Disclosure CSC has received research support, consultancy fees, travel support or speaker fees from Teva, Biogen Idec, Bayer Schering, Centocor, Merck-Serono, and GlaxoSmithKline, Roche, UCB, GW Pharmaceuticals, and Cephalon. SYL has been supported by an unrestricted grant from Teva.
Professor Cris S. Constantinescu, Division of Clinical Neurology, B Floor, Medical School, University of Nottingham, Nottingham NG7 2RD, UK Tel.: + 44 115 975 4598 Fax: + 44 115 970 9738 Email: firstname.lastname@example.org
The development of disease-modifying therapies (DMT) in multiple sclerosis (MS) has rapidly evolved over the last few years and continues to do so. Prior to the United States Food and Drug Administration approval of the immunomodulatory agent, interferon-β1b in 1993, no other drug had been shown to alter the course of the disease in a controlled study of MS. At present, there are five licenced disease-modifying agents in MS – interferon-β1b, interferon-β1a, glatiramer acetate, natalizumab and mitoxantrone. All have shown significant therapeutic efficacy in large controlled trials. However, current therapies are only partially effective and are not free from adverse effects. Moreover, available DMTs are overwhelmingly biased in favour of those with relapsing-remitting disease. Effective treatment for progressive MS is severely limited, with only interferon-β1b and mitoxantrone having licenced use in secondary progressive, but not primary progressive disease. Monoclonal antibodies, such as natalizumab selectively target immune pathways involved in the pathogenic process of MS. Alemtuzumab, daclizumab and rituximab are other notable monoclonal antibodies currently undergoing phase II and III trials in MS. Alemtuzumab has so far shown promising therapeutic benefit in relapsing disease, although immunological adverse effects have been a problem. Oral therapies have the benefit of improved tolerability and patient compliance compared with current parenteral treatments. Cladribine and fingolimod (FTY720) have shown encouraging results in their phase III clinical trials. It is also worth noting the evidence for starting DMT in patients with clinically isolated syndrome, whereby early treatment has shown to delay the onset of clinically definite MS in separate phase III studies.
Trials chosen for our review were the pivotal and newer studies of licenced treatments for MS and those of promising disease-modifying therapies, which had completed or are at least currently in phase II testing. We conducted an on-line literature search using PubMed for relevant studies and clinical trials. We also referred to abstracts from recent international conferences, individual drug-makers’ websites and http://clinicaltrials.gov for further details and updates on said trials.
Message for the Clinic
Evidence from clinical trials suggests that treatment with DMT in the appropriate MS patients improves disease activity and severity. In addition, treatment can delay the onset of clinically definite MS in patients presenting with their first attack of demyelination. A number of DMTs are currently being developed with the prospect of having comparable or improved therapeutic efficacy, safety profile and tolerability to existing therapies, broadening our future therapeutic options.
Multiple sclerosis (MS) is a chronic, potentially disabling, immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). The multifocal nature of the disease manifests clinically as a range of sensorimotor, cerebellar, visual, sphincteric, cognitive, and neuropsychiatric symptoms. Most patients present with a relapsing and remitting course, which is characterised by recurring attacks of acute neurological deficits or exacerbations of existing deficits (relapses) followed gradually by partial or full recovery (remission). Although the clinical course may vary considerably between individuals, secondary progression eventually occurs in the majority, characterised by irreversible, progressive disability (1). The immune pathogenesis of MS is thought to be heterogenous, with recent studies showing the involvement of distinct subsets of T-cells (2), and the crucial role of B cells and antibodies (3). The exact aetiology is unknown, although it is likely to stem from the loss of immune regulation, leading to the breakdown of immune tolerance, influenced by genetic susceptibility. Focal CNS inflammation, demyelination, axonal loss and eventual neuronal death are typical features although pathologically there is heterogeneity.
Multiple sclerosis is a challenging disease to treat, not least because of its significant heterogeneity and unpredictable clinical course. Traditional immunosuppressants such as cyclophosphamide and azathioprine have been used in MS for some time, showing a variable degree of benefit (4–6). However, the risk of serious infections amongst other significant side effects, and the emergence of new immunomodulatory drugs, has limited their use.
Immunomodulatory agents, which became available from the early 1990s, aim to prevent relapses, minimise disability and may reduce disability progression (particularly relapse-related disability) without significant immunosuppressive effects. The immunomodulatory agents interferon (IFN)-β1a, 1b and glatiramer acetate are first-line therapy in MS. For more severe disease, second-line therapy consisting of the monoclonal antibody natalizumab and cytotoxic agent mitoxantrone are used.
Increasingly, new and novel therapeutic agents are being trialled in MS centres worldwide. These include monoclonal antibodies and oral agents for relapsing and progressive forms of the disease. In this non-systematic review, we outline the existing disease-modifying agents; briefly discuss the promising new drugs currently in development and look at the current evidence for disease-modifying therapies (DMT) in early MS.
Interferon-β and glatiramer acetate
Two formulations of interferon treatment are available: IFN-β1b (Betaferon; Schering AG, Berlin, Germany or Betaseron; Berlex, Montville, NJ) and IFN-β1a (Rebif; Merck Serono, Geneva, Switzerland and Avonex; Biogen Idec, Zug, Switzerland). Both are type 1 interferons, which share anti-inflammatory and antiviral properties, but differ slightly in their pharmacodynamics and pharmacokinetics (7). IFN-β has been shown to inhibit T-cell activation and reduce blood brain barrier permeability to inflammatory cells, although it in itself may not cross the blood brain barrier (8). Avonex is given intramuscularly once a week (30 μg), Betaferon or Betaseron subcutaneously on alternate days (0.25 mg) and Rebif subcutaneously three times a week (22 or 44 μg).
Glatiramer acetate (Copaxone; Teva Neuroscience, Kansas City, MO) is a synthetic co-polymer structurally similar to myelin basic protein (MBP), a major component of myelin (9). It is given as a daily subcutaneous injection (20 mg). It is thought to produce anti-inflammatory effects mainly via functional inhibition of MBP-reactive T-lymphocytes and induction of Th 2 (T helper) lymphocytes in the CNS (10,11).
Pivotal phase III studies of IFN-β and glatiramer acetate have all demonstrated a significant reduction in relapse rate (by approximately 30%, see Figure 1) and improvement in magnetic resonance imaging (MRI) measures of disease activity in relapsing-remitting MS patients (12–15). These were conducted as 2-year, double-blinded, randomised, placebo-controlled, multicentre trials. It is difficult to perform an accurate cross-trial comparison of the pivotal studies because of the differences in the study design and patient population, but this has nonetheless been systemically analysed and reported in detail elsewhere (16,17).
Recent head-to-head comparison trials, specifically the REGARD (Rebif 44 μg vs. Copaxone)(18) and BEYOND (Betaferon/Betaseron vs. Copaxone)(19) trials give a more accurate view of the comparative efficacy between these drugs. They have so far shown largely similar efficacy between the IFN-β treatments and glatiramer acetate. The REGARD trial evaluated the efficacy of three times a week 44 μg subcutaneous IFN-β1a compared with daily subcutaneous 20 mg Copaxone in 764 patients with relapsing-remitting multiple sclerosis (RRMS) (18). No significant difference was noted between both treatments in the study end-points, which included time to first relapse and change in the volume of T2 and contrast-enhancing MRI lesions (18). The BEYOND trial (Betaferon/Betaseron yielding outcomes of a new dose in MS) compared the efficacy of alternate day 250 and 500 μg subcutaneous Betaferon/Betaseron to daily subcutaneous 20 mg Copaxone in 2244 treatment-naïve patients with RRMS (19). There was no significant difference between the three treatment arms in terms of relapse risk, the proportion of relapse-free patients, time to first relapse, disability accumulation and most MRI parameters (19).
Interferon-β and glatiramer acetate are generally safe and well-tolerated, although adverse effects may be experienced, such as flu-like symptoms and lymphopenia with the interferons and skin reactions with glatiramer acetate(18,19). Furthermore, neutralising antibodies to IFN-β can develop in some patients, usually following the first year of therapy. Although the long-term consequences of these antibodies are yet to be fully ascertained, current evidence shows that they may reduce the efficacy of the drug (20–22). The antibodies tend to cross-react with different IFN-β formulations (23), therefore switching to another IFN-β drug is unlikely to be helpful in the first instance, leaving one to consider alternative DMTs.
Co-administration of corticosteroids with IFN therapy can reduce the production of neutralising antibodies and may enhance IFN therapy (24,25). In a relatively small study involving 130 patients, Sorensen et al. reported that 4-weekly pulses of 100 mg oral Methylprednisolone given in addition to subcutaneous IFN-β1a (Rebif) for 96 weeks resulted in a significant reduction in relapse rates compared with patients taking the placebo-Rebif combination (annualised relapse rate 0.22 for methylprednisolone vs. 0.59 for placebo, p < 0.0001)(25). Moreover, another cohort of patients using a similar combination (Methylprednisolone plus IFN-β1a, Avonex) in the multicentre MECOMBIN trial from the start of DMT had a significant reduction in relapse rate compared with IFN-β1a and placebo, suggesting added benefit that might be of use not only in non-responders (26).
Recommendations for starting first-line disease-modifying therapy vary worldwide. In the UK, the Association of British Neurologists advocates their use in patients who have had at least two clinically disabling relapses in the last 2 years, but continue to remain ambulatory (27). However, as earlier treatment is increasingly favoured and expectations for disease control higher, a new set of criteria may emerge soon.
Patients are being involved more in choosing the appropriate first-line therapy, and may wish to consider factors such as side effects and dosage frequencies. While IFN-β treatment is seen by some to be more beneficial with higher and more frequent dosing (28,29), this is not universally shared and needs to be balanced against increased convenience of less frequent administration and lower likelihood of neutralising antibodies. Unfortunately, because of the parenteral mode of administration, problems with compliance and tolerability still remain an issue for many patients.
Natalizumab (Tysabri; Biogen Idec) is a humanised monoclonal antibody to the α4 subunit of α4β1 integrin (VLA-4), a protein found on the surface of lymphocytes. α4β1 Integrin interacts with the vascular-cell adhesion molecule 1 (VCAM-1) expressed on endothelial cell surface, including CNS vasculature, allowing adhesion and subsequent migration of inflammatory cells into the brain and spinal cord (30,31). Natalizumab selectively blocks this interaction, thus preventing the transmigration of inflammatory lymphocytes across the blood brain barrier into the CNS (30,31).
Natalizumab is to date, the only monoclonal antibody currently licenced for use in MS in the US and Europe and is recommended for patients with more aggressive, rapidly evolving relapsing disease and in those who have failed to respond to first-line DMTs. It is given as an intravenous infusion. There are no guidelines on the optimal duration of therapy, and patients may continue to receive the drug if perceived to be efficacious to their disease.
Phase II (32–34) and III (35,36) studies on Natalizumab provide good evidence for its use in MS. In the AFFIRM study, a randomised, double-blind, placebo-controlled phase III trial, patients on Natalizumab demonstrated a 68% reduction in annualised relapse rate (p < 0.001) and 42% reduction in sustained disability progression over 2 years (p < 0.001) compared with placebo (35). Furthermore, MRI findings from the study showed a 92% reduction in gadolinium-enhancing lesions (p < 0.001) (35). The SENTINEL study was a 2-year, randomised, double-blind, placebo-controlled phase III trial whose subjects had previously responded poorly to IFN-β1a therapy (Avonex). It showed a promising 53% reduction in relapse rate in patients on Natalizumab/IFN-β1a combination therapy, compared with those who remained on IFN-β1a monotherapy (p < 0.001) (36).
In 2005, shortly after being licenced for use, natalizumab was withdrawn from the market when two fatal cases of progressive multifocal leucoencephalopathy (PML), caused by latent JC virus infection, were reported in patients taking natalizumab in combination with IFN-β1a as part of the SENTINEL study (36). A third fatal case was subsequently reported in a Crohn’s patient who received natalizumab following previous immunosuppressive treatment (37).
A subsequent safety evaluation of the drug estimated the risk of PML to be 1 in 1000 (0.1%) over an 18-month treatment period (38). Following this report, natalizumab was reapproved as monotherapy for active MS in July 2006. At the time of writing, about 56,500 patients have been treated with the drug in the postmarketing setting, with over 18,000 having received at least 18 months of therapy and 30,600 having received at least 1 year of therapy (39). Since July 2006, 11 cases of natalizumab-associated PML have so far been reported (39). This could imply that the true risk of PML associated with natalizumab monotherapy is lower than previously thought. It is usually accepted that the beneficial effects of natalizumab in active relapsing disease outweigh the risk of developing PML, as supported by a recent risk-benefit analysis (40). Risk-management programmes have been put in place to monitor and further evaluate patient safety on natalizumab, i.e. The TYSABRI Outreach: Unified Commitment to Health Prescribing Program (TOUCH) and the TYSABRI Global Observation Program in Safety (TYGRIS).
Natalizumab has also been associated with the development of neutralising antibodies, which may persist in up to 6% of patients, potentially causing hypersensitivity reactions and loss of drug efficacy over time (41). Patients who develop a reaction to the drug or show poor response to therapy may warrant being tested for antibodies. Around four cases of natalizumab-associated malignant melanoma have also been reported, which are reviewed in detail elsewhere (42).
Whilst relapsing-remitting MS patients gain therapeutic benefit from IFN-β, glatiramer acetate and natalizumab, treatment for the progressive forms of MS is much more limited. Mitoxantrone and IFN-β1b (Betaferon, Betaseron) are licenced for use in secondary progressive MS, whereas there are no effective treatments currently licenced for primary progressive MS.
Mitoxantrone is an anthrecenedione, a cytotoxic agent with immunosuppressive properties used in various malignancies (43). In 2000, it was approved for treatment of worsening relapsing-remitting MS, progressive relapsing MS and secondary progressive MS based on evidence from a phase II (44) and a later phase III study of the drug (45). Mitoxantrone is thought to act via a wide range of mechanisms, which include inhibition of T-cell activation, suppression of T-cell, B-cell and macrophage proliferation, impaired antigen presentation, prevention of macrophage-mediated demyelination and reduction of pro-inflammatory cytokines (46–48). In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), mitoxantrone was shown to effectively suppress disease activity (49,50).
In the phase III study (45), 194 patients with worsening relapsing-remitting and secondary progressive MS were randomised to either 12 mg/m2 mitoxantrone, 5 mg/m2 mitoxantrone or a placebo every 3 months for 2 years. The primary outcome measure was disease progression, measured using a composite score consisting of the patient’s Expanded Disability Status Scale (EDSS) score, ambulation, number of treated relapses, time to first treated relapse and change in their standardised neurological status. Patients in the 12 mg/m2 mitoxantrone treatment group showed a significant improvement (p < 0.0001) in their composite score, including a 69% reduction in the number of treated relapses (45). MRI outcomes from the study; however, were less robust with most MRI parameters showing no difference between the groups, except for the reduction of T2 lesions in the high-dose Mitoxantrone group over the placebo group at year 2 (p = 0.027) (51).
In MS patients, the recommended dose of mitoxantrone is 12 mg/m2 every 3 months, with a maximum cumulative lifetime dose of 140 mg/m2 (52). Although Mitoxantrone is generally reserved for patients with more active, progressive disease and those who had previously failed to improve on DMT, it may have an additional role as an induction therapy in treating early, aggressive MS. In their open label study, Ramtahal et al. demonstrated a 90% reduction in annualised relapse rate (p < 0.001) after Mitoxantrone induction followed by long-term Copaxone in a cohort of patients with very active early MS (53). A similar study of mitoxantrone and Rebif is currently on-going in the UK (NCT00283140).
Although rare, the most serious adverse effects of mitoxantrone treatment are cardiotoxicity and acute leukaemia. In a report by Ghalie et al., the risk of congestive heart failure was observed to be < 0.20% with a mean cumulative dose of 60.5 mg/m2 (54). The team also noted that 2.2% of patients experienced an asymptomatic reduction in left ventricular ejection fraction to < 50%, which did not bear a significant correlation to the cumulative dose. Recently, the risk of therapy-related acute leukaemia was reported to be around 0.74% (55), significantly higher than previous estimates (56,57). It is highly important therefore to perform regular cardiac function and haematological monitoring following mitoxantrone therapy, as well as ensuring only appropriate patients are selected for treatment.
Monoclonal antibodies in development
Alemtuzumab (Campath-1H; Genzyme, Cambridge, MA) is a humanised monoclonal antibody to CD52, a cell surface antigen present on all lymphocytes and monocytes. It was developed in Cambridge, UK and is used to treat chronic lymphocytic leukaemia. It has also been trialled as an antirejection therapy and as treatment for other autoimmune diseases. Given intravenously, the drug causes a rapid and prolonged lymphopenia (58).
An early open label Cambridge trial of alemtuzumab in 36 secondary progressive MS (SPMS) patients and 22 RRMS patients showed some promising results, in particular demonstrating more benefit if given earlier in the disease course, i.e. at the relapsing-remitting stage (59). The secondary progressive patients who received alemtuzumab also had significantly fewer relapses, but had continued to progress both clinically and radiologically. The authors suggested that this implied neurodegeneration in secondary progressive disease occurs independently of inflammation, albeit dependent on previous inflammatory activity (59). The authors further suggest that a therapeutic window of opportunity exists, whereby effective anti-inflammatory treatment early on in the disease can prevent the later-onset, irreversible degenerative processes from occurring.
In the more recent phase II trial of alemtuzumab vs. IFN-β-1a (CAMMS223), 334 patients with early RRMS were randomised to receive either 44 μg subcutaneous IFN-β1a (Rebif) three times a week or intravenous pulses of 12 or 24 mg/day Alemtuzumab for 3–5 days at months 1, 12 and 24 (60). All patients were previously untreated, and had an EDSS of 3.0 or lower, with disease duration of 3 years or less. During the trial, a total of six patients on alemtuzumab developed immune thrombocytopenic purpura (ITP), one of whom died, resulting in the suspension of therapy in the active drug arm. As a result, only about 20% of patients received the full 3-year treatment course. Nevertheless, the results showed that alemtuzumab effectively prolonged the time to sustained disability and improved clinical and MRI markers of disease activity in the short-term. Compared with IFN-β1a, alemtuzumab reduced the risk of progression to sustained accumulation of disability by 71% (p < 0.001) and reduced relapses by 74% (p < 0.001). There was no significant difference in the efficacy between the lower and higher dose regimes.
Autoimmune effects are the main concern with alemtuzumab therapy. Apart from ITP there is a risk of about 20% of developing autoimmune thyroid disease (61). Other side effects include susceptibility to infections and infusion-related reactions, the latter of which is caused by cytokine release in response to the drug and require corticosteroid pretreatment (58).
Despite the safety concerns, these studies have demonstrated a significant benefit in treating early relapsing-remitting MS patients with alemtuzumab. Further studies are needed to assess the long-term effects associated with therapy. Two phase III studies are currently underway comparing the efficacy of alemtuzumab to IFN-β1a (Rebif) in RRMS patients who have relapsed on conventional disease-modifying agents (CARE-MS II study, NCT00548405) and in those who are treatment-naïve (CARE-MS I study, NCT00530348).
Rituximab (Roche, Basel, Switzerland) is a chimeric (human/murine) monoclonal antibody to CD20, an antigen expressed on mature and preB-lymphocytes. It effectively depletes B-lymphocytes via complement-dependent cell lysis and antibody-dependent cellular toxicity (62,63). Rituximab is used in the treatment of certain B-cell malignancies as well as a growing number of refractory autoimmune conditions. B cells are a potential therapeutic target in MS as there is increasing evidence, both in vivo and in the animal model, for the involvement of the humoral immune system in the pathogenesis of MS (3). Most notably, intrathecal oligoclonal bands are found in up to 75% of MS patients (64).
In the phase II study of rituximab in relapsing-remitting MS patients, a significant reduction in both MRI and clinical markers of disease activity was shown (65).A total of 104 patients with RRMS were randomised to 2 × 1000 mg IV rituximab or placebo and monitored for 48 weeks. The rituximab group showed a significant reduction in the number of contrast-enhancing MRI lesions (p < 0.001) and volume of T2 lesions (p = 0.04) compared with the placebo group at weeks 24 and 36 respectively. A reduction in annualised relapse rate was further shown in the rituximab group, which was statistically significant at 24 weeks, but not at 48 weeks (65).
Rituximab was shown to be relatively safe in the study, with no significant opportunistic infections reported in the treatment group. Patients however, commonly experienced infusion-related reactions, although most of these were mild or moderate (65). There have been reports of severe viral infections associated with rituximab therapy, including reactivation of JC virus, in patients with lymphoproliferative and other autoimmune disorders (66). The true risk of rituximab-associated PML is difficult to ascertain and this topic has been comprehensively reviewed by Carson et al. (67).
The role of B-lymphocytes in progressive MS is less certain. Immunohistochemical studies at postmortem have identified B-cell follicles in the meninges of a proportion of patients with secondary progressive MS, but not in primary progressive disease (68,69). An early study of rituximab in primary progressive MS patients showed that B-lymphocytes were not as effectively depleted in the cerebrospinal fluid compared with the periphery (70). A subsequent phase II/III trial of rituximab in primary progressive patients failed to provide evidence for a significant impact on disease progression (71).
Rituximab has also been trialled in neuromyelitis optica (NMO), a subtype of MS predominantly affecting the eye (optic neuritis) and spinal cord (transverse myelitis), which is mediated by autoimmune B cells. In a small open label study, eight patients with NMO refractory to immunosuppressive therapy experienced a significant improvement in relapse rate and relapse recovery following treatment with rituximab (72). A further retrospective study of 25 patients confirms these beneficial effects (73), making rituximab a favourable option in those with more severe illness.
Daclizumab is a humanised monoclonal antibody against the α subunit of interleukin-2 receptor (CD25), which is present on activated T-cells. Blockage of this receptor subunit prevents the binding of interleukin-2, limiting T-cell expansion (74). Daclizumab is mainly used in the treatment of graft rejection in renal transplant patients and has also shown efficacy in trials of non-infectious uveitis and MS (75,76). The exact mechanism of action of daclizumab in treating autoimmunity has not been fully elucidated. In a study on MS patients, it was shown that daclizumab treatment mainly causes an expansion of CD56 (bright) natural killer cells, which in turn inhibits the survival of peripheral T-cells and corresponds with a reduction in CNS inflammation (77). Three different formulations have been used in trials, which are discussed below.
In open label studies (78–82), it was observed that MS patients with relapsing disease despite conventional therapy responded favourably to intravenous daclizumab (Zenapax; Roche). Daclizumab was given either mainly as monotherapy (78) or combined with IFN-β (79–82). The vast majority of subjects showed either a significant improvement in disease activity or disease stabilisation, as measured by standardised disability scores and MRI parameters. It was also noted that some patients who worsened on daclizumab monotherapy or in combination with IFN-β, subsequently responded to a higher dose of the drug (80,81).
A recently completed phase II, double-blinded, placebo-controlled trial (CHOICE) looked at the efficacy and safety of 1 and 2 mg/kg of subcutaneous daclizumab (DAC-Penzberg) as an add-on therapy to IFN-β in 230 relapsing-remitting patients with active disease (83). Subjects had an EDSS score of 5.0 or less, and had continued to relapse whilst on IFN-β therapy. Preliminary results based on 24 weeks of trial data showed that patients on biweekly 2 mg/kg of daclizumab had a significant reduction of 72% in the total number of new or enlarged contrast-enhancing lesions on brain MRI compared with the placebo group (p = 0.04) (83). The study was not powered to compare relapse rates; although a non-significant reduction in annualised relapse rate by about 35% was noted in the daclizumab group. Monitoring is planned for up to 72 weeks, following which further results of the outcome measures should be available.
An on-going phase II study is investigating the safety and efficacy of daclizumab HYP (DAC HYP) monotherapy in relapsing-remitting patients with active disease (NCT00390221). Patients are being trialled on 4-weekly subcutaneous daclizumab 150 mg, 300 mg or a placebo. The primary outcome measure is the annualised relapse rate. Secondary outcomes include MRI markers, proportion of relapsing subjects and quality of life. The trial is currently in the extension phase.
Safety data collected so far from the above-mentioned studies showed that daclizumab was generally well-tolerated. Although overall rates of infection between treatment and placebo groups were comparable in the CHOICE study, there was an increased risk of severe infections (5.2% of infections were grade 3 vs. 0% in placebo group) and cutaneous events in the daclizumab group (83).
Oral therapies in development
Fingolimod (FTY720; Novartis, Basel, Switzerland) is a sphingosine-1-phosphate receptor (S1P1) modulator, which binds to S1P1 receptors on T-cells, affecting the receptor’s signalling pathways. The result is an inhibition of T-cell migration from lymphoid tissue into the peripheral circulation and target organs, including the CNS, thus attenuating inflammation without affecting their function (84,85). In the animal model of MS, fingolimod treatment has shown to protect against disease development and cause a rapid and sustained improvement in neurological deficits (86,87). In in vitro studies, fingolimod induced a functional effect on oligodengrocyte progenitor cells, suggesting an additional role in CNS remyelination (88).
In a 6-month, phase II controlled trial in RRMS, fingolimod significantly lowered annualised relapse rates by over 50% (p = 0.009 for 1.25 mg/day and p = 0.01 for 5 mg/day) and reduced the cumulative number of contrast-enhancing MRI lesions (p < 0.001 for 1.25 mg/day and p = 0.006 for 5 mg/day) compared with placebo (89). These findings were corroborated in the recently completed 12-month, phase III controlled trial (TRANSFORMS) (90).A total of 1292 patients with active relapsing-remitting disease with a mean EDSS score of 2.2 were randomised to 0.5 mg or 1.25 mg daily oral Fingolimod or 30 μg once-weekly intramuscular IFN-β1a (Avonex). Fingolimod significantly reduced annualised relapse rates (52% for 0.5 mg and 38% for 1.25 mg, both p < 0.0001) and MRI measures of inflammation compared with Avonex. Safety data showed that the drug was generally well-tolerated, although there was an increased rate of localised skin malignancies and two fatalities from severe herpes infection.
A further multicentre, phase III, 24-month controlled study is currently comparing the efficacy and safety of 0.5 and 1.25 mg daily oral fingolimod to a placebo in relapsing-remitting MS patients (FREEDOMS I and II; NCT00289978 and NCT00355134 respectively). End-points include relapse-related outcome measures, MRI markers of inflammatory change and drug safety profile. As of yet, an interim analysis is not available, although one a case of haemorrhagic focal encephalitis in a FREEDOMS II trial patient was recently reported (91). The efficacy of fingolimod in primary progressive MS is currently being investigated in a double-blinded, controlled trial (INFORMS; NCT00731692). The main outcome measure is the time to sustained disability progression.
Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analogue with lymphotoxic effects. It is resistant to adenosine deaminase, mimicking the immune-deficient state of hereditary adenosine deaminase deficiency (92). It causes an accumulation of deoxyneuclotides in selected T-lymphocytes, which is detrimental to the cell’s function and proliferation, resulting in their sustained depletion (92). It is approved for the treatment of hairy cell leukaemia and lymphoma.
Encouraged by the results of early controlled studies (93–95), cladribine has recently re-emerged as an effective oral therapy for relapsing-remitting MS. In the recent randomised, double-blind, placebo-controlled phase III study (CLARITY), 1326 patients with relapsing-remitting MS were randomised to 1.75 or 3.5 mg/kg cumulative dose of cladribine tablets or a placebo (in 2–4 courses) in the first year (96). A second year of re-treatment followed where patients were given either the lower dose of cladribine or a placebo in two courses. Both cladribine groups showed a rapid, sustained and statistically significant reduction in relapse rates. Specifically, patients in the 1.75 and 3.5 mg/kg treatment groups showed a significant reduction in annualised relapse rates of 58% (p < 0.001) and 55% (p < 0.001) respectively, compared with the placebo (96). MRI evaluations were also significantly improved in both Cladribine groups. As with the earlier studies, lymphopenia was seen as an expected dose-dependent effect of cladribine, although good tolerability was reported overall.
At present there are on-going studies investigating the safety and efficacy of oral cladribine as an add-on therapy in MS patients who have continued to relapse on IFN-β (ONWARD study; NCT00436826) and as monotherapy in clinically isolated syndrome (ORACLE MS study; NCT00725985).
The sustained immunosuppressive effects of cladribine make it ideal for intermittent dosing, which should improve patient adherence and tolerability especially as it can be taken in tablet form. It is not yet licenced for use in MS; however, given the positive results of the trials so far this is likely to change in the near future.
Teriflunomide is the active metabolite of leflunomide, a novel immunosuppressant effective in the treatment of autoimmune disorders, especially rheumatoid arthritis. Leflunomide is rapidly converted to its active metabolite in vivo (97). Although the exact mechanism of action of teriflunomide has not yet been fully elucidated, its main immunomodulatory effect is thought to be the inhibition of dihydro-orotate dehydrogenase, an enzyme involved in the biosynthesis of pyramidine, a metabolic component crucial to the expansion and differentiation of lymphocytes (97). Further effects on inflammatory cell recruitment and other in vivo immunomodulatory processes have been postulated (98). In the animal model of MS (EAE), leflunomide/teriflunomide was shown to be effective in mitigating the disease course and symptoms (99,100).
The first phase II study of oral teriflunomide in MS reported a reduction in both MRI and clinical disease parameters (101). A total of 179 patients with relapsing MS were randomised to 7 or 14 mg daily terflunomide or a placebo. As a primary end-point, the study group assessed the number of combined unique (CU) active lesions, which consisted of new and persisting contrast-enhancing and T2 lesions on MRI. Both teriflunomide treatment groups showed a significant reduction of over 61% in the number of CU active lesions compared with the placebo group (p < 0.03 and p < 0.01 for 7 and 14 mg respectively). The study was not powered to measure clinical end-points of the disease; however, the group did observe a trend towards lower annualised relapse rates and fewer numbers suffering an increase in disability amongst the teriflunomide-treated patients. The overall safety profile of the drug was good, in keeping with previously observed data from leflunomide trials in rheumatoid arthritis (102,103). Notably, no opportunistic infections were reported.
Teriflunomide is currently being trialled in a number of phase III clinical studies. The phase III TEMSO (NCT00134563) and TOWER (NCT00751881) studies are investigating the safety and efficacy of 7 and 14 mg daily teriflunomide compared with a placebo in patients with relapsing MS. Primary outcome measures are EDSS and annualised relapse rate respectively. A third phase III trial will include an IFN-β1a – control arm (TENERE study, NCT00883337) to compare the effectiveness and safety of 7 and 14 mg teriflunomide to IFN-β1a in relapsing MS patients.
It remains to be seen if clinical end-point measures, especially relapse rate and disability progression, are met in the phase III studies of teriflunomide. If so, teriflunomide will offer an effective and convenient alternative to current DMT.
Laquinimod (ABR-215062) is a linomide-related synthetic compound developed to provide effective immunomodulation without significant adverse immunosuppressive effects. Taken orally, laquinimod prevents the migration of peripheral lymphocytes into the CNS, although its exact mode of action has not been fully elucidated (104). Successful studies in the animal model (EAE) of acute and chronic relapsing disease demonstrate its therapeutic potential in MS (104).
In the first phase II clinical study of the drug (105), patients with active relapsing MS taking 0.3 mg/day laquinimod demonstrated a significant reduction of 44% in active MRI lesions compared with a placebo (p = 0.0498). A larger phase II study (106) also demonstrated a reduction of about 40% in active MRI lesions in relapsing-remitting patients taking a slightly higher dose of laquinimod (0.6 mg daily), compared with the placebo (p = 0.0048). Neither of these studies was powered to provide efficacy data based on clinical outcome measures such as EDSS score and rate of relapses.
Two multicentre phase III studies of laquinimod in active relapsing-remitting MS are currently taking place. In the first study, the efficacy and safety of laquinimod 0.6 mg/day will be compared with a placebo (NCT00509145). The second study is a parallel-group comparing the safety and efficacy of laquinimod 0.6 mg/day to intramuscular IFN-β and a placebo (NCT00605215). Outcome measures in both studies include relapse rate (primary), disability progression and MRI parameters. It is estimated that both studies will run until 2011.
Dimethyl fumarate (BG00012)
BG00012 is an oral formulation of dimethyl fumarate, an antipsoriatic agent with anti-inflammatory and neuroprotective properties. An early clinical study of Fumaderm, another fumaric acid ester, demonstrated the therapeutic potential of fumarate in MS (107). BG0002 is a potent activator of nuclear factor E2-related factor 2 (Nrf2), a transcription factor, which plays a crucial role in neuronal protection during oxidative stress and chemical insults (108,109) and in the maintenance of CNS myelin (110). Further in vitro studies have also shown that it inhibits expression of pro-inflammatory cytokines and cell adhesion molecules, providing an anti-inflammatory effect (111,112).
A double-blind, placebo-controlled, dose-ranging phase II study of BG00012 in RRMS showed that it was effective in reducing MRI measures of disease activity (113).A total of 257 patients with relapsing-remitting disease were randomised to receive oral BG00012 120 mg once daily, 120 or 240 mg three times a day or a placebo for 24 weeks. The study found that treatment with 240 mg three times a day significantly reduced the number of contrast-enhancing MRI lesions by 69% compared with placebo (p < 0.0001), alongside other MRI parameters. The study was not powered to compare clinical outcomes; although a reduction of about 32% in annualised relapse rate was observed in the high-dose active treatment group. BG00012 was shown to be safe and generally well-tolerated, although gastrointestinal effects were commonly reported in the earlier stages of treatment.
Two on-going, phase III, dose-ranging, placebo-controlled studies, DEFINE (NCT00420212) and CONFIRM (NCT00451451) are evaluating the safety and efficacy of oral BG00012 in patients with relapsing-remitting MS. Patients in both studies will be randomised to BG00012 240 mg twice daily or three times a day or a placebo. The CONFIRM study will have an added glatiramer acetate treatment arm, given as a 20 mg daily subcutaneous injection, for further comparison.
Firategrast (SB-683699) is, like natalizumab, a α4-integrin antagonist which interferes with the binding of α4β1 and α4β7 integrins to its ligand, VCAM-1, preventing the migration of immune cells to the site of inflammation (114). Unlike natalizumab; however, it is a small molecule in the form of an oral preparation, which has the benefit of a more convenient mode of delivery and reduced drug costs.
A multicentre, phase II trial (NCT00395317) is currently investigating the MRI efficacy and safety of Firategrast in relapsing-remitting patients. Around 350 patients have been enrolled in the study, with preliminary result still pending.
DMT in CIS
Clinically isolated syndrome (CIS) may represent the first demyelinating attack of MS in a large proportion of patients. For many, there is already radiological evidence of MS at this stage (115–117). Using defined MRI criteria, we are able to gauge the risk of a patient developing a second clinical attack diagnostic of MS (118–120). However, irrespective of the patient’s MRI findings, the current trend is such that the vast majority of CIS patients with little or no disability are given the ‘wait and see’ approach to therapy.
There is growing evidence that early treatment in MS may significantly alter the course of the disease. Axonal degeneration, which is responsible for the permanent disability in MS, is seen to occur early on in the disease process (121–123). Studies have suggested a causal link between acute inflammation and axonal loss (123) along with the accepted role of chronic demyelination. Furthermore, highly active disease early on correlates to increased disability at a later stage and increased likelihood of secondary progression (124). Thus, early anti-inflammatory treatment could potentially delay or prevent the onset of permanent disability.
Evidence from a number of phase III clinical trials supports this. The CHAMPS study group reported on the outcome of a randomised, double-blind, placebo-controlled trial of 30 μg intramuscular IFN-β1a (Avonex) weekly in patients presenting with CIS (125). They showed that early treatment significantly lowered the probability of developing clinically definite MS (CDMS) at 3 years compared with placebo (hazard ratio 0.56, p = 0.002). In their 10-year follow-up study, the group continued to show a reduced conversion rate to CDMS in patients who had early treatment compared with those who delayed therapy (hazard ratio 0.64, p = 0.03) (126).
The ETOMS study investigated the efficacy of 22 μg subcutaneous IFN-β1a (Rebif) weekly in a similar trial (127). They also demonstrated significantly lower numbers of patients who converted to MS after 2 years of treatment (34% of Rebif group vs. 45% of placebo, p = 0.047). The BENEFIT study group followed suit with positive result from their study of alternate day 250 μg subcutaneous IFN-β1b (Betaferon/Betaseron) in CIS (128). In particular, treatment with IFN-β1b for 2 years significantly delayed the conversion to CDMS, and McDonald-criteria defined MS (hazard ratio 0.50, p < 0.0001 and 0.54, p < 0.00001 respectively) compared with placebo-treated patients. A recent Cochrane meta analysis of the above CIS studies concluded that IFN-β treatment in CIS significantly lowered the proportion of patients who converted to CDMS at year 1 (pooled odds ratio 0.53, p < 0.0001) and year 2 of therapy (pooled odds ratio 0.52, p < 0.0001) compared with those on a placebo (129).
The study group for the PreCISe trial of glatiramer acetate (Copaxone) in CIS recently revealed the results of their interim analysis on data accumulated from approximately 80% of the three-year study exposure (130). Compared with placebo, the risk of conversion to CDMS in patients who received 20 mg daily subcutaneous Copaxone was reduced by 45% (p < 0.0001). Moreover, the time for 25% of patients to develop CDMS was prolonged by 115% in the Copaxone group (p = 0.0005).
A prospective, double-blind, placebo-control phase III trial is currently underway, investigating the effectiveness of subcutaneous 44 μg IFN-β1a (Rebif) in delaying the conversion of CIS to CDMS. Two other similar phase III trials are also investigating oral cladribine (NCT00725985) and teriflunomide (NCT00622700) in CIS patients, with time to conversion to CDMS as the primary outcome measures.
Although the logical conclusion from the above studies is that DMT should be initiated at the onset of the first clinically demyelinating event, this may not be an advantage for all patients. Many may have a favourable or mild disease course (131), making lifelong treatment unnecessary. Moreover, the inconvenience of parenteral therapy and possible side effects may make it difficult for many patients to comply with long-term treatment. Ultimately, the decision on when to commence disease-modifying therapy should be jointly made by the neurologist and patient after considering all the available evidence.
DMT in progressive MS
Irreversible progression is attributed to neurodegeneration, implying that standard anti-inflammatory disease-modifying agents may not have an impact on disease progression, as shown to be the case in many of the above-mentioned studies. Primary progressive MS also differs from secondary progressive and relapsing-remitting disease in their pathological features, whereby in primary disease, more diffuse inflammation affecting the so-called normal-appearing white and grey matter is seen.
Far fewer therapeutic agents are currently being trialled in progressive MS in comparison to relapsing-remitting MS, although a small number have been completed in the last few years. The European and North American Study Groups of Interferon-β1b in secondary progressive MS showed positive results with regards to relapse rate and MRI evidence of disease activity (132,133). In the European study, IFN-β1b significantly delayed the time to confirmed disability progression, i.e. increase in EDSS of 1.0 point, by 9–12 months (odds ratio 0.65, p = 0.0008). The North American group however, did not achieve this (133). Nonetheless the results of the European study subsequently led to the approval of IFN-β1b therapy for secondary progressive MS.
Rebif was trialled in SPMS in the SPECTRIMS study, a multicentre, placebo-controlled trial using two doses of the drug, 22 and 44 μg. The study drug failed to show a significant effect on disability progression, although it improved relapse rates (p < 0.001 for both doses) (134). Similarly, Avonex failed to show a significant impact on EDSS progression in a SPMS trial (IMPACT study), although it benefited Multiple Sclerosis Functional Composite scores (p = 0.033), relapse rates (p = 0.008) and MRI measures of disease activity (p < 0.001) (135).
In two small, separate primary progressive MS trials, neither Avonex (n = 50) nor Betaferon (n = 73) showed a significant impact on disease progression and brain and spinal cord atrophy (136,137). The efficacy of glatiramer acetate in primary progressive MS (PPMS) was evaluated in a large placebo-controlled, double-blinded trial involving 943 patients. Results showed a non-significant delay in the progression of disability in the active treatment group, although there was a significant improvement in MRI markers of disease activity (p = 0.0193) (138). Other agents that have recently failed to show a significant impact on disability progression in PPMS include mitoxantrone (139) and rituximab (as detailed elsewhere in the text)(71).
In trials involving both primary and secondary progressive patients, cladribine failed to show any significant impact on disease progression although it improved some MRI-defined outcome measures (94). On the other hand, a relatively small study of monthly intravenous immunoglobulin (IVIg) therapy showed a positive reduction in the proportion of patients with sustained disability progression compared with a placebo, which was significant in PPMS, but not in SPMS patients (140). Previous findings in SPMS also failed to show any significant benefit of IVIg (141). This could indicate that IVIg has a potentially favourable effect in PPMS, but not in SPMS, although further study is warranted.
Other forms of therapy currently being assessed for the treatment of progressive MS include the aforementioned oral disease-modifying agent fingolimod and haematopoietic stem cell transplantation (HSCT). The efficacy of HSCT in progressive MS has been controversial, especially regarding MRI evaluation of disease progression and the high mortality risk faced by more severely disabled patients. This subject matter has been comprehensively reviewed by Saccardi et al. (142).
A trial of cannabinoids as disease-modifying treatments in progressive MS is underway.
Increasing knowledge of the pathological process of MS has allowed us to continue developing highly selective immunomodulatory therapies. The main aim of treatment thus far has been to reduce the frequency and severity of relapses, likely delaying the onset of irreversible disability. We have only partially achieved this with current DMT. Encouragingly, the emergence of several agents showing early promise in clinical trials may soon help realise this and offer patients a wider repertoire to choose from. Alemtuzumab appears to be a promising monoclonal antibody treatment for MS; however, the results of larger phase III studies are still awaited. Rituximab may benefit patients with MS and other autoimmune conditions, although further risk/benefit analysis would be required given the reported cases of PML so far. Of the oral agents, Fingolimod and cladribine have shown positive results as disease-modifying agents in large phase III studies, although their long-term safety and efficacy in MS have yet to be established. Many more experimental therapies beyond the scope of this review are currently being explored at various stages, including autologous haematopoietic stem cell transplantation for more aggressive forms of MS, Ataticept (a recombinant fusion protein, which inhibits B-cell stimulation and proliferation, currently in phase II RRMS trials; NCT00642902 and NCT00853762) and other drugs that may offer neuroprotection. Trials that re-evaluate ‘traditional’ immunosuppressive agents such as azathioprine and cyclophosphamide may also provide fresh evidence for treating refractory cases of MS. The choice of disease-modifying treatment is increasingly individualised depending on the disease characteristics, patient lifestyle and drug risks/benefits. Within the established first-line therapies, the risk of flu-like symptoms need to be weighed against the inconvenience of daily injections. As for newer and novel therapies, their immunosuppressive properties and our less than abundant experience with them need to be balanced against the safety and relative predictability of established treatments.