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CNS & Neurological Disorders - Drug Targets, 2012, 11, 000-000 1 Disease Modifying Drugs in Multiple Sclerosis: Mechanisms of Action and New Drugs in the Horizon Monica Marta*,1 and Gavin Giovannoni1 1 Queen Mary University of London, Blizard Institute, Barts & The London School of Medicine and Dentistry, London, UK Abstract: The term “disease modifying drugs” (DMD) is taken from rheumatologists who coined it after the use of immunosuppressive drugs and, more recently, the association of “biological drugs” that changed the degenerative course of rheumatic disease. In the treatment of multiple sclerosis (MS), the advent of interferon (IFN), which caused a reduction in the number of relapses and possibly improvement in disability outcomes, was the first strategy to prevent inflammatory damage in the central nervous system (CNS). Soon after, glatiramer acetate showed similar results. It would be more than a decade before natalizumab was licensed, showing a much better efficiency in relapse reduction than was seen after first-line therapies failed. The pipeline is now much larger with several drugs on the horizon. Overall, the anti-inflammatory strategy has been mostly successful but drugs that have protection and repair mechanisms are still missing. Keywords: multiple sclerosis, treatments, mechanisms of action FIRST-LINE DISEASE MODIFYING DRUGS Mechanisms of Action Interferon- Since IFN- was shown to have a beneficial effect in MS, its mechanisms of action have been investigated, but the biological effects are wide and can be opposing in different cell types. Interferons are naturally occurring glycoproteins that function as signals between cells -hence called cytokines. They have roles in hematopoiesis and innate and acquired immunity to infection, cancer and autoimmunity through the activation of immune cells, increased recognition of infected or tumour cells by upregulation of antigen presentation and other mechanisms. In humans, IFNs are divided into three groups: type I IFNs include IFN- , IFN- and IFN-, type II IFNs include IFN- , and type III IFNs include IL10R2 and CRF2-12 [1]. The IFNs pathways are central to innate immunity mechanisms and are activated upon ligation of pathogen- and danger-associated molecular patterns (PAMP and DAMP) to pattern recognition receptors (PRR). The toll-like receptor (TLR)-dependent expression of IFN- is one of the links between innate and adaptive immunity, as type I IFN (IFNAR1 and IFNAR2c) are present in antigen presenting cells but also T-cells. Type I IFNs also induce the synthesis of several key antiviral mediators including 2'-5' oligoadenylate synthetase (2'-5'OAS), 2-microglobulin, neopterin and protein kinase receptor (PKR). For commercial use, human IFN- 1a is produced in mammalian cells (Chinese Hamster Ovary cells), has 166 residues and is glycosylated like mammalian proteins. On the other hand, human IFN- 1b is produced in E. coli, has no carbohydrates on any of the 165 residues, and there is a substitution of cysteine 17 with serine in comparison with the naturally occurring IFN- 1a. *Address correspondence to this author at the Barts & The London School of Medicine and Dentistry, London, UK; Tel: ++44 20 78822677; Fax: +44 20 78822180; E-mail: [email protected] 1871-5273/12 $58.00+.00 Overall, we currently consider there are inhibitory effects on proliferation of leukocytes and less efficient antigen presentation. Furthermore, IFN- modulates the profile of cytokine production toward that of the anti-inflammatory phenotype, and this appears to occur not only in the systemic compartment but also within the CNS. Finally, IFN- can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases (MMP) [2]. In vitro studies show that IFN- inhibits the proliferation of T-cells, and reduces T-cell production of IFN- and tumour necrosis factor (TNF)-[3]. Surprisingly, it increases interleukin (IL)-6 production in peripheral blood mononuclear cells (PBMC) of MS patients [4] but decreases the number of circulating IFN- and IL-4 producing T-cells over time [5], simultaneously prolonging the survival of memory T-cells. When subsets of PBMCs were analyzed, IFN- showed regulatory effects on CD4+ T-cells production of osteopontin, IL-17 and IL-21 in MS patients when compared with healthy controls (HC) [5]. A major change in the interpretation of the studies came when the T-helper (Th) 1 versus Th2 dogma was challenged and Th17 cells were shown to be involved in the pathology of MS. In a longitudinal follow-up of 18 MS patients treated with IFN- , Th17 cells were generally inhibited by IFNand their numbers were higher in active in comparison with inactive MS [6]. In response to IFN- , IFN- receptor 1 expression, STAT (signal transducers and activators of transcription)-1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. A recent study detected induction of apoptosis in specific leukocyte subsets and enhanced expression of TNFSF10 (TRAIL) (which © 2012 Bentham Science Publishers 2 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 sensitizes cells to apoptosis) on monocytes and granulocytes was proposed as a response marker [7]. Changes were detected not only at the cellular level but could also be detected in serum samples. A one year prospective study showed that serum MMP-8, MMP-9, IL12p40 and IL-23, but not IL-17, were decreased in MS patients treated with IFN-1b; this laboratorial feature correlated with a decrease in the number of contrastenhanced T1 magnetic resonance imaging (MRI) lesions [8]. IFNdecrease the permeability of the blood brain barrier (BBB). Serum from IFN- 1b-treated patients with early MS stabilized an in vitro model of the BBB [9]. Indeed, IFNregulates CD73 and adenosine expression on the BBB [10]. Importantly, the mechanisms of reduction of lymphocyte transmigration through the BBB are currently better understood and are affected by IFN- . Transmigration involves increased expression of ecto-5'nucleotidase both on the BBB and astrocytes. CD73 is required for efficient entry of lymphocytes into the CNS system during experimental autoimmune encephalomyelitis (EAE) and is strongly expressed in the microvasculature in postmortem MS brains [11]. After many studies in MS and experimental autoimmune encephalomyelitis (EAE), the reason why IFN- works in some MS patients but not on others is still unknown. In fact, except for some recent publications [12-14] that identify an IFN pathway signature in MS patients who are nonresponders or responders, the initiation of therapy is still a trial. Clinical Trials of IFN- in Patients with Relapsing MS (Table 1) The initial clinical trial for IFN- in relapsing-remitting (RR)MS eventually led to the licensing of IFN- 1b 250 μg subcutaneous every other day (SC eod) (Betaseron in USA and Betaferon in Europe) in this stage of disease [15, 16]. A trial with IFN-1a 30 μg intramuscular (IM) weekly (Avonex ) followed and the results were similarly encouraging [17-19], with the benefit of being a drug closer to the naturally occurring IFNs but also with a once weekly formulation that constitutes an appealing feature. The same IFN- 1a 22-44 μg three times per week (ttw) was later used in a high dose/ high frequency (HD-HF) scheme formulation (Rebif ); the clinical trial enrolled the largest number of RRMS patients and had positive effects in relapse rate and MRI markers) [20, 21]. Another trial was performed to compare the effect of the two formulations of IFN- 1a, Avonex and Rebif . Only when higher dose/ higher frequency Rebif showed better results was it licensed by the Food and Drug Administration (FDA) [22]. The long-term follow up studies tend to follow mostly patients who stayed on medication, who were the ones who were most likely to have benefited from the drug [23-24]. In clinical practice, the safety of all IFN- drugs in the short term is a critical point. There are risks of lymphopenia and rarely neutropenia, which are not associated with a higher frequency of viral, bacterial or fungal infections. There is a risk of hepatic toxicity that is usually mild but can be severe when not detected and may need steroid treatment. Marta et al. Regular blood tests, including full blood counts and liver function tests, are required and when an abnormality is detected and deemed clinically significant, the dose is reduced or the medication is temporarily suspended. In most cases, IFN- can be reintroduced when the values return to normal. The most common side-effects, almost in every person in the initial injections, are flu-like symptoms. These can be improved with pain killers, and anti-pyrexials such as nonsteroidal anti-inflammatories and paracetamol, and tend to improve after about 3 months, but constitute an important cause for discontinuation of therapy. Injection site reactions are also very common, with different size erythematous and oedematous lesions that can be pruriginous and last 2-20 days, very rarely leaving any scars. Strategies that include rotation of injection sites, room temperature injections for formulations that need to be kept cold, local ice postinjection and moisturizing creams are helpful. The benefit of IFN- drugs in RRMS patients is accepted by most neurologists and the regulatory authorities, and current trials in these patients rarely use placebo arms. The benefit for individual patients is sometimes difficult to assess as the course of MS is unpredictable and disease can be clinically dormant for several years. Also, there is no data to predict a positive response or failure of treatment beforehand. A close clinical and imaging observation after about one year can predict the longer term benefit: new significant clinical relapses, new MRI lesions and the occurrence of both are signs of treatment failure and good indicators for a medication switch. Clinical Trials of IFN- in Patients with Clinically Isolated Syndrome (Table 2) The effect of IFN- s in patients with clinically isolated syndrome (CIS) suggestive of MS has been tested and the clinical trials described below have shown general benefits in the rate of conversion to clinically definitive (CD) MS, time to conversion to CDMS, and MRI markers. Depending on the countries, the results have been more difficult to translate to clinical practise. A placebo-controlled trial of IFN-1b (Betaseron /Betaferon ) early after CIS compared with IFN-1b after CDMS showed benefit of early treatment in measures related to conversion to CDMS. Important information was gained from a late subgroup analysis [23, 27] that showed that the risk of developing CDMS was greater in patients who were on placebo (45%), who had positive CSF (49%), had needed high dose steroid treatment for the attack (48%) or if they were younger (<30 years 60%). The characteristics of the MRI that increased the risk of CDMS for patients who were on placebo were: nine or more MRI T2-lesions (48%) or one or more Gad-enhancing T1 lesions (52%) or higher if they had both (75%). Interestingly, five years after enrolment, a delay in treatment by up to two years did not affect long-term disability outcomes [26, 29-30]. IFN- 1a (Avonex ) was compared with placebo after a CIS with characteristics of demyelination and at least two characteristic T2 brain MRI lesions in the CHAMPS study [27]. The trial was stopped after a preplanned interim analysis showed benefit of the active arm in the delayed development of CDMS and less brain MRI Recent Gains in Clinical Multiple Sclerosis Research CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 3 Table 1. Clinical Trials of IFN- in Patients with Relapsing MS 1. Betaferon - IFN- 1b Randomized Double-blind Placebocontrolled 372 RRMS patients EDSS <5.5 2 attacks in prior 2 years Placebo or 1.6MIU=50μg 8MIU=250μg SC EOD 2 years 2 attacks in prior 3 years Placebo or IFN 1-a 6MIU=30μg/wee k IM 2 years But only 172 at 2 years Relapse rate reduction IFN 1-b vs placebo: 34%, p<0.0001 MRI medium number T2 active lesions: -83%, p<0.009 15-16 MRI T2 median disease burden -17.3%, p<0.16 2. Avonex - IFN- 1a Multicentre Randomized Placebocontrolled 301 RRMS patients EDSS 1-3.5 1-point EDSS progression rate: -37% p<0.02 Relapse rate reduction: 18% p<0.04 MRI medium number of Gad enhancing lesions: 33%, p<0.05 MRI total volume of T2 lesion: ns 17-19 3. Rebif - IFN- 1a PRISMS (Prevention of Relapses and Disability by IFNbeta1a Subcutaneously in Multiple Sclerosis) Multicentre Randomized Double-blind Placebocontrolled Blinded Long-term follow-up Unblinded 560 RRMS patients EDSS <5.5 2 attacks in prior 2 years Placebo or 6MIU=22μg or 12MIU=44μg ttw Placebo started on 44μg TTW 2 years 4 years 7-8 years post baseline 382/560 initial RRMS Relapse rate reduction 44μg TTW vs placebo: 32%, p<0.005 1-point EDSS progression rate: -30% p<0.05 Sustained clinical (relapse rate and disability progression) benefit from the two doses Patients earlier on 44μg TTW showed lower EDSS progression and relapse rate 75/381 were SPMS MRI medium number of active T2 lesions: -78%, p<0.0001 20 Volume of T2 white matter disease: -14.7%, p<0.0001 Sustained MRI benefit from both doses but 21 better with 44μg TTW Patients earlier on 44μg TTW showed lower T2 burden of disease 23 4. Rebif - IFN 1-a EVIDENCE (Evidence of Interferon Dose Response: European North American Comparative Efficacy) Randomized Controlled Assessor blinded Parallel-group 677 RRMS patients EDSS<6.0 2 attacks in prior 2 years IFN 1-a 44μg ttw SC vs 30μg/week IM 24 and 48 weeks 24 weeks: 75% patients on 44μg TTW vs 63% patients on IM 30μg/week were relapse free 48 weeks: the odds-ratio of remaining relapse free on 44μg TTW decreased from 90% at 24 weeks to 50% Combined MRI measure (new or enlarging T2 lesions and T1 Gadenhancing lesions) and use of steroids, time to first relapse and disability progression were improved on higher dose 22 5. Copaxone - Glatiramer Acetate (GA) Randomized Double-blind Placebocontrolled Multicentre 251 RRMS patients All on 20mg GA SC blinded Open-label Placebo or 20mg GA SC 208 MS patients All on 20mg GA SC 2 years Reduction in relapse rate (29%, p=0.07), annualized rate was 0.59 on GA and 0.84 on placebo Reduced median time to first relapse Further 1-11 months Confirmed reduced relapse rate (the relapse rate for the switch from placebo to GA decreased) and slower neurological disability 35 Risk of T1 Gadenhancing lesions was 2.5 higher and cerebral atrophy worse for patients on prior placebo 36 MRI features of 69 patients who were initially on GA and 66 36 months 37-38 patients initially on placebo with no major differences 4 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 Runia et al. (Table 1) contd….. 6. Copaxone - Glatiramer Acetate (GA) Randomized Double-blind Placebocontrolled Long term follow-up 239 RRMS patients At least 1 relapse in prior 2 years and T1 Gadenhancing lesion 142 patients 73 patient initially treated with GA Placebo or 20mgGA SC 9/12 blinded followed by 9/12 open label with 224 patients All on 20mgGA Mean 5.8 years (5.36.4) Total number of Gadenhancing lesions on monthly brain MRI (1ry end-point) was reduced (-10.8%, p=0.003) in GA treated group. Benefit for 39 GA group in proportion of patients with Gadenhancing lesions, number of new T2 lesions and change in volume of T1-weighted lesions. Proportion of patients who had EDSS<6.0 was lower in group initially treated with placebo. MRI measures similar in group initially on GA and initially on placebo. 40 the 96 patients on IFN- 1b showed less new MRI active lesions 34,44 Head-to-Head Studies 7. INCOMIN Randomized open-label IFN- 1b 250μg EOD SC vs IFN1a 30μg week IM RRMS No differences between the two therapies during the initial 6 months; the benefit 2 years of the high dose-high frequency only detected at one and two years 8. EVIDENCE IFN- 1a 44μg SC ttw and IFN- 1a 30μg/week IM Randomized open-label 1-2 years Significant benefit of IFN1a 44μg SC ttw IFN- 1a over 30μg/week IM during 22 the initial 24 weeks, but not maintained for the following 24 weeks 9. Danish Study Randomized Open-label 303 RRMS patients of IFN- : 8 MIU 1b SC every other day with 6 MIU IFN- 1a SC every week No difference was recorded in any clinical outcome measure between the two doses of IFN- MRI outcomes suggested that the higher dose of 45 IFN- 1b might be superior 10. REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) Randomized Open-label Sub-study 764 RRMS patients 230 patients one or more relapses in the prior 12 months no significant difference in the time to first relapse IFN- 1a 44 μg SC ttw or GA 20μg SC daily 46 (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64) patients on IFN- 1a had significantly fewer brain Gad-enhancing T1 MRI lesions than patients on GA (0.24 vs 0.41 lesions per patient per scan, 95% CI -0.4 to 0.1; p=0.0002) In REGARD study 11. BEYOND Prospective randomized IFN- 1b SC eod 250μg or 500μg vs GA 20μg SC daily 2244 RRMS patients 2-3.5 years No differences in relapse risk, EDSS progression, T1-hypointense lesion 47 volume, or normalised brain volume among treatment groups 12. BECOME Randomized 75 RRMS or CIS patients triple-dose Gadolinium and 3-Tesla MRI IFN- 1b SC eod 250μg vs GA 20μg SC daily 2 years No differences in clinical exacerbations over 2 years No significant differences in combined active lesions: all enhancing lesions and non-enhancing new T2/fluid-attenuated inversion recovery lesions. 48 Recent Gains in Clinical Multiple Sclerosis Research changes. This study showed the benefit of IFN- 1a independent of clinical syndrome, brain MRI or combined clinical-MRI outcomes [28]. More than half of the patients from both the delayed (DT) and immediate treatment (IT) groups enrolled in the CHAMPIONS study that compared clinical features and MRI characteristics of patients 5 years post-CHAMPS randomization. Overall, 28% of patients who enrolled in CHAMPIONS had developed CDMS during the 2 years of CHAMPS study. The cumulative probability of developing CDMS was lower for the IT group (36% 9 versus 49% 10; p<0.03) and few patients in either group developed major disability after 5 years; most patients (71%) had an (expanded disability scale score) EDSS < 1.5 and 13% had an EDSS> 2.5 [29]. Over the years there have been changes to the definition of CIS and the risk of development of CDMS that some clinical and MRI features entail. This prompted a reanalysis of CHAMPS data, which confirmed the beneficial effect of IFN1a in delaying conversion to CDMS irrespective of the characteristics of CIS [30]. The following trial in CIS (ETOMS or Early Treatment Of Multiple sclerosis Study group) [31] randomized patients to 22 μg IFN- 1a SC ttw (not 44 μg) or placebo. Patients in the active arm group had a lower conversion to CDMS and better Scripps Neurologic Rating Scale score and MRI measures. For the first time, MRI measures showed a reduction of the progressive brain volume loss with early treatment [32], although this was only detected in a post-hoc study. The results from ETOMS were quite noteworthy as the patients enrolled had more active disease (multifocal onset was possible and MRI with more lesions), the patients were followed longer, and the efficacy was maintained. There is an ongoing debate whether a high dose-high frequency (HD-HF) of IFN- causes a significant difference in the efficacy of therapy both for RRMS and CIS. ETOMS used a lower dose of IFN- than that approved for use in RRMS and showed that it is effective in CIS patients, in contrast to data obtained in RRMS patients. Data from the two years REFLEX phase III study (Rebif Flexible Dosing in Early MS - a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI) show the benefit of even lower doses, as both doses delayed clinical relapses and MRI activity [33]. The INCOMIN [34] and EVIDENCE [22] studies, described below, show a limited benefit from HD-HF that was not statistically sound. In clinical practice it is most often a compromise between the formulations that best adapt to the balance between perception of risk and life-style choices that dictates which formulation to choose. Glatiramer Acetate in MS and CIS (Tables 1 and 2) Glatiramer acetate (GA - Copaxone ) is a random polymer of glutamate, lysine, alanine and tyrosine, four amino acids found in myelin basic protein. The proposed mechanisms of action for GA include shifts of T-cells from pro-inflammatory Th1 phenotype to Th2 less aggressive phenotypes that suppress the inflammatory response; and a possible diversion of an autoimmune response against myelin. The function of the BBB does not seem affected. Overall, there are very few scientific clues as to the effect of GA in MS. CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 5 The efficacy of GA in patients with RRMS was shown in several trials detailed in Table 1. The initial placebocontrolled trial in RRMS patients showed a 29% reduction (p=0.07) of relapse rate in the patients who were on GA. The proportion of patients who did not have a relapse and the median time to first relapse was improved by GA, and the risk of worsening neurological disability was worse in the placebo group [35]. This study had a blinded extension phase where the benefit of GA was confirmed for reduced relapse rate and slowing of neurological disability [36]. An openlabel extension study followed all 208 RRMS patients on GA every six months and/or when a relapse was suspected [37]. Interestingly, the mean annualized relapse rate (ARR) of the patients who had GA initially was 0.42 (95% confidence interval (CI)=0.34 - 0.51) and the rate/year dropped to 0.23 on the 6th year [38]. The available brain MRI scans showed no major differences between the two groups. Furthermore, the ongoing follow-up study to this original pivotal GA trial, now extending beyond 15 years, continues to support the safety of GA. A second placebo-controlled trial of GA assessed RRMS patients clinically and with MRI monthly over nine months and again showed a reduction in relapse rate by 33%, as well as a reduction in number of Gad- enhancing T1 and other MRI lesions [39]. Finally, long-term follow-up clinical and MRI evaluations were done after a mean of 5.8 years. The MRI measures were similar in both initially GA treated and initially placebo groups, but the proportion of patients who had EDSS <6.0 was lower in the latter group (P=0.034) [40]. The efficacy of GA in patients with CIS was established recently (the PreCISe trial) (Table 2). Patients with a CIS with unifocal manifestation and at least two T2-weighted brain MRI lesions >5 mm were assessed for 36 months or up to CDMS conversion. GA reduced the risk to CDMS conversion by 45% compared to placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005) [41]. It is worth noting that for some experts, the evidence that early treatment (after CIS) with GA or IFN- reduces conversion to CDMS, relapse rate and evidence for MS activity on MRI, does not outweigh the side-effects and costs. This is mainly because of the lack of strong evidence that supports a reduced disability progression in the longterm. Head-to-Head Studies (Table 1) Studies that directly compare two drugs are considered the best way to determine which has the best efficacy. These studies are usually flawed by the natural assumption that one is better and there can be a bias towards the favourite drug. In particular in MS, borderline events are the responsibility and interpretation ultimately of the investigators, even after blinded assessors are used [42]. Further, the ARR of patients on IFN- in the initial trials was between 0 6 and 0 8; in subsequent trials, patients on IFN- have relapse rates of 0 2-0 3 per year. This can reflect the fact that MS patients are being enrolled and exposed to treatments earlier or with milder disease in view of the relatively mild long-term associated risks [43], and has necessarily affected the power calculations of recent studies. 6 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 Runia et al. Table 2. Clinical Trials of IFN- in Patients with Clinical Isolated Syndrome 1. Betaferon IFN- 1b BENEFIT (Betaseron in Newly Emerging MS for Initial Treatment) Multicentre Randomized Blinded Follow-up at the end 468 CIS patients EDSS <5.5 2 attacks in prior 2 years 358 postBENEFIT patients Placebo until relapse (176) 2-3.5 years IFNb1b 250μg Sub-cut EOD (292) 123 Initial placebo 235 initial IFNb1b Relapse rate reduction IFN vs placebo: -34%, p<0.0001 5 years after initial randomization MRI medium number T2 active lesions: -83%, p<0.009 24 MRI T2 median disease burden -17.3%, p<0.16 Early treatment reduced risk of CDMS by 37% (HR- 0.63, 95% CI 0.48-0.83, p=0.003). No change in disability outcome for delayed treatment 26 2. Avonex IFN- 1a CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study) Randomized Double-blind 383 CIS patients >1 characteristic T2 lesion in brain MRI High dose IV steroid in all Placebo (DT) 30μg/week IM (IT) Stopped after planned interim analysis Lower probability to develop CDMS in IFNb1a (0.56%, 95% CI 0.38-0.81, p=0.002) Reduction of volume of brain T2 lesions (p<0.001) and fewer T1 Gadenhancing lesions 27-28 IT after monofocal CIS delayed CDMS (p=0.0013) irrespective of presence of T1 Gad-enhancing lesions 29-30 Reduction of progression of brain volume loss with early treatment 31-32 Avonex CHAMPIONS (Post-CHAMPS) 203 postCHAMPS patients Included patients who had stopped IFNb1a and 28% were CDMS after CHAMPS DT (100 of 190) and IT (103 of 193) CHAMPS patients 5 years after initial randomization Lower probability to develop CDMS (IT= 36% 9 vs DT= 49% 10; p<0.03) Disability levels (EDSS) were low in both groups (71% had EDSS<1.5) 3. Rebif IFN- 1a ETOMS (Early Treatment of Multiple Sclerosis Study Group) Lower probability to convert to CDMS with IFNb1a (34% vs 45%, p=0.047) Longer time to convert to CDMS on IFNb1a (569 vs 252 days) Placebo 309 patients with CIS suggestive of MS 6MIU=22μg Sub-cut TTW TTW=3X/week 4. Copaxone - Glatiramer Acetate (GA) - PreCISe Trial Multicentre Randomized Double-blind 481 CIS patients with focal manifestation >1 T2 brain lesions (at least 6mm diameter) 20mg GA sub-cut daily INCOMIN [34] compared IFN- 1b (Betaferon ) with IFN- 1a (Avonex ) in RRMS patients for 2-years and EVIDENCE [22] compared two IFN- 1a treatment regimens in MS (44 μg Rebif and 30 μg Avonex ) for 1-2 years. INCOMIN showed the benefit of the HD-HF at one and two years, not 6 months, and the clinical results were supported 36 months or up to CDMS conversion Risk of CDMS conversion was decreased by 45% (HR 0.55, 95% CI 0.40-0.77, p=0.0005) in GA treated group vs placebo 41 by MRI outcomes [44,52]. Significantly though, important differences existed in the baseline demographic and clinical characteristics of the patients, which biased the interpretation of results. In EVIDENCE, the benefit of HD-HF occurred during the initial 24 weeks, but was not maintained for the following 24 weeks. The Danish open-label study [45] Recent Gains in Clinical Multiple Sclerosis Research compared two doses of IFN- : 8 MIU -1b SC eod with 6 MIU IFN- 1a SC every week in 303 RRMS patients but only the MRI outcomes suggested the higher dose of IFN1b might be superior and no differences were seen in clinical outcomes. Some investigators claim the lack of differences were due to bias regarding the equivalence of the different formulations [42]. Studies comparing different doses and formulations of IFN- with GA, such as the REGARD [46], the BEYOND [47] or the BECOME [48] studies, did not detect significant differences in efficacy between IFN- or GA in clinical measures and only in MRI characteristics in some studies. Some studies suggest that the inflammatory activity driving the relapses is independent of the degenerative pathology that drives disability [49, 50] and IFNs or GA mainly affect relapses and MRI measures hence have very limited effect on MS course. On the other hand, in our opinion and those of others, there is an early window of opportunity to change the course of disease [51]. In general, it seems fair to claim that IFN- s and GA all reduce the relapse rate in RRMS, and delay the conversion of CIS to CDMS. Considering the perceived but not proven benefit with HD-HF IFN- s [52, 53] and a similar effect compared to GA, most neurologists would not strongly influence the choice of one formulation of IFN- or GA by people with RRMS. In clinical practice, it is impossible to determine if a patient will do well on one medication, so it is important to detect failure of treatment as early as possible. A number of studies have demonstrated a relationship between the development of new MRI lesions and a suboptimal clinical response to IFN- treatment. Among a cohort of more than 400 RRMS patients, the ones who developed new T2 lesions on MRI after one year of therapy had an increased risk of poor response to treatment (hazard ratio 16.8; P <0.001). The level of risk increased with the number of lesions observed independently of new relapses or disability progression [54, 55]. Not surprisingly, the presence of neutralizing antibodies (Nabs) to IFN- is associated with MRI evidence of disease activity such as Gad-enhancing T1 lesions and new or enlarging T2 lesions on MRI [44]. DRUGS USED IN SECOND LINE TREATMENT Natalizumab (Tysabri ) The first humanized monoclonal antibody to be licensed in RRMS, natalizumab was designed to recognize and block the cellular adhesion molecule 4-integrin on the surface of inflammatory cells. The integrin interacts with vascular cell adhesion protein (VCAM)-1 on endothelial cells of the brain (and gut) vessels to slow the movement of lymphocytes and allow them to cross the endothelium. Natalizumab is administered monthly through an intravenous infusion and has been licensed for relapsing MS. In the UK, NICE approved the use of natalizumab every 4 weeks for highly active MS (as defined by two significant relapses in the prior 12 months) and it can be used as first line therapy. Natalizumab decreases the numbers of CD4+ and CD8+ T-cells, CD19+ B-cells, and CD138+ plasma cells in the CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 7 cerebrospinal fluid (CSF) of MS patients and the effect is maintained 6 months after discontinuation [56-59]. When natalizumab is used for longer than 30 months, the PBMC composition in MS patients can shows an increase of T-, NK- or particularly B-cells, probably due to an induced release of lymphoid- but not myeloid precursor cells. The recent thymic emigrants, naïve, effector or memory T-cells, remained unchanged, but there were more memory- and marginal zone-like, but not naïve B-cells, reflecting the ability of natalizumab to influence B-cell migration and homeostasis through the splenic marginal zone [60, 61]. The clinical trials enrolled people with active RRMS (at least one clinical relapse during the prior year) and an EDSS between 0 and 5. Natalizumab was shown to reduce relapses by 68% compared to placebo and slowed the progression of disability [62-64]. Subsequent studies showed reduced visual loss, more disease-free individuals, better assessments of health-related quality of life, reduced cognitive decline in some individuals with MS, reduced hospitalizations and steroid use and fewer new MRI lesions [64-68], as well as improvement in several MRI measures [65, 69]. Natalizumab was approved in 2004 by the FDA after the release of the interim results but after three deaths due to progressive multifocal leukoencephalopathy (PML), it was suspended. After a safety review and no further deaths, the drug was returned to the US market in 2006 and European market in 2007 under a special prescription program. Significantly, it is effective in MS patients who did not respond or responded poorly to IFN and GA, as a second line therapy and in highly-active MS in particular [70-72]. Approximately 6% of individuals on natalizumab develop persistent antibodies to the drug, which reduces its efficacy [73] and causes infusion reactions. Unfortunately, the effect of natalizumab is not sustained after drug cessation but the evidence for rebound activity is not significant [74]. According to Biogen-Idec monthly natalizumab safety update and PML risk stratification programme, there were 193 cases of PML as of 1 st December 2011, with death resulting in 20% of the cases. The expected benefits of natalizumab treatment have to be weighed and the risk of PML can be stratified [75]. People who have undetectable anti-JCV antibodies (JCV is the virus that causes an asymptomatic infection and that in immunosuppressive conditions can cause PML) have a negligible risk of developing PML. People who are JCV antibody positive and who have received immunosuppressive drugs, such as mitoxantrone or cyclophosphamide, are at much higher risk. For MS patients who have not taken such drugs, the risk is higher after two years of uninterrupted infusions. In the STRATIFY-1 study of the prevalence of anti-JCV antibodies in MS patients, a rate of 50-60% and an association of increasing age and male gender was detected but not natalizumab treatment nor prior immunosuppression [76]. Despite the risk of PML, natalizumab remains an extremely effective drug for RRMS and it is as effective in a regular clinical environment as seen in pivotal and post hoc studies [77]. Further, natalizumab is effective as second line therapy in the treatment of relapsing remitting multiple sclerosis [71, 72, 78]. 8 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 Fingolimod (FTY720 or Gilenya®) Fingolimod is the first oral therapy for RRMS licensed by the FDA and European Medicines Agency (EMA) for second line treatment. It is a structural analogue of sphingosine that needs to be phosphorylated in the cell by sphingosine kinase 2 [79]. The effect on RRMS depends on the activity on one of the five sphingosine-1-phosphate receptors, S1PR1, defining it as an S1PR modulator, as seen in animal models [80]. It involves the sequestration of lymphocytes in lymph nodes, preventing egression from most secondary lymphoid organs and trafficking into the CNS [81, 82]. The recognized side-effects, which include viral infections, macular oedema and brady-arrhythmia, can be understood by potent lymphopenia, vascular leak phenomena, and presence of S1PRs in the cardiovascular system, respectively [83]. The results of two clinical trials led to fingolimod approval by the FDA and EMA as a second-line drug for highly active RRMS. A 24-month, double-blind study enrolled 1272 active (one or more relapses in the previous year or two or more in the previous two years) RRMS patients, with a EDSS below 6.0. Patients were randomized to 0.5 mg or 1.25 mg daily fingolimod or placebo. Patients on fingolimod had reduced risk of disability progression over the 24-month period (17.7% and 16.6% vs 24.1%) and both doses were superior to placebo in brain MRI new or enlarged lesions on T2-weighted images, Gad-enhancing lesions, and brain-volume loss (p<0.001 for all comparisons) [84]. The second study, TRANSFORMS [85], followed 1292 RRMS patients randomized to 1.25 or 0.5 mg fingolimod daily or 30 g IM IFN- 1a weekly. The ARR was lower in both fingolimod groups than IFN- 1a (p<0.001 for both comparisons), fingolimod had greater efficacy on relapse rates than IFN-1a, and the MRI findings supported the clinical results. Unlike the 24 months study, there were no significant differences in disability progression. Two fatal infections (one disseminated primary varicella zoster and one herpes simplex encephalitis) occurred in the high dose group [85]. An extension study [86] after TRANSFORMS followed patients for a further 24 months of fingolimod and showed persistent benefits in ARR; for the patients who initially had IFN-1a, clinical and MRI measures improved when compared with the previous 12 months of IFN [86]. The effect that fingolimod has on PBMCs and CSF cells was investigated in studies with healthy people and MS patients. The peripheral blood T-cell population of 16 MS patients treated with fingolimod showed a reduction of 80% of CD4+ and 60% of CD8+ when compared to PBMCs from IFN treated and untreated patients. The naive (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) T(TCM) were selectively reduced and the effector memory (EM) (CCR7-CD45RA- and CCR7CD45RA+) Twere relatively increased. Remaining peripheral blood T-cells secreted less IL-2 and proliferated less but promptly secreted IFN- . This is presumably because naive Tand TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues. These effects were not reproduced in an in vitro study of fingolimod [87]. The CD8+ T-cell population was enriched with CD27- CD28- (late effector) memory [88]. Th17 cells, phenotypically characterized as TCM, were reduced in Runia et al. blood of treated people, probably retained in secondary lymphoid organs [89]. CD56(bright) and CD56(dim) NKsubsets from healthy people exposed to fingolimod showed reduced migration but similar ability to secrete cytokines when compared to NK-cells from people not exposed [90]. The effect on CSF cells is distinct from the effect on peripheral blood cells. The CSF lymphocyte counts are significantly reduced, but the oligoclonal bands and intrathecal IgG synthesis are unchanged. he proportion of CSF CD4+ T-cells decreased but less than in the peripheral blood. While strongly reduced B-cells in the periphery, it had little impact on B-cells in the CSF. The percentage of CSF CD8+ T-cells, NK-cells, and monocytes increased compared to treatment-naive patients [91]. Early reports showed a rapid reconstitution of the peripheral blood cells populations. This view was challenged by a recent report showing two of five MS patients to be lymphopenic 9 and 34 months after fingolimod discontinuation following prolonged treatment (1-5 years) [92]. Fingolimod is an effective drug in RRMS that reduced not only the relapse rate and MRI markers of activity but also reduced disability progression and brain volume loss, suggesting preservation of tissue. It is a great addition to the available MS drugs, but the novelty and small numbers treated so far warrant increased attention to side-effects and a wise risk assessment consideration. UNLICENSED ORAL THERAPIES IN THE PIPELINE Positive results were reported for new oral drugs cladribine, laquinimod, teriflunomide and dimethyl fumarate/BG12 - in phase II or phase III studies; data is still scarce and safety issues are unknown for most, so the role these drugs will play in the treatment for MS is still provisional. The results from long-term safety studies and the potential for some neuroprotective effects the drugs may have will be of particular importance [93]. The development of cladribine for RRMS was halted by Merck-Serono following regulatory agencies requests for further clinical trials, despite the encouraging results from the phase III CLARITY study [94-96]; it is still licensed for hairy cell leukemia. Teva Pharmaceutical Industries announced it will not be filing for FDA approval of laquinimod in the near future, following disappointing initial results from the Phase III BRAVO and ALLEGRO studies, showing a failure to meet the primary endpoint, the reduction of ARR, despite promising results in the MRI activity markers in the phase II trials [97, 98], and being safe and well tolerated. BG-12 (Dimethyl Fumarate - Biogen Idec) Dimethyl fumarate is a fumaric acid ester that was used to treat psoriasis in some European countries. The mechanism of action is not completely elucidated but involves changes in the inflammatory profile of peripheral blood lymphocytes and the cytokines they secrete. The direct protective effect on neurons is still controversial, but dimethyl fumarate can cross the BBB. In a phase II trial, 257 RRMS patients were randomized to receive 120 mg BG-12 once daily, 120 mg three times Recent Gains in Clinical Multiple Sclerosis Research CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 9 daily (tid) or 240 mg tid or placebo for 24 weeks. There was a 24 week safety extension period where the patients on placebo received 24 mg BG-12 tid. This dose reduced the total number of new Gad-enhancing T1 MRI lesions by 69% from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001), as well as reduced the number of new or enlarging T2- (p=0.0006) and new T1- (p=0.014) lesions compared with placebo. Clinically, BG-12 reduced ARR by 32% (0.44 vs 0.65 for placebo; p=0.272). The adverse event profile was mild with abdominal pain and flushing, headaches and fatigue [99]. The brain MRI of 38 RRMS patients initially on placebo and 18 patients on 240 mg BG12 tid who had a least one new Gad-enhancing lesion from week 4 to 12 were retrospectively studied. When compared with placebo, BG-12 not only reduced the frequency of new Gad-enhancing lesions, but also reduced probability that they would evolve to T1-hypointense lesions [100, 101]. MONOCLONAL ANTIBODIES The results from DEFINE and CONFIRM confirmed the reduced ARR of over 50% when compared to placebo and by 29% when compared to GA, respectively. In the DEFINE study, but not the CONFIRM, the disability progression was reduced by 38%. There seems to be a dose dependent efficacy, with higher doses achieving better results. The publication of the results and detailed analyses are eagerly awaited, and this may become a very important new drug because of a combination of efficacy and a good safety profile and experience in use. The development of alemtuzumab for RRMS has been a long-term project that met many hurdles. The success perceived in series and descriptions of individual patients treated off-license was finally recognized with the publication of the results of the phase II, CAMMS 223 trial. This was a blinded study of 334 treatment naïve early RRMS patients (less than 3 years disease duration) involving previously untreated, early RRMS subjects who were randomized to receive44 g SC TIW IFN- 1a or annual intravenous infusions of 12 or 24 mg of alemtuzumab for 36 months. Alemtuzumab significantly reduced the rate of sustained accumulation of disability, as compared with IFN1a (p<0.001) and the ARR (p<0.001). The brain MRI T2 lesion burden was reduced and from month 12 to 36, brain volume increased in the alemtuzumab group but decreased in the interferon beta-1a group (P=0.02). The serious adverse events included 23% autoimmune thyroid disorders, 3% immune thrombocytopenic purpura (ITP) and infections (66% vs 47%). The two doses showed similar results [106108]. The profile of antibody mediated autoimmune disorders arising post-alemtuzumab was confirmed [109] and is possibly associated with pre-treatment levels of IL-21 [110]. Teriflunomide (Aubagio® - Sanofi Aventis) Teriflunomide is the active metabolite of leflunomide, a standard rheumatoid arthritis drug. Its specific mechanism of action is to inhibit pyrimidine synthesis, which reduces proliferation of T and B peripheral blood lymphocytes, particularly activated T cells [102]. The mechanism of action may involve blockage of the transcription factor NF- B and inhibition of tyrosine kinase enzymes (the latter at higher than tested doses). The recent phase III, double blind, TEMSO study of teriflunomide in RRMS, randomized 1088 RRMS patients with EDSS lower than 6.0 and at least one relapse in the previous year, to 14 mg and 7 mg daily teriflunomide or placebo for 108 weeks [103]. significantly reduced relapse rates, disability progression (at 14 mg) and brain MRI markers of activity, as compared with placebo [104]. The drug was well tolerated, but adverse events included nausea and diarrhoea, hair thinning and abnormalities in liver function tests. Two more phase III studies of teriflunomide in RRMS, TOWER and TENERE, are ongoing. The TENERE compares 7 mg and 14 mg teriflunomide with SC ttw IFN- 1a in 300 MS patients over 48 weeks. The primary outcome is the time to treatment failure: the first occurrence of a relapse or withdrawal from the study. Estimated completion date is July 2012. The TOWER study is a double blind trial where 1110 MS patients were randomized to 7 mg or 14 mg teriflunomide or placebo for 48 weeks. The primary outcome measure of this study will be the number of relapses per year and the estimated completion date is February 2013. Alemtuzumab (Lemtrada® - Sanofi Genzyme) Alemtuzumab is a humanized monoclonal antibody that targets glycoprotein CD52 on the surface of mature lymphocytes but not stem cells. The profound depletion of B- and T-cells is reversed earlier (around month 3) and with a degree of overshoot for B-cells. The CD4+ and CD8+ lymphopenia is sustained for 3-9 months and in some cases is permanent [105]. The targeted cells undergo apoptosis through antibody-dependent cell-mediated cytotoxicity, the mechanism probably responsible for the infusion sideeffects. Alemtuzumab is approved for chronic lymphocytic leukemia, cutaneous T-cell lymphoma and T-cell lymphoma and is sometimes used in conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation. There were two phase III trials, CARE-MS I that recruited early treatment naïve RRMS patients and CAREMS II that recruited 840 patients who had at least one breakthrough relapse on other therapies in the previous year. The results of CARE-MS II have just been released and the study met both its co-primary end-points: significantly decreased relapse rate and decreased sustained accumulation of disability in RRMS patients on alemtuzumab (5 consecutive days of 12 mg/day on the first year and 3 consecutive days of 12 mg/day on the second year) when compared with SC TIW IFN- 1a. In the CARE-MS II trial, the relapse rate was significantly reduced when compared to IFN- 1a, but the reduction in disability progression was not significant. The proportion of patients who remained relapse free after two years was over 75%. Common adverse events were infusion associated reactions: headache, rash, nausea, hives, fever, itching, insomnia, and fatigue. Infections were common in both groups with a higher incidence in the 10 CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 alemtuzumab group and included upper respiratory and urinary infections and reactivation of herpes simplex. About 16% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event and approximately one percent developed immune thrombocytopenia during the two-year study period. Alemtuzumab offered great results in the phase II trial but there was a degree of disappointment after the phase III results were made public. It is still the drug with best reduction of relapse rate and one that offers the possibility of being disease free for longer. The benefits seem to be more significant when used early in disease but the risks and longterm side-effects may cause the regulatory authorities to limit its use to second-line therapy. Daclizumab (Zenapax® - Hoffmann-La Roche) Daclizumab, a humanized anti-CD25 monoclonal antibody, reduced MS disease activity in inital nonrandomized studies. In a phase II randomized, double-blind, placebo-controlled study, 230 RRMS patients who were on IFN- 1a were randomized to receive add-on SC daclizumab 2 mg/kg every 2 weeks, daclizumab 1 mg/kg every 4 weeks, or placebo for 24 weeks. The association reduced the number of new or enlarged Gad-enhancing T1 brain MRI lesions compared with IFN- 1a alone but the significance was limited [111]. The phase III trial is still ongoing. Anti-CD20 Monoclonal Antibodies: Rituximab and Ocrelizumab - (Hoffmann-La Roche's Subsidiary Genentech, and Biogen Idec) Studies of rituximab (a chimeric anti-CD20 mousehuman monoclonal antibody) in RRMS, active naïve patients showed a degree of benefit with an apparent reduction in relapses [112] This was also observed over 72 weeks compared with the year before therapy with fewer new Gadenhancing T1 or new T2 lesions [113, 114]. This benefit was again detected in breakthrough MS activity [115]. The development of rituximab was halted and a programme to investigate ocrelizumab, another humanized anti-CD20 monoclonal antibody was initiated. In a phase II, examining physician blinded study, 218 RRMS patients were randomized to receive 600 mg, 2000 mg in two doses (day 1 and day 15) or 30 μg IM IFN- 1a weekly or placebo. At week 24, patients in the initial placebo, 600 mg ocrelizumab and IFN- 1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. At week 24, the number of Gad-enhancing T1 lesions was 89% lower in the 600 mg ocrelizumab group than in the placebo group (p<0 0001), and 96% lower in the 2000 mg group (p<0 0001). There were pronounced effects of B-cell depletion with both ocrelizumab doses, on MRI and around 80% relapse reduction [116]. The development of ocrelizumab is pursued in both RR and progressive MS, but was stopped in rheumatoid arthritis and lupus because of several fatal opportunistic infections. The results in MS were extremely promising and we expect to learn a great deal more in terms of pathology of MS from the use of B-cell therapies. Runia et al. CONCLUSION These are exciting times with several important breakthroughs in the treatment of RRMS patients. New drugs with increased efficacy and different safety profiles are in the pipeline and the accumulated knowledge will ensure that the risks associated with the new drugs will be limited and worth taking. It is of major importance to switch our efforts to the development of drugs and strategies that offer neuroprotection and eventually repair for MS: what we can offer MS patients who suffer with progressive disease is still extremely limited and provides no significant changes in disease course. ABBREVIATIONS 2’-5' Oligoadenylate synthetase 2'-5'OAS = ARR = Annualized relapse rate BBB = Blood brain barrier CD = Clinically definitive CIS = Clinically isolated syndrome CNS = Central nervous system CI = Confidence interval CSF = Cerebrospinal fluid DAMP = Danger-associated molecular patterns DT = Delayed treatment DMD = Disease modifying drug EMA = European Medicines Agency Eod = Every other day EDSS = Expanded disability scale score EAE = Experimental autoimmune encephalomyelitis FDA = Food and Drug Administration GA = Glatiramer acetate HC = Healthy controls HD-HF = High dose/high frequency IgG = Immunoglobulins IT = Immediate treatment IFN = Interferon IL = Interleukin IM = Intra-muscular MRI = Magnetic resonance imaging MMP = Matrix metalloproteinases MS = Multiple sclerosis NK = Natural killer PAMP = Pathogen-associated molecular patterns PRR = Pattern recognition receptors PBMC = Peripheral blood mononuclear cells PML = Progressive multifocal leukoencephalopathy Recent Gains in Clinical Multiple Sclerosis Research PKR = Protein kinase receptor RR = Relapsing-remitting S1PR = Sphingosine-1-phosphate receptors SC = Subcutaneous STAT = Signal Transducers and Activators of Transcription Th = T-helper Tid = Three times daily Ttw = Three times per week TLR = Toll-like receptor TNF = Tumour necrosis factor VCAM = Vascular cell adhesion protein CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 5 [14] [15] [16] [17] REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] de Weerd, N.A.; Samarajiwa, S.A.; Hertzog, P.J. 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