A Study to Learn About the Safety of Diroximel Fumarate (DRF) and Dimethyl Fumarate (DMF) and Their Effects on Relapses in Pediatric Participants With Relapsing Forms of Multiple Sclerosis (RMS)

The primary objectives of this study are to evaluate the safety, tolerability of diroximel fumarate (DRF), the noninferiority of the clinical efficacy of monomethyl fumarate (MMF) (pooled DRF and dimethyl fumarate \[DMF\] treatment) compared to that of fingolimod and long-term safety and tolerability of DRF in participants who completed Week 96 of the Treatment Period. The secondary objectives of this study are to characterize the pharmacokinetic (PK) profile of DRF metabolites (MMF and 2-hydroxyethyl succinimide \[HES\]), additional safety and tolerability of DRF, noninferiority of the radiological efficacy of MMF (pooled DRF and DMF treatment) compared to that of fingolimod, and to further describe the safety and long-term multiple sclerosis (MS) outcomes of DRF in participants who completed Week 96 of the Treatment Period.

• Diroximel Fumarate (Drug), also known as Vumerity, BIIB098, ALK8700: Oral capsule
• Dimethyl Fumarate (Drug), also known as Tecfidera, BG00012: Oral capsule
• Fingolimod (Drug), also known as Gilenya: Oral capsule
• Placebo matching DRF (Drug): Oral capsule
• Placebo matching DMF (Drug): Oral capsule
• Placebo matching fingolimod (Drug): Oral capsule

Primary outcomes

• TP Cohort A and OLE Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation [Cohort A: From first dose of study drug up to end of follow-up (up to Week 104), OLE: Baseline (Week 96) up to the end of OLE period (up to Week 196)]
• TP Cohort B: Annualized Relapse Rate (ARR) Through Week 96 [Baseline (Day 1) up to Week 96]

Secondary outcomes

• TP Cohorts A and B: Maximum Observed Concentration at Steady State (Cmax,ss) of Monomethyl Fumarate (MMF) [Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Minimum Observed Concentration at Steady State (Cmin,ss) of MMF [Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Cmax,ss of 2-Hydroxyethyl Succinimide (HES) [Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A and B: Cmin,ss of HES [Predose and at multiple timepoints post dose up to Week 96]
• TP Cohorts A, B and OLE Period: Number of Participants with Potentially Clinically Serious (PCS) Change from Baseline in Vital Sign Parameters [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants With Change From Baseline in Clinically Relevant Electrocardiogram (ECG) Abnormalities [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants with PCS Change from Baseline in Clinical Laboratory Parameters [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Height [Cohorts A and B: Baseline up to Week 104, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Weight [Cohorts A and B: Baseline up to Week 104, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Tanner Score [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]: Assessment of Tanner stage will be performed by a healthcare professional experienced with this assessment. Tanner score ranges from Stage 1 (childhood) to Stage 5 (full physical maturity). Information regarding Tanner staging will be collected for all male participants with bone age < 16 years and for female participants who are premenarche and have a bone age of < 16 years and will be stopped once the participant's bone age reaches ≥ 16 years or once the participant is postmenarche.
• TP Cohorts A, B and OLE Period: Change From Baseline in Bone Age [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Number of Participants with Change From Baseline in Endocrine Tests [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]: Endocrine parameters to be tested will include insulin-like growth factor 1, and insulin-like growth factor binding protein for both females and males; follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E-2) for females; and testosterone, FSH, and LH for males. All endocrine tests will stop being performed once the participant has reached a bone age of ≥ 16 years or the participant is postmenarche.
• TP Cohorts A, B and OLE Period: Change From Baseline in Depression Monitored Using the Children's Depression Rating Scale for Participants <18 Years or the Hamilton Rating Scale for Depression (HAMD-17) for Participants ≥18 Years [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]
• TP Cohorts A, B and OLE Period: Change From Baseline in Depression Monitored Using the Columbia Suicide Severity Rating Scale (C-SSRS) [Cohorts A and B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]: The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assesses whether participant experiences any of the following 1. completed suicide, 2. suicide attempt (response of "yes" on "actual attempt"), 3. preparatory acts toward imminent suicidal behavior ("yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), 4. any suicidal behavior or ideation, suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent"), 5. self-injurious behavior, no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior").
• TP Cohort B: Change From Baseline in Annualized Rate of New/Newly Enlarging (N/NE) T2 Hyperintense Lesions Through Week 96 [Baseline (Day 1) up to Week 96]
• TP Cohort B: Time to First Relapse [Baseline (Day 1) up to Week 96]
• TP Cohort B: Percentage of Participants Free of Relapse up to Week 96 [Baseline (Day 1) up to Week 96]
• TP Cohort B and OLE Period: Change From Baseline in Expanded Disability Status Scale (EDSS) Score [Cohort B: Baseline up to Week 96, OLE: Baseline (Week 96) up to Week 196]: The EDSS is a method of quantifying disability and monitoring changes in the level of disability over time. EDSS score ranges from 0 (normal neurological exam) to 10 (death from MS) with higher scores indicating more disability.
• TP Cohort B: Change From Baseline in Number of N/NE T2 Hyperintense Lesions on Brain Magnetic Resonance Imaging (MRI) Scans at Weeks 48 and 96 [Baseline up to Weeks 48 and 96]
• TP Cohort B: Number of Gadolinium (Gd)-Enhancing Lesions on Brain MRI Scans at Baseline and at Weeks 48 and 96 [At Baseline, Weeks 48 and 96]
• TP Cohort B: Number of Participants With T1 Hypointense Lesions at Week 96 [At Week 96]
• TP Cohort B: Change From Baseline in Percentage of Participants Free of N/NE T2 Hyperintense Lesions on Brain MRI Scans at Weeks 24, 48, and 96 [Baseline up to Weeks 24, 48, and 96]
• TP Cohort B: Change From Baseline in Percentage of Participants Free of New MRI Activity at Weeks 24, 48, and 96 [Baseline up to Weeks 24, 48, and 96]: Free of new MRI activity is defined as free of Gd-enhancing lesions and free of N/NE T2 MRI lesions on brain MRI scans.
• TP Cohort B: Number of Participants With TEAEs, SAEs and AEs Leading to Treatment Discontinuation [From first dose of study drug up to end of follow-up (up to Week 104)]
• OLE Period: ARR at Weeks 144 and 192 [At Weeks 144 and 192]

Sex: All, ages: 10 Years to 17 Years

Key Inclusion Criteria:

Treatment Period:

* Must have a diagnosis of pediatric MS (as defined by the revised consensus definition of pediatric MS).
* Must have an Expanded Disability Status Scale (EDSS) score between 0 and 5.0, inclusive.
* Must have experienced at least 1 of the following conditions:

  1. greater than or equal to 1 relapse in the 12 months prior to the Baseline Visit (Day 1),
  2. greater than or equal to 2 relapses in the 24 months prior to the Baseline Visit (Day 1), or
  3. evidence of gadolinium (Gd)-enhancing lesions of the brain on magnetic resonance imaging (MRI) within 6 months prior to the Baseline Visit (Day 1).
* Participants must be neurologically stable with no evidence of relapse within 30 days prior to the Baseline Visit (Day 1).

Open-Label Extension Period:

\- Participants who completed the study treatment in Cohorts A or B through the Week 96 Visit.

Key Exclusion Criteria

Treatment Period:

* History of progressive MS.
* History of disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis and neuromyelitis optical spectrum disorder), systemic autoimmune disorders (e.g., Sjögren's disease and lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders.
* History of severe allergic or anaphylactic reactions or any allergic reactions that in the opinion of the Investigator are likely to be exacerbated by any component of the study treatment.
* History of, or ongoing, malignant disease, including solid tumors, skin malignancies, and hematologic malignancies.
* History of gastrointestinal (GI) surgery (except appendectomy or cholecystectomy that occurred more than 6 months prior to the Screening Visit), inflammatory bowel disease (Crohn's disease, ulcerative colitis), or another clinically significant and active GI condition at the Investigator's discretion.
* Known hypersensitivity to fumaric acid derivatives or any excipients of DRF or DMF.
* Diagnosis of macular edema prior to randomization.

Open-Label Extension Period:

* Any significant changes in medical history occurring after enrollment in the Treatment Period, including laboratory test abnormalities or current clinically significant conditions that, in the opinion of the Investigator, would have excluded the participant's participation in the Treatment Period. The Investigator must reassess the participant's medical fitness for participation and consider any factors that would preclude treatment.
* Participants who discontinued study treatment due to tolerability issues.
* Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the participant unsuitable for participation in the OLE Period.

NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

• Medical Director, Study director, Biogen

NIH grants: 2023