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Medical information request
Medical information request

Overview

Key safety topics within the siponimod website such as infections, CM, and reproductive toxicity will be updated biannually in line with the PSUR, except for COVID-19 and PML which will be updated quarterly. This section covers information from:

1. Clinical trial data, which include controlled and long-term safety pools

  • Controlled pool1: Double-blind, placebo-controlled core part of studies BOLD and EXPAND
  • Long-term pool2: Target siponimod 2 mg or 10 mg treatment period in the core (controlled and open-label) and/or extension phases of studies BOLD and EXPAND

2. Post-marketing experience, which is estimated based on the sales data in different countries where siponimod is approved2

  • BOLD3: Double-blind, randomized, adaptive, dose-ranging, placebo-controlled, parallel-group Phase 2 study
    • N=297 RRMS patients
    • Siponimod: 10 mg, 2 mg, 0.5 mg, 1.25 mg, 0.25 mg vs placebo
  • BOLD Extension4: Dose-blinded phase lasted up to 24 months followed by open-label siponimod
    • N=184 RRMS patients
    • Placebo-siponimod and continuous siponimod: 10 mg, 2 mg, 0.5 mg, 1.25 mg, 0.25 mg
    • Open-label: Siponimod 2 mg (1 mg if lymphocyte counts [ALC] <200/μL, at repeat testing, 2 weeks apart)
  • EXPAND5: Double-blind, randomized, parallel-group, placebo-controlled, event-driven, exposure-driven, core-part, Phase 3 trial (up to 36 months), followed by an open-label extension part (up to 7 years/84 months)
    • N=1651 SPMS patients
    • Siponimod: 2 mg vs placebo
BOLD was a double-blind, adaptive dose-ranging Phase 2 study in adults (aged 18–55 years) RRMS where two patient cohorts were sequentially tested, separated by an interim analysis at 3 months. The study determined the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterize safety and tolerability in patients with RRMS. Patients in cohort 1 (1:1:1:1) received once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. Patients in cohort 2 (4:4:1) were randomly allocated to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo3
BOLD Extension presented the safety and efficacy data for 5 siponimod doses during the dose-blinded phase of up to 24 months to understand whether treatment effects in the BOLD study were maintained and assessed the mitigating effect of siponimod dose titration on heart rate changes during treatment initiation4
EXPAND was a Phase 3 randomized, parallel-group, double-blind, placebo-controlled, event-driven, and exposure-driven core part (up to 3 years) followed by an open-label extension part (up to 7 years), which collected long-term data to evaluate the efficacy and safety of siponimod, for up to 10 years. Patients (aged 18–60 years) with SPMS and EDSS score of 3.0–6.5 were randomly assigned (2:1) to receive once-daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of CDP events. The primary endpoint was time to 3-month CDP. CDP was defined as a 1-point increase in EDSS if the baseline score was 3.0–5.0, or a 0.5-point increase if the baseline score was 5.5–6.5, confirmed at a scheduled visit at least 3 months later. The two key secondary endpoints were time to 3-month CDP of at least 20% from baseline in the T25FW test and change from baseline in T2 lesion volume5
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Abbreviations
AEs, adverse events; ALC, Absolute lymphocyte counts; BOLD, BAF312 (siponimod) on MRI Lesion given once-Daily; CDP, confirmed disability progression; CM, cryptococcal meningitis; EDSS, Expanded Disability Status Scale; EXPAND, EXploring the efficacy and safety of siponimod in PAtients with secoNDary progressive multiple sclerosis; PSUR, periodic safety update report; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; T25FW, timed 25-foot walk; VZV, varicella zoster virus
References
1. Data on File, cutoff date 6-Apr-2020, Novartis Pharma AG.
2. Data on File, PSUR 2, cutoff date 25-Sep-2020, Novartis Pharma AG.
3. Selmaj K, et al. Lancet Neurol. 2013;12:756–767.
4. Kappos L, et al. JAMA Neurol 2016;73:1089–1098.
5. Kappos L, et al. Lancet. 2018;391:1263–1273.

The Pregnancy outcome Intensive Monitoring (PRIM) program is based on enhanced pharmacovigilance of the Novartis spontaneous reporting system. PRIM is an adverse event outcomes intensive monitoring program to collect information (targeted follow-up checklists) about pregnancy in patients exposed to siponimod immediately before or during pregnancy and infant outcomes 12 months after delivery.