An open-label study to investigate the safety, tolerability, and Pharmacokinetics/Pharmacodynamics of risdiplam (RO7034067) in adult and pediatric patients with spinal muscular atrophy

1. Males and females 6 months to 60 years of age inclusive (at screening)
2. Confirmed diagnosis of 5q-autosomal recessive SMA, including:
- Genetic confirmation of homozygous deletion or heterozygosity predictive of
loss of function of the SMN1 gene.
- Clinical history, signs, or symptoms attributable to SMA.
3. Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier
RO6885247 or previous treatment with any of the following:
- Nusinersen (defined as having received >=4 doses of nusinersen, provided that
the last dose was received >= 90 days prior to screening)
- Olesoxime (provided that the last dose was received <= 18 months and >= 90 days
prior to screening)
- AVXS-101 (provided that the time of treatment was >= 12 months prior to
screening)
4. Able and willing to provide written informed consent and to comply with the
study protocol according to International Conference on Harmonization (ICH) and
local regulations. Alternatively, a legally authorized representative must be
able to give consent for the patient according to ICH and local regulations and
assent must be given whenever possible.
5. Adequately recovered from any acute illness at the time of screening and
considered well enough to participate in the opinion of the Investigator.
6. For women of childbearing potential: negative blood pregnancy test at
screening, agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures, and agreement to refrain from
donating eggs, as defined below:
- Women must remain abstinent (refrain from heterosexual intercourse) or use
two adequate methods of contraception, including at least one method with a
failure rate of < 1% per year, during the treatment period and for at least 28
days after the final dose of study drug. Women must refrain from donating eggs
during this same period.
- A woman is considered to be of childbearing potential if she is
postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months
of amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus). The
definition of childbearing potential may be adapted for alignment with local
guidelines or regulations.
- Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, established and proper
use of hormonal contraceptives that inhibit ovulation, hormone-releasing
intrauterine devices, and copper intrauterine devices.
- A vasectomy is a highly effective birth control method provided that the
partner is the sole sexual partner of the woman of child bearing potential
trial participant, and provided the vasectomized partner has received medical
assessment of the surgical success.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
post-ovulation methods) and withdrawal are not acceptable methods of
contraception. If required per local guidelines or regulations, locally
recognized acceptable methods of contraception and information about the
reliability of abstinence will be described in the local Informed Consent Form.
7. For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures and agreement to refrain from
donating sperm, as defined below:
- With a female partner of childbearing potential, men must remain abstinent or
use a condom plus an additional contraceptive method that together result in a
failure rate of <1% per year during the treatment period and for at least 4
months after the final dose of study drug. Men must refrain from donating sperm
during this same period. This period is required for small molecules with
potential for genotoxic effect and includes the spermatogenic cycle duration
and drug elimination process.
- With a pregnant female partner, men must remain abstinent or use a condom
during the treatment period and for at least 28 days after the final dose of
study drug.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception.
8. For patients aged 2 years or younger at screening:
- Receiving adequate nutrition and hydration (with or without gastrostomy) at
the time of screening, in the opinion of the Investigator.
- Medical care meets local accepted standard of care, in the opinion of the
Investigator.
- Would be able to complete all study procedures, measurements and visits, and
the parent or caregiver of the patient has adequately supportive psychosocial
circumstances, in the opinion of the Investigator.
- Parent or caregiver of patient is willing to consider nasogastric,
naso-jejunal or gastrostomy tube placement, as recommended by the Investigator,
during the study (if not already in place at the time of screening) to maintain
safe hydration, nutrition and treatment delivery.
- Parent or caregiver of patient is willing to consider the use of non invasive
ventilation, as recommended by the Investigator during the study (if not
already in place at the time of screening).

1. Inability to meet study requirements.
2. Concomitant participation in any investigational drug or device study.
3. With the exception of studies of olesoxime, AVXS-101, or nusinersen:
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.
4. Any history of gene or cell therapy, with the exception of AVXS-101.
5. Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular
system diseases as considered to be clinically significant by the Investigator.
6. Inadequate venous or capillary blood access for the study procedures, in the
opinion of the Investigator.
7. For patients aged < 2 years, hospitalization for a pulmonary event within 2
months prior to screening and pulmonary function not fully recovered at the
time of screening.
8. Lactating women.
9. Suspicion of regular consumption of drugs of abuse.
10. For adults and adolescents only, i.e., aged > 12 years, positive urine test
for drugs of abuse or alcohol at screening or Day -1 visit.
11. Cardiovascular, blood pressure, and heart rate:
- Adults: Sustained resting systolic blood pressure (SBP) > 140 mmHg or < 80
mmHg, and/or diastolic blood pressure (DBP) > 90 mmHg or <40 mmHg; a resting
heart rate < 45 bpm or > 100 bpm if considered to be clinically significant by
the Investigator.
- Adolescents (12*17 years of age): SBP and/or DBP outside the 95th percentile
for age; resting heart rate < 50 bpm or > 100 bpm if considered to be
clinically significant by the Investigator.
- Children (6*11 years of age): SBP and/or DBP outside the 95th percentile for
age; resting heart rate < 60 bpm or > 120 bpm, if considered to be clinically
significant by the Investigator.
- Children (2*5 years of age): SBP and/or DBP outside the 95th percentile for
age; resting heart rate < 70 bpm or > 140 bpm if considered to be clinically
significant by the Investigator.
- Children (6 months to < 2 years of age): SBP and/or DBP outside the 95th
percentile for age; resting heart rate <70 bpm or > 170 bpm, if considered to
be clinically significant by the Investigator.
12. Presence of clinically significant ECG abnormalities before study drug
administration (e.g., second or third degree AV block, confirmed QTcF >460 msec
for patients aged >= 10 years, or QTcB > 460 ms for children up to age 10 years
(Bazett*s correction is more appropriate in young children) from the average of
triplicate measurements, or cardiovascular disease (e.g., cardiac
insufficiency, coronary artery disease, cardiomyopathy, congestive heart
failure, family history of congenital long QT syndrome, family history of
sudden death) indicating a safety risk for the patient as determined by the
Investigator.
13. History of malignancy if not considered cured.
14. For patients aged > 6 years, significant risk for suicidal behavior in the
opinion of the Investigator, as assessed by the Columbia-Suicide Severity
Rating Scale (C-SSRS).
15. Any major illness within 1 month before the screening examination or any
febrile illness within 1 week prior to screening and up to first dose
administration
16. Use of any OCT-2 and MATE substrates within 2-weeks before dosing
(including but not limited to: amantadine, cimetidine, memantine, amiloride,
famotidine, metformin, pindolol, ranitidine, procainamide, varenicline,
acyclovir, ganciclovir, oxaliplatin, cephalexin, cephradine, fexofenadine)
including the mother, if breastfeeding the patient.
17. Use of the following medications within 90 days prior to enrollment:
riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate
derivatives, creatine, carnitine, growth hormone, anabolic steroids,
probenecid, agents anticipated to increase or decrease muscle strength, agents
with known or presumed histone deacetylase (HDAC) inhibitory effect, and
medications with known phototoxicity liabilities (e.g., oral retinoids
including over-the-counter formulations, amiodarone, phenothiazines and chronic
use of minocycline). (Patients who are on inhaled corticosteroids, administered
either through a nebulizer or an inhaler, will be allowed in the study).
18. Recently initiated treatment for SMA (within 6 weeks prior to enrollment)
with oral salbutamol or another B2-adrenergic agonist taken orally is not
allowed. Patients who have been on oral salbutamol (or another B2-adrenergic
agonist) for >= 6 weeks before enrollment 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.
19. Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or
thioridazine, is not allowed. Use of other medications known to or suspected of
causing retinal toxicity within one year prior to enrollment is not allowed.
20. Clinically significant abnormalities in laboratory test results, e.g., ALT
values exceeding 1.5 fold the upper limit of normal, unless the elevated ALT
level is considered of muscular origin (i.e., in the absence of other evidence
of liver disease) which is supported by elevated creatine kinase and LDH. Out
of range creatine kinase levels should be reviewed in light of the underlying
SMA pathology of the patient; elevated levels per se do not disqualify the
patient from the study. In the case of uncertain or questionable results, tests
performed during screening may be repeated before enrollment to confirm
eligibility.
21. Donation or loss of blood >= 10% of blood volume within 3 months prior to
screening.
22. Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction)
to risdiplam or to the constituents of its formulation.
23. Concomitant disease or condition that could interfere with, or treatment of
which might interfere with, the conduct of the study, or that would, in the
opinion of the Investigator, pose an unacceptable risk to the patient in this
study.
24. Recent history (less than 1 year) of ophthalmological diseases (e.g.,
glaucoma not controlled by treatment, central serous retinopathy,
inflammatory/infectious retinitis unless clearly inactive, retinal detachment,
retinal surgery, intraocular trauma, retinal dystrophy or degeneration, optic
neuropathy, or optic neuritis) that would interfere with the conduct of the
study as assessed by an opthalmologist. Any other abnormalities detected at
screening (e.g., retinal layer abnormalities, edema, cystic or atrophic
changes) should be discussed with the Investigator, the Ophthalmologist, and
with the Sponsor, who will jointly make the decision if the patient may be
enrolled in the study. Patients in whom SD-OCT measurement of sufficient
quality cannot be obtained at screening will not be enrolled.
25. Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2
weeks (or within 5 elimination half-lives, whichever is longer) prior to
dosing.