^*General population

• Rates of infection in patients with MS after MS diagnosis were compared with a matched population of patients without MS. The MS cohort included patients who had MS diagnosed and were treated between January 2004 and August 2017¹
• Patients had medical history available for at least 1 year before MS diagnosis and at least one prescription for an MS disease-modifying treatment¹
• Patients without MS were matched to patients with MS 10:1 based on age, sex, geographic region, and cohort entry date. For each patient, the researchers identified the first diagnosed infection of each type after cohort entry. Patients were followed until loss of eligibility, death, or end of data collection¹
• In all, the study included 8695 patients with MS and 86,934 matched patients without MS. The median age at cohort entry was 41 years, and 71% were female. Median duration of follow-up after study entry was about 6 years. Patients with MS were more likely to have an infection in the year before cohort entry, compared with non-MS patients (43.9% vs. 36.3%)¹

Siponimod and infections

• The immune system effects of siponimod may increase the risk of infections. A core pharmacodynamic effect of siponimod is a dose-dependent reduction in peripherals lymphocyte due to the reversible sequestration of lymphocytes in lymphoid tissues

Overall infection rates in siponimod clinical trials

Controlled pool³ (median exposure: 17 months)

• Infections were most frequently reported AEs in the controlled period
• In the controlled pool, overall rate of infections was similar between siponimod and placebo groups
  • Risk of serious infection with siponimod was similar to placebo
• Nasopharyngitis, UTI, URTI, and influenza were the most common infections

Long-term pool^4,** (median exposure: 48.6 months)

• As of 06-April-2020, no increase in the overall incidence of infections was observed in the siponimod-treated patients and was consistent with the controlled pool. As observed in the controlled period, there was no change in the type or pattern of reported infections over time
• UTI was the most common serious infection reported in the siponimod group

**Long term estimate obtained using cumulative incidence function
Controlled pool³ included double-blind, placebo-controlled core part of studies BOLD and EXPAND. Long-term pool⁴ included 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

Postmarketing experience⁴

• As of 25-September-2020, an estimated 5000 patients with RMS and active SPMS started siponimod treatment outside of clinical trials, corresponding to an exposure of 2278 PY
• Of 2383 total postmarketing cases (602 HCPs; 1781 consumers) with AEs, 253 events were related to infections and infestations in 221 cases (47 HCP; 174 consumer)
  • Of these, 23 events in 20 cases were reported serious by HCPs and 71 events in 63 cases by consumer
  • Most commonly reported serious infections were UTI and pneumonia
• Outcome was reported as fatal in three cases related to infections
  • One patient died with congestive heart failure case and bronchial pneumonia; no further details were available
  • Two female patients aged 51 and above 70 years had fatal outcome due to COVID-19; no further details were available
• No particular pattern of infection was identified and consistent with S1P modulations

Abbreviations

AE, adverse event; CI, confidence interval; HCP, healthcare professional; IR, incidence rate; MS, multiple sclerosis; PY, patient-years; RMS, relapsing multiple sclerosis; SPMS, secondary progressive multiple sclerosis; URTI, upper respiratory tract infection; UTI, urinary tract infection