplam for 72 weeks. Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.

Group II: Placebo + Risdiplam Active Control 2 Interventions

Participants who have not previously been treated with risdiplam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization. Participants enrolled in Part 1 will receive placebo (low or high dose-matched) + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks. Participants enrolled in Part 2 will receive risdiplam for 8 weeks and then treatment with placebo + risdiplam for 72 weeks. Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.

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

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]

Risdiplam, an oral treatment for spinal muscular atrophy (SMA), was well tolerated in a study of 25 healthy male volunteers, showing a linear pharmacokinetic profile and a long half-life of 40-69 hours.

The highest dose of risdiplam (18.0 mg) resulted in a significant increase of approximately 41% in SMN2 mRNA, demonstrating its mechanism of action and supporting further Phase 2/3 studies in SMA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Sturm, S., Günther, A., Jaber, B., et al.[2021]

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]

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

Risdiplam in non-sitter patients aged 16 years and older with 5q spinal muscular atrophy. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. [2021]

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

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

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

Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service. [2023]