Disease-modifying therapies: long-term results


REPORT FROM THE ACTRIMS-ECTRIMS – BOSTON, MA, SEPTEMBER 10-13, 2014 – Numerous extension and long-term observational studies were presented at ACTRIMS/ECTRIMS 2014 for current disease-modifying therapies (DMT). The following is a summary by treatment.

Natalizumab: There are very few long-term studies of natalizumab since the duration of use is associated with an increasing risk of progressive multifocal leukoencephalopathy (PML). An Italian study analysed data for 378 MS patients (mean age 35 years; median EDSS 3.0) treated for six years with natalizumab (Prosperini et al. ECTRIMS 2014; abstract P292). Overall, 46% of patients discontinued treatment, and 20% interrupted therapy (>3 months) during the observation period; 72% of patients discontinued/interrupted treatment due to concerns about PML. Worsening of disability was more common in patients who discontinued (39%; 9-fold more common) or interrupted therapy (23%; 4-fold more common) compared to those continuing on treatment (6%). However, the odds of disability progression did not differ significantly for patients temporarily interrupting therapy compared to those continuing on treatment.

Fingolimod: Data from the FREEDOMS phase III trial and its extension were analysed to determine if the extent of brain volume loss at 24 months was predictive of disability progression over a 4-year observation period (Jeffery et al. ECTRIMS 2014; abstract PC2.3). A total of 1,029 subjects were categorized by quartile according to percentage brain volume change (PBVC) from baseline to month 24; mean annualized PBVC was determined for each quartile. PBVC was assessed with SIENA (Structural Image Evaluation, using Normalization, of Atrophy). Mean annualized PBVC for the four quartiles was -1.5% (quartile 1), -0.6% (Q2), -0.2% (Q3), and +0.2% (Q4). There was a larger proportion of women in the group with the greatest brain volume loss at baseline (74.6% vs. male 68.7%). In comparing those with the most (Q1) versus the least (Q4) brain volume loss at baseline, there were substantial differences in mean EDSS score (2.7 vs. 2.1), T2 lesion volume (11.3 vs. 3.3 cm3), T1 lesion volume (3.6 vs. 1.0 cm3), and number of gadolinium-enhancing lesions (5.6 vs. 0.6). A total of 30.3% of Q1 patients were EDSS >4 compared to 11.4% of Q4 patients at month 24; and 35.8% and 13.8%, respectively, at month 48. Moreover, 14.8% of Q1 patients were EDSS >6 compared to 1.1% of Q4 patients at month 24; and 19.2% and 3.1%, respectively, at month 48. The group concluded that brain volume loss at 24 months may be associated with progression of disability.

Teriflunomide: Long-term MRI results from the phase II trial of teriflunomide were available for 64 patients completing 480 weeks of treatment (Li et al. ECTRIMS 2014; abstract P079). The mean number of Gd-enhancing lesions was 1.60 at the end of the core study and 0.29 at week 480 for patients in the teriflunomide 14 mg/day group. The mean number of newly active T2 lesions declined from 3.11 at the end of the core study to 1.21 at week 480. The mean change from baseline in T2 lesion volume was 2352 mL; mean change in cerebral volume was -3.276% with teriflunomide 14 mg at week 432.

Dimethyl fumarate: ENDORSE is the extension of the DEFINE and CONFIRM phase III trials of DMF. In the subgroup receiving continuous DMF 240 mg BID for four years, the adjusted annualized relapse rate remained low in years 3 (0.138) and 4 (0.142) (Gold et al. ECTRIMS 2014; abstract P110). ARR was also low in those previously in the placebo and glatiramer acetate arms (0.126 and 0.128, respectively in year 4). In the newly-diagnosed subgroup, ARR for the entire four-year period was 0.142 (Gold et al. ECTRIMS 2014; abstract P064).

A separate analysis of MRI findings examined data for 206 patients completing four years of treatment with DMF 240 mg BID (Arnold et al. ECTRIMS 2014; abstract P059). In year 4 of treatment, 68% had no new/enlarging T2 lesions, 76% had no new T1 lesions and 88% had no new enhancing lesions. For the placebo/DMF group (n=96), 33% had no new/enlarging T2 lesions after one year of active treatment, and 78% had no new T2 lesions in year two of treatment.

Alemtuzumab: Four-year follow-up data were reported for the phase III studies of alemtuzumab in newly-diagnosed (CARE-MS I) and previously treated (CARE-MS II) patients. In the CARE-MS program, patients received alemtuzumab infusions for five days, followed by a second three-day course a year later. For the extensions, patients were redosed (12 mg IV x 3 days) as needed or allowed to use another DMT if there was evidence of MRI activity; patients in the control arm (IFNb-1a SC) received two courses of alemtuzumab.

In the CARE-MS I extension, 73% were not redosed; 21% received one additional course, 5% received two additional courses and less than 5% received another DMT (Coles et al. ECTRIMS 2014; abstract P090). Nine of 349 patients (2.6%) in the alemtuzumab arm discontinued the study, and 8 of 144 (5.6%) in the IFN/alemtuzumab arm. ARR in years 3 and 4 was 0.19 and 0.14 (0.16 for the 4-year period); and disability scores remained stable or improved in 73% of patients.

MRI activity remained low from year 2 to year 3 with respect to the proportion with enhancing lesions (7% vs. 9.8%), and new/enlarging T2 lesions (22.2% vs. 27.7%) (Arnold et al. ECTRIMS 2014; abstract FC2.2). A total of 72% were MRI activity-free in year 3.

In the CARE-MS II extension, 68% of alemtuzumab-treated patients received no additional courses; 24% and 7% received one or two additional courses, respectively (Hartung et al. ECTRIMS 2014; abstract P043). A total of 25 of 393 patients (6.4%) in the alemtuzumab arm discontinued the study, and 7 of 146 (4.8%) in the IFN/alemtuzumab arm. In year 3, 68% of patients were free of MRI activity (Fisher et al. ECTRIMS 2014; abstract P103). T2 and T1 lesion volumes remained at or below baseline, with a progressive decrease in the rate of brain volume loss over time.

Guest Reviewer: Dr. Daniel Selchen, St. Michael’s Hospital, Toronto, Ontario.

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