Effect of Long-Term Teriflunomide Treatment on Lymphocyte Counts and Infection Rates in Pooled Data from Temso, Tower, and TOPIC Core and Extension Studies

Background: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing forms of MS (RMS). In TEMSO (NCT00134563) and TOWER (NCT00751881), teriflunomide was associated with lymphocyte count reductions during the first 3 months of treatment; mean counts remained within the normal range. In a long-term extension of TEMSO (NCT00803049), lymphopenia was uncommon, no higher than Grade 2, and not associated with increased infections.

Objectives: To evaluate lymphocyte counts and infection rates during long-term teriflunomide treatment in a pooled analysis of data from 3 phase 3 core studies and their extensions.

Methods: Data from 3 placebo-controlled, randomized core studies (TEMSO, TOWER, TOPIC [NCT00622700]) and their extensions were pooled. Patients with RMS (TEMSO and TOWER) or a first clinical episode suggestive of MS (TOPIC) were treated for up to 11 years. Analysis included all patients who received teriflunomide 14 mg at any time during the core or extension studies. In TEMSO and TOWER, lymphocyte counts were obtained every 2 weeks until Week 24. In TOPIC, counts were assessed at Weeks 2 and 6, and then every 6 weeks until Week 24. Thereafter, lymphocyte counts were assessed every 24 weeks in all studies. Lymphopenia (2 consecutive lymphocyte counts <lower limit of normal) was graded by the Common Terminology Criteria for Adverse Events, Version 4.0.

Results: The cumulative duration of exposure to teriflunomide 14 mg was 5273 patient-years. In pooled core and extension studies (N=1636), 92.2% (n=1508/1636) of patients experienced no lymphopenia, and few patients experienced Grade 1 (5.4%; n=89/1636) or 2 (2.4%; n=39/1636) lymphopenia. Infections were reported in 61.8% (n=55/89) and 53.8% (n=21/39) of patients with Grade 1 or 2 lymphopenia, respectively, vs 55.6% (n=838/1508) without lymphopenia. Serious infections occurred in 3.4% (n=3/89) and 7.7% (n=3/39) of patients with Grade 1 and 2 lymphopenia, respectively, vs 3.6% (n=55/1508) without lymphopenia. Analysis of lymphocyte counts by year on treatment showed a decline in the occurrence of lymphopenia over time; at Year 9 and beyond, there were no cases of lymphopenia.

Conclusions: In this pooled analysis of TEMSO, TOWER, and TOPIC, and their extensions, long-term teriflunomide treatment was not associated with high-grade lymphopenia, and low-grade lymphopenia was uncommon. Infection rates were similar in patients with or without lymphopenia, consistent with an immunomodulatory mechanism of action of teriflunomide.