Teriflunomide Selectively Impacts the Immune System and Does Not Impair Protective Responses: Preclinical and Clinical Data

Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing–remitting multiple sclerosis (MS). Teriflunomide inhibits the enzyme dihydroorotate dehydrogenase, required for de novo pyrimidine synthesis in rapidly dividing lymphocytes, thereby limiting proliferation of stimulated T and B cells.

Objectives: To present preclinical and clinical evidence supporting preservation of protective immunity under teriflunomide treatment.

Methods: We summarize preclinical and clinical data related to the selective mechanism of action (MoA) of teriflunomide and its effect on immune responses. In vitro murine T-cell proliferative responses to cognate peptides of various affinities were measured. In vivo primary and memory antiviral antibody responses were evaluated in teriflunomide-treated animals inoculated with adenovirus. Immune response to seasonal flu vaccine and to rabies vaccination was measured in human subjects treated with teriflunomide.

Results: Teriflunomide most strongly inhibited the proliferation of murine T cells stimulated with high-affinity peptides. Teriflunomide-treated mice effectively mounted specific primary and memory antibody responses to adenovirus, with only a slight delay in response. In clinical trials of patients with MS, therapeutic doses of teriflunomide showed no clinical evidence of immunosuppression. Incidences of infection, serious opportunistic infection and malignancy were comparable to placebo. Mean leukocyte counts were reduced (<15% from baseline), but remained within the normal range. Open-label extension study patients have received teriflunomide for up to 12 years. In healthy volunteers, teriflunomide did not impair development of seroprotective immune responses to rabies vaccine neoantigen, though antibody titers were lower in subjects receiving teriflunomide than in those receiving placebo. Patients with MS treated with teriflunomide for >6 months mounted effective memory immune responses to seasonal influenza vaccination (NCT01403376).

Conclusions: Therapeutic teriflunomide doses demonstrating consistent, beneficial effects on relapses and disability progression in phase 3 MS clinical trials do not appear to compromise protective immunity or antibody responses to either recall or neoantigen vaccines. Combined with preclinical data, these findings confirm teriflunomide has a selective immunomodulatory MoA that preserves protective immune responses.