Spinal Muscular Atrophy (SMA)
Conditions
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.
Interventions
DRUGRO7204239
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.
DRUGPlacebo
Placebo will be administered Q4W by SC injection into the abdomen.
DRUGRisdiplam
Risdiplam will be administered orally once daily (QD) for the duration of the study.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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) |
| 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 - 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 |
Secondary
| Measure | Time frame |
|---|---|
| Part 2 - Ctrough of risdiplam | Week 32 |
| Part 2 - Incidence of ADAs | Through Week 80 |
| 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) |
| Part 2 - Percentage of participants with adverse events (AEs) | Up to 4.5 years |
| Part 2 - Serum concentration of RO7204239 | Through Week 80 |
| Part 2 - Cmax of RO7204239 | Through Week 80 |
| Part 2 - AUC of RO7204239 | Through Week 80 |
| Part 2 - Ctrough of RO7204239 | Through Week 80 |
| Part 2 - Plasma concentration of risdiplam | Week 32 |
| Part 2 - Plasma concentration of risdiplam metabolite (M1) | Week 32 |
| Part 2 - Cmax of risdiplam | Week 32 |
| Part 2 - AUC of risdiplam | Week 32 |
Countries
Australia, Belgium, Canada, Croatia, Italy, Japan, Netherlands, Poland, Portugal, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed