Escalation from Low Efficacy RIP?

About Time!

Paradigm shifts: Early initiation of high-efficacy disease-modifying treatment in multiple sclerosis.Hartung HP, Meuth SG, Thompson AJ.Mult Scler. 2021;27(10):1473-1476. doi: 10.1177/13524585211033190.PMID: 34472985 No abstract available.

Clinical development of disease-modifying drugs for the treatment of multiple sclerosis (MS) has been exceedingly successful over the past three decades. This in part reflects advances in our knowledge of the pathogenetic underpinnings of the disease and improvement in trial design permitting more rapid translation. The available arsenal contains up to 18 drugs depending on countries location and income that differ in efficacy, route and timing of administration, side effects, risks and tolerability. Starting with the injectable interferons and glatiramer acetate, the introduction of the first monoclonal antibody curtailing lymphocyte invasion of the central nervous system (CNS), the first long-awaited oral agents and the high-efficacy lymphocyte-depleting monoclonal antibodies, many patients with the relapsing forms of MS and fewer with progressive disease clearly receive therapeutic benefit from these disease-modifying agents.

Real world evidence, which defines treatment effectiveness and implementation in an environment beyond the strict confines of randomized drug trials, is collected from large data sets, health insurance databases, comprehensive national registries and international databases.

The importance of early treatment initiation was the clear message from the Swedish STOP-MS project which adopted this approach. They compared patients who started DMTs after 3 years of disease onset with those who embarked on DMTs within 1 year of disease onset. Later, DMT commencement carried a hazard ratio of 2.64. For each year of treatment delay, the risk to reach the Expanded Disability Status Scale (EDSS) 4 increased by 7.4%. These results were recently confirmed independently on a much larger patient cohort in the first report emanating from the Big Multiple Sclerosis Data (BMSD) network 

Drawing on data from 11,871 patients, the authors determined four outcomes: 3- and 12-month confirmed disability worsening and assignment of irreversible EDSS 4 and EDSS 6. Delayed first treatment was associated with an elevated risk to develop 3- or 12-month confirmed disability worsening (18% and 31%, respectively) and increased the risk of reaching EDSS 4 and EDSS 6 by 40% and 53%, respectively.

In aggregate, studies clearly underscore the greater benefits people with MS receive when DMTs are commenced early after disease onset. Given the ever broadening armamentarium to treat MS and the appearance over time of more effective DMTs, two fundamental management approaches have been developed and differentially adopted by neurologists but accumulating evidence may well shift the balance.

The escalation approach, long in favour, advocates use of a moderately or medium effective DMT initially and switching or escalating to other more efficacious and potentially higher risk agents should disease activity be insufficiently controlled. This philosophy is clearly dominated by safety concerns and the assumption that in many instances the disease may not run a severe course.

Early high-efficacy or early intensive therapy is based on the idea that one should capitalize on a window of opportunity open for drugs to unfold their maximal anti-inflammatory actions when they are most likely to be most beneficial. Patients deemed to have a poorer prognosis with clinical and radiological evidence of high disease activity would receive high-efficacy or intensive therapy. Natalizumab, alemtuzumab, rituximab, ocrelizumab, ofatumumab, cladribine or mitoxantrone are considered to belong to his group. Most experts would include the sphingosine-1-phosphate receptor modulators in this category.

Exploration of the relative merits of either strategy is best done using the gold standard of a randomized controlled trial. In fact, two such studies are currently underway: the Traditional versus Early Aggressive Therapy for MS (TREAT-MS) trial (NCT03500328) recruiting 900 participants is a pragmatic randomized single-masked controlled study. The Determining the Effectiveness of earLY Intensive versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial (NCT03535298) enrolling 800 patients is open label. Neither trial will read out before 2024/2026……….

While it is now undisputable that early initiation of DMT generates greater benefit to patients both in the short- and long-term, deliberations are still ongoing as to whether the escalation approach commencing with medium-efficacy DMTs should be superseded by the high-efficacy/early intensive management approach. Given the large body of convergent evidence that has been accumulated recently through careful interrogation of large databases, there may now be sufficient evidence for the community to consider a new treatment paradigm now rather than waiting until the conclusion of the two ongoing controlled trials.

Iaffaldano, P, Lucisano, G, Butzkueven, H, et al. Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network. Mult Scler 2021; 27(10): 1543–1555.

Background:

The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.

Objective:

The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.

Methods:

Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.

Results:

A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower (p < 0.0004) for the first quintile patients’ group.

Conclusion:

Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.