Interferon-beta therapy in multiple sclerosis

Approximately 85% of patients with multiple sclerosis (MS) have a relapsing–remitting course at onset characterised by episodes of neurological symptoms and signs, called relapses or attacks, initially often with full recovery and later with incomplete recovery. The first demyelinating episode is called a clinical isolated syndrome. The diagnosis of MS usually requires two clinical episodes, disseminated in time and space, or at least one episode supported by magnetic resonance imaging (MRI) showing dissemination in time and space.(1) The majority of patients with relapsing–remitting MS (RRMS) will develop secondary progressive MS (SPMS) after an average of 10–12 years. This phase of the disease is characterised by steadily progressive deterioration of neurological function with or without superimposed relapses.(1) Approximately 15% of patients have primary progressive MS (PPMS) with continuous deterioration of neurological symptoms from the onset, typically spastic paresis of the legs, without signs of remission. 

Since 1993, interferon-b (IFNb) has been used in the treatment of RRMS.(2) There are two different forms of recombinant IFNb: IFNb-1a and IFNb-1b. IFNb-1a is marketed as Avonex (Biogen Idec, Cambridge, MA, USA) administered as 30µg intramuscularly (IM) once per week and Rebif (Merck Serono International, Geneva, Switzerland) administered as 44µg or 22µg subcutaneously (SC) three times per week. IFNb-1b is available as Betaferon (Bayer Schering, Berlin, Germany) and Extavia (Novartis, Basel, Switzerland), both administered subcutaneously as 250µg every other day. While IFNb-1a has an amino acid sequence identical to that of endogenous human IFNb, the amino acid sequence in IFNb-1b differs, and as a consequence it requires higher doses of IFNb-1b than IFNb-1a to achieve the same biological effect. IFNb and glatiramer acetate (Copaxone) are the only approved first-line therapies in Europe. 

Other drugs such as natalizumab, mitoxantrone and fingolimod are used mainly as second-line therapies in patients who do not respond satisfactorily to a first-line therapy (Table 1).

The effects of IFNb on the immune system include effects on processes implicated in the pathogenesis of MS. In general, IFNb inhibits activation of certain white blood cells, T-cells, and their migration into the central nervous system (CNS). IFNb inhibits activation of inflammatory Th1 cells, which are central players in the formation of inflammatory demyelinating lesions in the CNS, which characterises MS.(1) 

IFNb inhibits the migration of inflammatory T-cells across the blood–brain barrier (BBB) by reducing the quantity of the functional adhesion molecules on the vascular vessel wall, the presence of which is necessary for T-cells to cross the BBB. Additionally, IFNb down-regulates matrix metalloproteinases, used by T-cells to penetrate the BBB.

In MS, the function of regulatory T-cells, which down-regulate the activity of pro-inflammatory cells, is impaired.(1) Recently, it has been shown that IFNb may contribute to improvement in regulatory T-cell activity in MS patients.(3)

Placebo-controlled clinical trials often run for two years in patients with RRMS and for three or more years in patients with PPMS and SPMS. In other clinical trials, two different medications may be compared in a head-to-head study. In studies of RRMS, the primary outcome measure is usually the annualised number of new relapses. Other clinical outcomes include the time to the first relapse, the proportion of relapse-free patients, the time to progression on the Expanded Disability Status Scale (EDSS), which is the most widely used rating scale for measuring neurological deficits and disability in MS, and the proportion of progression-free patients. Together with clinical endpoints, MRI of the brain is always used as an outcome measure. Traditional measures of disease activity on MRI are the number of contrast-enhancing lesions after intravenous injection of gadolinium contrast, which is a measure of recent inflammatory activity, and new lesions on T2-weighted images. 

The total volume of T2 lesions on MRI indicates the burden of disease and brain atrophy is a measure of tissue loss. 

The therapeutic efficacy of IFNb has been documented in placebo-controlled clinical trials in patients with clinically isolated syndromes and in patients with RRMS, whereas the effect in patients with SPMS is questionable, and no effect has been shown in patients with PPMS.

There is a growing body of evidence suggesting that irreversible damage to the CNS in patients with MS occurs even in the very early stages of the disease, and knowing the devastating nature of MS affecting young people in their most productive years, there is a need to control the inflammatory disease activity at the earliest phase of the disease, in clinically isolated syndrome. IFNb has a safety profile that makes it possible to recommend long-term treatment in patients with very early MS. In patients with clinically isolated syndrome, treatment with IFNb reduced the risk of having a second relapse and thereby develop clinically definite MS.(4)

Large placebo-controlled, randomised studies of both IFNb-1a and IFNb-1b have shown that over a two-year study period, the number of relapses is reduced by approximately 30% and the risk of developing increased disability is reduced by 25–35%.(5–7) The effect on disease activity seen in MRI is much more impressive, typically with reductions of 60–80% in patients treated with IFNb compared with placebo.(5–7)

The result of IFNb therapy varies between patients. Approximately 40% of patients have an excellent response, 20% a reasonable response, and 40% an unsatisfactory response. The treatment effect can to some extent be predicted by relapses and MRI activity in the one-to-two years preceding treatment start, and the therapeutic response during the first year of therapy can predict the disease activity and progression in the following three-to-six years.(8,9)

In SPMS, the therapeutic benefits of IFNb are much less clear. However, the assessment of studies in SPMS suggests that IFN-b might still be beneficial in SPMS patients with either rapid disability progression or continued relapse activity, indicating that inflammation is still an important pathophysiological component.(10) Patients with primary progressive MS do not benefit from IFN-b.

It has been debated whether differences in therapeutic efficacy exist between the different IFN-b preparations. As indicated in Table 2, the effect seems quite similar between the various IFN-b preparations.

A direct head-to-head comparison of IM IFNb-1a 30µg once weekly and subcutaneous (SC) IFNb-1a 44µg three times weekly (EVIDENCE Study) indicated that the more frequent administration and higher weekly dose of SC IFNb-1a had a faster and possibly a greater effect. After 24 weeks of treatment, patients randomised to IFNb-1a SC 44µg three times a week had a significantly lower relapse rate compared to the patients treated with IFNb-1a IM 30µg once a week, but at week 48, only a small and non-significant difference in relapse rate was observed.(11)

Two studies have compared IFNb with the other approved first-line therapy, glatiramer acetate. In the REGARD study IFNb-1a SC 44µg three times weekly was compared with glatiramer acetate 20mg SC daily for two years. There was no difference between the two groups in the time to first relapse or the annualised relapse rate, and the change in EDSS score was identical in the two groups. However, on MRI the number of gadolinium enhancing lesions was significantly lower in the IFNb-1a group than in the glatiramer acetate group.(12)

The BEYOND study compared IFNb-1b 250µg and 500µg every other day with glatiramer acetate and found no difference in the effect of IFNb-1b and glatiramer acetate on any clinical efficacy measure.(13) 

Taken together, the results of the REGARD and BEYOND studies indicate that there are no signs of superiority in treatment efficacy of any IFNb compared with glatiramer acetate.

As double-blind, placebo-controlled or comparative studies can only be performed for a period of two-to-three years for practical and ethical reasons, the long-term effects of IFNb have been assessed in observational studies. These studies are often extensions of placebo-controlled trials in which all patients who complete the placebo-controlled part of the trial continue with the same IFNb preparation for several years. Long-term follow-up of the patients who took part in the large pivotal, placebo-controlled studies suggests that the beneficial effect of continuous IFNb therapy is present even after 10 or 15 years. Such studies should, however, be interpreted with caution as they have not been blinded after the initial two years with placebo control and it has not been possible to follow all patients for a prolonged period. 

Other studies describe the effect of IFNb therapy in large cohorts of patients, and in some studies the observed outcome in IFNb-treated patients is compared with the disease evolution in historical cohorts of untreated patients. In an Italian study the progression in EDSS score and development of secondary progressive MS was delayed in relapsing-remitting MS (RRMS) patients treated with IFNb (Fig. 1), and a Swedish study reported similar findings.(14,15) 

Treatment of RRMS with IFNb is only partially effective, but safe. Hence, more effective and safe strategies are needed, and one of these is the add-on of a well-known oral drug to IFNb. 

Two Danish studies have shown that a significant reduction in the relapse rate and MRI activity can be achieved by adding monthly three-to-five days cycles of methylprednisolone tablets 200–500mg daily to standard treatment of IFNb.(16,17) By contrast, the addition of simvastatin, a lipid-lowering drug that has shown immunomodulatory properties, to IFNb had a negative effect on some efficacy endpoints.(18) 

The most frequently reported side-effects to IFNb, both administered IM and SC, are flu-like symptoms, which may include headache, fatigue, myalgia, chills and fever, and injection site reactions.(5–7) Flu-like symptoms can be satisfactorily controlled in most patients by premedication with paracetamol or non-steroidal anti-inflammatory drugs (NSAID) just before the injection and if necessary repeated after four-to-six hours. Flu-like symptoms tend to get milder or disappear after three-to-six months. 

Non-symptomatic elevation of alanine aminotransferase occurs frequently (up to 30% of patients) and is the most common abnormal laboratory test. Symptomatic liver involvement with jaundice or even fulminant liver necrosis has also been reported, but only rarely.(19)

Other side-effects include mild asymptomatic and reversible haematological abnormalities; particularly during the first months of therapy, the white blood cell count is frequently lowered.(5–7) 

Treatment with IFNb-1a requires periodic surveillance with blood tests for liver function and haematology. Thyroid dysfunction occurs frequently during therapy with IFNb, both hypothyroidism and hyperthyroidism, but is most often subclinical and transient. 

Like all other biopharmaceuticals, IFNb is immunogenic and can induce the formation of binding and neutralising antibodies (NAbs).(5,7,20) The presence of NAbs diminishes, and at high concentrations abolishes, the effect of IFNb, because it prevents the IFNb molecule from binding to its receptor, which is a prerequisite for a biological response to IFNb.(5,7,20) NAbs usually occur six-to-18 months after start of IFNb therapy.(21)

Since 1993, IFNb has been the mainstay of treatment for RRMS. Together with glatiramer acetate, the different IFNb preparations are first-line therapies in patients with RRMS and in patients with clinically isolated syndromes at high risk of developing clinically definite MS. The current second-line treatments, natalizumab, fingolimod and mitoxantrone, are more efficacious, but carry the risk of serious adverse effects, and are only used in patients who fail IFNb therapy or, occasionally, as first-line treatment in patients with very high disease activity. Other therapies are still under investigation and are considered experimental therapies, as is intensive cytostatic treatment followed by autologous bone marrow transplantation. The current treatment algorithm is shown in Fig. 2.

New formulations of IFNb are currently being tested, including pegylation of IFNb to improve the pharmacokinetic properties and efficacies of the drug. Pegylated forms of IFNb may increase the efficacy, reduce side-effects and reduce the frequency of administration to once or twice monthly.

Within the next four-to-five years, several new disease-modifying drugs for MS will appear on the market. These include some promising new oral therapies that may become preferred first-line options if the ongoing Phase III trials show that they have comparable or superior efficacy to that of IFNb. Still, for several years, IFNb will remain an important therapeutic option in patients starting treatment for MS. l F

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