A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy

Study Overview
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Brief Summary
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This is a multi-center, exploratory, non-comparative, and open-label study to investigate the safety, tolerability, PK, and PK/PD relationship of risdiplam in adults, children and infants with Spinal Muscular Atrophy (SMA) previously enrolled in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated with nusinersen, olesoxime or AVXS-101.

Official Title
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An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Risdiplam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of 5q-autosomal recessive SMA Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previous treatment with any of the following: 1.) Nusinersen (defined as having received >= 4 doses of nusinersen, provided that the last dose was received >= 90 days prior to screening) or 2.) Olesoxime (provided that the last dose was received <= 12 months and >= 90 days prior to screening) or 3.) AVXS-101 (provided that the time of treatment was >= 12 months prior to screening) Adequately recovered from any acute illness at the time of screening and considered well enough to participate in the opinion of the Investigator 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 for at least 28 days after the final dose of study drug For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm For participants aged 2 years or younger at screening: 1.) Parent or caregiver of participant is willing to consider nasogastric, naso-jejunal or gastrostomy tube placement, as recommended by the Investigator, during the study to maintain safe hydration, nutrition and treatment delivery; 2.) Parent or caregiver of participant is willing to consider the use of non-invasive ventilation, as recommended by the Investigator during the study Exclusion Criteria: Inability to meet study requirements Concomitant participation in any investigational drug or device study 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 Any history of gene or cell therapy, with the exception of AVXS-101 Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator Inadequate venous or capillary blood access for the study procedures, in the opinion of the Investigator 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 Lactating women Suspicion of regular consumption of drugs of abuse For adults and adolescents only, positive urine test for drugs of abuse or alcohol at screening or Day -1 visit Presence of clinically significant electrocardiogram (ECG) abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease History of malignancy if not considered cured For participants 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) Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration Recently initiated treatment for spinal muscular atrophy (within <6 weeks prior to enrollment) with oral salbutamol or another beta 2-adrenergic agonist taken orally Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the constituents of its formulation 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 participant in this study Recent history (less than one year) of ophthalmological diseases 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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Risdiplam<br>Participants will receive multiple doses of risdiplam orally once daily for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label extension (OLE) phase. | Drug: Risdiplam<br>* Risdiplam will be administered orally once daily.<br>* Other names: RO7034067;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Scale, V 4.0 |  | Baseline up to 5 years | 
| Percentage of Participants With Emergence or Worsening of Symptoms As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) (Adult Version for Adults and Adolescents, Pediatric Version for Patients Aged 6-11 Years) |  | Baseline up to 5 years | 
| Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments |  | Baseline up to 5 years | 
| Percentage of Participants With Protocol Defined Clinically Significant Changes in Neurological Assessments |  | Baseline up to 5 years | 
| Tanner Staging Among all Participants Aged From 9 to 17 Years |  | Baseline up to 5 years | 
| Mean Plasma Concentration of Risdiplam |  | Up to 2 years | 
| Maximum Plasma Concentration (Cmax) of Risdiplam |  | Up to 2 years | 
| Area Under the Plasma Concentration Versus Curve (AUC) of Risdiplam |  | Up to 2 years | 
| Concentration of Risdiplam at the End of Dosing Interval (Ctrough) |  | Up to 2 years | 
| Mean Plasma Concentration of Risdiplam Metabolite |  | Up to 2 years | 
| Cmax of Risdiplam Metabolite |  | Up to 2 years | 
| AUC of Risdiplam Metabolite |  | Up to 2 years | 
| Ctrough of Risdiplam Metabolite |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SMN messenger Ribonucleic Acid (mRNA) Level in Blood |  | Up to 2 years | 
| SMN Protein Levels in Blood |  | Up to 2 years |