High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease that causes accumulating damage to the central nervous system (CNS). It can lead to significant neurological disability, particularly in untreated individuals [1, 2]. Currently, there are over 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of relapsing forms of MS (RMS) [3‐6]. Given the multitude of available treatment options and recent international consensus guidelines offering differing recommendations [7, 8], there is broad heterogeneity in how DMTs are used in clinical practice [9].

Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Most patients (85–90%) present with relapsing–remitting MS (RRMS) at disease onset [10‐12]. Historically, an escalation approach to DMT was used for this population, but the evidence for early high-efficacy therapy (HET) is emerging. Therefore, in this review, we discuss the rationale and evidence for use of the early HET approach in newly diagnosed patients with RRMS.

Neurological damage begins in the early stages of MS, prior to manifestation of clinical MS symptoms, as evidenced by elevated levels of serum neurofilament light proteins detected several years prior to clinical presentation [13]. Moreover, accelerated brain atrophy has been observed in asymptomatic individuals with radiologically isolated syndrome [14‐16], as well as in patients with clinically isolated syndrome (CIS) [17, 18].

Once MS is clinically evident, focal inflammation dominates the early phase of disease. This MS-related inflammation is most evident in younger patients and decreases with age (Fig. 1). In RRMS, some inflammatory attacks in the CNS cause clearly defined neurological symptoms (relapses), followed by periods of full or partial recovery from new or existing symptoms (remissions) [12]. In addition to these clinically apparent events, clinically silent inflammation contributes to neuronal loss, axon destruction, and demyelination, ultimately leading to irreversible neurologic disability [19]. Accelerated brain atrophy during early inflammatory disease may not initially be associated with noticeable neurologic worsening. This largely subclinical manifestation of disease activity may be due to the brain’s capacity to compensate for a certain degree of neuronal injury and recover from relapses, as attributed to the concept of ‘neurological reserve.’ Upon loss of reserve due to MS and normal aging, the ensuing effects of brain/neuronal loss are unmasked, presenting as the onset of a progressive phase of MS (Fig. 1) [20]. Early termination of the immune attack on the CNS with DMTs may therefore enhance long-term clinical outcomes by minimizing the accumulation of neurological damage that may occur early in the disease course. MS symptoms, accrual of tissue damage, and prognosis vary substantially between patients [21, 22], and there are clearly responders and non-responders to therapy currently on the market [23‐25]. Although a personalized approach to management is appropriate, at present it is not possible to predict the responder/non-responder status of individuals without having them try (and potentially fail) multiple MS drugs [26, 27]. Each drug failure can add cumulative neurologic disability, fueling the discussion about the most appropriate strategy to select a treatment for newly diagnosed patients [26].

Given the ongoing neurological damage from the early stages of MS, initial treatment with effective DMTs and close monitoring are crucial to slow/stop disease progression over the lifetime of the patient. Treatment goals have evolved to include treat-to-target strategies that monitor clinical and neuroimaging disease activity beyond clinical relapses [28]. With the emergence of highly efficacious DMTs, no evidence of disease activity (NEDA) is emerging as a popular clinical outcome measurement [28]. NEDA-3 is a composite of three measures of disease activity: no clinical relapses; no confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS); and no new magnetic resonance imaging (MRI) lesion activity [28, 29]. While NEDA captures confirmed disability worsening as measured by the EDSS, it remains strongly focused on the inflammatory component of the disease and is thought to be insensitive to neurodegenerative processes that may be more relevant to the long-term outcomes of people with MS. It has been proposed to expand the definition of NEDA to address microscopic injury and incorporate additional parameters, such as brain atrophy (NEDA-4) and/or neurofilament light protein levels in cerebrospinal fluid or blood (NEDA-5); however, these parameters are not yet established for routine clinical use [28, 29].

Understanding and incorporating individual patient goals and values into treatment decisions is another important component of patient-centered MS care [30]. A patient survey study found that patients prioritized preserving brain health (memory, thinking, brain) over physical disability concerns (walking, strength, vision) [31]. Treatment efficacy and the likelihood of serious side effects were the most important considerations for these patients when choosing a DMT. These findings highlight the need for routine assessment of non-physical MS symptoms, including cognitive and mental health issues and the importance of using shared decision-making to personalize MS care [32, 33].

Data in pivotal phase III randomized controlled trials for HETs with active comparators of lower efficacy (as summarized in Supplementary Table 1, see ESM) show that ofatumumab (ASCLEPIOS; vs teriflunomide), ocrelizumab (OPERA; vs IFNβ-1a), and alemtuzumab (CARE-MS; vs IFNβ-1a) reduced annualized relapse rates (ARR), disability worsening, new/enlarged MRI lesions, and brain volume loss in patients with RMS versus their respective active comparators [44‐46, 48]. In the ASCLEPIOS and OPERA trials, a higher proportion of patients achieved NEDA-3 with ofatumumab (vs teriflunomide) and ocrelizumab (vs IFNβ-1a), respectively [44, 47]. These data offer a direct comparison of efficacy between HETs and lower-efficacy therapies. Placebo-controlled phase III trials of natalizumab and cladribine are summarized in Supplementary Table 2 (see ESM).

Long-term open-label extension (OLE) studies of these randomized clinical trials (Supplementary Table 3, see ESM), in which patients originally randomized to the lower-efficacy comparator therapy are switched to the HET after completion of the randomized treatment period, enable limited comparative evaluation of HET treatment effects delayed by up to 2 years following earlier lower-efficacy therapy. In the OLE studies for alemtuzumab and ocrelizumab, the patients switching from the lower-efficacy IFNβ-1a during the OLE phase responded to the HET similarly to those continuing on HET in terms of ARR and MRI disease activity. However, patients switching from IFNβ-1a had persistently higher disability levels, and exhibited more whole-brain volume loss, than those who had initiated earlier HET treatment [77, 78]. These findings highlight the clinical benefits of early use of HETs (vs delayed intervention) in RMS to optimize short-term and long-term outcomes. Efficacy data up to 4 years for the ongoing OLE study for ofatumumab are forthcoming in 2022 and will explore similar long-term efficacy outcomes versus patients on teriflunomide during the randomized treatment period (NCT03650114).

Findings from real-world studies suggest clinical benefits associated with HETs as first-line therapy in treatment-naïve patients, compared with first-line treatment with lower-efficacy therapies. A nationwide study in Denmark (n = 388) found that treatment-naïve patients with RMS receiving HET (defined as natalizumab, fingolimod, or alemtuzumab) as their first MS treatment had a lower probability of first relapse and of 6-month confirmed EDSS score worsening at 4 years of follow-up compared with a matched sample starting on a low/moderate-efficacy DMT (defined as IFNβ, teriflunomide, dimethyl fumarate, or glatiramer acetate) [66]. Another study in the United Kingdom (n = 592) found that patients with MS initially started on HETs (defined as alemtuzumab or natalizumab) had lower EDSS scores after 5 years of follow-up compared with those whose first treatment was a low/moderate-efficacy DMT (defined as IFNs, glatiramer acetate, dimethyl fumarate, fingolimod, or teriflunomide) [64]. A study in Italy (n = 2702) found increasing differences in disability trajectory over up to 10 years of follow-up between treatment-naïve patients who received a HET (defined as fingolimod, natalizumab, mitoxantrone, or cladribine) as their first treatment within 13 months of disease onset compared with their propensity score matched counterparts who received the HET after ≥ 1 year of low/moderate-efficacy treatment (glatiramer acetate, IFNs, or azathioprine) [79].

Studies assessing the timing of initiating treatment with HETs along the MS disease spectrum also generally support the notion of ‘earlier is better.’ An analysis of data from the MSBase registry (n = 308) and the Swedish MS registry (n = 236) found less disability after 6–10 years in patients who started HET (defined as rituximab, mitoxantrone, alemtuzumab, or natalizumab) within 2 years of disease onset compared with those who started 4–6 years after disease onset [80]. A systematic review evaluating the effect of HETs (defined as fingolimod, natalizumab, or alemtuzumab) at different stages of MS found that early HET initiation more potently suppressed relapse activity compared with delayed initiation; whether early versus delayed treatment initiation was associated with improved disability and MRI outcomes was inconclusive [65]. Another study found that initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to SPMS versus initial treatment with glatiramer acetate or IFNβ-1a, and probability of conversion was lower when treatment was started within 5 years of disease onset versus after 5 years [81]. Of note, the real-world studies/analyses assessing long-term clinical outcomes described above include few/no patients on ofatumumab, ocrelizumab, and cladribine due to timings of study publications (2017–2021) and regulatory approvals (2017–2020; Table 1). It is important to note that in real-world evidence studies, assignment to HET or a lower-efficacy treatment is based on individual patient characteristics such as disease activity, rather than random assignment as in randomized controlled trials [64, 79]. While this limits direct comparisons of early HET versus an escalation strategy, these studies add support to the use of HET in the first-line setting, as patients with more active disease who were treated with HET experienced better outcomes than those with less active disease who were not treated with HET. Nevertheless, prospective head-to-head studies of first-line HET versus treatment escalation are required; the ongoing DELIVER-MS (NCT03535298) and TREAT-MS (NCT03500328) trials are directly comparing early intensive versus escalation approaches in a randomized pragmatic design to ascertain if systemic application of early HET improves the prognosis for patients with RRMS [82‐84].

The improved efficacy outcomes with HETs might seem to mandate their use for all newly diagnosed patients with MS. When practitioners consider HETs, their main concerns relate to potential adverse events, which are perceived to occur more frequently among patients treated with HETs. Safety data in pivotal phase III trials for HETs with active comparators of lower efficacy offer a comparison of serious adverse event (SAE) rates between therapies (Supplementary Table 1, see ESM) [43, 45, 46, 48], while extension studies [77, 78, 85‐87], pooled analyses, and post-marketing surveillance can provide additional information on rare, delayed, or cumulative SAEs as these arise over time. SAEs associated with HETs vary by class of therapy and may include increased risk of hematologic abnormalities, infections, malignancy, secondary autoimmunity, neurovascular events, and teratogenicity.

The MS treatment landscape has evolved in recent years with the increasing availability of high-efficacy DMTs with good safety profiles, including anti-CD20 monoclonal antibodies with fewer safety monitoring requirements compared with other HETs. Several classes of MS therapies are currently in clinical development (their relative clinical efficacy yet to be determined), including Bruton’s tyrosine kinase inhibitors [142], and Epstein-Barr virus–specific T-cell therapy [143, 144]. Autologous hematopoietic stem cell transplantation (AHSCT) has been of increasing interest in recent years as an MS treatment option. Several clinical trials and meta-analyses have reported that, in some patients with relapsing disease, AHSCT was able to induce long-term disease remission, delay disease progression compared with DMTs (including HETs), and even halt all detectable CNS inflammatory activity, although methodological differences within and across the existing studies limited their interpretability [145‐148]. Ongoing randomized clinical trials (e.g., BEAT-MS [NCT04047628] and STAR-MS [ISRCTN registry identifier: ISRCTN88667898]) are comparing AHSCT versus HETs (cladribine, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab) and will help better define the optimal utilization of AHSCT. At present, AHSCT is an option, albeit limited in access outside of clinical trials, for patients with aggressive RMS, or those who exhibit high clinical or MRI activity despite HET treatment [149‐151]. While AHSCT may become an important component of the MS armamentarium, it remains to be determined whether it would be suitable for treatment-naïve patients.

Clinical evidence of a narrow therapeutic window for effective MS treatment in the early stages of disease is emerging. Currently, it is not possible for clinicians to accurately predict prognosis and treatment response at disease onset at an individual patient level [27], and subclinical disease processes may occur despite treatment. MS relapses, and the formation of new MRI lesions in the CNS indicating inflammatory activity, are well established contributors to neurological disability and correlate with prognosis in the short term [19, 29]. While these parameters meaningfully contribute to long-term disability [152], disability worsening may also occur in the absence of relapses or new brain lesions [19]. The inability to predict poor clinical outcome at an individual patient level, coupled with the potential for disability progression independent of relapse activity, support the use of HETs as first-line treatment for most newly diagnosed patients with RMS. In addition, the labels of some HETs, such as ocrelizumab and natalizumab, have been expanded from RMS to encompass any ‘active’ form of MS, including CIS and active SPMS [37, 75]. However, safety concerns around HET use, as well as the variability of MS severity, may support arguments against their use in all such patients. Additional data on long-term safety of these DMTs, as well as an increased understanding of predictors of poor clinical outcomes, would help clinicians and patients to decide whether treatment with HETs is right for them. Ongoing clinical trials assessing early RRMS treatment with HETs compared with other treatment approaches include DELIVER-MS (study completion in 2026) [67] and TREAT-MS (NCT03500328; estimated study completion in 2025). Based on the need for efficacious treatment in the early stages of MS disease, we believe HETs are appropriate for most patients with RMS as a first-line treatment option. However, a shared decision-making approach should occur between the patient and their care teams, including comprehensive discussions on available treatment options as well as the benefits and risks of early HET use, to ensure that an informed decision is made as a team on the appropriate treatment.