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Disease modifying therapies for Multiple Sclerosis (MS)

By January 22, 2017 No Comments

Lisa Costelloe

Now more than ever the process of informed consent and the implementation of monitoring protocols are of paramount importance for long term patient safety.

Multiple Sclerosis (MS) is characterised pathologically by inflammation and demyelination of the optic nerves, brain, and spinal cord which results in axonal loss and atrophy even in the earliest stages of the disease.

For most patients the disease manifests initially as acute attacks or relapses from which there is a variable recovery (relapsing remitting MS, RRMS),usually followed by a gradual accumulation of disability over time (secondary progressive MS, SPMS). A minority present with progressive disability from the outset (primary progressive MS, PPMS). The goal of disease modifying therapies (DMTs) is to reduce the number of clinical relapses and MRI evidence of inflammation early in the course of the illness in order to prevent relapse associated disability and delay the onset of progressive disease. The earlier the treatment is started the better the long term outcome.

There are currently 12 available DMTs licensed for use in patients with RRMS in Ireland. To date there is no licensed DMT for progressive forms of the disease though a number of agents are showing promise in clinical trials. The choice of which DMT to prescribe in a patient with RRMS is complex and needs to be individualised. The choice will depend on the degree of disease activity, the safety and tolerability of the drug, as well as the reproductive plans and co-morbidities of the patient.

In practice DMTs are broadly categorised as “first line” and “second line” drugs. The first line drugs tend to be used in newly diagnosed patients without clinical or radiological evidence of very aggressive disease. They are moderately effective in reducing disease activity and are not associated with a high incidence of serious adverse events though none are without side effects (see Table). Until recently, these drugs were all self-injected agents, either an interferon-beta preparation (Avonex, Rebif, Betaferon, Plegridy, Extavia) or glatiramer acetate (Copaxone). All of these drugs reduce the annual relapse rate by approximately 33 per cent when compared to placebo and all have the advantage of being proven to be very safe in the long term.

More recently a dimethyl-fumarate based medication (BG-12, Tecfidera) has been licensed which reduces the annual relapse rate by about 54 per cent compared to placebo and has the advantage of avoiding self injection. However, this agent has been associated with more serious infections including progressive multifocal leucoencephalopthy (PML), albeit in a handful of patients worldwide. PML is an opportunistic infection of the brain which occurs due to reactivation of the JC virus in the context of immunosuppression. It was well described in the AIDS population but more recently has been associated with the use of powerful immune modulating drugs used in MS and other inflammatory conditions. Another first line tablet called teriflunomide (Aubagio) is also licensed though is rarely prescribed in Ireland due to its potential for teratogenicity.

The goal of disease modifying therapies (DMTs) is to reduce the number of clinical relapses and MRI evidence of inflammation early in the course of the illness in order to prevent relapse associated disability and delay the onset of progressive disease

The second line drugs are reserved for the minority of patients with more active disease; either those who have failed a first line drug or those with more aggressive disease from the outset. One such medication called fingolimod (Gilenya) is available in tablet form and has a novel mechanism of action whereby it traps activated lymphocytes within secondary lymphoid tissue, thereby preventing them from entering the brain and causing inflammation. It reduces the annualised relapse rate by 54 per cent compared to placebo. Fingolimod has been associated with PML in a very small number of patients worldwide. The first dose must be administered in the hospital setting due to the risk of first dose bradyarrythmias.

The other two second line drugs are administered intravenously in hospital. Natalizumab (Tysabri) is a highly effective drug which reduces the relapse rate by about 68 per cent per year when compared to placebo. It is given as a monthly infusion and is well tolerated though PML is well described and the risk can be calculated based on a number of clinical factors. Alemtuzumab (Lemtrada) has been licensed more recently as another highly active DMT which reduced the relapse rate by 55 per cent when compared to an active comparator (Rebif 44) in trials. It is administered intravenously over five days at baseline followed by another three days of infusion one year later. While the risk of viral infections is increased after treatment, it has not been associated with PML to date. However, it is associated with a risk of developing a second autoimmune condition (most commonly thyroid disease) in more than one third of treated patients several years after therapy.

Recent advances in translational research have led to the availability of more effective and more targeted immunotherapies for patients with relapsing forms of MS. However, with greater drug potency comes the greater risk of serious infections and other significant side effects. Now more than ever the process of informed consent and the implementation of monitoring protocols are of paramount importance for long term patient safety. Several more DMTs are in the pipeline including some that have shown efficacy in the progressive forms of MS for the first time in clinical trials. The expanding therapeutic repertoire provides hope for patients with MS and the doctors who look after them.

Dr Lisa Costello is a neurologist at Beaumont Hospital, Dublin

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