What is the mechanism of action of this treatment?

Risdiplam works by increasing the production of survival motor neuron (SMN) protein throughout the body, which helps prevent the loss of motor neurons that are crucial for muscle movement. RO7204239 is an investigational anti-myostatin antibody that inhibits myostatin, a protein that regulates muscle growth, thereby potentially increasing muscle size and strength. For SMA patients, these mechanisms are vital as they address the core issues of the disease: the loss of motor neurons and muscle weakness. By increasing SMN protein levels and inhibiting myostatin, these treatments aim to improve motor function and overall clinical outcomes, offering hope for better management of SMA symptoms.

What side effects are associated with this type of intervention?

Risdiplam, which increases SMN protein levels, is generally well-tolerated but can cause side effects such as fever, diarrhea, rash, and upper respiratory tract infections. Other treatments that increase SMN protein, like nusinersen, may cause side effects including headache, back pain, and post-lumbar puncture syndrome. RO7204239, an investigational myostatin inhibitor, aims to increase muscle size and strength, but specific side effects are not well-documented yet. However, myostatin inhibitors in general may cause muscle pain, increased creatine kinase levels, and injection site reactions.

What prior FDA approvals exist?

The FDA has approved several treatments for Spinal Muscular Atrophy (SMA) that focus on increasing SMN protein levels. Notably, Risdiplam (Evrysdi) is an oral medication that helps the body produce more SMN protein, improving motor function in SMA patients. Another significant treatment is Nusinersen (Spinraza), an intrathecal injection that also increases SMN protein production by modifying SMN2 gene splicing. Additionally, Onasemnogene abeparvovec-xioi (Zolgensma) is a gene therapy that delivers a functional copy of the SMN1 gene to restore SMN protein production. While there are no FDA-approved treatments specifically targeting myostatin inhibition for SMA, investigational drugs like RO7204239 aim to enhance muscle growth and strength by inhibiting myostatin.

What other types of research exist?

Promising novel alternatives for SMA treatment in 2024 include gene therapy approaches such as onasemnogene abeparvovec (Zolgensma), which delivers a functional copy of the SMN1 gene, and investigational drugs like branaplam, which also aims to increase SMN protein levels. Additionally, SRK-015 (apitegromab), an anti-myostatin antibody, is being studied for its potential to improve muscle strength in SMA patients.

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Small Molecule

RO7204239 + Risdiplam for Spinal Muscular Atrophy (MANATEE Trial)

Phase 2 & 3

Recruiting

Research Sponsored by Hoffmann-La Roche

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants who are ambulant, where ambulant is defined as able to walk/run unassisted (i.e., without the use of assistive devices such as canes, walking sticks, crutches, walkers, person/hand-held assistance, braces, orthoses, over the malleoli insoles or any other type of support) 10 meters in </= 30 as measured by the Timed 10-Meter Walk/Run Test [10MWRT] seconds at screening

Participants who are 2 to 10 years of age inclusive at screening

Must not have

Received any multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening

Hereditary fructose intolerance

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects are not explicitly listed but may include reactions at the injection site due to RO7204239 and general drug-related risks such as allergic reactions or impacts on liver function which will be monitored throughout the trial.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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I am between 2 and 10 years old.

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I have a genetic diagnosis of 5q-SMA.

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I have a genetic diagnosis of 5q-SMA.

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I am between 2 and 25 years old, depending on the study part.

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I can walk or run 10 meters unassisted in less than 30 seconds.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I have hereditary fructose intolerance.

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I have a history of cancer.

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I do not have any major issues with my digestive, kidney, liver, hormone, or heart systems.

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I have been treated with anti-myostatin therapies.

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I haven't had scoliosis or hip surgery in the last 6 months and don't plan to in the next 9 or 21 months.

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I need a machine to help me breathe during the day.

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I have had cell therapy in the past.

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I have had a condition where my lymphocytes multiply unusually.

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I have not had a major illness in the last month.

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I do not have serious heart issues that could make the trial unsafe for me.

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I have no skin issues on my abdomen that would affect injection site monitoring.

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I was hospitalized for a lung problem in the last 2 months or expect to be soon.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Side effects data

From 2023 Phase 2 trial • 231 Patients • NCT02908685

22%

Nasopharyngitis

15%

Upper respiratory tract infection

13%

Vomiting

13%

Pyrexia

10%

Headache

10%

Cough

Diarrhoea

Gastroenteritis

Pneumonia

Respiratory tract infection

Abdominal pain

Bronchitis

Pharyngitis

Rash

Ear pain

Back pain

Nausea

Arthralgia

Influenza

Limb injury

Oropharyngeal pain

Rhinorrhoea

Eczema

Constipation

Influenza like illness

Ear infection

Contusion

Erythema

Urinary tract infection

Sinusitis

Arthropod bite

Gastritis

Decreased appetite

Pain in extremity

Dry skin

Pruritus

Gastrointestinal infection

Ocular hyperaemia

Infective thrombosis

Encephalitis

Brain contusion

Nephrolithiasis

Atelectasis

Neck pain

Amenorrhoea

Dysmenorrhoea

Pneumonia mycoplasmal

Rhinitis

Scarlet fever

Tonsillitis

Dehydration

Device related infection

Herpes zoster

Post procedural infection

Pyelonephritis

Viral upper respiratory tract infection

Partial seizures

Haematuria

Pneumonitis aspiration

Pneumothorax

Dizziness

Nasal congestion

Rhinitis allergic

Tachycardia

Asthma

Epistaxis

Productive cough

Acne

Alopecia

Blister

Dermatitis

Abdominal pain upper

Aphthous ulcer

Asthenia

Seborrhoeic dermatitis

Hypersensitivity

Conjunctivitis

Cystitis

Groin infection

100%

80%

60%

40%

20%

Study treatment Arm

Part 2 OLT: Risdiplam/Risdiplam

Part 2 OLT: Placebo/Risdiplam

Part 2 OLE: Risdiplam

Part 1 Group B: Children (0.25 mg/kg Risdiplam)

Part 1 Group A: Adolescents and Adults (3 mg Risdiplam)

Part 1 Group A: Adolescents and Adults (5 mg Risdiplam)

Part 1 Group B: Children (Placebo-Control Period Pooled)

Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled)

Part 1 Group B: Children (0.02 mg/kg Risdiplam)

Part 1 Group B: Children (0.05 mg/kg Risdiplam)

Part 1 Group B: Children (0.15 mg/kg Risdiplam)

Part 1 Group A: OLE

Part 1 Group B: OLE

Part 2 Placebo-Controlled: Risdiplam

Part 2 Placebo-Controlled: Placebo

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: RO7204239 + RisdiplamExperimental Treatment2 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 + RisdiplamActive Control2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Risdiplam

2016

Completed Phase 2

~420

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Risdiplam works by increasing the production of survival motor neuron (SMN) protein throughout the body, which helps prevent the loss of motor neurons that are crucial for muscle movement. RO7204239 is an investigational anti-myostatin antibody that inhibits myostatin, a protein that regulates muscle growth, thereby potentially increasing muscle size and strength. For SMA patients, these mechanisms are vital as they address the core issues of the disease: the loss of motor neurons and muscle weakness. By increasing SMN protein levels and inhibiting myostatin, these treatments aim to improve motor function and overall clinical outcomes, offering hope for better management of SMA symptoms.