A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Participants With Spinal Muscular Atrophy

NCT05115110 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: BN426442023-506761-65-00
• Study Type: interventional
• Target: 259
• Locations: 12 countries
• Sites: 35

Brief Summary

Risdiplam works by helping the body produce more survival motor neuron (SMN) protein throughout the body. This means fewer motor neurons - nerve cells that pass impulses from nerves to muscles to cause movement - are lost, which may improve how well muscles work in people with SMA. RO7204239 is an investigational anti-myostatin antibody that is designed to target myostatin. Myostatin plays an important role in the regulation of skeletal muscle size by controlling growth. Inhibiting myostatin may help muscles grow in size and strength. RO7204239 in combination with risdiplam, which is designed to increase the amount of SMN protein throughout the body, has the potential to further improve motor function and clinical outcomes for people living with SMA. 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 parts; Part 1 is the dose-finding part in SMA patients that are either ambulant (aged 2-10 years) or non-ambulant (aged 5-10 years) within separate cohorts, and Part 2 is the pivotal part in SMA patients aged 2-25 years that are ambulant.

Conditions

Spinal Muscular Atrophy (SMA)

Outcome Measures

Primary Outcomes (18)

• Part 1 - Percentage of participants with adverse events (AEs)

  Up to 4.5 years

• Part 1 - Incidence of relevant echocardiographic parameter z scores > 2

  Up to 4.5 years

• Part 1 - Serum concentration of RO7204239

  Through Week 96

• Part 1 - Time to maximum serum concentration (Cmax) of RO7204239

  Through Week 96

• Part 1 - Area under the curve (AUC) of RO7204239

  Through Week 96

• Part 1 - Trough concentration (Ctrough) of RO7204239

  Through Week 96

• Part 1 - Plasma concentration of risdiplam

  Week 21

• Part 1 - Plasma concentration of risdiplam metabolite (M1)

  Week 21

• Part 1 - Cmax of risdiplam

  Week 21

• Part 1 - AUC of risdiplam

  Week 21

• Part 1 - Ctrough of risdiplam

  Week 21

• Part 1 - Incidence of anti-drug antibodies (ADAs)

  Through Week 96

• Part 1 - Change from baseline in serum concentration of total myostatin

  Through Week 85

• Part 1 - Change from baseline in serum concentration of free latent myostatin

  Through Week 85

• Part 1 - Change from baseline in serum concentration of mature myostatin

  Through Week 85

• Part 1 - Percent change from baseline in the contractile area of skeletal muscle in the dominant thigh muscles as assessed by magnetic resonance imaging (MRI) in participants aged at least 5 years

  Week 24 of combination treatment

• Part 1 - Percent change from baseline in the contractile area of skeletal muscle in the dominant calf muscles as assessed by MRI in participants aged at least 5 years

  Week 24 of combination treatment

• Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score

  Week 72 of combination treatment (study Week 80)

Secondary Outcomes (16)

• Part 2 - Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score

  Week 72 of combination treatment (study Week 80)

• Part 2 - Change from baseline in MFM-32 total score

  Week 72 of combination treatment (study Week 80)

• Part 2 - Change from baseline in time taken to rise from the floor as measured by RHS Item 25

  Week 72 of combination treatment (study Week 80)

• Part 2 - Change from baseline in time taken to walk/run 10 meters as measured by RHS Item 19

  Week 72 of combination treatment (study Week 80)

• Part 2 - Percent change from baseline in lean mass as assessed by full body dual energy X-ray absorptiometry (DXA) scan in participants aged at least 5 years

  Week 72 of combination treatment (study Week 80)

Study Arms (2)

RO7204239 + Risdiplam

EXPERIMENTAL

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.

Drug: RO7204239; Drug: Risdiplam

Placebo + Risdiplam

ACTIVE COMPARATOR

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.

Drug: Placebo; Drug: Risdiplam

Interventions

RO7204239 DRUG

RO7204239 will administered every 4 weeks (Q4W) by subcutaneous (SC) injection into the abdomen. RO7204239 will be investigated at low- and high-dose in Part 1.

RO7204239 + Risdiplam

Placebo DRUG

Placebo will be administered Q4W by SC injection into the abdomen.

Placebo + Risdiplam

Risdiplam DRUG

Risdiplam will be administered orally once daily (QD) for the duration of the study.

Also known as: RO7034067, Evrysdi

Placebo + Risdiplam; RO7204239 + Risdiplam

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age at screening: Part 1 Cohorts A (ambulant participants), B (ambulant participants), and D (non-ambulant participants): 5-10 years, inclusive; Part 1 Cohort C (ambulant participants): 2-4 years, inclusive; Part 2 (ambulant participants): 2-25 years, inclusive
• Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
• Symptomatic SMA disease, as per investigator's clinical judgement
• Participants who have received previous SMA disease-modifying therapies may be included provided that: Onasemnogene abeparvovec was received at least 90 days prior to screening. Participants should be tapered off steroids prior to receiving risdiplam. In addition, participants should have normal levels of liver function tests, coagulatory parameters, platelets, and troponin-I at 90 days after administration of onasemnogene abeparvovec or at least 1 month after tapering off corticosteroids, whichever comes later; Nusinersen last dose was received at least 90 days prior to screening; Risdiplam is switched to the investigational medicinal product (IMP) provided by the site
• 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 seconds as measures by the Timed 10-Meter Walk/Run Test \[10MWRT\] at screening
• Participants who are able to sit, defined by: A score of 3 on Item 9 of the MFM32 (sitting without upper limb support while maintaining contact between the two hands for 5 seconds); A score of at least 2 on Item 10 of the MFM32 (while seated, leaning forward to touch a tennis ball and sitting back again, either with or without upper limb support)
• Participants who are able to raise a standardized plastic cup with a 200g weight in it to the mouth, using both hands if necessary, defined by a score of 3 on the entry item of the Revised Upper Limb Module (RULM)

You may not qualify if:

• Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening or 5 half-lives of the drug whichever is longer, with the exception of those who have completed a risdiplam study, or participated in a nusinersen or onasemnogene abeparvovec study
• Receiving or have received previous administration of anti-myostatin therapies
• Any history of cell therapy
• Hospitalization for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
• Past surgery for scoliosis or hip fixation in the 6 months preceding screening or planned within the next 9 months (Part 1) or 21 months (Part 2)
• Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant
• Clinically significant ECG abnormalities at screening from average of triplicate measurement, abnormal findings at echocardiography, or cardiovascular disease indicating a safety risk for participants at the time of screening
• Any major illness within 1 month before screening
• Received any multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening
• Hereditary fructose intolerance
• Used any of the following medications within 90 days prior to screening: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, acetyl cholinesterase inhibitors, agents that could potentially increase or decrease muscle strength, and agents with known or presumed histone deacetylase (HDAC) inhibitory effect
• Clinically significant abnormalities in laboratory test results at the time of screening
• Ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of its formulations
• Clinically relevant history of anaphylactic reaction requiring inotropic support
• Any abnormal skin conditions, pigmentation or lesions in the area intended for SC injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (35)

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Boston Childrens Hospital

Boston, Massachusetts, 02115, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Neurology & Neuromuscular Care Center

Flower Mound, Texas, 75028, United States

Location

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

Location

UZ Gent

Ghent, 9000, Belgium

Location

Chr de La Citadelle

Liège, 4000, Belgium

Location

British Columbia Children's Hospital

Vancouver, British Columbia, V6H 3N1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

McGill University Health Centre - Glen Site

Montreal, Quebec, H4A 3J1, Canada

Location

Clinical Hospital Centre Zagreb

Zagreb, 10000, Croatia

Location

Ospedale Pediatrico Bambino Gesù

Rome, Lazio, 00165, Italy

Location

Policlinico Agostino Gemelli

Rome, Lazio, 00168, Italy

Location

IRCCS Istituto Giannina Gaslini

Genoa, Liguria, 16147, Italy

Location

Fondazione IRCCS Istituto Neurologico ?Carlo Besta?

Milan, Lombardy, 20133, Italy

Location

Asst Grande Ospedale Metropolitano Niguarda

Milan, Lombardy, 20162, Italy

Location

Ospedali Riuniti Torrette di Ancona

Ancona, The Marches, 60126, Italy

Location

Kobe University Hospital

Hyōgo, 650-0017, Japan

Location

Kagoshima University Hospital

Kagoshima, 890-8520, Japan

Location

National Center for Global Health and Medicine

Tokyo, 162-0052, Japan

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Instytut Centrum Zdrowia Matki Polki

?ód?, 93-338, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gda?sk, 80-952, Poland

Location

Uniwersytecki Szpital Kliniczny w Poznaniu

Późna, 60-355, Poland

Location

Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie

Warsaw, 02-097, Poland

Location

Instytut Pomnik Centrum Zdrowia Dziecka

Warsaw, 04-730, Poland

Location

CHULC, E.P.E. - Hospital Dona Estefania

Lisbon, 1169-045, Portugal

Location

Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, 08950, Spain

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario la Fe

Valencia, 46026, Spain

Location

Birmingham Heartlands Hospital

Birmingham, B9 5SS, United Kingdom

Location

Great Ormond Street Hospital For Children

London, WC1N 3JH, United Kingdom

Location

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Risdiplam

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2021
• First Posted: November 10, 2021
• Study Start: June 2, 2022
• Primary Completion (Estimated): February 27, 2029
• Study Completion (Estimated): February 27, 2029
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (4); JP (3); IT (6); ES (4); CA (3); AU (1); CR (1); NL (1); PL (5); PT (2); BE (2); GB (3)