Overview of long-term data in RRMS


The following summarizes the long-term treatment data presented at ECTRIMS 2018.

Teriflunomide: The long-term (up to 12.5 years) efficacy and safety of teriflunomide were examined in a pooled analysis of phase II and phase III trials and their extensions (Freedman et al. ECTRIMS 2018; abstract P1233); cumulative drug exposure was 1357 patient-years. The annualized relapse for patients treated with teriflunomide 14 mg was 0.38 vs. 0.59 with placebo. The proportion of patients with serious adverse events and the proportion discontinuing due to adverse events was comparable with teriflunomide and placebo (12.4% vs. 12.8%; and 6.9% vs. 13.1%, respectively).

Dimethyl fumarate: Nine-year follow-up data for newly-diagnosed patients from the ENDORSE long-term extension dataset were presented (Gold et al. ECTRIMS 2018; abstract P920). Newly-diagnosed was defined as diagnosed within a year before entry into the DEFINE or CONFIRM pivotal trials and treatment-naive. At 9 years, 50% of patients in the DMF/DMF group and 45% from the PBO/DMF group remained in the study. ARR was 0.14 for the DMF/DMF group and 0.15 for the PBO/DMF group over 9 years. At the end of the observation period, 93% of patients in both groups were EDSS < 3.5.

Fingolimod: The LONGTERMS study included patients who completed phase II or III trials (Kappos et al. ECTRIMS 2018; abstract P916). Median exposure to fingolimod 0.5 mg was 8 years. ARR has decreased from 0.26 in year 1 of the extension to 0.14 for months 0-120. At year 5, 78.0% were free from 6-month confirmed disability progression. The annualized rate of brain atrophy was stable (-0.35% in month 120) for the duration of the observation period. The most common adverse events were upper respiratory tract infection (incidence rate 3.17), headache (IR 2.61) and hypertension (IR 2.08). The incidence rate of basal cell carcinoma was 0.18.

Natalizumab: The Tysabri Observational Program (TOP) presented data for patients (n=6148) treated for up to 10 years with natalizumab (Kappos et al. ECTRIMS 2018; abstract P908). Overall, 52.2% discontinued natalizumab and 34.4% withdrew from TOP. Median drug exposure was 38 doses; median follow-up was 62 months. ARR while on natalizumab was 0.15; ARR decreased 90-94% when switched from another DMD to natalizumab. At 10 years, the cumulative probability of 6-month confirmed disability progression was 27.8%; the probability of confirmed disability improvement was 33.1%. The incidence of serious adverse events was 13.5%. There were 52 cases of PML (0.8%) and 59 cases (1.0%) of malignancies.

Alemtuzumab: The ongoing TOPAZ extension study enrolled patients completing the two-year pivotal trial and four-year extension. For the CARE-MS II cohort of previously-treated patients, 8-year data are now available (Singer et al. ECTRIMS 2018; abstract P913). A total of 69% of CARE-MS II subjects have completed two years in TOPAZ. Overall, 56% have received additional treatment following the initial two courses: 29% have received one additional course and 22% have received >2 additional courses. ARR at year 8 was 0.18; 85% were relapse-free and 64% were free from 6-month confirmed disability progression. The mean change in EDSS score from core study baseline to year 8 was 0.17; 70% had stable or improved (47%) EDSS scores. In year 8, 89% had no Gd+ lesions and 70% had no new/enlarging T2 lesions. The median cumulative brain volume loss from baseline was -1.06%; brain volume loss was -0.19%/year or less in years 3-8. The cumulative incidence of thyroid events was 43.7% for years 1-8; the incidence of serious thyroid events was 5.1%. The incidence of infusion reactions declined from the first infusion (83.7%) to the fourth (64.7%). The incidence rate for malignancies was 0.3/100 PY for years 0-8.

Ocrelizumab: Data are now available for patients treated for up to five years in the OPERA I/II extensions (Hauser et al. ECTRIMS 2018; abstract P590). A total of 75.3% of OCR/OCR patients and 66.5% of PBO/OCR patients completed the three-year extension. ARR was 0.065 in the OCR/OCR group and 0.072 in the PBO/OCR group in year 5. The proportion of OCR/OCR patients with 6-month confirmed disability progression was 7.7%, 10.1%, 13.9% and 16.1% at the end of years 2-5; for the PBO/OCR group, the proportion with 6-month CDP was 12.0%, 15.6%, 18.1% and 21.3% for years 2-5. The proportion with 6-month confirmed disability improvement was 25.8% in the OCR/OCR group and 20.6% in the PBO/OCR group in year 5. There was a slight improvement (< 0.1 points) in mean EDSS score from core study baseline to year 5 in the continuous OCR group, and a slight worsening (<0.1 points) in the group started on placebo. The rate of whole-brain volume loss was -1.31% in year 3, -1.58% in year 4 and -1.87% in year 5 of continuous OCR (Arnold et al. ECTRIMS 2018; abstract P588).

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