Long-term efficacy, safety of DMTs in MS




Dimethyl fumarate

An accumulating body of evidence has indicated that sustained treatment with a disease-modifying therapy (DMT) can improve relapse recovery and slow the accumulation of disability in patients with relapsing MS.

For example, the MSBase group constructed a proportional hazards model to evaluate the cumulative hazard of disability progression confirmed at 12 months, disability improvement, and conversion to secondary progressive MS (Kalincik et al. ECTRIMS 2017; abstract P732). The analysis included 2194 patients followed for up to 22 years (cumulative 15,083 patient-years). Mean age was 31.9 years; and median EDSS was 2.0. The median duration of DMT exposure was 81% of the follow-up period. Treatment was associated with a 41% reduction in the risk of disability progression, and a significantly increased probability of disability improvement (odds ratio 1.4), effects that appeared to be sustained for up to 22 years. There was no difference in the proportion of patients who developed secondary-progressive MS.

Clinical disability improvement (CDI) has emerged as an important benchmark of treatment efficacy, as highlighted in recent DMT studies. The following is a summary of key findings reported at ECTRIMS-ACTRIMS 2017, with a focus on long-term data and CDI results.

Teriflunomide: At the completion of the 36-week phase II study, 173 subjects enrolled in the long-term extension and received teriflunomide 7 mg/day or 14 mg/day for up to 14 years (Freedman et al. ECTRIMS 2017; abstract P1203). At the start of the extension, mean age was 40 years; 72-76% were female; and mean duration of MS was 9-10 years. In the group receiving teriflunomide 14 mg/day, mean EDSS score decreased from 2.45 at baseline to 2.14 at Year 10, and remained stable thereafter. EDSS scores were stable or improved in 69.5%. MS severity scores also showed steady improvement over the duration of the observation period.

An analysis of patients in the phase III TEMSO and TOWER extensions found that EDSS scores at 5 years were stable or improved in a majority of patients (females 75.7%; males 76.8%) (Vermersch et al. ECTRIMS 2017; abstract P1191). Disability outcomes were consistent across different subgroups, including younger vs. older patients (stable/improved < 38 years, 76.7%; >38 years, 75.5%), baseline EDSS score (< 3.5, 75.5%; >3.5 years, 77.6%), and prior DMT exposure (Yes, 77.3%; No, 75.1%).

Long-term treatment with teriflunomide 14 mg was associated with improvements in cognition, as evaluated in the TEMSO extension cohort (Sprenger et al. ECTRIMS 2017; abstract P685). Improvements from baseline in PASAT-3 z-scores were recorded at weeks 96, 156, and 276. Improvements in PASAT scores were significantly higher in patients with the least amount of brain volume loss. A separate analysis of patients in the TOPIC trial of CIS/early MS found that teriflunomide 14 mg reduced the median change in percent cortical grey matter volume (CGMV) by ≥40% vs placebo at all time points (Zivadinov et al. ECTRIMS 2017; abstract P671). CGMV loss was significantly associated with conversion to clinically-definite MS: at 1 year, there was a 12.4% increased risk of MS for every 1% decrease in CGMV.

Dimethyl fumarate: Subjects completing the phase III DEFINE and CONFIRM trials of DMF were eligible to enter the ENDORSE long-term follow-up study. Subjects received DMF 240 mg BID or TID; TID patients were subsequently switched to BID dosing. A new analysis examined long-term outcomes (median 7.5 years) in the newly-diagnosed subgroup (n=229); all were treatment-naïve at entry into the core studies (Gold et al. ECTRIMS 2017; abstract P661). The adjusted annualized relapse rate over 8 years was 0.14 for patients on continuous DMF. Mean EDSS scores improved slightly, from 1.89 at entry into ENDORSE to 1.80 at 8 years. The proportion of patients on continuous DMF with EDSS scores < 3.5 remained steady: 93% at Year 2, and 92% at Year 8. Moreover, 52.1% of DMF patients remained free of relapses and 24-week confirmed disability progression.

Fingolimod: Two studies reported on disability outcomes during long-term treatment with fingolimod. With data from the TRANSFORMS extension, Cree and colleagues examined the proportion of patients with baseline EDSS scores >2 who experienced clinical disability improvement (CDI), defined as >1-point decrease in EDSS confirmed at 6 months (Cree et al. ECTRIMS 2017; abstract P672). The cumulative probability of CDI at 8-year follow-up was 36.9% for patients on continuous fingolimod 0.5 mg/day, and 35.1% for patients who switched after one year from interferon-beta-1a IM to fingolimod. The group also evaluated CDI-plus, defined as EDSS decrease >1 point, or a 20% improvement in Timed 25-Foot Walk or 9-Hole Peg test over a six-month period. The proportion of patients achieving CDI-plus was 52.0% with continuous fingolimod 0.5 mg, and 48.3% for the placebo/fingolimod switch group.

The quality of recovery was examined in a pooled analysis of 505 patients from the FREEDOMS/FREEDOMS II trials (Reder et al. ECTRIMS 2017; abstract P1186). At 8 years, 54.4% of patients on continuous fingolimod 0.5 mg had achieved CDI or minimal EDSS change, 17.2% had fluctuating EDSS scores, and 28.5% had worsening disability. Similar results were seen in the placebo/fingolimod switch groups: 45% were improved/stable, 22.5% had fluctuating disability scores, and 32.5% worsened. Patients with CDI were more likely to be males, with a shorter disease course, lower T2 lesion volume and less brain volume loss.

Alemtuzumab: Following completion of the phase III CARE-MS I and II studies and their 4-year extensions, patients could enrol in TOPAZ, an ongoing 5-year follow-up study. At Year 7 (core + extensions + 1 year of TOPAZ), 59% of the CARE-MS I cohort had received no further treatment after the initial two-year course of alemtuzumab: 24% received 1, 9% received 2, 6% received 3 and 0.6% received four retreatments. The annualized relapse rate for the CARE-MS I cohort continued to be low (0.13 in Year 7; 0.15 for years 3-7) and 78% had a stable or improved EDSS score (Coles et al. ECTRIMS 2017; abstract P1188). The proportion with 6-month clinical disability improvement was 21%, and 74% were progression-free. With respect to MRI measures, 68% were free of new/enlarging T2 lesions, 91% had no Gd+ lesions and 85% had no new T1 hypointense lesions (Arnold et al. ECTRIMS 2017; abstract P1189). Brain atrophy, as assessed by brain parenchymal fraction (BPF), was normalized in Year 2 of treatment (-0.25%), and remained low in Years 6 (-0.17%) and 7 (-0.16%). In the group originally randomized to IFN-beta-1a SC, the percent change in BPF decreased from -0.50% at the time of switch, to -0.13% in Year 5 of alemtuzumab (Rovira et al. ECTRIMS 2017; abstract P728).

Among CARE-MS II patients entering TOPAZ, 47% received no further treatment after the initial two courses of alemtuzumab (Singer et al. ECTRIMS 2017; abstract P736). ARR remained low (0.14 in Year 7). Overall, 69% were free of 6-month confirmed disability progression; 44% had confirmed disability improvement through Year 7. The proportion free of MRI activity and new/enlarging T2 lesions was 67%, A total of 90% of patients had no new Gd+ lesions and 88% had no new T1 hypointense lesions (Pelletier et al ECTRIMS 2017; abstract P741). The median yearly BPF change remained low: -0.07% in Year 5, -0.10% in Year 6, and -0.14% in Year 7. In the group originally randomized to IFN-beta-1a SC, the proportion with no MRI activity increased from 47% at the time of switch to 81% in Year 3, and 67% in Year 5; 85% had no Gd+ lesions (Pelletier et al. ECTRIMS 2017; abstract P724). The median annual rate of brain atrophy was -0.33% at the time of switch to -0.08% in Year 5 of alemtuzumab.

For the safety analyses, the overall incidence of adverse events declined with longe-term observation. The incidence of serious adverse events was 12.0% in Year 1, and 5.9% in Year 7 for the CARE-MS I group (Coles 2017), and 12.6% and 9.5%, respectively, in the CARE-MS II group (Singer 2017). The most common adverse events were infections (30.8% and 34.2% in the two cohorts). The rate of serious infections was 0.9% and 3.3%, respectively. The rate of thyroid adverse events was 1.6% in CARE-MS I patients (serious, 0%), and 2.4% in CARE-MS II patients (serious, 0.3%). There were no cases of immune thrombocytopenia in Year 7 in either cohort. The overall malignancy rate in Year 7 was 0.3%.

Two other analyses were noteworthy. Horakova and colleagues examined the rate of conversion to SPMS through six years for the pooled CARE-MS populations (Horakova et al. ECTRIMS 2017; abstract P1195). SPMS was defined according to criteria developed by Lorscheider et al: disability progression in the absence of relapses, a 1-point worsening of EDSS point score confirmed over ≥3 months within the leading Functional System, and requiring an EDSS score ≥4 and pyramidal score ≥2 (Lorscheider et al. Brain 2016; 139:2395-2405). Overall, the estimated rate of conversion to SPMS was about 3.0% with alemtuzumab at 6-year follow-up. This compares favourably with the estimated rate of conversion to SPMS (2-3% per annum) reported in natural history studies (Vukusic & Confavreux. J Neurol Sci 2003; 206:135-137).

Traboulsee and colleagues reported on the long-term outcomes of the 27% of CARE-MS patients who received a third course of alemtuzumab; median time to re-dosing was 2.6 years after the second course (Traboulsee et al. ECTRIMS 2017; abstract P727). ARR was 0.74 in the year prior to re-dosing, declining to 0.06 in the year after the third course and remaining low (0.08) at Year 6. The proportion with clinical disability improvement increased from 5.0% to 17.5% after re-dosing, but remained lower than the rest of the CARE-MS population.

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