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

Spinal Muscular Atrophy (SMA) Clinical Trial

— MANATEE  

Official title:

A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Patients With Spinal Muscular Atrophy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05115110
• Other study ID #: BN42644
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: June 2, 2022
• Est. completion date: June 27, 2026

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: BN42644 https://forpatients.roche.com
• Phone: 888-662-6728
• Email: global-roche-genentech-trials[@]gene.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 259
• Est. completion date: June 27, 2026
• Est. primary completion date: June 27, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 25 Years

Eligibility

Inclusion Criteria:

• 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

Inclusion Criteria for Part 1 Cohorts A, B, and C and Part 2 only:

• 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

Inclusion Criteria for Part 1 Cohort D only:

• 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)

Exclusion Criteria:

• 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

• Immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening

Exclusion Criteria for Part 1 Cohorts A and B only:

• Participants with contraindications for MRI scan (including, but not restricted to, claustrophobia, pacemaker, artificial heart valves, cochlear implants, presence of foreign metal objects in heart or body, including spinal rods, intracranial vascular clips, insulin pumps, etc.), difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI

Exclusion Criteria for Part 1 Cohort D only:

• Participants who are unable to adopt the correct position to endure adequate quality of DXA scan acquisition, as determined by the DXA scan technologist

• Participants who have contractures at screening that would interfere with DXA scan acquisition or functional assessments, as confirmed by the DXA scan technologist and clinical evaluator

• For participants able to take steps only: Able to walk 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 measured by the timed 10MWRT at screening

• Participants who have severe scoliosis (curvature > 40°) at screening based on the participant's most recent X-ray as performed per standard of care or scoliosis that would interfere with functional assessments, as confirmed by the clinical evaluator. An X-ray is not required if it is not clinically indicated (e.g., in participants with mild scoliosis)

• Participants who require invasive ventilation, tracheostomy, or the use of noninvasive ventilation (e.g., bilevel positive airway pressure) during the daytime

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy (SMA)

Intervention

Drug:
• RO7204239
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.
• Placebo
Placebo will be administered Q4W by SC injection into the abdomen.
• Risdiplam
Risdiplam will be administered orally once daily (QD) for the duration of the study.

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI)	Randwick	New South Wales
Belgium	UZ Gent	Gent
Belgium	Chr de La Citadelle	Liège
Canada	McGill University Health Centre - Glen Site	Montreal	Quebec
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Italy	Ospedali Riuniti Torrette di Ancona; Centro NeMO	Ancona	Marche
Italy	IRCCS Istituto Giannina Gaslini; U.O.S.D. Centro di Miologia e Patologie Neurodegenerative	Genova	Liguria
Italy	ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Centro clinico NEMO (NEuroMuscular Omnicentre)	Milano	Lombardia
Italy	Fondazione IRCCS Istituto Neurologico ?Carlo Besta?; UO di Neurologia dello Sviluppo	Milano	Lombardia
Italy	Policlinico Agostino Gemelli; Dipartimento di Neuropsichiatria Infantile	Roma	Lazio
Japan	Kobe University Hospital	Hyogo
Japan	Kagoshima University Hospital	Kagoshima
Japan	Center Hospital of the National Center for Global Health and Medicine	Tokyo
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Poland	Instytut Centrum Zdrowia Matki Polki; Klinika Neurologii Rozwojowej i Epileptologii	?ód?
Poland	Uniwersyteckie Centrum Kliniczne; Klinika Neurologii Rozwojowej	Gda?sk
Poland	Uniwersytecki Szpital Kliniczny w Poznaniu; Od. Kliniczny Neurologii Dzieci i M?odziezy	Pozna?
Poland	Instytut Pomnik Centrum Zdrowia Dziecka; Klinika Neurologii i Epileptologii	Warszawa
Poland	Klinika Neurologii I Wydzialu Lekarskiego WUM w Warszawie	Warszawa
Portugal	CHULC, E.P.E. - Hospital Dona Estefania; Servico de Neuropediatria	Lisboa
Portugal	Hospital de Santa Maria; Serviço de Pediatria	Lisboa
Spain	Hospital Vall d'Hebron; Servicio de Neurología	Barcelona
Spain	Hospital Sant Joan De Deu	Esplugues De Llobregas	Barcelona
Spain	Hospital Universitario La Paz; Servicio de Neurologia	Madrid
Spain	Hospital Universitario la Fe; Servicio de Neurologia	Valencia
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Great Ormond Street Hospital For Children; Neurology	London
United Kingdom	John Radcliffe Hospital	Oxford
United States	Boston Childrens Hospital	Boston	Massachusetts
United States	Neurology & Neuromuscular Care Center	Denton	Texas
United States	Columbia University Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Croatia,  Italy,  Japan,  Netherlands,  Poland,  Portugal,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1 - Percentage of participants with adverse events (AEs)		Up to 4.5 years
Primary	Part 1 - Incidence of relevant echocardiographic parameter z scores > 2		Up to 4.5 years
Primary	Part 1 - Serum concentration of RO7204239		Through Week 96
Primary	Part 1 - Time to maximum serum concentration (Cmax) of RO7204239		Through Week 96
Primary	Part 1 - Area under the curve (AUC) of RO7204239		Through Week 96
Primary	Part 1 - Trough concentration (Ctrough) of RO7204239		Through Week 96
Primary	Part 1 - Plasma concentration of risdiplam		Week 21
Primary	Part 1 - Plasma concentration of risdiplam metabolite (M1)		Week 21
Primary	Part 1 - Cmax of risdiplam		Week 21
Primary	Part 1 - AUC of risdiplam		Week 21
Primary	Part 1 - Ctrough of risdiplam		Week 21
Primary	Part 1 - Incidence of anti-drug antibodies (ADAs)		Through Week 96
Primary	Part 1 - Change from baseline in serum concentration of total myostatin		Through Week 85
Primary	Part 1 - Change from baseline in serum concentration of free latent myostatin		Through Week 85
Primary	Part 1 - Change from baseline in serum concentration of mature myostatin		Through Week 85
Primary	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
Primary	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
Primary	Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score		Week 72 of combination treatment (study Week 80)
Secondary	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)
Secondary	Part 2 - Change from baseline in MFM-32 total score		Week 72 of combination treatment (study Week 80)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Part 2 - Percentage of participants with adverse events (AEs)		Up to 4.5 years
Secondary	Part 2 - Serum concentration of RO7204239		Through Week 80
Secondary	Part 2 - Cmax of RO7204239		Through Week 80
Secondary	Part 2 - AUC of RO7204239		Through Week 80
Secondary	Part 2 - Ctrough of RO7204239		Through Week 80
Secondary	Part 2 - Plasma concentration of risdiplam		Week 32
Secondary	Part 2 - Plasma concentration of risdiplam metabolite (M1)		Week 32
Secondary	Part 2 - Cmax of risdiplam		Week 32
Secondary	Part 2 - AUC of risdiplam		Week 32
Secondary	Part 2 - Ctrough of risdiplam		Week 32
Secondary	Part 2 - Incidence of ADAs		Through Week 80