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Multiple Sclerosis (MS) Learning Zone
Declaration of sponsorship Novartis Pharma AG

High-Efficacy Therapies in MS

Declaration of sponsorship Novartis Pharma AG
Read time: 50 mins
Last updated:22nd Dec 2021
Published:22nd Dec 2021

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

  • This tab summarises recent advances in high-efficacy therapies (HET) for relapsing-remitting MS [RRMS] and secondary progressive MS [SPMS])
  • Download an infographic summarising the ASCLEPIOS I and II clinical trials
  • Download an infographic showing the Phase 3 EXPAND siponimod trial and its main findings

Treatment advances for multiple sclerosis

Choosing the right treatment option at the right time is critical to 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
  • Continue to the next sections to download infographics of the Novartis-sponsored ASCELPIOS I and II trial in RRMS and EXPAND clinical trial in SPMS

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 functioning3–6.

Safety data from recently available HETs, including B-cell therapy and sphingosine-1-phosphate receptormodulators, demonstrates that high-efficacy is not always associated with high-safety risk in patients with MS, compared with older HETs4,7–9.

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.

The animated video below presents a brief summary of the key pathophysiological mechanisms of MS.


Early preclinical studies demonstrated a role for T cells in MS pathophysiology
11; 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 ofatumumab7,14,15.

Anti-CD20 mediated B-cell depletion has shown a high level of success in limiting new relapses and silent progression in RMS7,14,15, 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 recently approved HETs.

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ASCLEPIOS – High-efficacy therapy (HET) pivotal trial

The Novartis Pharma AG-sponsored ASCLEPIOS I and II trials are randomised, Phase 3 studies, evaluating the HET ofatumumab versus teriflunomide in adults with relapsing-multiple sclerosis (RMS).

  • Download an infographic summarising the ASCLEPIOS I and II clinical trials
  • In the ASCLEPIOS study, ofatumumab treated patients had lower annualised relapse rates than teriflunomide – see the core data in the infographic
  • Are you aware of the secondary endpoints in ASCLEPIOS? The infographic has these covered

Progress in the treatment of MS has improved the long-term prognosis for many people with MS. A conceptual shift in understanding the immune pathology of MS, away from a purely T-cell-mediated model to recognition that B cells have a key role in pathogenesis, has also occurred in recent years. The emergence of HETs requiring less frequent administration have made these preferred options for people with MS in terms of tolerability and adherence. HETs are now advised as first-line treatment for many people with early MS, before permanent disability is evident10.

Approximately 85% of people with MS are initially diagnosed with RRMS36. RRMS involves episodes of new or increasing neurologic symptoms (‘relapses’, ‘exacerbations’), followed by partial or complete recovery (‘remissions’)36. RRMS can be ‘active’ (relapses and/or evidence of new magnetic resonance imaging [MRI] activity over time) or ‘not active’, and ‘worsening’ (confirmed increase in disability following a relapse), or ‘not worsening’36.

B-cell depleting therapy can be effective against relapsing-remitting multiple sclerosis (RRMS)10,37. Ofatumumab, a fully human monoclonal antibody to the B-lymphocyte antigen CD20, is a subcutaneous treatment for RRMS. Ofatumumab binds to a distinct epitope, encompassing small and large extracellular loops of the CD20 molecule, giving rise to a slow off-rate and high binding affinity38.

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EXPAND – High-efficacy therapy (HET) pivotal trial

Sponsored by Novartis Pharma AG, EXPAND study is a double-blind, placebo-controlled, Phase 3 study comparing the efficacy and safety of the active HET siponimod versus placebo in secondary-progressive multiple sclerosis (SPMS).

  • Download an infographic showing the Phase 3 EXPAND siponimod trial and its main findings
  • The siponimod EXPAND study is the first large trial to show superiority over placebo in terms of disability progression in patients with SPMS – don’t miss this opportunity to learn more
  • The EXPAND data is clear: siponimod can delay physical and cognitive deterioration in a broad range of patients with SPMS

Advances have been achieved in the treatment of MS following progress in understanding the pathogenesis and course of the disease. The development of HETs has produced greater control of relapsing disease and brain inflammation10.

Some people with RRMS transition to a secondary progressive phenotype, which involves progressive deterioration of neurologic function (accumulation of disability) over time36. SPMS can be ‘active’ (relapses and/or evidence of new magnetic resonance imaging [MRI] activity during a period of time) or ‘not active’, and further characterised ‘with progression’ (evidence of disability accumulation over time, with or without relapses or new MRI activity), or ‘without progression’36.

Approximately 25%–40% of people with RRMS progress to SPMS, with a median time to transition ranging from 10–23 years43–46.

Most HETs for MS are indicated for relapsing (‘active’) forms of the disease. However, some HETs do not reliably show efficacy in slowing disability progression in subgroups of people with SPMS10,47.

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