High-efficacy DMTs – Early treatment and novel endpoints



The recently concluded European Committee on Treatment and Research in MS (ECTRIMS) annual meeting presented a number of new approaches for evaluating the efficacy of high-efficacy disease-modifying therapies.

In recent years there has been a trend to earlier use of high-efficacy DMTs and three studies examined the potential benefits of this approach. A retrospective analysis of the Danish and Swedish MS registries compared disability outcomes for patients initiating treatment in the period 20213-2016 (Spelman et al. ECTRIMS 2021; P815). A higher proportion of patients in Sweden started with a high-efficacy therapy (37.6% vs. 7.5% for Denmark). At four years, the rate of 24-week confirmed disability progression (CDP) was 29% lower in Sweden; time to first relapse was delayed 56%.

In Norway, as in other countries, high-efficacy DMTs can be the starting therapy only in patients with high disease activity. A registry study examined the impact of treatment selection on the likelihood of achieving no evidence of disease activity (NEDA) (Simonsen et al. ECTRIMS 2021; P677). Patients who started on a moderate-efficacy DMT had a lower likelihood of achieving NEDA in years 1 and 2 (36% and 19%, respectively) compared to those starting with a high-efficacy DMT (68% and 52%). NEDA was 7-fold more likely in year 1 for patients starting on natalizumab compared to an injectable DMT. Patients starting with a moderate-efficacy DMT were also more likely to discontinue treatment (45% vs. 14%), which may be due in part to a perceived lack of benefit. Taken together, these Scandinavian studies indicate that national treatment strategies that necessitate an escalation approach to MS treatment can result in poorer clinical outcomes.

The Big MS Data Network conducted an analysis of DMTs in PPMS patients (Lorscheider et al. ECTRIMS 2021; P115). As expected, there was no significant impact of treatment on disability outcomes at three years compared to matched untreated controls. An interesting observation, however, was that treatment did appear to slow disability worsening in the subgroup of PPMS patients with an aggressive disability trajectory. Treatment did not have a significant effect on relapses, suggesting that the disability benefit may have been due in part to an effect on non-relapsing biology.

This was also the conclusion of a subgroup analysis of patients with non-active SPMS in the ASCEND study (Chen et al. ECTRIMS 2021; P123). In the original trial, natalizumab failed to meet its primary endpoint of a reduction in disability progression; no treatment effect was seen on EDSS or Timed 25-Foot Walk (T25FW) (Kapoor et al. Lancet Neurol 2018;17:405-415). There was a 44% reduction in progression on the 9-Hole Peg Test (9HPT), but it was unclear if this was due to natalizumab’s effects on inflammatory disease activity. A new post-hoc analysis reported a significant effect of natalizumab on 6-month confirmed 9HPT progression in patients with no disease activity, including those with no relapses (odds ratio 0.56) and those with no new MRI lesions (OR 0.57). The treatment effect appeared to be greater in the subgroup with EDSS >6.0. Further analyses are needed to determined the impact of high-efficacy therapies on the compartmentalized inflammation that is characteristic of progressive MS.

“Cognitive NEDA”
NEDA has become something of a treatment goal although its value as a predictor of disability is decidedly mixed. A new meta-analysis found that predictive value for no worsening was 86-90% (Rotstein et al. ECTRIMS 2021; P796). That said, a majority of patients with evidence of disease activity did not show disability worsening. The authors concluded that other measures are needed to identify at-risk patients.

One group has proposed a multidomain cognitive NEDA to provide a more complete measure of cognitive decline than traditional measures such as SDMT or BICAMS (Kaczmarek et al. ECTRIMS 2021; P809). The study used a multidomain computerized assessment battery (CAB) to evaluate seven domains: memory, executive function, attention, information processing speed, verbal function and motor skills (the seventh was not mentioned). Scores were averaged to create a global cognitive summary score. Cognitive impairment was defined as >1 SD below normative values for the domain. During five years of treatment with natalizumab, the average number of impaired cognitive domains decreased from 1.80 to 1.30 at year 1 and remained below baseline thereafter (1.03 at year 4, 1.30 at year 5). The average global cognitive summary score remained stable over the five-year period.

Quality of life
MS PATHS analysed the time to improved quality of life for matched cohorts receiving either ocrelizumab (n=632) or natalizumab (n=146) (Hersh et al. ECTRIMS 2021; P252). Quality of life was evaluated with the patient self-assessed Neuro-QoL over a 14-month follow-up period. The ocrelizumab group was somewhat older (mean 43.3 vs. 38.7 years) and had a longer duration of MS (10.4 vs. 7.2 years). The time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for the domains of Cognitive Function (event time ratio 0.45) and Satisfaction with Social Roles and Activities (event time ratio 0.47). There were no significant differences between treatments for the other Neuro-QoL domains. Sleep disturbance showed earlier improvement with natalizumab in the sensitivity analysis. There was a trend to earlier improvement in upper limb function with natalizumab that did not achieve significance. The MS PATHS group previously reported improvements in 9 of 12 NeuroQoL domains with natalizumab and 4 of 12 domains with ocrelizumab (Hersh et al. Mult Scler J Exp Transl Clin 2021;7:20552173211004634). There were significant between-group differences in the domains of positive affect and well-being, sleep, and Satisfaction with Social Roles favouring natalizumab.

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