Treatments for relapsing–remitting multiple sclerosis: summarising current information by network meta-analysis

Objectives  

Oral drugs for relapsing–remitting multiple sclerosis (RRMS) have been recently investigated and, one of these, fingolimod, is already available in several countries. In this framework, an analysis of the data in terms of the comparative effectiveness for all treatments thus far approved for RRMS can be useful to reappraise their place in therapy.     

Emerging oral drugs for relapsing–remitting multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), traditionally considered to be an autoimmune, demyelinating disease. The last two decades have witnessed the introduction of several therapies for MS. At present, there are five licensed first-line, disease-modifying drugs (DMDs) in MS and two second-line treatments. Nevertheless, in clinical practice DMDs or immunosuppressive treatments are frequently associated with suboptimal response in terms of efficacy and several side effects leading to poor patient adherence.

Areas covered: Since MS is a chronic disease, DMDs require long-term, regular injection or monthly parenteral infusions, which may be uncomfortable and inconvenient for the patient. Thus, there is an important need for new therapeutic strategies, especially those that may offer greater patient satisfaction in order to optimize therapeutic outcomes. Currently, five oral therapies are in Phase III development or have recently been approved for the treatment of relapsing–remitting MS: cladribine and fingolimod, the first approved in Russia and Australia, the latter is more widespread. Fumaric acid (BG-12), teriflunomide (A77126 or HMR1726) and laquinimod (ABR-215062) are in Phase III trials. Details of these five drugs will be covered in this review.

Expert opinion: Preliminary results indicate that oral medications are as effective as, or possibly more effective than, current injectable formulations. It is believable that improved outcomes will translate into higher real and perceived efficacy rates and contribute to improved adherence. The decision to switch established patients from injectable to oral medications will be made on balancing the efficacy and tolerability of the patient's existing therapy and their compliance history, even though safety is likely to become the most important factor in the future development of MS drugs.     

Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system leading to progressive neurodegeneration and disability. Until 2010, all approved disease-modifying drugs for MS required parenteral administration, which is associated with suboptimal adherence. It was anticipated that new approaches to treatment, including oral agents such as cladribine tablets, may improve adherence. In 2011, the development of cladribine tablets was stopped following negative feedback from the EMA and FDA.

Areas covered: This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS. Key efficacy and safety data from the pivotal Phase III CLARITY study are presented, providing context for the opinion received from the regulatory agencies.

Expert opinion: Despite the promising efficacy data observed in the cladribine tablets clinical trial program, regulatory agencies identified a potential risk of increased malignancies, and raised concerns about the implications of sustained lymphocyte depletion. Following the feedback received from the regulatory agencies, Merck Serono made the decision to withdraw the agent from the regulatory approval process. The experience gained will benefit other research efforts to address the outstanding unmet treatment needs of patients with relapsing MS.     

Laquinimod,a once-daily oral drug in development for the treatment of relapsing–remitting multiple sclerosis

Laquinimod is a novel, small, orally administered medication that has demonstrated efficacy in the treatment of multiple sclerosis, a chronic inflammatory demyelinating disease of the CNS. In preclinical testing, laquinimod inhibited the development of both acute and chronic paralysis in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Furthermore, laquinimod reduced inflammation, demyelination and axonal damage in experimental autoimmune encephalomyelitis in mice treated at disease induction or at clinical disease onset. Recent findings from the clinical trials indicate that laquinimod has significant effects in reducing relapse rate and has more pronounced effects in reducing sustained disability progression as well as brain atrophy, with a good safety profile. In conclusion, preclinical studies show that laquinimod’s unique mechanisms of action, including its immunomodulatory and CNS-protective effects, translate into clinical benefits in relapsing–remitting multiple sclerosis patients.     

Sequencing of disease-modifying therapies for relapsing–remitting multiple sclerosis: a theoretical approach to optimizing treatment

Multiple sclerosis (MS) is a chronic disease which usually begins in young adulthood and is a lifelong condition. Individuals with MS experience physical and cognitive disability resulting from inflammation and demyelination in the central nervous system. Over the past decade, several disease-modifying therapies (DMTs) have been approved for the management of relapsing–remitting MS (RRMS), which is the most prevalent phenotype. The chronic nature of the disease and the multiple treatment options make benefit–risk-based sequencing of therapy essential to ensure optimal care. The efficacy and short- and long-term risks of treatment differ for each DMT due to their different mechanism of action on the immune system. While transitioning between DMTs, in addition to immune system effects, factors such as age, disease duration and severity, disability status, monitoring requirements, preference for the route of administration, and family planning play an important role. Determining a treatment strategy is therefore challenging as it requires careful consideration of the differences in efficacy, safety and tolerability, while at the same time minimizing risks of immune modulation. In this review, we discuss a sequencing approach for treating RRMS, with importance given to the long-term risks and individual preference when devising a treatment plan. Evidence-based strategies to counter breakthrough disease are also addressed.     

Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing–remitting multiple sclerosis

Objective: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing–remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA?+?DAT), using systematic literature review (SLR) and network meta-analysis (NMA).

Methods: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety.

Results: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p?p?Conclusion: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA?+?DAT populations.     

First-line disease-modifying drugs in relapsing–remitting multiple sclerosis: an Italian real-life multicenter study on persistence

Objective: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing–remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation.

Methods: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued.

Results: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n?=?62, 24%) or on injectable (n?=?60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences.

Conclusion: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.     

Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide.

Areas covered: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing–remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups.

Expert opinion: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.     

The mechanism of action of interferon-β in relapsing multiple sclerosis

Multiple sclerosis (MS) is characterized by autoimmune inflammation and subsequent neurodegeneration. It is believed that early in the disease course, proinflammatory T cells that are activated in the periphery by antigen presentation cross the blood-brain barrier (BBB) into the CNS directed by various chemotaxic agents. However, to date, there has been no formal demonstration of a specific precipitating antigen. Once inside the CNS, activated T cells including T helper-1 (T(h)1), T(h)17, γδ and CD8+ types are believed to secrete proinflammatory cytokines. Decreased levels of T(h)2 cells also correlate with relapses and disease progression in MS, since T(h)2-derived cytokines are predominantly anti-inflammatory. In healthy tissue, inflammatory effects are opposed by specific subsets of regulatory T cells (T(regs)) including CD4+, CD25+ and FoxP3+ cells that have the ability to downregulate the activity of proinflammatory T cells, allowing repair and recovery to generally follow inflammatory insult. Given their function, the pathogenesis of MS most likely involves deficits of T(reg) function, which allow autoimmune inflammation and resultant neurodegeneration to proceed relatively unchecked. Interferons (IFNs) are naturally occurring cytokines possessing a wide range of anti-inflammatory properties. Recombinant forms of IFNβ are widely used as first-line treatment in relapsing forms of MS. The mechanism of action of IFNβ is complex, involving effects at multiple levels of cellular function. IFNβ appears to directly increase expression and concentration of anti-inflammatory agents while downregulating the expression of proinflammatory cytokines. IFNβ treatment may reduce the trafficking of inflammatory cells across the BBB and increase nerve growth factor production, leading to a potential increase in neuronal survival and repair. IFNβ can also increase the number of CD56bright natural killer cells in the peripheral blood. These cells are efficient producers of anti-inflammatory mediators, and may have the ability to curb neuron inflammation. The mechanistic effects of IFNβ manifest clinically as reduced MRI lesion activity, reduced brain atrophy, increased time to reach clinically definite MS after the onset of neurological symptoms, decreased relapse rate and reduced risk of sustained disability progression. The mechanism of action of IFNβ in MS is multifactorial and incompletely understood. Ongoing and future studies will increase our understanding of the actions of IFNβ on the immune system and the CNS, which will in turn aid advances in the management of MS.     

Comparative effectiveness of atypical antipsychotics in schizophrenia: what have real-world trials taught us?

Real-world, effectiveness studies add an important new dimension to the evaluation of the benefits of individual antipsychotics. Efficacy studies have already shown the unique effectiveness of clozapine, and suggested improved outcomes for olanzapine compared with some atypical antipsychotics and a reduced tendency to produce acute and chronic movement disorders for atypical compared with typical drugs. Recent effectiveness studies largely confirm these prior observations. The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and SOHO (Schizophrenia Outpatient Health Outcomes) programmes confirmed the superiority of clozapine over other antipsychotics; CATIE and SOHO also confirmed olanzapine as probably the second most effective antipsychotic. Effectiveness studies have confirmed the high incidence of adverse metabolic effects with clozapine, olanzapine and (with less certainty) quetiapine but the ZODIAC (Ziprasidone Observational Study of Cardiac Outcomes) study found no excess cardiovascular events or deaths for olanzapine compared with ziprasidone. Prior observations on reduced frequency of movement disorders for second-generation versus first-generation antipsychotics were also largely (but not uniformly) supported. Overall, recent real-world studies have done much to confirm prior observations from efficacy-based randomized, controlled trials.     

Subcutaneous recombinant interferon-β-1a (Rebif®): a review of its use in the treatment of relapsing multiple sclerosis

Subcutaneous recombinant interferon-β-1a (SC IFNβ-1a) [Rebif?] is indicated as monotherapy for the prevention of relapses and progression of physical disability in patients with relapsing multiple sclerosis (MS). This article reviews the efficacy and tolerability of SC IFNβ-1a in this indication, with further discussion of its pharmacological properties and pertinent pharmacoeconomic studies. SC IFNβ-1a efficacy and tolerability were evaluated in randomized, double-blind, multinational trials in patients with relapsing-remitting MS (RRMS). Its efficacy was demonstrated in the 2-year PRISMS trial, as SC IFNβ-1a 22 or 44 μg three times weekly (tiw) significantly reduced relapse rates, with an ≈30% relative risk reduction compared with placebo. SC IFNβ-1a was also associated with significantly delayed progression of disability, and lower disease activity according to MRI, relative to placebo. In the 24-week EVIDENCE trial, a significantly higher proportion of SC IFNβ-1a 44?μg tiw than intramuscular IFNβ-1a (Avonex?) 30 μg once weekly recipients remained relapse free. A serum-free formulation of SC IFNβ-1a 44?μg tiw was more efficacious than placebo in preventing the development of brain lesions in the 16-week IMPROVE trial. In the 96-week REGARD trial, the efficacy of SC IFNβ-1a 44?μg tiw was not significantly different to that of glatiramer acetate for clinical endpoints, although it was associated with reduced development of brain lesions compared with glatiramer acetate, according to some MRI endpoints. In the 36-month CAMMS223 trial, alemtuzumab led to significantly lower relapse rates and risk of developing sustained disability than SC IFNβ-1a 44 μg tiw, and was generally more efficacious according to other clinical and MRI endpoints. Across trials, influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities were the most common treatment-emergent adverse events occurring with SC IFNβ-1a. In the PRISMS trial, SC IFNβ-1a 22 and 44 μg tiw recipients had more injection-site reactions than placebo recipients and, at the higher dosage, haematological disturbances and increases in ALT levels were also significantly more frequent than with placebo. Pooled data from clinical trials and postmarketing surveillance indicate that haematological and hepatic adverse events are generally asymptomatic and rarely result in treatment discontinuation. Nevertheless, some cases of serious hepatic complications have been reported. In cost-utility studies, first-line therapies for RRMS, including SC IFNβ-1a, all exceeded commonly accepted US thresholds for incremental cost per quality-adjusted life-years gained relative to symptomatic treatment. However, because of patient need and the difficulty in adequately assessing cost utility in a gradually progressive disease, these agents have been made available to many patients worldwide through special access programmes. Overall, SC IFNβ-1a has a favourable risk-benefit ratio and is a valuable first-line treatment option for patients with relapsing MS.     

Sex hormones: a role in the control of multiple sclerosis?

Several lines of evidence suggest that gender affects the susceptibility and course of multiple sclerosis. A higher disease prevalence, as well as an overall better prognosis, in women than men is observed. This sex dimorphism may be explained by the effect of sex hormones on brain damage and repair mechanisms. Experimental, clinical and MRI evidence confirms a pathogenetic link between sex hormones and multiple sclerosis, also suggesting sex-specific effects of hormones in multiple sclerosis pathology and therapy. A gender-based approach to multiple sclerosis could provide further benefits for its treatment and management.     

PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis

Achieving optimal patient benefit from biological therapies can be hindered by drug instability, rapid clearance requiring frequent dosing or potential immune reactions. One strategy for addressing these challenges is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are covalently attached to a biological or small-molecule drug, effectively transforming it into a therapy with improved pharmacokinetic and pharmacodynamic properties. Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. A PEGylated form of interferon-β-1a (PEG-IFNβ-1a) is being developed to address an unmet medical need for safer, more effective and more convenient therapies for multiple sclerosis (MS). Phase I study data suggest that PEG-IFNβ-1a should provide patients with a first-line therapy with a more convenient dosing regimen while maintaining the established efficacy, safety and tolerability of presently available IFNβ-1a. The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNβ-1a in patients with relapsing MS.     

Estimating the comparative efficacy of cladribine tablets versus alternative disease modifying treatments in active relapsing–remitting multiple sclerosis: adjusting for patient characteristics using meta-regression and matching-adjusted indirect treatment comparison approaches

Objectives: To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) – fingolimod, natalizumab, alemtuzumab and ocrelizumab – in adults with active relapsing–remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results.

Methods: A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data.

Results: The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching.

Conclusion: This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS.     

Is natalizumab a breakthrough in the treatment of multiple sclerosis?

In patients with either relapsing-remitting or secondary-progressive multiple sclerosis, there were fewer new lesions/patient with natalizumab (0.7 and 1.1 with natalizumab 3 and 6 mg/kg every 28 days, respectively) than in the placebo group (9.6 new lesions/patient) over 6 months. There were also fewer relapses in the natalizumab groups than the placebo group. However, there were no changes in the Expanded Disability Status Scale scores in any of the groups. Natalizumab was well-tolerated. Thus, the initial results with natalizumab treatment over 6 months in multiple sclerosis are encouraging.