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Dimethyl fumarate

The following summarizes key studies of disease-modifying therapies presented at ECTRIMS 2017.

Teriflunomide: In phase III trials (TEMSO, TOWER), there was a low rate of lymphopenia in teriflunomide-treated patients (Grade 2, 1.4%), and only 1 patient with Grade 2 lymphopenia experienced a serious infection. During the longer-term extensions, lymphopenia remained uncommon (Grade 1, 3.0%; Grade 2, 2.5%; no cases of Grades 3-4) (Comi et al. ECTRIMS 2017; abstract P742). The rate of serious infections was low in patients with Grade 1 (0.1%) and Grade 2 (0.2%) lymphopenia.  A separate analysis of the effect of teriflunomide on immune subsets reported that the drug significantly reduces CD19+ B cell subsets (mature and regulatory), with lesser effects on T cell subsets (trends for effector CD4+ and Tregs). There was no effect on NK cells (Gandoglia et al. ECTRIMS 2017; abstract P701). An analysis from the TOPIC trial in CIS/early MS reported that teriflunomide 14 mg reduced the change from baseline in cortical grey matter volume (CGMV) by ≥40% versus placebo (Zivadinov et al. ECTRIMS 2017; abstract P671). CGMV loss was significantly associated with conversion to CDMS: there was a 12.4% increased risk of conversion to CDMS at 12 months for every 1% decrease in CGMV.
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Dimethyl fumarate: Persistent lymphopenia (ALC < 0.5 x 109/L for ≥6 months) has been reported to occur during treatment with DMF. An integrated analysis of phase II/III studies (N=2470) reported that the incidence of persistent lymphopenia was 2.1% (Fox et al. ECTRIMS 2017; abstract P743). Most cases of persistent lymphopenia (83%) occurred in the first 3 years of treatment. At 6 months after drug discontinuation, 41% had recovered to Grade 1 lymphopenia.
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Fingolimod: In the TRANSFORMS extension, an estimated 36.9% of patients on continuous fingolimod 0.5 mg/day had confirmed disability improvement (CDI) at 8 years (Cree et al. ECTRIMS 2017; abstract P672). The rate of CDI in the group that switched from IFNbeta-1a IM to fingolimod was 35.1%. In addition, 52% of fingolimod-treated patients achieved CDI-plus, defined as a ≥1 decrease in EDSS score lasting ≥166 days, a ≥20% improvement in 9HPT score, and a ≥20% improvement in T25FW.
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Cladribine: Three studies reported on the effect of oral cladribine on lymphocyte counts. An analysis of the CLARITY extension reported that treatment/retreatment guidelines appear to be effective in minimizing severe lymphopenia (Cook et al. ECTRIMS 2017; abstract P666). The guidelines recommend initiating oral cladribine in patients with normal lymphocyte counts, and re-treating only in patients with Grade 0 or 1 lymphopenia. Among patients in the extension who received cladribine 3.5 mg/kg and were rerandomized to 3.5 mg/kg (cumulative 7.0 mg/kg over 4 years), no patient had Grade 4 lymphopenia at the end of the treatment year (week 48); the rate of Grade 3 lymphopenia at week 48 was 1% after Year 2, and 0% at the end of Years 3 and 4. Grade 3 lymphopenia was reported in < 18% at any given time point. Lymphocyte kinetics were examined in a separate study of patients in the CLARITY trial receiving two annual courses of cladribine and no further treatment (Soelberg Sorensen et al. ECTRIMS 2017; abstract P655). ALC nadir was at week 9 post-treatment in Year 1, and week 3 post-treatment in Year 2. CD4+ nadirs occurred at week 16 post-treatment in Year 1, and week 8 post-treatment in Year 2. CD19+ B cell nadirs were reached in weeks 9 of Year 1, and week 1 of Year 2. ALC recovered to within normal range in 75% of patients by week 144. Lymphocyte recovery to threshold values was observed at 7.5 months for ALC, 12 months for CD19+ B cells, and 18 months for CD4+ T cells. A pooled analysis of CLARITY/extension and ORACLE MS reported that B cells were reduced about 80% from baseline, with reconstitution toward baseline in weeks 24-48. T cell depletion was less marked (CD4+ 55%; CD8+ 48% at nadir), but with slower reconstitution (Stuve et al. ECTRIMS 2017; abstract P690). An integrated safety analysis found that infection rates were higher during periods of severe lymphopenia, but the type of infections was similar (Cook et al. ECTRIMS 2017; abstract P1142). The most common infections were nasopharyngitis and upper respiratory tract infections. The incidence of herpes zoster was 2.4 per 100 patient-years in patients with grade 3-4 lymphopenia versus 0.73/100 PY in patients without severe lymphopenia. Zoster cases were dermatomal and mild to moderate in severity.
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Alemtuzumab: Most alemtuzumab-treated patients in the phase III trials have not required re-treatment during long-term follow-up. A new analysis has reported on outcomes in the subgroup of patients who received a third course of alemtuzumab in CARE-MS I (24% of patients) and CARE-MS II (30%) through Year 6 of follow-up (Traboulsee et al. ECTRIMS 2017; abstract P727). The mean time to initiation of the third treatment course was 2.6 years after the second course. The annualized relapse rate decreased from 0.74 to 0.06 at 12 months after the third course; ARR remained low (0.08) at the end of Year 6. Mean EDSS scores improved (-0.12) at 12 months after the third course; the proportion with stable/improved EDSS increased from 62% to 71% (improved: 5.0% to 17.5%). A retrospective study from the University of British Columbia MS clinic reported on its experience with alemtuzumab (Yong et al. ECTRIMS 2017; abstract P681). A total of 73 RRMS patients received at least one course of alemtuzumab. Mean ARR was 0.13. Mean EDSS scores improved by 0.5 points at 12 months. EDSS scores improved in 39%, were stable in 39%, and worsened in 22%.
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Ocrelizumab: An updated safety analysis of phase II/III studies (n=2301) reported that the overall incidence of adverse events was 226 per 100 patient-years (Hauser et al. ECTRIMS 2017; abstract P676). The incidence of serious adverse events was 7.18/100 PY. The incidence of infections and serious infections was 71.3 and 1.86/100 PY, respectively. The incidence of malignancies was 0.454/100 PY. Rates of no evidence of disease activity (NEDA) in different subgroups were also reported (Turner et al. ECTRIMS 2017; abstract P688). The overall NEDA rate in OPERA I/II was 47.7%. NEDA rates were somewhat lower in patients younger than age 40 years (44.3% vs. 52.8% in >40 years), males (44.0% vs. 49.7% in females), previously-treated patients (42.8% vs. 49.5% if untreated in prior 2 years), and patients with greater baseline disability (39.6% with baseline EDSS >4 vs. 50.3% for < 4).
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