The following summarizes studies of disease-modifying therapies presented at ECTRIMS 2016.
Teriflunomide: Seven-year results are available for the TOPIC study of CIS (Miller et al. ECTRIMS 2016; abstract P690). The risk of relapse (i.e. diagnosis of MS) was significantly lower in the group on continuous teriflunomide 14 mg versus placebo patients switched to 14 mg (delayed treatment group): mean 0.529 vs. 0.883. In the 6-year follow-up to the TEMSO/TOWER studies, 93.7% of patients on teriflunomide 14 mg/day with baseline EDSS < 6 had not progressed to EDSS >6 (Lublin et al. ECTRIMS 2016; abstract P691).
Dimethyl fumarate: Six-year results for the ENDORSE extension of the DEFINE/CONFIRM trials have been reported (Gold et al. ECTRIMS 2016; abstract P631). For the subgroup with early MS at entry (n=144), relapse rates remained low (0.14) with continuous DMF 240 mg BID; 56.3% were relapse-free. The proportion with 6-month confirmed disability progression was 15.7%. In addition, two studies reported on lymphopenia with DMF exposure. To date, 190,000 patients have received DMF (218,988 patient-years). A safety analysis of phase II and III trials (n=2513; 8,293 patient-years) found that mean absolute lymphocyte count (ALC) declined 30% in year 1 (Fox et al. ECTRIMS 2016; abstract P716). In the subgroup receiving DMF >6 months (n=2098), 2.5% developed lymphopenia (ALC < 0.5 x 109/L) persisting >6 months; 10.9% had moderate lymphopenia (ALC < 0.8 x 109/L) persisting for >6 months. A greater reduction was seen in CD8+ versus CD4+ cells. A separate study examined T cell counts in 174 patients (mean age 46.9 years) during DMF exposure (Spinelli et al. ECTRIMS 2016; abstract P703). Average duration of DMF use was 25 months. Mean ALC decreased 27%. A total of 21% had severe lymphopenia according to CD8+ counts (< 100/mm3); this included 9% with severe CD8+ lymphopenia, but only grade 1 ALC lymphopenia. DMF was discontinued in 61 patients (35%) due to lymphopenia; CD8+ counts remained persistently low in 29% at 2.5 months after drug discontinuation. The authors suggested periodic monitoring of CD8+ counts, which may be a better predictor of PML risk than ALC.
Fingolimod: Data were analysed for 3,956 patients (7869 patient-years) treated with fingolimod in Canada (Bhan et al. ECTRIMS 2016; abstract P640). Mean age was 41 years. During the 58-month observation period there was >80% adherence. The most common reason for discontinuation was adverse effects; the most common AE associated with discontinuation was low lymphocyte counts. A separate study examined the effect of fingolimod on cognition in 105 patients treated for up to 3 years (Ozakbas et al. ECTRIMS 2016; abstract P619). Fingolimod-treated patients showed improvements from baseline in the Symbol Digit Modalities Test (SDMT), and the California Verbal Learning Test-2 (CVLT2) at 6 months. An estimated 28-46% of patients with cognitive impairment at baseline had no cognitive impairment after initiating fingolimod.
Alemtuzumab: In the CARE-MS II extension, by year 6, 50% had received no additional treatment after the initial two courses of alemtuzumab (LaGanke et al. ECTRIMS 2016; abstract P681). In year 6, 85% had no evidence of clinical activity, and 69% had no new MRI activity. The NEDA rate in year 6 was 60%. Data were also analysed for the highly-active subgroup (n=103) in the CARE-MS II extension (Comi et al. ECTRIMS 2016; abstract P613). A total of 62% received two treatment courses. A majority had NEDA in any given year of follow-up: 92% had no Gd+ lesions, 70% had no new/enlarging T2 lesions and 89% had no new T1 hypointense lesions in year 5. Median brain volume loss was -0.13%/year in year 5. In the cohort initially randomized to interferon-beta, ARR decreased from 0.52 during IFN-beta to 0.17 in year 4 of alemtuzumab (Boyko et al. ECTRIMS 2016; abstract P680). Eighty percent had no evidence of 6-month confirmed disability progression.
Cladribine: Two studies have examined oral cladribine in RRMS: the phase III placebo-controlled CLARITY trial (Giovannoni et al. N Engl J Med 2010;362:416-26; free full text at www.nejm.org/doi/pdf/10.1056/NEJMoa0902533); and the phase II ONWARD trial of cladribine as an add-on to IFN-beta-1a (Montalban et al. AAN 2016; abstract 3285). For the CLARITY extension, after a median treatment interruption of 41 weeks, patients initially randomized to cladribine 3.5 or 5.25 mg/kg were randomized to 3.5 mg/kg or placebo; and the placebo cohort was switched to cladribine 3.5 mg (Giovannoni et al. ECTRIMS 2016; abstract P636). The 5 extension cohorts accordingly received a cumulative dose of cladribine 3.5 mg/kg (Clad 3.5/placebo; Placebo/Clad 3.5); 5.25 mg/kg (Clad 5.25/placebo); 7 mg/kg (Clad 3.5/clad 3.5); or 8.75 mg/kg (Clad 5.25/clad 3.5). The proportion relapse-free at 123 weeks ranged from 75.3% (clad 5.25/placebo) to 81.2% (clad 3.5/clad 3.5). The proportion without 3-month confirmed disability progression at 121-124 weeks ranged from 81.6% (clad 3.5/placebo) to 90.2% (clad 5.25/placebo). There were no new Gd+ lesions in 73.0% (clad 3.5/placebo) to 89.9% (clad 3.5/clad 3.5) of patients.
In a pooled analysis of patients from CLARITY/ONWARD (n=1067), patients receiving a cumulative dose of cladribine 3.5 mg/kg had a 57% reduction in ARR, a 39% in 3-month confirmed disability progression, an 87% reduction in the risk of new Gd+ lesions and a 71% reduction in the risk of active T2 lesions versus placebo (the ONWARD placebo group also received IFN-beta) (Giovannoni et al. ECTRIMS 2016; abstracts P642 and 643). In an integrated safety analysis, herpes zoster was the only severe infection seen with cladribine; herpes infections were more common in patients with Grade 3 or 4 lymphopenia (Leist et al. ECTRIMS 2016; abstract P635).