Treatment advances in MS

Choosing the right treatment option at the right time is critical for managing multiple sclerosis (MS).

• This section summarises recent advances in high-efficacy therapies (HET) for relapsing-remitting MS [RRMS] and secondary progressive MS [SPMS])
• There has been a conceptual shift in understanding the immune pathology of MS – learn about the effects of this shift on disease-modifying therapies for MS

Traditionally, HETs have been used following a platform of disease-modifying therapies (DMT) which have resulted in suboptimal outcomes¹.

However, accumulating evidence demonstrates the benefits of HET early or first-line clinical use².

Early, first-line intervention with HETs can maximise the chances of altering the course of MS before the disease progresses further, even if the disease minimally impacts the patient’s functioning^3-6.

Safety data from recently available HETs, including B-cell therapy and sphingosine-1-phosphate receptor modulators, demonstrates that high-efficacy is not always associated with high-safety risk in patients with MS, compared with older HETs^3,7-9.

The past decade has advanced the knowledge in MS pathophysiology, from the earlier model of MS as a T-cell-mediated autoimmune disorder, to a greater understanding of the role of B cells in MS pathogenesis¹⁰.

Early preclinical studies demonstrated a role for T cells in MS pathophysiology¹¹; however, clinical trials with only T-cell-based treatments were ineffective in relapsing forms of MS¹². By comparison, treatments that inhibited lymphocyte access to the central nervous system (CNS) by blocking adhesion sequestering lymphocytes in lymphoid organs, such as the sphingosine-1-phosphate (S1P) receptor modulators, were effective in MS and experimental autoimmune encephalomyelitis¹⁰.

More recently, disease models that closely replicated the pattern of tissue damage in MS led to new knowledge of humoral immunity in MS pathogenesis¹³. This stimulated clinical trials of B-cell depleting therapies, initially with the anti-CD20 monoclonal antibody rituximab, followed by ocrelizumab and ofatumumab^7,14,15.

Anti-CD20 mediated B-cell depletion has shown a high level of success in limiting new relapses and silent progression in RMS^7,14,15, and in reducing disability progression in primary-progressive MS (PPMS)¹⁶.

The following sections describe in more detail HETs approved for relapsing forms of MS. The HETs are divided into those in longer clinical use, compared to more recently approved HETs.

HETs in longer clinical use for RMS

Alemtuzumab

Alemtuzumab is a humanised anti-CD52 monoclonal antibody. It works through depletion and subsequent repopulation of circulating T lymphocytes and B lymphocytes. This action leads to changes in the number, proportions, and functions of some lymphocyte subsets¹⁷. Intravenous alemtuzumab was approved for RMS (first line) by the European Medicines Agency (EMA) in 2014¹⁰.

In the Phase 3 CARE-MS1 clinical trial¹⁸, 59% of people with RRMS in the interferon β-1a group were relapse-free at 2 years compared with 78% of people with RRMS in the alemtuzumab group. 20 (11%) people in the interferon β-1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group.

Infusion-associated reactions are common with alemtuzumab, some of which are serious¹⁸. In CARE-MS1, infections, predominantly mild or moderate in severity, occurred in 253 (67%) people with RRMS treated with alemtuzumab compared with 85 (45%) people treated with interferon β-1a¹⁸.

Cladribine

Intracellular accumulation of the active metabolite of cladribine, 2-chlorodeoxyadenosine triphosphate, disrupts cellular metabolism, inhibits DNA synthesis, repair, and subsequent apoptosis¹⁹. Accumulation of the cladribine nucleotide reduces CD4+, CD8+, and CD19+ B cells, with relative sparing of other immune cells²⁰. Oral cladribine is indicated for RMS (second or third-line), and was EMA approved in 2017¹⁰.

In the CLARITY study²¹, in people with RRMS who received cladribine tablets (3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualised rate of relapse (ARR) than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001), a lower risk of 3-month sustained progression of disability, and significant reductions in the brain lesion count on magnetic resonance imaging (MRI).

Adverse events that were more frequent in the cladribine groups included lymphocytopenia and herpes zoster²¹.

The CLARITY extension study treated 98 of the original 870 participants who were given placebo (after taking cladribine in the original study) for 2 more years²². The same benfits were seen as those who were only treated with cladribine during CLARITY²². It was concluded that cladribine may reduce both the number and severity of relapse events for up to 5 years²².

In addition, the phase 4 CLARIFY MS study is currently underway to assess the quality of life in people with RRMS who are taking cladribine²³.

Fingolimod

Fingolimod was the first oral therapy approved for RMS (EMA approved in 2010). It is a S1P inhibitor that prevents egress of lymphocytes from secondary lymphoid organs, blocking infiltration of autoreactive lymphocytes into the CNS. Fingolimod is well tolerated; although adverse events include mild abnormalities, such as elevated liver function tests or lymphopenia²⁴. Oral fingolimod for paediatric RRMS was EMA approved in 2018. It is indicated as a second-line treatment for RMS¹⁰.

Ocrelizumab

Ocrelizumab, a humanised monoclonal antibody against the CD20 molecule on the surface of mature B cells, is highly effective against relapses and silent progression in RMS patients, and can halt the growth of new white matter lesions detected by magnetic resonance imaging (MRI)¹⁴. Intravenous ocrelizumab for RRMS and PPMS was EMA approved in 2017. It is indicated for RMS and progressive-primary MS (PPMS), first line¹⁰.

Ocrelizumab is well-tolerated and it has been shown that clinical benefits are maintained for over 7.5 years of treatment²⁵.

In the OPERA clinical trial, ocrelizumab showed a 47% relative reduction in the ARR in people with RMS, compared with Interferon-β-1a¹⁴. Common adverse events associated with ocrelizumab include infusion-related reactions, nasopharyngitis, upper respiratory tract infection, headache, and urinary tract infection¹⁴.

Across the OPERA I, II and ORATORIO phase 3 trials B-cell depletion in blood was higher with increasing ocrelizumab exposure²⁶.The ONTARIO-HAND study is investigating how upper limb function is effected by ocrelizumab in patient with PPMS²⁷.

Natalizumab

Natalizumab, a humanised monoclonal antibody, is an inhibitor of the α4β1 integrin, an adhesion molecule expressed on the surface of lymphocytes and involved in transmigration across endothelia into the CNS. Natalizumab is administered as an intravenous infusion once every 4 weeks. One of the first HET for MS, intravenous natalizumab was EMA approved in 2004.

In the AFFIRM clinical trial, natalizumab was highly effective in reducing relapses and slowing disease progression in people with RMS, compared with placebo (68% relative reduction in ARR)²⁸. Natalizumab is generally well tolerated; however, fatigue and allergic reaction are typically associated adverse events²⁸. Long-term treatment carries risk of progressive multifocal leukoencephalopathy, occurring in ~0.4% of natalizumab-treated patients²⁹.

A 10-year analysis of the Tysabri Obervational Programme (TOP), real-world, open-label and multinational obervational study, showed 13.5% (n=829) experienced more than 1 serious adverse event (SAE) and the ARR was 0.15³⁰. This demonstrates the increasing evidence of natalizumab’s long term safety and efficacy³⁰.

Siponimod

Historically, the mean time to development of SPMS in patients diagnosed with RMS was approximately 19 years post-onset. Current treatments have considerably lengthened this time, and HETs have reduced or eliminated relapses¹⁰.

Siponimod is a selective S1P modulator that is approved for relapsing forms of MS, including active SPMS, which includes patients with SPMS who have had recent clinical relapses or evidence of new or enlarging MRI lesions⁸. Oral siponimod for active SPMS was EMA approved in 2020. It is also indicated for clinically isolated syndrome (CIS)¹⁰.

In the Phase 3 EXPAND clinical trial, the effect of siponimod on disability progression was investigated, and found a 21% relative risk reduction in 12-week confirmed disability progression (CDP), compared to placebo⁸. Headache, nasopharyngitis, urinary tract infection, and falls, are common safety concerns associated with use of siponimod⁸.

The AMASIA study began in February 2020 and aims to assess the long-term efficacy and safety of Siponimod for people with SPMS in 250 centres across Germany. It is expected to terminate in 2025³¹.

More recently approved HETs for RMS

Ofatumumab

Ofatumumab is a fully human anti-CD20 monoclonal antibody administered by monthly subcutaneous injection at home. It is indicated first-line for RMS, and was EMA approved in 2021.

Ofatumumab shows an efficacy profile similar to ocrelizumab, with a high degree of safety in the phase 3 trials for RRMS or active SPMS⁷. It is the first B-cell therapy that can be self-administered³². Injection-related reactions, nasopharyngitis, headache, upper respiratory tract infection, and urinary tract infection, are common associated adverse events⁷.

The ASCLEPIOS I and II phase 3 trials assessed ofatumumab compared to terflunomide⁷. Findings from a longer-term study (ALITIOS) found ofatumumab to be well tolerated over 3.5 years³³.

Ozanimod

Ozanimod, a sphingosine 1-phosphate receptor modulator that selectively binds to sphingosine 1-phosphate³⁴. It is indicated for CIS, RMS, and active SPMS¹⁰. It was EMA approved in 2020.

In the RADIANCE Phase 3 clinical trial³⁵, adjusted ARRs were 0.17 (95% CI 0.14–0.21) for ozanimod 1.0 mg, 0.22 (0.18–0.26) for ozanimod 0.5 mg, and 0.28 (0.23–0.32) with interferon β-1a, with rate ratios compared with interferon β-1a of 0.62 (95% CI 0.51–0.77; P<0.0001) for ozanimod 1.0 mg and 0.79 (0.65–0.96; P=0.0167) for ozanimod 0.5 mg.

The incidence of treatment-emergent adverse events was higher in the interferon beta-1a group (365 [83.0%] of 440 participants) than in the ozanimod 1.0 mg group (324 [74.7%] of 434) or the ozanimod 0.5 mg group (326 [74.3%] of 439). More participants in the interferon beta-1a group had treatment-emergent adverse events leading to treatment discontinuation than in the ozanimod groups. Incidences of infections and serious treatment-emergent adverse events were similar across treatment groups. No cases of ozanimod-related symptomatic reduction in heart rate and no second-degree or third-degree cases of atrioventricular block were reported³⁵.

In the SUNBEAM Phase 3 trial it was found ozanimod was moderately beneficial for cognitive processing speed in people with RMS³⁶.There is a current ongoing phase 3 trial called ENLIGHTEN which is assessing the cognitive processing speed related to ozanimod in people with RRMS³⁷.

Patients from the RADIANCE and SUNBEAM trials with RRMS were also enrolled in the recent DAYBREAK phase 3 trial³⁷. Safety results were consistent with previous trials and the ARR was 0.124. A reduction from 0.246 to 0.123 was seen in those who switched from interferon beta-1a³⁷.

Ponesimod

Oral ponesimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate³⁸. It induces a rapid, dose-dependent, and reversible reduction of peripheral blood lymphocyte counts by blocking the egress of lymphocytes from lymphoid organs³⁹. Ponesimod is indicated for CIS, RMS, and active SPMS. It was EMA approved in 2021.

In the OPTIMUM Phase 3 clinical study⁴⁰, the ARR for ponesimod compared with teriflunomide was 30.5% (0.202 vs 0.290; P<0.001). The relative risk reduction in combined unique active lesions per year, 56% (1.405 vs 3.164; P<0.001); the reduction in time to 12-week and 24-week confirmed disability accumulation risk estimates, 17% (10.1% vs 12.4%; P=0.29) and 16% (8.1% vs 9.9; P=0.37), respectively. Brain volume loss at week 108 was lower by 0.34% (–0.91% vs –1.25%; P<0.001). The odds ratio for No Evidence of Disease Activity (NEDA-3) achievement was 1.70 (25.0% vs 16.4%; P<0 .001).

Incidence of treatment-emergent adverse events was similar for ponesimod and teriflunomide. Treatment discontinuations due to adverse events was more common in the ponesimod group (49 of 565 [8.7%] compared with 34 of 566 [6.0%])⁴⁰.

An extension the OPTIMUM trial (OPTIMUM-LE) to evaluate the long-term safety and tolerability in people with RMS is ongoing⁴¹.

Other approved HETs for RMS

Dimethyl fumarate

Dimethyl fumarate (DMF) exerts anti-inflammatory and cytoprotective effects through activation of the nuclear factor (erythroid-derived 2)−like 2 (Nrf2) pathway and Nrf2-independent pathways⁴². Dimethyl fumarate is linked with progressive multifocal leukoencephalopathy risk⁴³. Oral DMF, indicated first-line for RMS, was EMA approved in 2013.

In the final phase 3 ENDORSE clinical trial results, the safety and efficacy of DMF in people with RRMS was followed for up to 13 years. In total 32% (551) people experienced SAEs, mostly MS relapse or fall. The overall ARR remained low at 0.151⁴⁴.

Interferon-beta (IFN-β)

IFN-β is a class I interferon whose mechanism of action involves immunomodulation through downregulating expression of major histocompatibility complex molecules on antigen-presenting cells, decreasing proinflammatory and increasing anti-inflammatory cytokines, inhibiting T-cell proliferation, and blocking trafficking of inflammatory cells to the CNS⁴⁵. In 1993, subcutaneous IFN-β-1b was the first drug approved for RRMS.

IFN- β can reduce the ARR and MRI measures of disease activity and slows accumulation of disability^46,47. Common adverse events include flu-like symptoms and mild abnormalities on routine laboratory evaluation, and injection-site reactions with subcutaneous administration⁴⁶.