Effect of Teriflunomide on Lymphocyte Counts and Infections over the Long-Term in the TEMSO Extension Study

Background: In TEMSO (NCT00134563), teriflunomide significantly reduced clinical and MRI disease activity in patients with relapsing forms of MS, and a favorable benefit:risk profile was observed for patients with up to 10.5 years of exposure in the long-term extension (NCT00803049). Results from the 2-year core study demonstrated that lymphocyte count reductions occurred during the first 6 weeks of teriflunomide treatment and largely remained within the normal range. Results of studies evaluating responses to recall antigens or neoantigens suggest that teriflunomide does not adversely impact normal protective immunity.

Objectives: To describe the effect of teriflunomide on lymphocyte counts and infection rates in the TEMSO core and extension trials.

Methods: In the extension study, teriflunomide-treated patients continued with teriflunomide treatment and placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Lymphocyte counts were obtained every 6 weeks until Week 24, and every 24 weeks thereafter. Lymphopenia was identified from 2 consecutive assessments of lymphocyte counts that remained below the lower limit of normal, and graded according to Common Terminology Criteria for Adverse Events (CTCAE).

Results:  Overall in the TEMSO core study (N=1086), Grade 1 (1.4%; n=15) and Grade 2 (0.8%; n=9) lymphopenias were infrequent. In patients with Grade 1 or 2 lymphopenias, 60.0% (n=9) and 44.4% (n=4) experienced any infection, respectively, compared with 60.3% (n=640) of patients without lymphopenias. Serious infections only occurred in patients without lymphopenias (2.2%) in the core study. In the core plus long-term extension (N=962), few patients experienced Grade 1 (3.1%; n=30) or Grade 2 (2.0%; n=19) lymphopenias, and infections were reported in 76.7% (n=23) and 63.2% (n=12) of these patients, respectively, vs 71.4% (n=652) of patients without lymphopenias. Serious infections were infrequent and occurred in patients without lymphopenias (5.4%; n=49) and in patients with Grade 1 (6.7%; n=2) or Grade 2 (15.8%; n=3) lymphopenias. No cases of Grade 3 or 4 lymphopenias were reported in the core or extension.

Conclusions: There was a low incidence of low-grade lymphopenias, and no cases of high-grade lymphopenias, with up to 10.5 years of teriflunomide treatment in the TEMSO core and extension studies. Rates of infections and serious infections were similar in patients with or without lymphopenias. These data are consistent with an immunomodulatory mechanism of action of teriflunomide.