ReviewTherapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy
Introduction
In Part 2 of this review of disease modifying therapy (DMT) in multiple sclerosis (MS) we look at recently approved therapies and the emerging therapies that have recently completed phase III clinical trials or, as in the case of stem cell therapies, are already being used in selected patients. We then go on to review efficacy factors that influence treatment choice in individual patients and look at the initial trials of combination therapies.
Section snippets
Teriflunomide
Teriflunomide, a once-daily oral therapy, selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase, which is required for de novo pyrimidine synthesis in proliferating lymphocytes [1]. Teriflunomide is a hepatic metabolite of leflunomide, an established therapy for rheumatoid arthritis [2]. In a phase III clinical trial, teriflunomide 14 mg reduced annualised relapse rate (ARR) by 32% versus placebo, and the risk of sustained (>12 weeks) disability progression by
Laquinimod
Laquinimod, or quinolone-3-carboxamide, attenuates disease in experimental autoimmune encephalomyelitis (EAE) with improvements in both central nervous system (CNS) demyelination and chronic axonal loss [21]. Several studies involving EAE models have shown that laquinimod decreases pro-inflammatory cytokines [21] and promotes a deviation from the pro-inflammatory T helper (Th)-1 pattern to the anti-inflammatory Th-2/Th-3 cytokine milieu [22]. A phase III study showed a non-significant 23%
Comparative efficacy
There are considerable difficulties in comparing between placebo-controlled, pivotal trials undertaken at different times in different locations and with subtle differences in inclusion criteria. It has been noted that the background ARR in the placebo arms of clinical trials has been gradually falling [63]. This is almost certainly due to a combination of factors, including patients with lower levels of disease activity being enrolled in placebo-controlled trials in more recent years,
Combination therapy
The findings of clinical trials looking at combinations of effective therapies are summarised in Table 4. Whilst seemingly safe in the short term, azathioprine [108], [109], [110] and methotrexate [111], [112] do not appear to confer any additional benefit over and above injectable DMT on their own [108], [112]. Conversely, cyclophosphamide and mitoxantrone, both as add-on and induction therapy, appear to provide additional efficacy [113], [114], [115], but this comes with a cost in terms of
Conclusions
The recent further expansion of treatment options available for people with MS undoubtedly offers a greater range of efficacy levels and the promise of yet more individualised medicine allowing treatment options to be tailored according to disease severity and stage, as well as tolerability. In Part 3 of this review we will cover the many issues that impact on treatment choice aside from efficacy. These include the re-emergence of disease on therapy, issues of pregnancy and breast feeding,
Conflicts of Interest/Disclosures
MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec.
BJB has received honoraria as an advisory board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec; has received travel sponsorship from Abbott and Viiv Healthcare, and has received research support funding from EI Lilly,
References (134)
- et al.
Immune mechanisms of new therapeutic strategies in MS: teriflunomide
Clin Immunol
(2012) - et al.
Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group
Lancet
(1999) - et al.
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial
Lancet
(2012) - et al.
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Lancet
(2012) - et al.
Autoimmune thyroid disease in the use of alemtuzumab for multiple sclerosis: a review
Endocr Pract
(2013) - et al.
Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis
J Neuroimmunol
(2010) - et al.
Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue
Neuropharmacol
(2002) - et al.
Getting specific: monoclonal antibodies in multiple sclerosis
Lancet Neurol
(2008) Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing-remitting multiple sclerosis
Clin Immunol
(2012)- et al.
Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta
Lancet Neurol
(2010)
Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial
Lancet
Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial
Lancet
Autologous haematopoietic-stem-cell transplantation for multiple sclerosis
Lancet Neurol
Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis
Exp Hematol
Autologous haematopoietic stem-cell transplantation in multiple sclerosis
Lancet Neurol
Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life
Blood
Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies
Biol Blood Marrow Transplant
Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study
J Neuroimmunol
Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy
Blood
Possible induction of acute disseminated encephalomyelitis (ADEM)-like demyelinating illness by intrathecal mesenchymal stem cell injection
J Clin Neurosci
Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN)
Lancet
250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study
Lancet Neurol
Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial
Lancet Neurol
Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study
Lancet Neurol
Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study
Lancet
Randomized trial of oral teriflunomide for relapsing multiple sclerosis
N Engl J Med
Leflunomide: long-term clinical experience and new uses
Expert Opin Pharmacother
Effects of dimethyl fumarate on neuroprotection and immunomodulation
J Neuroinflammation
Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases
Br J Dermatol
Effect of BG-12 on contrast-enhanced lesions in patients with relapsing–remitting multiple sclerosis: subgroup analyses from the phase 2b study
Mult Scler
Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis
N Engl J Med
Clinical efficacy of BG-12 in relapsing-remitting multiple sclerosis (RRMS): data from the phase 3 CONFIRM study
Use of fumaric acid esters in psoriasis
Indian J Dermatol Venereol Leprol
PML in a patient treated with dimethyl fumarate from a compounding pharmacy
N Engl J Med
PML in a patient treated with fumaric acid
N Engl J Med
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis
N Engl J Med
Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial
Neurology
Infectious complications associated with alemtuzumab use for lymphoproliferative disorders
Clin Infect Dis
Alemtuzumab vs. interferon beta-1a in early multiple sclerosis
N Engl J Med
Placebo-controlled trial of oral laquinimod for multiple sclerosis
N Engl J Med
Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta
Proc Natl Acad Sci U S A
Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody
Ann Neurol
Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results
Neurology
Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis
Arch Neurol
Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial
Ann Neurol
B-cell depletion with rituximab in relapsing-remitting multiple sclerosis
N Engl J Med
Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature
Medicine (Baltimore)
Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis
Arch Neurol
Beneficial plasma exchange response in central nervous system inflammatory demyelination
Arch Neurol
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Disease-modifying therapies do not affect sleep quality or daytime sleepiness in a large Australian MS cohort
2023, Multiple Sclerosis and Related DisordersUtilisation of disease modifying treatment and diversity of treatment pathways in relapsing remitting multiple sclerosis
2022, Multiple Sclerosis and Related DisordersCitation Excerpt :All DMTs for RRMS are immunomodulatory and work by either suppressing or inducing immune pathways (WHO Collaborating Centre for Drug Statistics Methodology, 2020). They have demonstrated efficacy through decreased annualised relapse rates and short–term safety in clinical trials, however a few DMTs have been associated with serious adverse drug reactions (ADRs) (Broadley et al., 2014b). The most common ADRs associated with DMTs reflect their immune activity and include allergic reactions, serious infections and development of additional autoimmune diseases (Chisari et al., 2019; Broadley et al., 2015).
Impact of remoteness on patient outcomes for people with multiple sclerosis in Australia
2021, Multiple Sclerosis and Related DisordersCitation Excerpt :The available 11 DMTs included: interferon β-1b (Betaferon), interferon β-1a (Rebif), interferon β-1a (Avonex), pegylated interferon β-1a (Plegridy), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), dimethyl fumarate (Tecfidera), alemtuzumab (Lemtrada), and mitoxantrone (Novantrone). We classified these DMTs into three broad categories based on their recognised clinical efficacy derived from pivotal clinical trials (Tramacere et al., 2015; Broadley et al., 2014a, b, c). The category 1 DMTs (classic injectable DMTs) included β-interferons (Betaferon, Rebif, Avonex and Plegridy) and glatiramer acetate; the category 2 (oral therapies) included teriflunomide and dimethyl fumarate; and the category 3 (higher efficacy) included fingolimod (oral), natalizumab (infusion), alemtuzumab (infusion) and mitoxantrone (infusion) (Chen et al., 2018).
Myelin repair invivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF)
2015, BiomaterialsCitation Excerpt :MS pathology consists of inflammatory demyelination of CNS axons causing neurological symptoms initially, when saltatory conduction for efficient nerve impulse conductance becomes compromised, and later compounded by the loss of metabolic support from myelinating oligodendrocytes leading to irreversible neurodegeneration. Although there are now effective immunomodulatory treatments that reduce probability of new relapses [2], there are no treatments that reduce, slow or stop neurodegeneration and associated progressive disability. One potential neuroprotective therapeutic strategy is to enhance repair of demyelination (remyelination), carried out by endogenous oligodendrocyte precursor cells (OPCs) recruited to the area of damage, and which differentiate into mature oligodendrocytes (OD) able to remyelinate axons (reviewed in Ref. [3]).
Superior effects of natalizumab versus other DMTs on patient-reported outcomes in people with multiple sclerosis
2022, Journal of Neurology, Neurosurgery and PsychiatryThe emerging role of the chondroitin sulfate proteoglycan family in neurodegenerative diseases
2021, Reviews in the Neurosciences