Elsevier

The Lancet Neurology

Volume 10, Issue 11, November 2011, Pages 1026-1034
The Lancet Neurology

Rapid Review
Oral treatment for multiple sclerosis

https://doi.org/10.1016/S1474-4422(11)70228-9Get rights and content

Summary

Background

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs.

Recent developments

Positive results have been reported for five new oral drugs for RRMS—fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate—in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon.

Where next?

Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

Introduction

The armamentarium for the treatment of multiple sclerosis (MS) is fast increasing. Positive results have been reported for five new drugs in phase 3 studies; two of these drugs have been reviewed by regulatory agencies, and the other three will be reviewed within the next year. Therefore, a few new oral drugs are likely to be available soon for patients with relapsing-remitting MS (RRMS). This striking development will bring new options to patients, and will lead to both opportunities and challenges for the treatment of MS.

The need for oral drugs for patients with MS is obvious; before the approval of the first oral drug for MS in September, 2010, all approved disease-modifying treatments (DMTs) required injection or intravenous infusion. The first-line drugs—interferon beta-1a (administered intramuscularly; Avonex, Biogen Idec, Weston, MA, USA), interferon beta-1a (administered subcutaneously; Rebif, Merck Serono, Geneva, Switzerland), interferon beta-1b (administered subcutaneously; Betaferon, Bayer Schering, Leverkusen, Germany), and glatiramer acetate (administered subcutaneously; Copaxone, Teva, Petah Tiqva, Israel)1, 2, 3, 4—have been the most used treatments for MS. More effective drugs with greater toxicity—natalizumab (Tysabri, Biogen Idec) and mitoxantrone (Novantrone, EMD Serono, Rockland, MA, USA)—have been used largely as second-line treatments (administered by intravenous infusion) for patients who either did not respond satisfactorily to first-line drugs or did not tolerate injections.5, 6, 7 Although the first-line injectable DMTs have shown excellent safety profiles, they have low efficacy—ie, about 30% reduction in annual relapse rate (ARR).1, 2, 3, 4 Compliance is poor in many patients because of the low efficacy and frequent injections.8 Although second-line treatments are generally thought to have greater efficacy, there are many safety concerns.9, 10, 11

Results of phase 3 trials have been reported for cladribine and fingolimod (FTY720).12, 13, 14 Fingolimod was approved for RRMS by the US Food and Drug Administration (FDA) in September, 2010, and by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in January, 2011. Cladribine received a negative EMA and FDA response and the sponsor will be stopping development of oral cladribine for MS.15 Phase 3 trials of teriflunomide,16 laquinimod,17 and dimethyl fumarate (BG-12)18 have been completed, and positive results were reported for teriflunomide and laquinimod at academic meetings,19, 20 and for dimethyl fumarate in press releases (table 1).22

Despite the continuously evolving information about new MS drugs, we believe the reported data are adequate to provide an overview of the most recent developments for the five oral drugs that have shown efficacy in phase 3 trials. We describe the new challenges and complexities of these drugs, and draw attention to gaps in our knowledge that suggest the need for further research.

Section snippets

Fingolimod

Fingolimod modulates sphingosine-1-phosphate (S1P) receptors and has strong immunoregulatory features. The lysophospholipid S1P is crucial in many cellular processes.23, 24, 25 S1P1, S1P2, and S1P3 receptors are abundant in diverse tissue types. S1P4 is located on lymphoid and haemopoietic cells, whereas S1P5 is mainly expressed in the CNS. Fingolimod is phosphorylated immediately after oral administration and the phosphorylated form interacts with all S1P receptor subtypes except S1P2.23, 24,

Cladribine

The synthetic purine nucleoside analogue cladribine (2-chloro-2′-deoxyadenosine) enters the cell through purine nucleoside transporters and is phosphorylated by deoxycytidine kinase.34, 35 Lymphocytes have fairly high concentrations of this enzyme and low levels of 5′ nucleotidase, leading to a preferential accumulation in lymphocytes.34, 36 Cladribine nucleotide accumulation disturbs DNA synthesis and repair mechanisms, resulting in lymphocyte depletion and longlasting lymphopenia. The drug

Teriflunomide

Teriflunomide is the active metabolite of leflunomide,42 which is approved for use in patients with rheumatoid arthritis. It reduces the activity of the mitochondrial enzyme dihydroorotate dehydrogenase, which is crucial in pyrimidine synthesis. T-lymphocyte proliferation largely depends on pyrimidine synthesis. However, because the drug induces only a small degree of lymphocytopenia, these processes only partly account for its effects. The results of a phase 2 trial of teriflunomide in

Laquinimod

Laquinimod is a derivative of linomide (roquinimex). Linomide effectively prevented progression of experimental autoimmune encephalitis and preliminary clinical data have suggested efficacy in MS.44 However, a phase 3 trial had to be stopped because of unforeseen safety concerns.44, 45 Laquinimod seems to be much better tolerated than is linomide. It induces a cytokine shift towards T-helper-2 (Th2) and Th3 cytokines, without inducing much immunosuppression.46, 47, 48

Results of two phase 2

Dimethyl fumarate

BG-12, an oral formulation of dimethyl fumarate, is metabolised to monomethyl fumarate. Both dimethyl fumarate and its primary metabolite monomethyl fumarate induce activation of the nuclear factor E2-related factor-2 pathway, which protects against oxidative-stress-related neuronal death and damage to myelin in the CNS. Several neuroprotective and anti-inflammatory mechanisms have been attributed to the drug—ie, the expression of phase 2 detoxification enzymes in astroglial and microglial

Challenges in MS treatment

In less than 20 years, the number of approved DMTs for MS increased from none to eight, and this number is likely to continue to increase within the next few years. This advance presents not only opportunities and options, but also challenges for treatment. Probably the most important challenge is whether current DMTs, alone or in combination, are capable of completely arresting the MS process. With more potent drugs, such as natalizumab or alemtuzumab (which is still in development and not

Conclusions and future directions

Several oral drugs have shown benefit in patients with RRMS. Although the available first-line and second-line parenteral compounds have clearly changed the course of MS management over the past two decades, there is room for improvement. Oral drugs will generate significant interest because of the convenience of such administration. However, the availability of oral drugs will not necessarily mean a harmless and convenient treatment. On the basis of the safety and tolerability profiles

Search strategy and selection criteria

We searched PubMed for all English language papers of studies in people, using the combined search terms “multiple sclerosis” and “treatment” from January, 2010, to Sept 16, 2011. This search generated more than 2000 citations. Additionally, we checked relevant abstracts from recent meetings including the European Committee for Treatment and Research in Multiple Sclerosis, Americas Committee for Treatment and Research in Multiple Sclerosis, American Academy of Neurology, European Neurological

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