Review
Therapeutic 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

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Abstract

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

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,

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