Table of Contents  

Leutmezer: Immunomodulatory treatments for relapsing–remitting multiple sclerosis

Introduction

For most of the time since the first description of a (possible) case of multiple sclerosis (MS) in the fourteenth century,1 treatment was restricted to prayer, medical spa, silver iodide, mercury and blood-letting. It was 500 years before the first anti-inflammatory treatments, corticosteroids and azathioprine, became available in the 1950s.

Another milestone was the introduction of interferon (IFN)β-1b (Betaseron®/Betaferon®, Schering) in 1993 after completion of the first large double-blind placebo-controlled study in patients with relapsing–remitting MS (RRMS).2 In the same decade, glatiramer acetate (GA) (Copaxone®, Teva) and two IFNβ-1a preparations (Avonex®, Biogen Idec; and Rebif®, Merck) were also licensed.35

Although these disease-modifying treatments were only moderately effective, they were widely used in clinical practice, most probably because of a lack of competitors. This situation changed with the emergence of the first monoclonal antibody (mAb): natalizumab (Tysabri®, Biogen Idec). Natalizumab was able to reduce the annualized relapse rate (ARR) by almost 70%, an improvement on the 30% ARR reduction of IFNs and GA. These promising results gave impetus to the development of several other mAbs such as ocrelizumab (Ocrevus®, Roche), alemtuzumab (Lemtrada®, Sanofi Genzyme) and daclizumab (Zinbryta®, Biogen Idec).

In addition to safety issues, mAbs have to be administered by injection, which has led to the development of more convenient oral formulations such as fingolimod (Gilenya®, Novartis), teriflunomid (Aubagio®, Sanofi Genzyme), dimethyl fumarate (DMF) (Tecfidera®, Biogen Idec) and cladribine (Mavenclad®, Merck).

This review will give an overview of established drugs and their upcoming novelties, with special emphasis on efficacy and safety issues. Our attention will focus especially on both recently approved drugs and some promising drugs producing positive results in phase III clinical trials.

Therapies for mild/moderate relapsing–remitting multiple sclerosis

Interferon β-1a, interferon β-1b and pegylated interferon β-1a

Mode of action

A multitude of mechanisms have been proposed to account for the anti-inflammatory and immunomodulatory capacity of the different IFNβ preparations, although their in vivo relevance is still controversial. According to a recent review,6 the most relevant modes of action of IFNβ preparations in MS are (1) impairment of lymphocyte egress from the lymph node by up-regulating transcription of intracellular CD69, which selectively binds to sphingosine-1-phosphate (S1P) receptor 1 (S1P1), thus precluding its surface expression; (2) diminished ability of activated lymphocytes to cross the blood–brain barrier (BBB) by downsizing the density of adhesion molecules such as VLA-4 on their surface [while also mediating cleavage of the vascular cell adhesion molecule (VCAM) expressed on the surface of BBB endothelial cells to generate soluble VCAM]; (3) directly increased expression and concentration of anti-inflammatory agents (Th2 pathway) and down-regulation of the expression of proinflammatory cytokines of the Th1 phenotype; (4) increased numbers of CD56bright natural killer (NK) cells in the peripheral blood; and (5) down-regulation of MHC class II mRNA, which limits the competence and availability of antigen-presenting cells.7

Efficacy

Each of the three IFNβ preparations were licensed following a single multicentre double-blind placebo-controlled phase III trial:2 (1) IFNβ-1b subcutaneously every other day,3 (2) IFNβ-1a (Avonex) intramuscularly once weekly5 and (3) IFNβ-1a (Rebif) subcutaneously three times weekly. Although a recent Cochrane Review8 points towards a somewhat higher efficacy rate with higher dosage and higher administration frequency, a mean reduction in ARR and disability progression of around 30% over a 2-year period can be generally estimated.

Subsequently, IFNβ preparations were studied in patients with clinically isolated syndrome (CIS) and were shown to reduce the risk of conversion to clinically definite MS in this population, with the number needed to treat between 5 and 7.9,10 This positive effect was still evident at follow-up after 8 years.11 These results gave rise to a shift in the clinical paradigm, treating MS at earlier disease stages.

Although IFNβ preparations have satisfactory efficacy numbers together with a favourable long-term safety profile, their use is likely to peak and decline because the route and frequency of administration limit their patient convenience. This disadvantage was largely overcome with the introduction of pegylated IFN (PEG-IFN)β-1a (Plegridy®, Biogen Idec).

Pegylation of IFN means that at least one molecule of polyethylene glycol (PEG) is covalently added. This modification is a standard procedure to increase the stability, solubility, half-life and efficacy of a drug and is applied to several drugs and diseases. A global phase III clinical (ADVANCE) study12 investigated the efficacy of PEG-IFNβ-1a every 2 weeks in reducing the relapse rate in patients with RRMS. Compared with placebo, the ARR was reduced by about one-third, and the number of new or newly enlarging T2 brain lesions was reduced by two-thirds.12 Chronic administration of pegylated proteins, mostly at toxic concentrations, causes vacuolation of renal epithelium in animals, which – along with the occurrence of anti-PEG antibodies – needs to be addressed by phase IV studies.13

Safety and tolerability

The most common side-effects reported in phase III trials and post-marketing surveillance include flu-like symptoms, abnormal liver function tests and injection-site reactions. Rare cases of severe hepatic injury, depression and thyroid gland disorders have also been reported. However, more importantly, a global safety database that has been accumulated over 15 years in the post-marketing period for intramuscular IFNβ-1a showed no malignancy risk.14

Glatiramer acetate and glatirameroids

Mode of action

Glatiramer acetate, composed of four amino acids (l-glutamic acid, l-alanine, l-lysine and l-tyrosine), was initially developed to mimic myelin basic protein (MBP) in order to induce experimental autoimmune encephalomyelitis (EAE). However, GA unexpectedly inhibited EAE in both rodents and monkeys and was developed as an immunomodulatory treatment for MS.

Similar to IFNβ, a multitude of mechanisms have been proposed to account for GA’s efficacy in treating RRMS: GA (1) shifts the T cell repertoire from an inflammatory Th1 towards an anti-inflammatory Th2 phenotype; (2) inhibits myelin reactive T-cells; (3) enhances the suppressor activity of CD8+ T-cells towards CD4+ T-cells; (4) may exert neuroprotective effects by stimulating T-cells to produce brain-derived neurotrophic factor (BDNF); and (5) affects B-cells by modulating their cytokine pattern and altering the expression of CD80, CD86 and MHC II, which in turn affects co-stimulatory signals required by T-cells in the inflammatory cascade.15

Efficacy

Glatiramer acetate was licensed following a single multicentre randomized placebo-controlled trial. After 2 years, the drug showed a 29% reduction in ARR compared with placebo and a significant increase in the proportion of patients with an improved Expanded Disability Status Scale (EDSS) score.4 Although magnetic resonance imaging (MRI) measures were not included in the initial study, a subsequent multicentre double-blind placebo-controlled trial used MRI parameters as primary outcome parameters and showed a statistically significant difference in the number of gadolinium (Gd)-enhancing lesions, total T2 lesion volume and number of new T2 lesions between GA and placebo.9

Because high injection frequency and common local injection-site reactions are major confounders of convenience, and because they influence patients’ compliance negatively, a reduced dosing regimen has been investigated. A randomized double-blind placebo-controlled study16 was performed with > 1500 patients receiving either 40 μg of GA three times per week or placebo. The treatment group showed a 34.0% reduction in ARR and a 44.8% reduction in Gd-enhancing lesions or a 34.7% reduction in new or newly enhancing lesions. A dose of 40 μg of GA was safe and well tolerated. The most common adverse events (AEs) in the GA group were injection-site reactions.

Safety and tolerability

The most commonly reported AEs in patients receiving long-term GA included local injection-site reactions (e.g. erythema, pain, nodules and oedema) and symptoms associated with an immediate post-injection reaction, which include vasodilation, chest pain, palpitation, tachycardia and dyspnoea. Observational studies covering a period of up to 15 years did not show an increased risk of malignancies, haematological abnormalities and renal or hepatic failure.17

Teriflunomide

Mode of action

Leflunomide (Arava®, Sanofi Aventis) is the prodrug of teriflunomide and, after its approval for rheumatoid arthritis (RA) by the Food and Drug Administration (FDA) in 1998, its extension to other autoimmune diseases was a logical consequence.

Teriflunomide inhibits dihydroorotate dehydrogenase (DHODH) – the rate-limiting mitochondrial enzyme in de novo pyrimidine synthesis – by non-competitively antagonizing the binding of its substrate, dihydroorotate, and also competing with the binding of ubiquinone.18 Fast-proliferating lymphocytes are completely dependent on this enzyme to satisfy their pyrimidine need, whereas resting lymphocytes can use a salvage pathway to recruit pyrimidine independent of DHODH. Therefore, it is argued that teriflunomide acts as a selective immunomodulator rather than as an immunosuppressant.19

Additionally, teriflunomide may impair the migratory capacity of T-cells, shift the T-cell phenotype from a proinflammatory Th1 to an anti-inflammatory Th2 pattern, decrease T-cell-dependent antibody (Ab) production and modulate the expression of adhesion molecules on neutrophils and macrophages.18 In vitro experiments also suggest a possible neuroprotective effect by suppressing astrocytic inducible nitric oxide (NO) synthase-mediated NO production.20 However, in vivo evidence of this effect is still lacking and, for now, its clinical meaning remains uncertain.

Efficacy

The first randomized double-blind placebo-controlled phase III trial – the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial21 – compared two different doses of teriflunomide (7 mg and 14 mg) with placebo for 2 years in 1088 RRMS patients. Both doses reached the primary end point by significantly reducing ARR by 31%. However, a significant reduction in the rate of disability progression compared with placebo (by around 30%) was found only for the 14-mg group. Both dosing regimens also significantly influenced several MRI parameters to an extent that was similar to the currently available first-line immunomodulatory drugs used for MS.

The second randomized double-blind placebo-controlled phase III trial – the Teriflunomide Oral in People With Relapsing–Remitting Multiple Sclerosis (TOWER) trial22 – compared the same two doses with placebo in 1169 patients, with an average treatment duration of 18 months. Patients receiving 14 mg had a 36.3% reduction in ARR and a 31.5% reduction in 12 weeks sustained disability progression, both results meeting statistical significance. The 7-mg group also showed a 22.3% significant reduction in ARR, whereas there was no difference in the accrual of disability compared with placebo.

A third randomized double-blind placebo-controlled phase III trial – the Teriflunomide versus Rebif (TENERE) trial23 – used 44 mg of IFNβ-1a (Rebif) thrice daily as an active comparator to 7 mg and 14 mg of teriflunomide in 324 RRMS patients. The primary outcome parameter was time to treatment failure and was defined as either a further clinical relapse or trial withdrawal for any reason. No statistical difference was found between the three groups. ARRs were comparable between the IFNβ-1a group and patients randomized to 14 mg of teriflunomide.

A once-daily dose of 14 mg of teriflunomide was approved by the FDA in September 2012 and by the European Medicines Agency (EMA) in August 2013 for patients with RRMS.

Safety and tolerability

Although teriflunomide is a new drug for MS, significant data on the safety profile of the drug can be deduced from leflunomide, which was licensed by the FDA in 1998 for RA. The safety profile and side-effect profile of leflunomide do not seem to be substantially different from data derived for teriflunomide in phase II and III clinical trials.

Common AEs are predominantly gastrointestinal (and include abdominal pain, diarrhoea, dyspepsia, nausea, vomiting, oral ulcers and elevated liver enzymes). The incidence and severity of most of these are dose dependent.24 Furthermore, alopecia, skin rashes and hypertension are described in a significant proportion of patients.24 The incidence of diarrhoea, nausea, alopecia and elevated liver enzymes are dose related.24 In the phase II extension study, the safety profile was favourable overall, although the discontinuation rate was 42%, and 19% of the total number of patients were linked to treatment-related (non-severe) AEs.25

The incidence of serious AEs (SAEs) in the clinical trial programme of teriflunomide did not differ between the placebo and the 14-mg groups in terms of deaths, severe or opportunistic infections and malignancy. SAEs in leflunomide-treated patients included elevated liver enzymes, neutropenia, rare cases of interstitial lung disease and two cases of interstitial progressive multifocal leucoencephalopathy (PML).26 As these patients had a history of previous immunosuppression, no definite conclusions on the PML incidence risk of teriflunomide can be drawn.

Teratogenicity has been described in animal models, but reproductive toxicity data in humans are limited. Nevertheless, patients need to be made aware of the theoretical risk of teratogenicity based on animal data, and it is strictly required that pregnancy is excluded before initiation of teriflunomide treatment. Women must use effective contraception throughout the whole treatment period and for up to 1 year thereafter, as teriflunomide exerts long-lasting biological effects. Men are similarly cautioned to avoid fathering a child while on therapy.27 It is strongly advised that women who become pregnant during treatment use colestyramine (8 g three times a day for 11 days) as a washout procedure, which results in elimination rates of 90% at day 10. Breastfeeding is also not recommended for patients on teriflunomide.

Future prospects

In the Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis (TOPIC) trial,28 both 7 mg and 14 mg teriflunomide significantly reduced the risk of conversion of CIS to clinically definite RRMS compared with placebo. Nevertheless, the licensing of teriflunomide for patients after a first clinical symptom suggestive of MS is still pending.

Dimethyl fumarate

Mode of action

Dimethyl fumarate ester compounds are licensed in several countries around the world to treat patients with severe psoriasis, and during the last 15 years they have proven to be a safe and relatively convenient drug for this purpose. A direct comparison with its use in MS is hampered by different dosage regimens: DMF is used only periodically in psoriasis, whereas it is used for many years without treatment holidays in MS.

The use of DMF overcomes the problem of poor absorption rates of fumaric acid after ingestion. Potential ulcerogenic side-effects of these esters necessitate the use of enteric-coated formulations. After gastric passage, DMF is almost completely absorbed in the small intestine and hydrolysed to monomethylfumarate (MMF), the biologically active metabolite.

Although the exact mode of action is poorly understood, two main mechanisms of the drug seem to be responsible for its clinical effect in MS:

  1. DMF exerts anti-inflammatory effects on the immune system by (1) polarizing the immune system from a Th1 phenotype towards a Th2 phenotype, thus increasing the amount of anti-inflammatory cytokines compared with proinflammatory cytokines such as TNFα, interleukin (IL) 1β and IL-6; (2) preventing the nuclear translocation of cytoplasmic nuclear factor kappa B (NF-κB) and hence the NF-κB-driven transcription of proinflammatory cytokines; and (3) attenuating lipopolysaccharide-induced production of proinflammatory mediators including TNFα, IL-1β, IL-6 and NO from astrocytes and microglia.

  2. DMF exerts neuroprotective effects via activation of the NF-E2-related factor 2 (Nrf2) antioxidant pathway. DMF rescues neurons and glial cells in culture from oxidative stress-induced cell death by inducing Nrf2-mediated dependent pathways, which induces phase 2 detoxifying enzymes [e.g. NAD(P)H]. Moreover, DMF can reduce T-cell migration via the BBB by inhibiting the expression of adhesion molecules on the surface of lymphocytes.15

Efficacy

The Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS (DEFINE) study29 randomized 1237 RRMS patients with at least one relapse in the prior 12 months to 240 mg twice daily, 240 mg three times daily or placebo for 96 weeks. ARR was significantly reduced in both treatment arms with a 53% reduction in the 240 mg twice daily regimen. Twelve weeks sustained disability progression was also significantly reduced by 38% compared with placebo. In concordance with the clinical end points, DMF also showed statistically significant reductions in all relevant MRI parameters.

A second phase III trial – the Comparator and an Oral Fumarate in Relapsing–Remitting MS (CONFIRM) trial30 – also randomized patients to receive one of two different DMF doses or placebo, and additionally added a GA group as a fourth treatment arm. However, the study was not sufficiently powered to detect a difference between DMF and GA, which prevented a direct comparison. Furthermore, there was no blinding to GA treatment. All active treatment arms showed a significant reduction in ARR, the primary outcome parameter of the study, with a more prominent reduction in the two DMF groups (44% in the 480-mg group and 51% in the 720-mg group vs. 29% in the GA group). There were also statistically significant reductions in the number of new or enlarging T2 lesions (by 71% and 54% vs. 73%, respectively) and the proportion of relapsing patients (34% and 29% vs. 45%, respectively). In contrast, the reduction in disability progression confirmed at 12 weeks showed no statistically relevant difference.

Based on the results of these two studies, DMF was approved for RRMS as Tecfidera – in doses of 240 mg twice daily – by the FDA in May 2013 and by the EMA in January 2014.

Safety and tolerability

Adverse events occurring more frequently in DMF-treated patients in the phase II trials included gastrointestinal symptoms (nausea, diarrhoea and abdominal pain) and flushing, which typically occur within 30 minutes. The initial effect of MMF in enhancing TNFα would account for some of the AEs experienced in the initial period of DMF administration, especially flushing, diarrhoea and abdominal cramps.31 Other frequently reported side-effects include (dose-related) elevation of transaminase levels and lymphopenia. Lymphocyte counts decreased to 50% of baseline levels in up to 10% of patients within the first year of treatment. Nevertheless, in almost all patients, mean values remained within the normal range. Rare cases of proteinuria were described in both DEFINE and CONFIRM.

Although there was no difference in infection rates in the phase III trials, sporadic cases of PML have been reported with DMF compounds in the treatment of psoriasis,32 and with Tecfidera and other DMF compounds in MS.33 Older age and lower lymphocyte counts are discussed as probable risk factors for PML, although the overall low incidence precludes definite conclusions for now.

Future prospects

A phase III multicentre randomized double-blind assessment of DMF examining the time to a first attack in patients with radiologically isolated syndrome – the Assessment of Tecfidera® in Radiologically Isolated Syndrome (ARISE) study (NCT02739542)34 – is currently recruiting patients with incidental T2-hyperintense lesions suggestive of MS but without any clinical symptoms. The primary outcome parameter will be the time from randomization to the first demyelinating event (acute or development of an initial symptom resulting in a progressive clinical course). Results are expected in late 2020.

Therapies for highly active relapsing–remitting multiple sclerosis

Natalizumab

Mode of action

Natalizumab was the first mAb licensed for MS treatment. Natalizumab binds to the α4-integrin molecule, a component of VLA-4, on lymphocytes, thereby preventing binding to the ligand VCAM on endothelial surfaces. By this mechanism, the adhesion and subsequent migration of lymphocytes across the BBB is disabled, thus attenuating central nervous system (CNS) inflammation.35

Efficacy

Two pivotal phase III trials led to the licensing of natalizumab by the FDA in 2004 and by the EMA in 2006 for the treatment of RRMS. The first pivotal trial – the Natalizumab Safety and Efficacy in Relapsing–Remitting MS (AFFIRM) trial36 – assigned 942 RRMS patients in a 2 : 1 ratio to receive either natalizumab (300 mg) or placebo intravenously every 4 weeks for up to 116 weeks. Natalizumab reached the primary outcome parameter – reducing ARR by 68% compared with placebo – and secondary outcome measures, such as reducing sustained disability progression by 42% and MRI activity by up to 92%.

The second pivotal trial – the Safety and Efficacy of Natalizumab in Combination with IFNβ-1a in Patients with Relapsing–Remitting MS (SENTINEL) trial37 – randomly assigned 1171 patients who, despite IFNβ-1a treatment, had at least one relapse in the previous year. Patients were randomized to receive (in addition to IFNβ-1a) either 300 mg of natalizumab or placebo as a monthly infusion. Compared with the IFNβ-1a + placebo group, the combination therapy offered a reduction of > 50% in ARR and MRI activity, together with a reduction of 24% in sustained disability progression.

Safety and tolerability

In these pivotal trials, the only side-effects occurring more often in the natalizumab than in the placebo group were allergic reactions.

Following two cases of PML in the SENTINEL trial, natalizumab was voluntarily suspended by the manufacturer in 2005, but reintroduced in June 2006 with revised labelling and risk management programmes.38 As of August 2016, the overall incidence of PML in natalizumab-treated patients is 4.22 per 1000 patients. PML has been confirmed in 685 patients, of whom 77% are still alive with varying levels of disability. The duration of dosing prior to PML diagnosis ranged from 8 to 118 doses (Biogen, data on file). The most relevant risk factors are John Cunningham virus (JCV) exposure, indicated by the presence of anti-JCV Abs (anti-JCV Ab index), immunosuppressive treatment prior to natalizumab and longer treatment duration. Considering this, a more detailed risk stratification has been applied in recent years.39

Fingolimod

Mode of action

Fingolimod, which is derived from myriocin, a metabolite of the fungus Isaria sinclarii, was the first orally available immunomodulatory drug to be licensed in Europe and the USA. In vivo, fingolimod is phosphorylated to fingolimod phosphate, which acts as a functional antagonist at most S1P receptors. S1P receptors are found on T-cells and mediate the egress of activated T-cells from lymphoid organs into the blood, thus preventing their infiltration into the CNS, a crucial step in the pathophysiology of MS. Moreover, S1P receptors are found on virtually all neural cell lineages and in vitro data suggest that fingolimod could affect oligodendrocyte precursor cell survival, recruitment, activation and astrogliosis. However, the evidence is not consistent and supporting in vivo data are lacking.40

Efficacy

Data on clinical efficacy of fingolimod are mainly derived from two phase III trials. In the first trial – the FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) trial41 – 1272 RRMS patients were randomized to receive 0.5 mg or 1.25 mg of fingolimod or placebo for 24 months. Both dosing regimens showed a significant reduction in ARR, several MRI parameters and risk of disability progression compared with placebo. The second phase III trial – the Trial Assessing Injectable INF vs. FTY720 Oral in RRMS (TRANSFORMS) trial42 – tested whether or not fingolimod (either 0.5 mg or 1.25 mg daily) was superior to IFNβ-1a in 1292 subjects over 12 months. Although fingolimod again showed a significant reduction in ARR (40%), the progression of disability over a 1-year period showed only a trend in favour of fingolimod. Therefore, fingolimod was approved by the FDA in October 2010 and by the EMA in March 2011 for patients with RRMS. However, the EMA restricted the use of fingolimod to patients with poor response to IFNβ or to therapy-naive patients with a severe disease course from onset.

Safety and tolerability

The most common side-effects of fingolimod (seen in > 10% of patients) are flu infections, headache, cough, diarrhoea and back pain. Elevated liver enzymes (more than threefold the upper limit) were found in 9% and lymphopenia in 80% of patients. Less common side-effects include urinary tract infections, herpes infections (including rare cases of death due to herpes zoster virus infection), macula oedema and skin cancers. Rare cases of PML associated with fingolimod therapy have also been reported.33

Cardiac AEs include mild hypertension, first-dose bradycardia reaching its maximum within 6 hours of first administration, and first- and second-degree atrioventricular conduction block. Because of several unexpected deaths and serious cardiovascular events, the labelling of fingolimod has been modified. The FDA and the EMA concluded that, overall, the benefits of the drug outweighed the risks and recommended that the drug not be prescribed to patients with pre-existing cardiac or cerebrovascular diseases or to those taking antiarrhythmics; however, if treatment was deemed necessary, a prior cardiological opinion was advised. Furthermore, obligatory monitoring for 6 hours during the first dose with baseline electrocardiography (ECG) became a requirement for all patients. Patients who develop a cardiac abnormality during the monitoring period should be admitted to hospital for overnight continuous ECG monitoring.

Future prospects

More selective S1P1 agonists are currently being tested in phase III clinical trials in RRMS with preliminary positive results for ponesimod (Actelion) and ozanimod (Celgene).

Alemtuzumab

Mode of action

Alemtuzumab is a humanized derivate of the Campath-1 series, initially manufactured to treat lymphocytic malignancies and subsequently developed for MS by the Cambridge group.43 Alemtuzumab is a humanized immunoglobulin G (IgG)1 mAb directed against CD52: a small, 12-amino acid cell-surface protein abundantly expressed on B- and T-lymphocytes. To a small extent, CD52 is also expressed on monocytes, macrophages and NK cells with little or no expression on bone marrow stem cells, plasma cells and neutrophils. The biological role of CD52 is still unknown, but a role in T-lymphocyte migration and co-stimulation has been suggested. As CD52 knockout mice are phenotypically normal, CD52 may not be required for normal immune system function. Alemtuzumab produces a rapid (within 1 hour) and profound lymphopenia through two major mechanisms: Ab-dependent cellular cytolysis and complement-dependent cytolysis.44 Cell repopulation kinetics vary between different lymphocyte subsets. Whereas median B-lymphocyte numbers reappear after 3–6 months, memory B-cells remain substantially depleted for up to 12 months. In the case of T-cells, repopulation lasts for up to 5 years, with reappearance more rapid for CD8+ cells than for CD4+ T cells.45 Moreover, the newly appearing lymphocytes seem to have a different phenotype. For example, the percentage of cells with a Treg phenotype (CD4+/CD25high, FoxP3b expression) was increased for up to 6 months after alemtuzumab treatment.46 In addition, when specificially stimulated with MBP, peripheral blood mononuclear cells cultured from alemtuzumab-treated patients produced increased concentrations of BDNF and ciliary neurotrophic factor, both rising during the 12 months post treatment and, therefore, suggesting a potential for enhancement of endogenous neural repair mechanisms.47

Efficacy

Alemtuzumab has been used as an experimental treatment for MS in Cambridge since 1991.43 Although earlier studies in patients with secondary progressive MS (SPMS) showed a significant reduction in new Gd-enhancing lesions (GELs) on MRI and a reduction in the number of clinical relapses, patients still continued to accrue disability, and evidence of brain atrophy was demonstrated on MRI. This was in contrast to a cohort of relapsing patients, supporting the notion of a ‘window of opportunity’ with greater potential benefit from early immunotherapy in MS. As a result, the first randomized controlled phase II study comparing the effect of alemtuzumab with an established therapy of IFNβ-1a was performed, with a cohort of RRMS patients with a very short disease duration of ≤ 3 years and an EDSS score of ≤ 3.0. Patients randomized to alemtuzumab received intravenous cycles at a dose of either 12 or 24 mg per day on 5 consecutive days at month 0 and on 3 consecutive days at month 12. Both doses reduced ARR by 74% and risk of sustained disability progression by 71% compared with IFNβ-1a. Within the study period of 36 months, 80% of patients in the alemtuzumab group remained relapse free, compared with 52% in the IFNβ-1a group. Moreover, post hoc analysis revealed that a sustained improvement in disability was evident in 51.6% of alemtuzumab-treated patients compared with only 27.2% in the IFNβ-1a group.48 These data were confirmed in a 5-year follow-up study of the Campath-1H in MS (CAMMS223) cohort,49 with a reduction in risk of sustained disability accumulation of 72% and in risk of relapse of 69% compared with IFNβ-1a.

The first completed phase III trial – the Comparison of Alemtuzumab and Rebif Efficacy in MS (CARE-MS I) trial50 – was a 2-year trial with a similar design to CAMMS223 in comparing alemtuzumab to 44 μg of IFNβ-1a (Rebif) subcutaneously three times a week in 581 treatment-naive MS patients. In contrast to CAMMS223, only the 12-mg dose of alemtuzumab was used and a slightly longer disease duration of ≤ 5 years (compared with ≤ 3 years in CAMMS223) was eligible. The study reached the first of two co-primary outcomes with a 55% reduction in ARR at 2 years. However, the study failed to show superiority of 12 mg of alemtuzumab in reducing the number of patients with a sustained increase in the EDSS after 2 years (8% in the alemtuzumab group, compared with 11% in the IFNβ-1a group; P = 0.22). Nevertheless, when compared with IFNβ-1a, alemtuzumab reduced the proportion of patients with GELs, new or enlarging T2 lesions and brain volume loss, each at a significant level.

The second phase III trial – the CARE-MS II trial51 – included 840 patients with a longer disease duration of ≤ 10 years who had experienced at least one relapse on previous standard immunomodulatory treatment. Similar to CAMMS 223, the study was initialized with two different alemtuzumab doses (12 and 24 mg), with the 24-mg arm prematurely stopped after enrolment of 164 patients because of safety concerns. Both primary outcome parameters were reached, with a reduction in ARR of 49% and a reduction in sustained disability progression at 24 months of 42% compared with IFNβ-1a. Moreover, 29% of the alemtuzumab group experienced a sustained reduction in disabilities compared with only 13% of the IFNβ-1a group. MRI parameters were also statistically significant for alemtuzumab, leading to a reduction in the number of patients with new or enlarging T2 lesions or GELs. Only the change in T2 hyperintense lesion volume from baseline to year 2 was not significant. The results of CAMMS223 and CARE MS I and II finally led to EMA approval in September 2013 for patients with active RRMS (defined by clinical or imaging features). The FDA postponed approval until 14 November 2014 owing to insufficient evidence that the benefits of alemtuzumab outweigh its SAEs.

Safety and tolerability

The safety profile derived from the CAMMS223 study49 has been confirmed by the later CARE-MS I50 and II51 studies, with the following key safety issues.

Infusion reactions occurred in > 90% of patients, including SAEs in 3%. The most common infusion-related symptoms included rash, headache, pyrexia, nausea and flushing, all of which were related to acute cytokine release syndrome. The severity of these symptoms gradually decreased with the number of infusions received.

Infections occurred more often in the alemtuzumab group than in the INF group, with the most common infections being upper respiratory tract infections, urinary tract infections and herpes. Although increased numbers of herpes infections were noticed in CAMMS223 (8.3% in alemtuzumab-treated patients, compared with 2.8% in the IFNβ-1a-treated group), the high incidence of 16% in CARE-MS I and II led to a protocol amendment in 2009, determining that alemtuzumab-treated patients receive 200 mg of oral aciclovir twice daily during the infusion and for 28 days thereafter. This intervention decreased the frequency of herpetic infections from 3% to 1% following the second course of alemtuzumab in CARE-MS I, and from 2.8% to 0.5% in CARE-MS II.

Sporadic cases of malignancies were reported in the CAMM223 and CARE-MS I and II studies; however, there was no definite alert in terms of malignancy.

Autoimmune disorders continue to represent the major safety concern, with severe idiopathic thrombocytopenic purpura (ITP) and renal disorders being the more severe (but rare) AEs and thyroid disorders being the more common (but less severe) AEs. Severe ITP (including one death) was reported in CAMMS223 and CARE-MS I and II in a total of 16 patients treated with alemtuzumab, compared with only two patients receiving IFNβ-1a. One patient in CARE-MS I developed presumed autoimmune pancytopenia with fatal outcome; another patient developed glomerulonephritis. Outside clinical trials, other cases of Goodpasture syndrome have been reported in the Cambridge cohort.52

Thyroid disorders occurred in 18% of patients in the alemtuzumab group compared with 6% of patients in the IFNβ-1a group in CARE-MS I. Corresponding numbers in CARE-MS II were 16% and 19% (12  and 24 mg) of patients in the alemtuzumab group compared with 5% in the placebo group. Hypo- as well as hyperthyroid gland disorders were reported; however, most were medically controlled, with surgical therapy required in only rare cases.

A long-term follow-up of 248 patients treated with alemtuzumab reported newly emerging autoimmune disorders in 22.2%, with thyroid gland disorders being the most common, at 15.7%. The incidence peaked after 12–18 months of treatment with no new cases identified 5 years after treatment initiation.53 The risk of autoimmunity is thought to be driven by higher levels of IL-21, raising the possibility that this could serve as a biomarker to identify patients at risk.43

Daclizumab

Mode of action

Daclizumab is a humanized mAb directed against the α-subunit of the high-affinity IL-2 receptor, sparing the low-affinity IL-2 receptor. The blockage of this receptor prevents activation, differentiation and proliferation while the number of CD56bright NK cells is increased.54 Daclizumab was originally approved by the FDA in 1997 to prevent acute kidney transplant rejections.

Efficacy

The efficacy of daclizumab was tested in two randomized double-blind placebo-controlled phase III clinical trials. In the first trial – the Daclizumab High-Yield Process in Relapse–Remitting Multiple Sclerosis (SELECT) trial55 – a monthly subcutaneous injection of 150 mg of daclizumab showed a 54% reduction in ARR compared with placebo as the primary outcome parameter. At the same time, the secondary outcome parameter, confirmed disability progression, was also reduced by 56% compared with placebo. In the second trial – the Daclizumab HYP Versus Interferon β-1a in Relapsing Multiple Sclerosis (DECIDE) trial56 – daclizumab was compared with a standard treatment of IFNβ-1a once weekly. Again, daclizumab showed a significant reduction in ARR by 45%, while the secondary outcome parameter (reduction in confirmed disability progression) failed to reach statistical significance after 12 weeks.

Daclizumab was approved in 2016 by both the FDA and EMA for RRMS. However, its use was restricted by the EMA in 2017 to patients with highly active MS not controlled by other immunomodulatory treatments owing to safety concerns (fatal cases of liver injury).

Safety and tolerability

One of the most common side-effects of daclizumab is a (clinically asymptomatic) rise in liver enzymes, although rare cases of hepatic failure have been reported and finally led to restricted use in patients with otherwise uncontrolled disease activity. Moreover, monthly testing of liver enzymes during and 4 months after daclizumab therapy has been called for by the EMA.

Other side-effects include upper respiratory and urogenital tract infections, dermatological issues (rash, dermatitis, eczema) and gastointestinal side-effects (diarrhoea). Moreover, physicians should carefully observe newly arising clinical signs of other autoimmune disorders, as rare cases of autoimmune hepatitis and thyroiditis have been reported.57

Cladribin

Mode of action

Cladribin is a purine analogon that blocks DNA synthesis in proliferating cells. The compound is a prodrug that is converted to its active form by deoxycytidine kinase. This enzyme is mainly active in lymphocytes, rather than in monocytes and other cell types of the human body, therefore leading to a relatively specific suppression of activated T- and B-cells.58 Moreover, cladribine is a small molecule that can easily cross the BBB, resulting in speculation that it might also have beneficial effects within the CNS.

Efficacy

In a randomized double-blind placebo-controlled study – the CLAdRIbin Tablets treating multiple sclerosis orallY (CLARITY) study59 – cladribin showed a 57% reduction in ARR compared with placebo as well as a significant reduction in the proportion of patients with disability progression. Post hoc analysis showed a somewhat superior efficacy in patients with highly active RRMS, defined as patients with relapses despite immunomodulatory treatment or patients with at least two relapses in the previous year. In another randomized placebo-controlled trial,60 cladribine significantly reduced the risk of a second relapse and, consequently, the conversion to definite RRMS in patients with a CIS. The licensing of cladribin was initally postponed owing to safety concerns, but cladribine was approved in 2017 by both the FDA and EMA. Cladribine is taken orally for 4–5 days in week 1 and again in week 55. Thereafter, no further therapy is needed for at least 3 years. At present, there are only limited data on long-term therapy with cladribine.

Safety and tolerability

The most common side-effect of cladribine is lymphopenia. Therefore, white blood cell (WBC) counts should be taken before each treatment cycle and 2 and 6 months thereafter. In cases of lymphopenia, patients with WBC counts < 5.0 × 109/l should be monitored closely. Neutropenia, thrombocytopenia and anaemia occur only in rare cases. As latent tuberculosis and hepatitis infections can be reactivated during cladribine therapy, these should be tested for and cladribine avoided in patients with active hepatitis, tuberculosis or human immunodeficiency virus (HIV) infection. Moreover, varicella zoster virus (VZV) vaccination should be considered for patients with negative VZV immunity. Although malignancies were more common in the cladribine group than in the placebo group of the CLARITY trial (which caused the initial postponement of the licensing of the drug), further analysis revealed that this was due to an uncommonly low malignancy rate in the placebo group.61

Mitoxantrone

Mode of action

Mitoxantrone is a cytotoxic agent of the anthracenedione family that acts by intercalating with DNA and inhibiting topoisomerase II enzyme activity for DNA repair. It has immunosuppressive properties by reducing the number of B-cells, inhibiting T-helper cell function and augmenting T-cell suppressor activity. Having been widely used in the treatment of breast cancer and leukaemia, it has also been tested in patients with MS.62

Efficacy

A phase II randomized controlled trial63 in 51 patients with RRMS showed a significant reduction in ARR and disability progression over 2 years with a monthly dosage of 8 mg/m2 over 12 months. A second trial64 recruited 42 patients with very active MS and randomized them to receive either 1 g of methylprednisolone only or 1 g of methylprednisolone in combination with 20 mg of mitoxantrone monthly over 6 months. The combination therapy group showed a significant reduction in ARR and GELs as well as an improvement in mean EDSS scores at the end of the study.

Finally, the Mitoxantrone in MS (MIMS) study65 assigned a total of 194 patients with SPMS (with or without superimposed relapses) to receive 5 mg/m2 or 12 mg/m2 mitoxantrone or placebo every 3 months for a total of 2 years. Only patients receiving the higher dose showed a significantly reduced ARR and disability progression compared with placebo.

Based on these results, the FDA licensed mitoxantrone for use in MS in 2000. Mitoxantrone is also licensed for use in some European countries.

Different treatment regimens are used in different countries according to different regulatory demands. However, the two most common regimes used are 12 mg/m2 mitoxantrone intravenously every 3 months for 2 years (following the MIMS study) and 20 mg of mitoxantrone intravenously and 1 g of methylprednisolone every 4 weeks for 6 months.

Safety and tolerability

The most common side-effects of mitoxantrone include nausea, alopecia, increased risk of infections and infertility. Post-marketing surveillance also raised concerns about cardiotoxicity and treatment-related acute leukaemia (TRAL) and resulted in a 2005 FDA ‘black box’ warning. A prospective registry on mitoxantrone-related side-effects66 reported an incidence of congestive heart failure in 2% of patients and an incidence of TRAL in < 1% of patients in a cohort of 509 US patients with a follow-up of 5 years.

Summary and conclusions

Major advances in the therapeutic landscape of MS have been achieved in the last 20 years. In the late 1990s only IFN and GA were available; now neurologists are able to choose from six different injectables with moderate efficacy but well-known safety profiles, four oral drugs with enhanced efficacy and satisfactory safety profiles and three antibodies with exceptional efficacy but challenging safety concerns. Moreover, many new treatment options for RRMS are on the horizon, some of them already in phase III clinical trials.

The encouraging development of therapeutic options has raised expectations, especially concerning efficacy of immunomodulatory drugs. In the 1990s, a 30% reduction in relapse rate was deemed to be satisfactory efficacy but, with the introduction of natalizumab into the therapeutic arena, freedom from disease activity became the sticking point in MS therapy, at least in a proportion of patients. However, with the increasing number of therapeutic regimens available, identifying the most appropriate drug for any individual patient will be a challenge of the near future. One of the main goals in the future will be to balance the efficacy and risk of any particular drug for individual patients.

Another goal, particularly when a heterogeneous disease such as MS is concerned, is to tailor available treatments to individual needs. Population-based genomics as a screening tool to stratify patients to certain drugs and dosage regimens is currently under investigation and has already proven useful in other neurological diseases. The feasibility of such strategies will increase as new-generation DNA-sequencing techniques rapidly become available and allow affordable analyses of whole genomes within weeks or days, accelerating the identification of genetic variants associated with the magnitude of response to a particular drug, as already practised in cancer therapy.67

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