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Medical information request

Overview

The key safety topics selected for siponimod website are safety areas that are of interest to HCPs, such as infections including PML, CM and COVID-19 as well as reproductive toxicity that are related to the pharmacodynamic action of S1P modulators and effects of S1P modulators on the fetus

  • The overall rate of infections was similar between the siponimod and placebo groups in controlled clinical trials (controlled pool)1; no increase in the overall incidence of infections was observed in patients treated long-term with siponimod (long-term pool)2
    • To date, one case of PML has been reported for siponimod in clinical trial setting and two in postmarketing settings (1 attributed to siponimod and 1 to prior treatment with natalizumab)
    • There were two cases of CM reported in the clinical trial setting. So far, there are no cases in the post-marketing setting.
    • A total of 744 confirmed cases of COVID-19 were reported with siponimod treatment both in clinical trials and postmarketing setting; the majority (~80%) of the cases were non-serious
  • In total, 37 cases of pregnancy were reported in the Novartis safety database, and data do not reveal any new safety risk of reproductive toxicity. No cases of congenital malformation and fetal or maternal complications related to pregnancy and delivery were reported in pregnant women exposed to siponimod

The safety data in the website will be updated annually in line with the PSUR. The sources of information used are the following:

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

  • Controlled pool1: Double-blind, placebo-controlled core part of studies BOLD and EXPAND (siponimod 2 mg)
  • Long-term pool2: Siponimod 2 mg or 10 mg (10 mg up to 24 months in BOLD extension) 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 approved3

BOLD4: 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 Extension5: Dose-blinded phase lasted up to 24 months followed by open-label siponimod 2 mg for approximately 3 years

  • N=184 RRMS patients
  • Treatment groups: Placebo-siponimod and continuous siponimod: 10 mg, 2 mg, 0.5 mg, 1.25 mg, 0.25 mg
  • Open-label: Siponimod 2 mg

EXPAND6: 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 placebo.4
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 initiation.5
EXPAND a Phase 3 randomized, parallel-group, double-blind, placebo-controlled, event-driven, and exposure-driven core part (up to 3 years, completed) followed by an ongoing open-label extension part (up to 7 years). The study will provide long-term data to evaluate the efficacy and safety of siponimod for a total 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 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 volume.6
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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
References
1. Data on File, cutoff date 31-May-2017, Novartis Pharma AG.
2. Data on File, cutoff date 30-October-2020, Novartis Pharma AG.
3. Data on File, PSUR, cutoff date 25-March-2023, Novartis Pharma AG.
4. Selmaj K, et al. Lancet Neurol. 2013;12:756-767.
5. Kappos L, et al. JAMA Neurol. 2016;73:1089-1098.
6. Kappos L, et al. Lancet. 2018;391:1263-1273.
* Indication varies in different countries. Current website is a global information resource. Local Prescribing Information/ Summary of Product Characteristics approved by individual country’s regulatory authority is the primary source of information for the indication of siponimod in the individual country.

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.