Report on higher-efficacy therapies in MS – ECTRIMS 2019



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Recent studies and physician surveys have reported an increasing use of higher-efficacy disease-modifying therapies in the treatment of MS. An analysis of the NeuroTransData MS registry in Germany found that in the periods 2010-2012 and 2016-2017, DMT use increased from 68.4% to 76.8% (Bergmann et al. ECTRIMS 2019; abstract P1063). Treatment was initiated about 3-4 months earlier from first MS symptom (mean 224 to 108 days) with a higher proportion now starting therapy within six months of diagnosis (83% to 92%). However, there was also greater volatility in DMT use – the mean time to discontinuing a DMT decreased from 19.9 months to 6.1 months, primarily due to adverse effects (16%) or lack of efficacy (13.9%). Switching is now primarily to an oral DMT (65.2%) or a MAb (46.6%) rather than to an injectable (16.4%). Annualized relapse rates (ARR) have declined over the past decade (from 0.23 to 0.16) but are similar for injectables (0.16), orals (0.16) and MAbs (0.12). For the most recent cohort, the mean time from first MS symptom to EDSS >3.5 is now 18.8 years, with only a low number of patients (1.6%) converting to SPMS.

First-line use of MAbs has been largely driven by the approval of ocrelizumab. A chart review found that U.S. neurologists are now slightly more likely to use a MAb rather than an interferon as the initial treatment (18% vs. 17%) (Naismith et al. ECTRIMS 2019; abstract P973). However, neurologists said they were generally not comfortable prescribing ocrelizumab first-line. A separate U.S. study reported that patients with significant comorbidities were more likely to start treatment with ocrelizumab or natalizumab (Coyle et al. ECTRIMS 2019; abstract P1351).

In an examination of DMT use, a University of Colorado study found that younger patients (< 45 years) were more likely to have inflammatory disease activity and were less well-controlled with an oral DMT (DMF, fingolimod) than a MAb (ocrelizumab, rituximab) (Vollmer et al. ECTRIMS 2019; abstract 237). However, while the odds of experiencing disease activity were higher with an oral vs. MAb in younger patients (OR 2.67), there was no apparent advantage with MAbs vs. orals in patients >45 years (OR 1.16, NS). The authors suggested that higher efficacy therapies appear to have a disproportionately larger effect in younger patients, a conclusion that appears to be supported by the findings of a recent meta-analysis (Weideman et al. Front Neurol 2017;8:577). Interestingly, an analysis of DMT use in Denmark found that people starting a DMT after age 40 were most likely to receive teriflunomide, whereas those younger than age 40 were more likely to receive DMF (Sorensen et al. ECTRIMS 2019; abstract P1382). Higher-efficacy DMTs (fingolimod, natalizumab) were also more commonly used in younger patients. A further finding was that older patients were less likely to be adherent to a higher-efficacy drug regimen.

Earlier use of higher-efficacy therapies may be due, in part, a more urgent response to breakthrough disease activity and the availability of more treatment options. While no evidence of disease activity (NEDA) is difficult to achieve, a recent analysis by the Barcelona group has suggested that patients who do achieve NEDA for one year have a high probability (61%) of having no disease activity at three-year follow-up (Midaglia et al. ECTRIMS 2019; abstract P680). In the STRIVE-MS trial, 56.2% of patients treated with natalizumab achieved NEDA in the first year (Perumal et al. ECTRIMS 2019; abstract P1348). NEDA rates (noncumulative) remained >70% for each of the subsequent years in the four-year study. A separate study found that maintaining NEDA for the first two years predicted a low risk of three-month confirmed disability progression (CDP) at five and seven years (Tsantes et al. ECTRIMS 2019; abstract P1050). In contrast, the lesser benchmark of minimal evidence of disease activity (MEDA) was not predictive of disability outcomes.

Switching therapies

A number of studies presented at ECTRIMS examined the effectiveness, safety and tolerability of treatment switches. A post-hoc analysis of previously-treated patients enrolled in the CLARITY trial reported a significant reduction in ARR after initiating oral cladribine vs. placebo (0.22 vs. 0.42) (Vermersch et al. ECTRIMS 2019; abstract P624). According to the results of CLARINET, the real-world follow-up of Italian patients enrolled in cladribine clinical trials, most patients (62.2%) required no further treatment in the first few years after completing the two-year course of therapy (Patti et al. ECTRIMS 2019; abstract P617). For the CLARITY subgroup, the median time to treatment switch was three years after the last dose. Most patients were de-escalated to an injectable or teriflunomide while one-third received fingolimod or natalizumab. With these regimens, 58.9% of patients remained relapse-free and 51.9% had no three-month CDP at five-year follow-up.

The relative merits of escalation versus de-escalation after high-efficacy treatment were also examined at the Cleveland Clinic (Hersh et al. ECTRIMS 2019; abstract P972). A cohort of 556 patients discontinued natalizumab and were switched either to an oral DMT (DMF or fingolimod) or less commonly to a MAb (ocrelizumab, rituximab or alemtuzumab). As expected, patients who relapsed (9.9% vs. 4.8%), proportion with Gd+ lesions (12.6% vs. 7.1%) and new T2 lesions (15.3% vs. 13.3%) was higher after de-escalation vs. escalation. However, it was noteworthy that 63.3% of patients switched to DMF or fingolimod had no evidence of disease activity at 24 months after switching from natalizumab.

Delaying the switch to a higher-efficacy DMT appears to provide clinical benefits in some but not all domains. The PANGAEA study looked at older patients (mean age 47 years) with long-standing disease (mean 17 years) and/or moderate disability (mean EDSS 4.0) treated with multiple DMTs prior to switching to fingolimod (Ziemssen et al. ECTRIMS 2019; abstract P618). ARR improved by 77.9% in the two years after starting fingolimod and EDSS remained stable. However, this risk cohort had greater cognitive deficits at the time of starting fingolimod and had minimal improvement in their SDMT scores with treatment.

Two real-world analyses at ECTRIMS examined the effectiveness of switching to a high-efficacy MAb after one or more prior treatments. MSBase reported on 234 RMS patients who were switched from a DMT (primarily natalizumab or fingolimod) to ocrelizumab (Butzkueven et al. ECTRIMS 2019; abstract P1017). At >6 months after switching, 91.5% remained relapse-free. Similar benefits were seen in TREAT-MS, an ongoing real-world study of alemtuzumab (Ziemssen et al. ECTRIMS 2019; abstract P988). In the subgroup of patients previously treated with >3 prior DMTs, 73.1% were relapse-free, ARR decreased from 1.7 to 0.24, and EDSS scores were unchanged (mean -0.1) in the two years after switching.

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