INTRODUCTION TO INTERFERON-BETA-1a
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and one of the leading non-traumatic causes of neurological disability in young adults [1]. In temperate regions, the prevalence is greater than 1:1000, and the disease affects more than 2 million people worldwide [1,2]. The symptoms include visual disturbances, motor weakness and ataxia of the limbs, paresthesias and sensory disturbances, bladder, bowel and sexual dysfunction, and cognitive problems [1]. The mean age of onset is approximately 30 years and the disease occurs 2-3 times more frequently in women than in men [1]. After a subclinical period of varying length during which the patients are asymptomatic but disease activity is present on MRI, the majority of patients suffer their first clinical demyelinating attack [3]. This phase of the disease is classified as a clinically isolated syndrome. The diagnosis of MS usually requires two clinical episodes, disseminated in time and space [4], or at least one episode supported by magnetic resonance imaging (MRI) showing dissemination in time and space [5,6]. Approximately 85% of the patients have a relapsing-remitting course at onset characterized by episodes of neurological symptoms and signs, called relapses or attacks [7], initially often with full recovery and later with incomplete recovery [8]. During this phase of the disease, patients are neurologically stable between the relapses. The majority of patients with relapsing-remitting MS will develop secondary progressive MS (SPMS) [9] after an average of 10-12 years. This is characterized by steadily progressive deterioration of neurological function with or without superimposed relapses [7]. Approximately 15% of patients have primary progressive MS with continuous deterioration of neurological symptoms from the onset, typically spastic paraplegia, without signs of remission. Patients with a primary progressive disease course are usually older at disease onset and show no female preponderance [10].
Since 1993, IFN-β has been the mainstay in the treatment of relapsing-remitting MS [11]. There are two different forms of recombinant IFN-β: IFN-β-1a and IFN-β-1b. While IFN-β-1a has an amino acid sequence identical to that of endogenous human IFN-β and is glycosylated, IFN-β-1b differs in amino acid sequence and is not glycosylated [12]. As a consequence, it requires higher doses of IFN-β-1b than IFN-β-1a to achieve the same biological effect [13].
There are two recombinant IFN-β-1a products developed for use in MS: 1) IFN-β-1a for intramuscular (IM) use (Avonex®, Biogen Idec, Cambridge, MA) administered as 30 µg IM once a week and 2) IFN-β-1a for subcutaneous (SC) use (Rebif®, Merck Serono International, Geneva, Switzerland) administered as 44 µg or 22 µg SC three times a week.
PHARMACOLOGY
After a single dose of IFN-β-1a, whether administered IM or SC, serum concentration peaks at 12-16 hours, whereas pharmacodynamic markers such as neopterin and beta-2 microglobulin peak after 36 to 48 hours and return to baseline level after 4 to 5 days [14]. Dosing IFN-β-1a SC three times a week produces more sustained levels of markers of bioactivity than IFN-β-1a IM once a week [15]. However, it is not known to what degree a prolonged steady-state serum concentration and a sustained level of biomarkers of IFN-β activity relate to the therapeutic effect.
The exact mechanism of action of IFN-β-1a is not fully understood. A single injection of IFN-β-1a increases or decreases the expression of several hundreds of genes [16,17]. Among these is the MX1 gene that encodes for the MxA molecule, which is utilized to show the bioactivity of IFN-β and the negative effect of neutralizing antibodies [18,19]. The effects of IFN-β on the immune system are numerous and include effects on processes that are thought to be implicated in the pathogenesis of MS [20]. In general, IFN-β-1a exerts an inhibitory effect on T-cell activation and migration into the CNS [21], either directly or via modulation of the activities of interleukin (IL)-10 which has been shown to be reduced both intracellularly and in the CSF of MS patients [22]. Th1 cells that are regarded as pro-inflammatory cells are induced by IL-12 which is inhibited by IFN-β, and several studies have documented that IFN-β-1a reduces the production of pro-inflammatory cytokines. Traditionally, this has been alluded to as a shift from an inflammatory Th1 response to a favorable Th2 type response, although this paradigm has been challenged [20]. Recently, a new effector cell, Th17, secreting IL-17 has been identified as a key player in the inflammatory attack in MS. IL-23 contributes to the expansion of Th17, and IFN-β reduces IL-23 and IL-17 which have been reported to be increased in MS patients [23,24].
Another mechanism by which IFN-β may reduce levels of activated T-cells is promotion of T-cell apoptosis [25].
In MS, the activity of regulatory T-cells (CD25hi) is impaired [26,27]. Recently, it has been shown that IFN-β may contribute to improvement in regulatory T-cell activity in MS patients [28].
Also, IFN-β is known to moderate the expression of MHC class-II in antigen presenting cells in MS patients [29], including a reduction in circulating monocytes and lymphocytes expressing MHC class-II [30]. Additionally, IFN-β inhibits the migration of inflammatory T-cells across the blood-brain barrier by reducing the quantity of the functional endothelial adhesion molecules ICAM and VCAM [31], and by down-regulating the production of chemokines [23] and matrix metalloproteinases [32,33].
EVIDENCE OF EFFECT OF IFN-β-1a FROM CLINICAL TRIALS
The therapeutic efficacy of IFN-β-1a has been documented in placebo-controlled clinical trials in patients with clinically isolated syndromes at high risk of developing clinically definite MS and in patients with relapsing-remitting MS, whereas the effect in patients with secondary progressive MS is questionable, and no effect has been shown in patients with primary progressive MS.
CLINICALLY ISOLATED SYNDROMES
The CHAMPS study
Patients recruited to the CHAMPS study (Controlled High-risk subjects Avonex MS Prevention Study) had suffered their first isolated clinical episode consistent with demyelination in the form of optic neuritis, incomplete transverse myelitis, or brainstem or cerebellar symptoms [34]. On MRI, all patients had at least 2 subclinical brain lesions ≥3 mm in diameter, of which at least one was periventricular or ovoid. These patients were evaluated as having high risk of conversion to clinically definite MS. All patients were treated with intravenous corticosteroids and were thereafter randomized to receive either IFN-β-1a IM 30 μg once a week (n=193) or placebo (n=190). The primary end-point was development of clinically definite MS. The study was prematurely discontinued after a planned interim analysis at 22 months revealed superiority of IFN-β-1a over placebo. The cumulative probability of developing MS was 35% in the IFN-β-1a treated group and 50% in the placebo group (44% relative risk reduction; p = .002). The cumulative probability of conversion to clinically definite MS at 3 years was 35% in the IFN-β-1a group and 50% in the placebo group [34].
Post-hoc subgroup analysis showed that the treatment benefit was independent of the type of presenting event, baseline brain MRI, and demographic factors. In patients who fulfilled more stringent criteria of high-risk (≥2 T2-weighted hyperintense lesions and ≥1 gadolinium enhancing lesions on baseline MRI), the risk reduction was 66%. Also the volume and number of lesions on T2-weighted MRI showed a beneficial effect of the active treatment [35].
About half of the patients were examined in a 5-year follow-up study (CHAMPIONS). In patients, who had received immediate treatment with IFN-β-1a, 34% had developed clinically definite MS compared to 45% in the delayed treatment arm (odds ratio = 0.52, 95% CI = 0.31-0.86; p = .047 [36].
The ETOMS study
The ETOMS study (Early Treatment Of Multiple Sclerosis) compared IFN-β-1a SC 22 μg once a week with placebo in a 2-year study comprising 308 patients with clinically isolated syndromes [37]. After 2 years, 34% of patients treated with IFN-β-1a had converted to clinically definite MS compared with 45% in the placebo group, a 24% relative reduction (p = .047). Also the annualized relapse rate, T2-lesion volumes, new or enlarging T2-lesions, and brain volume loss were favorably affected by IFN-β-1a. It is of interest that the low dose of 22 μg once a week had an effect in patients with clinically isolated syndrome, since this dose did not show any positive effect on relapses after 1 year in the OWIMS Study (Once-Weekly Interferon for MS) in patients with relapsing-remitting MS [38].
The results of the CHAMPS and ETOMS studies in patients with clinically isolated syndromes have recently been confirmed in the BENEFIT study (BEtaseron in Newly Emerging multiple sclerosis For Initial Treatment) comparing IFN-β-1b 250 μg every other day with placebo [39,40].
RELAPSING-REMITTING MS
The pivotal placebo-controlled studies of IFN-β-1a were published in 1996 (IFN-β-1a IM) and 2001 (IFN-β-1a SC).
The MS Collaborative Research Group study
The MS Collaborative Research Group study randomized 301 patients to receive either IFN-β-1a IM, 30 μg once a week or placebo [34]. The primary end-point was time to onset of disability progression on the EDSS scale [41]. The study was prematurely discontinued because the study had attained sufficiently statistical power when only 57% of the patients had completed the 2-year follow-up. The proportion with progression of disability estimated from Kaplan-Meier curves was 21.9% in the IFN-β-1a group compared to 34.9% in the placebo group (p = .002). The premature discontinuation of the study was unfortunate as it had an impact on some of the secondary end-points. The annual exacerbation rate was 0.82 for placebo patients compared to 0.67 for IFN-β-1a patients, a relative reduction of 19% (p = .04). However, the reduction in annual exacerbation rate for patients who completed 2 years of the study was 0.61 for IFN-β-1a patients and 0.90 for placebo patients, a relative reduction of 32% (p = .002) (Figure 1). The number of gadolinium-enhancing lesions on MRI scans after 1 year and 2 years showed statistical benefit in favor of IFN-β-1a. The volume of T2-lesions was significantly lower in the IFN-β-1a group compared to the placebo group after 2 years (p = .03), but the percentage change from baseline to year 2 did not show any statistically significant difference between the 2 groups (p = .36) (Figure 2) [34].
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Figure 1. Mean annualized relapse rates in (A.) MS collaborative research study group, (B.) PRISMS (Prevention of Relapses and disability by Interferon-beta-1a Subcutaneously in MS) study, and (C.) OWIMS (Once Weekly Interferon for MS) study. |
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Figure 2. Percentage change in T2 lesion load from baseline in the MS Collaborative Research Group study, PRISMS (Prevention of Relapses and disability by Interferon-beta-1a Subcutaneously in MS) study, and OWIMS (Once Weekly Interferon for MS) study. |
The PRISMS study
The pivotal PRISMS study of IFN-β-1a SC (The Prevention of Relapses and disability in IFN-β-1a SC in Multiple Sclerosis Study) randomized 560 patients with relapsing-remitting MS to either IFN-β-1a SC 22 μg or 44 μg three times a week or placebo for 2 years [42]. The primary end-point was the annual relapse rate, and after 2 years, both doses of IFN-β-1a SC showed a significantly lower relapse rate compared to placebo (IFN-β-1a 44 μg: 0.87, IFN-β-1a 22 μg: 0.90, placebo: 1.29; relative difference 29% and 32% (p <.005) (Figure 1). The time to first relapse was significantly delayed in both groups receiving IFN-β-1a SC compared to placebo. The time to confirmed progression of one step on the EDSS scale sustained for 3 months was delayed in the 22 μg group (risk ratio for progression 0.68, 95% CI = 0.48-0.98) and the 44 μg group (risk ratio = 0.62, 95% CI = 0.43-0.91) compared with placebo. Also the percentage change in T2-lesion volume showed significant differences between both IFN-β groups and placebo (Figure 2) as did the number of MRI T2-active lesions. The benefits in MRI outcomes were more pronounced in the IFN-β-1a 44 μg group compared to the 22 μg group.
At the end of the 2 year double-blind study, patients in the placebo arm were re-randomized to receive either IFN-β-1a 22 µg or 44 µg and were followed for an additional 2 years (PRISMS-4 Study) [43]. Patients who had received active treatment with IFN-β-1a throughout the 4 years had significantly fewer relapses per year than the crossover group. During years 3 and 4, the IFN-β-1a 44 µg group showed a trend towards a lower relapse risk than the IFN-β-1a 22 µg group (p = .14) and had a significantly lower annual relapse rate compared with the groups that crossed over from placebo to IFN-β-1a (p = .014). Patients who had been treated with IFN-β-1a 44 µg throughout the study had a significantly lower risk of confirmed disability progression than patients who had been treated with placebo for 2 years and then crossed over to IFN-β-1a, supporting the concept that patients benefit from early initiation of high-dose, high-frequency IFN-β-1a therapy.
The OWIMS study
In the Once Weekly Interferon for MS study (OWIMS), 293 patients with relapsing-remitting MS were randomized to receive either IFN-β-1a SC 22 µg or 44 µg once a week or placebo [38]. The study showed no significant differences in relapse rate between the 2 active treatment groups and placebo, although there was a trend towards lower relapse rate in the IFN-β-1a 44 µg group (Figure 1). Only MRI measurements showed a significant treatment effect in the IFN-β-1a SC once a week groups (Figure 2). The OWIMS study clearly showed that IFN-β-1a SC 22 µg once a week did not induce clinically significant effects after 1 year in relapsing-remitting MS patients, although this dose had significant clinical effect in patients with clinically isolated syndrome [37].
SECONDARY PROGRESSIVE MS
While the European Interferon beta-1b Study In Secondary Progressive MS showed significantly prolonged time to disability progression as measured by EDSS in patients treated with IFN-β-1b [44], the Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon beta-1a in MS study (SPECTRIMS) did not meet the primary success criteria: progression in EDSS [45]. In the SPECTRIMS study, 618 patients with secondary progressive MS were randomized to receive either IFN-β-1a SC 22 μg or 44 μg three times a week or placebo for 3 years. After 3 years, no significant difference in disability progression was found between the 3 treatment groups, whereas there were significant benefits on the relapse rate (30% reduction in the 44 μg group). Also MRI outcome measures showed a more favorable response in the IFN-β-1a SC treatment groups [46].
The Nordic Secondary Progressive MS Trial studied the same low dose of IFN-β-1a SC as that used in the ETOMS trial [47]. In all, 371 patients were randomized to either IFN-β-1a SC 22 μg once a week or placebo for 3 years. The study showed no significant benefit of this low IFN-β-1a dose on disease progression or relapses.
In the International Multiple sclerosis secondary Progressive Avonex Clinical Trial (IMPACT), 427 patients with secondary progressive MS were randomized to receive either IFN-β-1a IM 60 μg once a week or placebo for 24 months [48]. In this study, the MS Functional Composite score (MSFC) was used as the primary outcome for the first time [49,50]. This outcome measure combines cognition, hand function, and walking ability in a composite Z-score. After 2 years, the worsening in MSFC was reduced by 40% in the IFN-β-1a arm compared to the placebo arm (p = .03). The difference was mainly seen in hand function as measured by the nine hole peg test. There was no difference in disease progression measured on EDSS, whereas there was a significant reduction in relapses [48].
Comparison of the European Interferon beta Secondary Progressive MS Study with the SPECTRIMS and IMPACT studies revealed that the former had included patients with much higher relapse activity, suggesting that some of these patients might still have been in the relapsing-remitting phase of the disease. The later North American Secondary Progressive MS Study (NA-SPMS) comparing IFN-β-1b and placebo administered for 3 years showed no significant differences between two IFN-β-1b groups and the placebo group [51].
An overall assessment of studies in secondary progressive MS suggest that IFN-β might still be beneficial in secondary progressive MS patients with either rapid disability progression or continued relapse activity, indicating that inflammation is still an important pathophysiological component.
PRIMARY PROGRESSIVE MS
Only a small exploratory randomized trial of IFN-β-1a IM once weekly has been performed in patients with primary progressive MS [52]. Fifty patients were randomized to either IFN-β-1a IM standard dose (30 μg once a week) or high-dose (60 μg once a week) or placebo. The primary outcome measure was progression on EDSS and the study showed no difference between the 3 groups. However, patients in the IFN-β-1a IM 30 μg group had a significantly lower rate of T2-lesion accumulation compared to placebo treated patients. The high-dose IFN-β-1a group had more severe flu-like symptoms and liver enzyme elevations compared with the standard dose.
COMPARATIVE STUDIES
The first open-label randomized head-to-head study, the Danish Comparative IFN-β Study, initiated in 1996 compared IFN-β-1a SC 22 μg once a week and IFN-β-1b 250 μg every other day in 301 patients [53]. The primary end-points were the annualized relapse rate and time to first relapse. There were no differences found between the treatment groups in either the annualized relapse rate (IFN-β-1a: 0.70; IFN-β-1b: 0.71), the time to first relapse or the time to sustained relapse. MRI performed in a subgroup of patients showed a trend towards a higher increase in mean T2-lesion load (p = .078). The lack of statistically significant difference in the MRI outcome measures was probably due to the low patient number yielding insufficient statistical power. However, it is difficult to explain the identical relapse rate and time to first relapse.
A randomized double-blind study compared IFN-β-1a IM 30 μg and 60 μg once a week for 36 months or more [54]. The primary end-point was disability progression and the groups showed an equal rate of disability progression on EDSS. Only the number of new or enlarging T2-lesions at month 36 as compared with month 24 showed a difference favoring the 60 μg dose, whereas all other secondary end-points did not exhibit any difference between the 2 groups. An extension of the study showed no significant differences between the 2 doses over 48 months in any of the clinical end-points [55].
In the EVIDENCE study (EVidence of Interferon Dose-response: European North American Comparative Efficacy), IFN-β-1a SC 44 μg three times a week was compared with IFN-β-1a IM 30 μg once a week [56]. The primary end-point was the proportion of patients remaining free of relapses for 24 weeks, expressed as the odds ratio (OR). Over the initial 24 weeks of treatment, 75% of patients in the IFN-β-1a SC 44 μg three times a week group and 63% of those in the IFN-β-1a IM 30 μg once a week group remained relapse free. The OR, adjusted for center, was 1.9 (95% CI, 1.3 to 2.6; p = .0005).
After 24 weeks of treatment, patients randomized to IFN-β-1a SC 44 μg three times a week had a significantly lower relapse rate compared to the patients treated with IFN-β-1a IM 30 μg once a week, but at week 48, only a small and non-significant difference in relapse rate was observed. MRI outcomes at week 24 and 48 were in favor of IFN-β-1a SC 44 μg (Figure 3). The mean number of T2 active lesions per patients was significantly lower in the IFN-β-1a SC 44 μg group both at 24 and 48 weeks (see Figure 3). After 48 weeks, patients treated with IFN-β-1a IM were given the option of switching to IFN-β-1a 44 μg SC three times a week for a further 8 months. Patients who switched therapy showed a 50% relative reduction after crossing over to IFN-β-1a SC 44 μg, and these patients also had a 30% relative reduction in the proportion of active MRI scans. The study demonstrated that high-dose, high frequency IFN-β-1a SC had a significantly higher treatment effect than low dose, low frequency IFN-β-1a IM, at least after 24 weeks.
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Figure 3. Results from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study. (A.) Mean number of relapses at 24 weeks and 48 weeks. (B.) Mean number of T2 active lesions per patient per scan at 24 weeks and 48 weeks. |
The INdependent COMparison of INterferon Trial (INCOMIN) was a 2-year prospective randomized multicenter study, in which 188 patients with relapsing-remitting MS were randomized to interferon β-1b 250 μg SC every other day or IFN-β-1a IM 30 μg once a week [57]. The study included patients with relapsing-remitting MS, at least 2 documented relapses in the preceding 2 years, EDSS between 1 and 3.5, and no previous IFN-β treatment. The primary outcome measures were the proportion of relapse-free patients and patients free of new T2 lesions on MRI. After 2 years, 51% of patients treated with IFN-β-1b remained relapse-free compared with 36% of patients treated with IFN-β-1a, a relative risk reduction of 24% (p <.03). On T2-weighted MRI, 55% of patients treated with IFN-β-1b SC remained free of new lesions compared with 26% of patients in the IFN-β-1a group; a relative reduction of 53% (p <.0003). The annualized relapse rate was 0.5 in patients treated with IFN-β-1b compared to 0.7 in patients treated with IFN-β-1a; a relative reduction of 29% (p = .03). Also, progression of 1 point in the EDSS, sustained for 6 months and confirmed at the end of the study, which is actually the correct way of assessing changes in the EDSS score, showed a 56% risk reduction (p = .005) since progression was observed in 13% of IFN-β-1b treated patients and 30% of IFN-β-1a treated patients. The study corroborated the assumption that high-dose, high-frequency IFN-β administration has a better effect on clinical and in particular, MRI outcome measures than low-dose, low-frequency IFN-β.
Recently, a comparative study of IFN-β-1a SC 44 μg three times a week and glatiramer acetate 20 mg SC daily for 2 years (REGARD study) included 764 patients with relapsing-remitting MS and at least 1 relapse within the last 12 months [58]. The primary end-point was the time to first relapse. No difference between the 2 groups was found in the time to first relapse (hazard ratio 0.94, p = .64). The annualized relapse rates were also similar (0.30 for IFN-β-1a and 0.29 for glatiramer acetate), but were much lower than those reported in landmark trials of IFN-β or glatiramer acetate. Change in EDSS score was identical in the 2 groups. On MRI there were no significant differences in the number of new or enlarging T2 lesions over 96 weeks, the proportion of patients with no T2-active lesions over 96 weeks, or change in T2 lesion volume from baseline between the 2 treatment groups. However, the number of gadolinium enhancing lesions/patient/scan over 96 weeks was significantly lower in the IFN-β-1a group than in the glatiramer acetate group, 0.24 vs. 0.41, p = .0002. There was no difference in new T1-hyperintense lesions between the groups and, interestingly, there was less reduction in brain volume in the glatiramer acetate.
How should these results be interpreted? In all open head-to-head studies, there is a risk of introducing bias in favor of the preparation that is thought or hoped to be superior. Even with the most rigorous relapse criteria there will always be borderline events that are left to the investigators’ personal judgement to interpret. If the expectations of the sponsors or initiators of the trial are transferred to the investigators and their patients, the relapse rate in one group might be underestimated in non-blinded studies. However, the results of the REGARD study differ from the results of other previous randomized open-label head-to-head studies (INCOMIN study, EVIDENCE study). Undoubtedly, the study was initiated in order to provide evidence that IFN-β-1a SC was superior to glatiramer acetate, and although the choice of primary efficacy outcome might have introduced a bias against glatiramer acetate because it was thought to have a slower onset of action, no difference in favor of IFN-β was found in any of the clinical or MRI outcome measures apart from the number of gadolinium enhancing lesions. However, the low event rates in the REGARD study might have made the study statistically underpowered to detect small differences between treatment groups. Taken together with the results of the BEYOND study comparing IFN-β-1b 250 μg and 500 μg every other day with glatiramer acetate [59], the results of the REGARD study indicate that there are no signs of superiority in treatment efficacy of any IFN-β compared to glatiramer acetate.
COMBINATION STUDIES WITH IFN-β-1a
Treatment of relapsing-remitting MS with IFN-β is only partly effective, but safe. Hence, new, more effective and safe strategies are needed, and one of these is the add-on of a well-known oral drug to IFN-β.
The NORdic trial of oral Methylprednisolone as add-on therapy to IFN-β-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS) study compared the add-on of methylprednisolone with the add-on of placebo to IFN-β-1a SC [60]. Eligible patients had relapsing-remitting MS and had suffered at least one relapse within the previous 12 months despite treatment with subcutaneous IFN-β-1a 44 μg three times a week. A total of 130 patients were randomized to add-on therapy with 200 mg methylprednisolone (n=66) or matching placebo (n=64), both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary end-point was the annualized rate of documented relapse, and patients treated with methylprednisolone had a mean yearly relapse rate of 0.22 compared with 0.59 for placebo (62% relative reduction, p <.0001) (Figure 4). The time to increased disability of 1 point or more on EDSS confirmed at 6 months showed a non-statistically significant 36% relative reduction in the methylprednisolone group (16% with progression) compared with the placebo group (25% with progression). On T2-weighted MRI, the mean number of new or enlarging lesions/patient/year was 2.7 in the methylprednisolone group compared with 3.5 in the placebo group (relative reduction 23%, p = .24). The increase in T2 lesion volume was significantly lower in the methylprednisolone group compared to the placebo group (p = .045), whereas no difference was found regarding changes in the normalized brain parenchymal volume (Siena). Many patients had adverse effects related to methylprednisolone, and a large proportion of patients withdrew from the study before week 96 (26% on methylprednisolone vs. 17% on placebo). Sleep disturbances and neurological or psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Because of the high drop-out rates, a number of sensitivity analyses were performed and they all showed that the results were robust.
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Figure 4. Mean annualized relapse rates in the NORMIMS (Nordic trial of ORal Methylprednisolone as add-on therapy to Interferon-beta-1a for treatment of relapsing-remitting MS) study and the MECOMBIN (MEthylprednisolone in COMBination with INterferon-beta-1a for the treatment of relapsing-remitting multiple sclerosis) study. |
Recently, the results were corroborated in the larger MEthylprednisolone in COMBination with INterferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis (MECOMBIN) study that randomized 341 treatment naïve patients to receive either methylprednisolone 500 mg per day for 3 days monthly, or placebo for 3-4 years as add-on to IFN-β-1a IM [61]. The study was negative in terms of the primary end-point: time to onset of disability progression on EDSS sustained over 6 months, but there was a 38% relative reduction in the annualized relapse rate (methylprednisolone 0.205; placebo 0.333; p <.001) (Figure 4). Additional secondary end-points favored add-on of methylprednisolone: time to first relapse (p <.02), changes in T1 lesion volume (p <.05), and changes in T2 lesion volume (p <.02). The study showed the well-known adverse events related to high-dose corticosteroids, but interestingly a bone density DEXA-scan at month 39 did not show any difference between placebo treated patients and methylprednisolone treated patients.
In a third study, the combination of IFN-β-1a IM and methylprednisolone was used: The Avonex Combination Therapy Study (ACT) had a complex design with 4 treatment groups: IFN-β-1a IM 30 μg once a week combined with either 1) bimonthly IV methylprednisolone 1000 g daily for 3 consecutive days, 2) methotrexate 20 mg daily, 3) combination of the 2 drugs, or 4) placebo [62]. The duration of the study was only 12 months and the annualized relapse rate was originally the primary outcome measure. However, the trial was discontinued after 313 patients were enrolled, and the primary end-point was changed to the number of new or enlarging T2 lesions on MRI. Also in this study, the dropout rate was high. Several outcome measures favored methylprednisolone, although the differences were not statistically significant: relapse ratio 0.7 (p = .17), odds ratio of change in EDSS score 0.76 (p = .25), odds ratio of new or enlarging T2 lesions 0.74 (p = .18). The explanation of the negative result may be that the study was underpowered to show effects on clinical end-points and possibly, the reduced frequency of methylprednisolone administration.
LONG-TERM EFFECTS OF IFN-β-1a
Approximately 50% of the patients participating in the CHAMPS study were identified and took part in an observational follow-up study after 5 years. Patients who originally were treated with placebo in the CHAMPS study were considered to be a delayed treatment group and were compared with patients who received IFN-β-1a IM 30 μg once a week from the study start, called the immediate treatment group. The median time to initiation of IFN-β-1a therapy in the delayed treatment group was 29 months. The cumulative probability of developing clinically definite MS was significantly lower at 5 years in the immediate treatment group compared with the delayed treatment group (p = .03). A multivariate analysis suggested that the only factors which were independently associated with an increased rate of development of clinically definite MS were delay of treatment and younger age at onset. The weaknesses of this follow-up study were that it was not planned from the start and that only half of the patients were followed-up [63].
A long-term follow-up of patients in the PRISMS study was performed 7-8 years after randomization into the 2-year double-blind study [64]. The long-term follow-up was attended by 68.2% of the original PRISMS study cohort, of whom 72% were still receiving IFN-β-1a SC 3 times weekly. Patients originally randomized to IFN-β-1a 44 μg SC showed less progression on the EDSS, a lower relapse rate, and lower T2-burden of disease on MRI compared to those originally treated with placebo. Overall, 19.7% of patients had progressed into the secondary progressive phase of the disease.
Patients from a dose comparison study of IFN-β-1a IM 30 μg vs. 60 μg once a week were followed for 48 months [55]. A little more than 50% (446/802) completed the 48 months of treatment in follow-up and there were no significant differences between 30 μg and 60 μg weekly in any clinical endpoints including the rate of progression on the EDSS (48 and 43% respectively). In both groups, the annualized relapse rate tended to decrease over 48 months.
A 6-year observational study compared patients treated with IFN-β-1a 30 μg IM once a week and IFN-β-1b SC 250 μg every other day. A reduction in the relapse rate compared to pre-treatment relapse rate was observed in both groups, but there was no statistically significant difference between the groups (p = .43). Also the mean EDSS score was similar in both groups. The study was an open, non-randomized study, and bias regarding treatment allocation cannot be ruled out [65].
A post-marketing surveillance study of the long-term effect of IFN-β-1a IM was performed in patients with relapsing-remitting MS and followed patients for 3 years [66]. At this time, 31% of the patients had discontinued treatment or switched to another therapy, mainly due to disease activity. After 3 years, the mean EDSS had increased by 0.4 points compared to baseline. The authors concluded that the results confirmed the safety and suggested a sustained effectiveness of IFN-β-1a IM, but the results are difficult to interpret due to a drop-out of 1/3 of the patients.
It is difficult to draw any firm conclusions from the long-term follow-up studies, mainly due to incomplete patient ascertainment in the extension of the randomized study and because of possible selection bias and high dropout rates. Taken together with other studies on the long-term effect of immunomodulatory therapy [67], these studies, however, contribute to the paradigm that immunomodulatory therapy has changed the natural history of MS.
ADVERSE EFFECTS OF IFN-β-1a
The most frequently reported side effects of IFN-β-1a, administered both IM and SC, are the well-known IFN-β side-effects [34,42]. The flu-like symptoms, which may include headache, fatigue, myalgia, chills and fever, can in most patients be satisfactorily controlled by premedication with paracetamol or non-steroidal anti-inflammatory drugs (NSAID) just before the injection and if necessary, repeated after 4-6 hours. Many patients employ the strategy of taking the injection at bedtime in order to reduce side effects. With IFN-β-1a SC 44 μg three times a week, gradual titration of the dose over the first 3-4 weeks is recommended. Flu-like symptoms tend to get milder or disappear after 3-6 months. This is more conspicuous with IFN-β-1a SC three times a week than with IFN-β-1a IM once a week, probably because the more frequent injection induces tachyphylaxis over time [68]. After 1 year, only 5% of patients treated with IFN-β-1a SC 44 μg three times a week complained of flu-like symptoms compared to 30% with IFN-β-1a 30 μg once a week (Table 1) [68]. Injection related reactions (pain, erythema, inflammation, and in rare cases necrosis) are frequently seen with IFN-β-1a SC, but are rare with IFN-β-1a IM [69]. The new formulation of IFN-β-1a SC 44 μg has reduced the incidence of injection related reactions, but increased the occurrence of flu-like symptoms [70].
 |
TABLE 1. Frequency of adverse effects occurring at 3 and 12 months (mo) in patients treated with IFN-β-1a. Skin or injection problems include both problems and pain associated with the injection and injection site reactions
(Adapted with permission from Sorensen PS, Koch-Henriksen N, Ravnborg M, et al. Immunomodulatory treatment of multiple sclerosis in Denmark: a prospective nationwide survey. Mult Scler 2006;12:253-264)
|
Also non-symptomatic elevation of alanine amino-transferase occurs frequently (up to 30% of patients) and is the most common abnormal laboratory test. Elevated liver enzymes (WHO ≥ grade 2 [71]) occurred in 1.9% of patients treated with IFN-β-1a IM and with an incidence of 6.6% in IFN-β-1a SC treated patients [72]. Elevation of liver enzymes occurs most frequently during the first 3-6 months of treatment. After 2 years, 11% of patients treated with subcutaneous IFN-β-1a 44 μg 3 three times a week had elevated alanine aminotransferase [73]. Elevation of liver enzymes is dose related and usually resolves spontaneously or with dose adjustment. The risk of developing liver test abnormalities is highest in patients with pre-existing liver abnormalities [73]. Rarely, symptomatic liver involvement with jaundice or elevation to WHO grade 3 occurs and even fulminant liver necrosis has been reported [74].
In the EVIDENCE study, the incidence of injection related reactions and elevated liver enzymes was higher with IFN-β-1a 44 μg SC three times a week than with IFN-β-1a 30 μg IM once a week. However, few patients experienced serious adverse events (AEs) (6% vs. 5%, respectively) or discontinued the study because of AEs (4.7% vs. 4.2%, respectively) [56].
Other side-effects included mild asymptomatic and reversible hematological abnormalities, particularly during the first month when the white blood cell count is frequently lowered [34,42].
Treatment with IFN-β-1a requires periodic surveillance with blood tests for liver function and hematology.
Thyroid dysfunction occurs frequently during therapy with IFN-β-1a, both hypothyroidism and hyperthyroidism, but is most frequently subclinical and often transient [75]. Pre-existing or incident autoimmunity is predictive for thyroid dysfunction development.
Rare adverse events include depression, which, however, was not reported more frequently with IFN-β-1a than with placebo in clinical trials [34,42].
NEUTRALIZING ANTIBODIES
Like all other biopharmaceuticals, IFN-β-1a is immunogenic and can induce the formation of binding and neutralizing antibodies (NAbs) [11,42,76-80]. The immunogenicity is dependent on the conformation of the recombinant IFN-β, but also on impurities and contamination originating from bacterial or mammalian cells, and the presence of aggregates is associated with induction of antibodies. The new formulation of IFN-β-1a SC has reduced immunogenicity significantly compared to the preparation used in the EVIDENCE and REGARD studies [70]. The frequency of NAbs at any time was reduced to 18.9% and at 24 months to 17.4% [70] compared with 24.3% in a pooled estimate of the proportion of NAb positive patients in the EVIDENCE [56] and REGARD [58] studies. NAbs are usually measured with a cytopathic effect assay that utilizes the protective effect of IFN-β on cells in a cell culture that is challenged with a lethal virus or an MxA assay that measures the production of MxA, either at the mRNA or protein level, when cells are stimulated by IFN-β [81].
The presence of NAbs diminishes the effect of IFN-β-1a [82] or at high concentrations, abolishes the effect, because it prevents the IFN-β molecule from binding to its receptor, which is a prerequisite for a biological response to IFN-β. NAbs usually occur 6-12 (18) months after start of IFN-β therapy [83]. Initially, antibodies have low affinity and may even be beneficial with a kind of chaperone effect that prevents the IFN-β molecule from degradation [84]. However, with affinity maturation, NAbs bind irreversibly to the IFN-β molecule and neutralize the effect. NAbs may disappear during continuous treatment with IFN-β, which in fact takes place more often with IFN-β-1b than with IFN-β-1a [83]. When NAb disappears, the effect of IFN-β is restored [85]. However, NAbs at high titers tend to be present for several years, whereas low-titer NAbs are more likely to disappear [86]. After discontinuation of IFN-β therapy, NAbs may be present for several years due to antibody production by long-lived plasma cells [87].
There has been debate regarding the detrimental effects of NAbs on treatment efficacy [88,89]. The main reasons have been ignorance of the dynamics of NAbs and studies that have been either too short or have lacked statistical power to test the effects of NAbs [90]. There is now consensus that NAbs reduce the therapeutic effect, both on relapses and on disease activity seen on MRI [91]. The negative effect of NAbs was already observed in the pivotal trial of IFN-β-1b, and in the PRISMS-4 trial, patients with NAbs had significantly higher relapse rates and MRI activity compared with NAb negative patients [43,92]. Post-hoc analyses disclosed that NAb positive patients experienced greater disability progression [92].
In fact, all major clinical trials in relapsing-remitting and secondary progressive MS of more than 2 years duration have shown that NAbs are associated with a reduction in treatment effect on relapses and MRI end-points (Table 2) [90]. Comparative studies have shown that IFN-β-1a IM is the least immunogenic preparation and that the frequency of injections is a major determinant for immunogenicity, whereas the dose of the single injection plays a minor role [82]. Recently, in vivo testing of IFN-β bioactivity has been introduced. The test measures the increase of MxA expression in peripheral blood mononuclear cells [93,94]. An absent MxA mRNA response indicates that induction of any of the hundreds of IFN-β inducible genes has been abolished and no signs of IFN-β bioactivity are left [95].
 |
TABLE 2. Frequencies of neutralizing antibodies (NAbs) in major studies of IFN-β therapy in patients with relapsing remitting and secondary progressive MS
(Adapted with permission from Hesse D, Sorensen PS. Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy. Eur J Neurol 2007;14:850-859) |
CHOICE BETWEEN IFN-β PREPARATIONS
All IFN-β preparations have a moderate effect on clinical disease activity and disease progression and a more pronounced effect on disease activity seen on MRI. The choice of IFN-β preparation is usually made taking into consideration convenience, efficacy, side-effects and immunogenicity.
IFN-β-1a 30 μg is administered once weekly, but intramuscularly, while IFN-β-1a 44 μg must be taken 3 times weekly, but subcutaneously. Head-to-head comparison studies have shown that high-dose interferon, particularly during the first 6 months of therapy, had a stronger effect on relapse rates and MRI efficacy measures [56]. However, head-to-head studies are difficult to interpret because patients, and in some studies, investigators, were not blinded to treatment group. Further, the dose-comparison study of IFN-β-1a IM 30 μg vs. 60 μg once weekly did not show any superior beneficial effects of the higher dose as compared to the lower dose [54]. Flu-like symptoms occur more frequently and for a longer period with IFN-β-1a IM compared to IFN-β-1a SC, whereas injection site reactions are more frequent with IFN-β-1a SC than with IFN-β-1a IM. However, with the new preparation of IFN-β-1a 44 μg SC, it seems like flu-like symptoms were more frequent and injection site reactions less frequent than with the old preparation [70]. The propensity for development of NAbs is higher with IFN-β-1a SC, although the new preparation is less immunogenic than the older preparation [70]. According to pharmaceutical company sponsored studies, NAbs occur in approximately 2-4% in patients treated with IFN-β-1a IM [54] compared to 18% in patients treated with IFN-β-1a SC [70]. Comparative trials showed NAbs after 24 months in 8.5% of patients treated with IFN-β-1a IM compared to 41.7% in patients treated with IFN-β-1a 22 µg SC three times a week (old preparation) [82].
The choice of product can vary from patient to patient and is based on the relative importance put on convenience, efficacy and risk of NAbs.
CURRENT STATUS OF IFN-β IN THE MANAGEMENT OF MS
Since 1993 IFN-β has been the mainstay in the treatment of relapsing-remitting MS. Together with glatiramer acetate, the different IFN-β preparations are first-line therapies in patients with relapsing-remitting MS and in patients with clinically isolated syndromes at high risk of developing clinically definite MS. Only a few patients are candidates for a more aggressive therapy from the start, either with natalizumab or with mitoxantrone induction followed by either IFN-β or glatiramer acetate. In patients who experience side-effects from IFN-β-1a SC or IM, an alternative IFN-β preparation can be tried or the patient can switch treatment to glatiramer acetate.
There are many algorithms for the treatment of patients with a suboptimal response to IFN-β. Some algorithms suggest a switch to a high frequency IFN-β preparation if patients have a suboptimal treatment response to IFN-β-1a IM, and patients with unacceptable disease activity on any IFN-β preparation may be switched to glatiramer acetate. There is, however, only limited evidence of a better therapeutic effect after switching therapy between the various first-line disease modifying drugs. A new option is add-on of methylprednisolone to patients with disease activity during treatment with IFN-β-1a [60,61].
The second-line treatments, natalizumab and mitoxantrone, are more efficacious, but carry the risk of serious adverse effects. The risk of acute leukemia in patients treated with mitoxantrone is about 1:100 [96], and the risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab is currently estimated to be 1:1000, but may actually be somewhat greater [97].
Currently, IFN-β-1a is still the most commonly used drug for the treatment of relapsing-remitting MS.
FUTURE POSITION OF IFN-β IN THE MANAGEMENT OF MS
New formulations of IFN-β-1a are currently being tested including pegylated IFN-β-1a. Pegylation of interferon-alpha has been successfully used to improve the pharmacokinetic properties and efficacies of the drug. Pegylated forms of IFN-β may increase the efficacy, reduce side-effects and reduce the frequency of administration.
Within the next 4 or 5 years, several new disease modifying drugs for MS will appear on the market. These include new monoclonal antibodies and oral therapies. The new monoclonal antibodies, rituximab and other anti-CD20 monoclonal antibodies, daclizumab, and alemtuzumab are very efficacious, but have a safety profile that makes it more likely that they will be relegated to second-line and not first-line drug therapy for the majority of MS patients. The oral preparations cladribine and fingolimod are expected to be the first oral therapies on the market for treatment of MS. Both drugs have shown efficacy in phase 2 and phase 3 trials, and the short-term safety profile looks favorable. However, the phase 3 placebo-controlled trials showed that these drugs may be associated with serious infections or may increase the risk of malignancies. With these new drugs, the benefits will need to be weighed against the risks, and extended long-term observation will be required to establish the safety beyond 2 years. Laquinimod, BG-12 (fumarate) and teriflunomide are oral treatments that appear safe and these drugs may be preferred first-line therapies if phase 3 trials show that the efficacy is comparable to that of the present first-line therapies.
CONCLUSION
Clinical trials have demonstrated that both IFN-β-1a IM and IFN-β-1a SC reduce the frequency of relapses and slow disability progression significantly in patients with relapsing-remitting MS, and delay the time to clinically definite MS in patients with clinically isolated syndromes. For the next 3 or 4 years, IFN-β-1a will probably still be the drug of choice for many patients starting therapy with a disease-modifying drug. The next 6 to 12 months will provide a more precise risk of PML in patients treated with natalizumab and will determine whether this drug will stay a second-line therapy or whether more patients will be treated with natalizumab as the first disease modifying drug. The long-term safety profile of cladribine and fingolimod will not be known for the next 2 or 3 years and, hence, until the long-term safety profile is clarified, these drugs will probably not be used in Western Europe and the United States as the first choice in the typical MS patient who is young and has no or only mild disability, but will be reserved for patients with aggressive relapsing-remitting MS or as second-line therapy in patients who fail first-line therapies.
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