To summarize the existing data on the incidence of herpes simplex virus (HSV), varicella-zoster virus (VZV), and Cryptococcus sp. infections with sphingosine-1-phosphate receptor (S1PR) modulators.

S1PR modulators are a novel class of disease-modifying therapies for multiple sclerosis (MS) that produce immunosuppression and potential lymphopenia. Herpesvirus and cryptococcal diseases were the most common opportunistic infections in clinical trials. Several post-hoc analyses have subsequently been published with revised incidence rates (IRs) for these conditions.

FINGOLIMOD:
Herpesvirus infection rates were similar between placebo (2.8%) and 0.5 mg (2.1%) but increased with 1.25 mg (5.5%) in the TRANSFORMS study. VZV rates were higher with fingolimod 0.5 mg (3.0%; 11 per 1000 patient-years [PY]) than with placebo (1.0%; 6 per 1000 PY), but comparable post-marketing. Cryptococcal infections (n=74) had an IR of 9 per 100,000 PY, and 13 cases were individually reported.

SIPONIMOD:
VZV reactivation occurred more frequently with siponimod (2%) than with placebo (1%); EXPAND extension analyses calculated an IR of 0.9 for HSV and 1.8 for VZV infections. One case of cryptococcal meningitis (from 7236 PY of exposure) was documented. 

OZANIMOD:
An integrated safety analysis reported oral herpes at 1.5%, VZV at 1.4%, and HSV at 0.5% from all clinical trials versus 0.7%, 0.6%, and 0.1% from the phase-3 trials. The IR of herpes zoster was 5.3/1000 PY.

PONESIMOD:
The incidence of herpetic infections was equal between both groups (4.8%) in the OPTIMUM trial. Cryptococcal infections have not yet been reported with ozanimod or ponesimod.