Oral therapy in the treatment of multiple sclerosis

Thomas Williams, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP

Multiple sclerosis (MS) is the most common chronic neurological condition of young adults, with a prevalence of 120 per 100,000. It is an autoimmune disease of the central nervous system (CNS), with multiple foci of demyelination which are characteristically disseminated in both time and space. In 80% of cases the disease follows a relapsing-remitting course, with episodes of demyelination, leading to motor, sensory and autonomic deficits, interspersed between asymptomatic periods. Over a variable number of years, patients’ recovery after each relapse starts to become incomplete. A gradual accumulation of neurological deficits therefore occurs, and a secondary progressive phase of the disease is entered.

Twenty years ago, the autoimmune aetiology of multiple sclerosis was only just being discovered, and there were no disease-modifying treatments (DMTs). Due to a highly active era of MS research, a wide variety of DMTs are now available, although those currently available to patients all require regular parenteral administration. This causes significant problems, with injection site reactions, development of needle-phobias and the need for supervised administration significantly compromising the quality of life of patients, and their adherence to treatment regimes. This news article will briefly review current injectable DMTs for MS, before going on to highlight the recent developments with oral treatments.

Injectable disease-modifying therapy

Interferon beta (IFNβ) therapy was first introduced based upon an assumed viral origin of MS. Despite now knowing that this is not the case, the 30% reduction in average relapse rate achieved with injectable IFNβ (Betaferon, Rebif, Avonex) via its ability to modulate the immune response means that they still form the mainstay of disease modifying therapy. Glatiramer acetate (copaxone) is an alternative injectable DMT available for first-line therapy, consisting of a polymer of a four amino acid sequence found in myelin-basic protein, a key antigen targeted on oligodendrocytes during active MS. It achieves similar reductions in relapse rates to interferon – it is assumed to act as an immunological decoy, reducing the attack upon oligodendrocytes themselves. The affects upon disability progression of both interferon and glatiramer acetate are very modest.

Natalizumab (Tysabri) is a humanised monoclonal antibody targeting α4-intergrin, which is required for the extravasation of lymphocytes into the CNS. It reduces relapses by up to 70% and disability progression by 40%. These favourable results are, however, accompanied by a one in 500 risk of the patient developing progressive multifocal leukoencephalopathy, a rapidly progressive and often fatal condition caused be uncontrolled infection of the CNS by the JC virus. For this reason it is only used as a second-line treatment. Alemtuzumab (campath-1H) is a humanised monoclonal antibody still unlicenced for the treatment of MS. It achieves prolonged lymphocyte depletion by targeting CD52. The efficacy seen in trials has been very promising(1), although problems of resulting immune dysregulation are still to be overcome.

Oral disease modifying therapies

Positive results from phase 3 trials have been reported for five new oral medications(2):

  • Fingolimod modulates sphingosine-1-phosphate (S1P) receptors, resulting in S1P1 receptor internalisation on lymphocytes. This prevents T- and B-lymphocytes from exiting lymph nodes, reducing circulating memory T-cells by more than 90%. The depletion lasts 4-6 weeks. Murine models have also suggested that the mechanism may involve a direct affect upon S1P receptors on astrocytes. Trials show reductions in annual relapse rates of around 60%, reduced disease activity detected on MRI, and significant reductions in disability progression; it has been shown to be significantly better than current interferon beta therapies. The US Food and Drug Administration (FDA) have approved it for first-line use in relapsing remitting cases of MS, whilst the European Medicines Agency (EMA) have restricted it to second line use; initial draft guidance from NICE did not recommend fingolimod on cost-effective grounds, although the full NICE appraisal is not due to be published until January 2012.
  • Cladribine is a purine nucleoside analogue that becomes preferentially accumulated in lymphocytes, disturbing DNA synthesis and resulting in a prolonged lymphopenia. Despite achieving favourable results on both relapse rate and disability progression, it failed to achieve FDA or EMA approval due to safety concerns.
  • Teriflunomide (leflunomide) targets dihydroorotate dehydrogenase, a mitochondrial enzyme necessary for pyrimidine synthesis. The only mild levels of lymphopenia produced, however, suggests that its mechanism is not only via preventing DNA replication in lymphocytes. Relapse reductions of 31% and reductions in disability progression of 29% have been reported.
  • Laquinimod (linomide derivative) induces a shift away from Th1 responses towards Th2 and Th3 cytokines. The level of immunosuppression in therefore mild, but similar reduction in relapse rates and disease progression are seen to those with teriflunomide.
  • Dimethyl fumarate (BG-12) induces activation of the nuclear factor E2-related factor 2 pathway, resulting in neuroprotective as well as anti-inflammatory mechanisms. Relapse reductions of 53%, MRI disease activity reductions of 90%, and disability progression reductions of 38% have been reported. In contrast to the other oral therapies, dimethyl fumarate also has the advantage of existing long-term safety data following 14 years of experience using it to treat psoriasis.

Impact on patients

The promising results summarised above have created much excitement in the MS community, especially amongst patients. Enhanced efficacy is only one aspect of this; those already using DMTs hope oral treatments will bring them freedom from the drawbacks of injectable treatment, and those who have opted not to start DMT because of relatively mild disease and the necessity of injections are now hoping to start oral therapy when they become available. Much research, however, is yet to be done. Few studies exist directly comparing the new therapies, and there are currently no biomarkers that might predict which therapies will be most effective in individual patients. Long-term safety concerns also exist, as, with the exception of dimethyl fumarate, sufficient experience with the treatments does not exist.

References: 

1. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD-D, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DAS. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol. 2011 Apr;10(4):338-348.
doi:10.1016/S1474-4422(11)70020-5

2. Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurol. 2011 Nov;10(11):1026-1034.
doi: 10.1016/S1474-4422(11)70228-9

Story image from Wikimedia Commons.