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
Rapid ReviewOral treatment for multiple sclerosis
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
References (64)
- et al.
Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial
Lancet
(2002) - et al.
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases
Lancet Neurol
(2010) - et al.
Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Lancet
(2008) - et al.
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Lancet
(2008) - et al.
Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study
Lancet Neurol
(2011) - et al.
Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine
Blood
(1993) - et al.
Cladribine in treatment of chronic progressive multiple sclerosis
Lancet
(1994) - et al.
Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis
Lancet Neurol
(2011) - et al.
The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis
J Neuroimmunol
(2002) - 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
Neuropharmacology
(2002)
Insight into the mechanism of laquinimod action
J Neurol Sci
Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes
Lancet Neurol
Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study
Lancet Neurol
Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study
Lancet
Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study
Lancet
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial
Lancet
Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis
Lancet Neurol
Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group
Neurology
Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group
Lancet
Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)
Ann Neurol
Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group
Neurology
A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis
N Engl J Med
Natalizumab plus interferon beta-1a for relapsing multiple sclerosis
N Engl J Med
Interrupted therapy: stopping and switching of the beta-interferons prescribed for MS
Neurology
Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Neurology
Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy
Neurology
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis
N Engl J Med
A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis
N Engl J Med
A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis
N Engl J Med
Merck Serono: Regulatory Update on Cladribine Tablets
A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses
Neurology
Clinical and MRI outcomes from a phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses
Neurology
Cited by (91)
Advances in oral immunomodulating therapies in relapsing multiple sclerosis
2020, The Lancet NeurologyLong-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab
2019, Multiple Sclerosis and Related DisordersUnderstanding the Patient's Journey in the Diagnosis and Treatment of Multiple Sclerosis in Clinical Practice
2018, Clinical TherapeuticsCitation Excerpt :The predominantly injectable DMTs, such as IM interferon (IFN)-β1a, SC IFN-β1b, glatiramer acetate, and SC IFN-β1a, rapidly became the standard of care because of their ability to reduce the frequency and severity of flares and slow the progression of MS.16,18 Rituximab has been used off-label for the treatment of MS for more than a decade, and was shown to be effective well tolerated in a recent study in Sweden.19 Other researchers point to the need for additional studies,20 although such off-label use could be a precursor for the development and approval of the monoclonal antibody agent ocrelizumab for MS.21 Since 2010, a number of oral DMTs (fingolimod [2010], teriflunomide [2012], dimethyl fumarate [2013]), injectable DMTs (daclizumab [2016]), and infusible DMTs (alemtuzumab [2014]) have been approved for use in the United States.22–25 Robust evidence characterizing the processes for diagnosing, evaluating, and treating patients with MS in clinical practice is largely absent.
Therapeutic Approaches to MS and Other Neurodegenerative Diseases
2017, Comprehensive Medicinal Chemistry IIICorrigendum to ‘Multiple sclerosis: New insights and trends’ (Asian Pacific Journal of Tropical Biomedicine (2017) 7(5) (493–504) (S2221169116302453) (10.1016/j.apjtb.2016.03.009))
2017, Asian Pacific Journal of Tropical BiomedicineSmoking increases the risk of progression in multiple sclerosis: A cohort study in Queensland, Australia
2016, Journal of the Neurological SciencesCitation Excerpt :In a smaller number of patients the disease is progressive from the outset [1]. The mechanisms that underlie progressive MS are poorly understood and treatment of this phase of the disease is challenging [2]. There are potential benefits in identification of modifiable risk factors for progressive disease.