RO7204239 + Risdiplam for Spinal Muscular Atrophy

(MANATEE Trial)

Not currently recruiting at 73 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two treatments, risdiplam and RO7204239, to assist people with spinal muscular atrophy (SMA). Risdiplam increases a protein that enhances muscle function, while RO7204239, an experimental treatment, aims to enlarge and strengthen muscles by blocking a protein that limits muscle growth. The trial seeks to determine if these treatments together can improve muscle function in people with SMA. Individuals with a confirmed SMA diagnosis and symptoms, who can walk or run unaided, might be suitable for this study. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in SMA treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is investigating the safety of combining RO7204239 with risdiplam for individuals with spinal muscular atrophy (SMA). Risdiplam, already approved for treating SMA, is generally considered safe. RO7204239, a new treatment, is being tested for its potential to promote muscle growth by affecting a protein that controls muscle size.

As this trial progresses, some evidence suggests the treatment might be safe for humans. However, specific information about side effects from using these treatments together is not yet available. The ongoing research aims to understand how these treatments interact and to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about RO7204239 combined with risdiplam for treating Spinal Muscular Atrophy (SMA) because of its unique approach. While most SMA treatments focus on enhancing the SMN protein production through existing drugs like nusinersen or gene therapies like onasemnogene abeparvovec, this combination offers a new angle. RO7204239 introduces a novel mechanism by potentially enhancing muscle function alongside risdiplam's ability to increase SMN protein levels. This dual-action could provide a more comprehensive treatment, offering hope for improved outcomes in SMA patients.

What evidence suggests that this trial's treatments could be effective for spinal muscular atrophy?

Research has shown that risdiplam helps the body produce more of a protein called SMN, crucial for maintaining the health of nerve cells that control movement. This can improve muscle function in people with spinal muscular atrophy (SMA). In this trial, some participants will receive a combination of RO7204239, an anti-myostatin antibody, and risdiplam. Studies suggest this combination might further enhance muscle size and strength. It works by targeting myostatin, a protein that usually limits muscle growth, potentially leading to better movement abilities. Early results indicate that using RO7204239 and risdiplam together might provide better outcomes for people with SMA. ^{1 2 5 6 7}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

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]

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]

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]

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. clinicaltrials.gov clinicaltrials.gov/study/NCT05115110

NCT05115110 | A Study to Investigate the Safety and ... This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in patients with spinal muscular atrophy (SMA).

2. forpatients.roche.com forpatients.roche.com/content/patient-platform/global/en/trials/muscle-and-peripheral-nerve-disease/sma/a-study-to-investigate-the-safety-and-efficacy-of-ro720-92328.pdf

A clinical trial to look at how safe RO7204239 plus risdiplam is ... RO7204239 with risdiplam may have a combined effect to improve muscle function in people with SMA. This clinical trial aims to compare the effects, good or bad, ...

3. neurology.org neurology.org/doi/10.1212/WNL.98.18_supplement.2586

MANATEE: A Study of RO7204239 in Combination with ... The combination of RO7204239 and an SMN2 splicing modifier was found to further improve muscle size and strength compared with treatment with SMN2 splicing ...

4. mdaconference.org mdaconference.org/abstract-library/manatee-a-study-of-gym329-ro7204239-in-combination-with-risdiplam-treatment-in-pediatric-patients-with-sma/

MANATEE: A study of GYM329 (RO7204239) in ... This study will provide valuable information about safety and efficacy of GYM329 in combination with risdiplam treatment in ambulant pediatric patients with SMA ...

5. clinicalresearch.com clinicalresearch.com/en/find-trials/Study/NCT05115110

NCT05115110 This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in patients with spinal muscular atrophy (SMA). The trial has two ...

6. genentech-clinicaltrials.com genentech-clinicaltrials.com/en/trials/muscle-and-peripheral-nerve-disease/sma/a-study-to-investigate-the-safety-and-efficacy-of-ro720-92328.html

Clinical Trial – Spinal Muscular Atrophy – Safety, Tolera... RO7204239 with risdiplam may have a combined effect to improve muscle function in people with SMA. This clinical trial aims to compare the effects, good or bad, ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05115110/a-study-to-investigate-the-safety-and-efficacy-of-ro7204239-in-combination-with-risdiplam-ro7034067-in-participants-with-spinal-muscular-atrophy

A Study to Investigate the Safety and Efficacy ... This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in patients with spinal muscular atrophy (SMA). The ...