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

• Confirmed genetic diagnosis of 5q-autosomal recessive SMA
• Part 2 only: available SMN2 gene copy number as previously determined by
genetic testing and recorded in the participant's medical history
• Symptomatic SMA disease, as per investigator*s clinical judgement
• Age at screening:
- Part 1 Cohorts A, B, and D: 5-10 years, inclusive
- Part 1 Cohort C: 2-4 years, inclusive
- Part 2: 2-25 years, inclusive
• 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 measured by
the Timed 10-Meter Walk/Run Test [10MWRT]) at screening
• 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)
• For Part 1 Cohort D only: Participants who are able to raise a standardized
plastic cup with a 200 g 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).
• Participants who have received previous SMA disease-modifying therapies may
be included provided that
o 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
o Nusinersen last dose was received at least 90 days prior to screening
o Risdiplam is switched to the investigational medicinal product (IMP) provided
by the site
• Signed Informed Consent Form
• Signed Assent Form when appropriate and whenever possible, as determined by
patient's age and individual site and country standards.
• Signed Caregiver Informed Consent Form (for part II only)
• Participants who are able and willing to comply with the study protocol and
to complete all study procedures, measurements, and visits
• Negative pregnancy test at screening for females of childbearing potential
• Females of childbearing potential or who may reach childbearing potential
during the study: must agree to remain abstinent (refrain from
heterosexual intercourse) or use contraception during the treatment period and
for both 17 months after the final dose of RO7204239 and 28
days after the final dose of risdiplam
• For males who are expected to reach sexual maturity during the study:
participants must agree to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive methods, and agree to refrain from donating
sperm during the treatment period and for 28 days after the final dose of
risdiplam and 4 months after the final dose of RO7204239

• For Part 1 cohorts A and B only: Participants with contraindications for
magnetic resonance imaging (MRI) scan, difficulties maintaining a prolonged
supine position, or any other clinical history or examination finding that
would pose a potential hazard in combination with MRI
• Part 1 Cohort D only:
- Participants who are unable to adopt the correct position to ensure 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
non-invasive ventilation (e.g., bilevel positive airway pressure) during the
daytime.
• For Part 2 only: Participants who recently initiated treatment (within 6
months prior to screening) with oral salbutamol or another B2-adrenergic
agonist taken orally. Participants who have been on oral salbutamol (or
another B2-adrenergic agonist) for 6 months or longer before screening and have
shown good tolerance are allowed. The dose of B2-adrenergic agonist should
remain stable as much as possible for the duration of the study. Use of
inhaled B2-adrenergic agonists (e.g., for the treatment of asthma) is allowed.
• 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. For those who have completed a risdiplam study, or participated in
a nusinersen or onasemnogene abeparvovec study, the same criteria as described
in Section 5.1 apply.
• Received previous administration of anti-myostatin therapies
• Any history of cell therapy
• Participants who have been hospitalized for a pulmonary event within the last
2 months or planned hospitalization at the time of screening
• Participants who have had 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)
• Participants who have unstable gastrointestinal, renal, hepatic, endocrine,
or cardiovascular system diseases considered to be clinically significant
• Participants who have clinically significant electrocardiography (ECG)
abnormalities at screening
• Participants with clinically significant abnormal findings at
echocardiography at screening
• Participants who have had any major illness within 1 month before screening
• Participants who have received any MATE1/2K substrates within 2 weeks before
screening
• Participants with hereditary fructose intolerance
• Use 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
• Participants who have clinically significant abnormalities in laboratory test
results
• Participants who have ascertained or presumptive hypersensitivity to
RO7204239 or risdiplam, or to the constituents of their formulations
• Participants with concomitant disease or a condition that could interfere
with, or treatment of which might interfere with, the conduct of the study, or
that would pose an unacceptable risk to the participant in this study
•History of any malignancy (except in situ basal cell carcinoma of the skin and
in situ carcinoma of the cervix of the uterus that have been excised and
resolved with documented clean margins on pathology)
• Participants who have any clinically relevant history of anaphylactic
reaction requiring inotropic support
• Participants who have any abnormal skin conditions, pigmentation or lesions
in the area intended for subcutaneous (SC) injection (abdomen) and that would
prevent visualization of potential injection site reactions to RO7204239
• Participants with immobilization, surgical procedures, fracture, or trauma to
the upper or lower limbs within 90 days prior to screening
• Female participants who are pregnant or breastfeeding, or intending to become
pregnant during the study or within either 17 months after the final dose of
RO7204239 or 28 days after the final dose of risdiplam